Setting up a quantitative SPECT imaging network for a European multi-centre dosimetry study of radioiodine treatment for thyroid cancer as part of the MEDIRAD project

Background: Differentiated thyroid cancer has been treated with radioiodine for almost 80 years, although controversial questions regarding radiation-related risks and the optimisation of treatment regimens remain unresolved. Multi-centre clinical studies are required to ensure recruitment of sufficient patients to achieve the statistical significance required to address these issues. Optimisation and standardisation of data acquisition and processing are necessary to ensure quantitative imaging and patient-specific dosimetry. Material and methods: A European network of centres able to perform standardised quantitative imaging of radioiodine therapy of thyroid cancer patients was set-up within the EU consortium MEDIRAD. This network will support a concurrent series of clinical studies to determine accurately absorbed doses for thyroid cancer patients treated with radioiodine. Five SPECT(/CT) systems at four European centres were characterised with respect to their system volume sensitivity, recovery coefficients and dead time. Results: System volume sensitivities of the Siemens Intevo systems (crystal thickness 3/8″) ranged from 62.1 to 73.5 cps/MBq. For a GE Discovery 670 (crystal thickness 5/8″) a system volume sensitivity of 92.2 cps/MBq was measured. Recovery coefficients measured on three Siemens Intevo systems show good agreement. For volumes larger than 10 ml, the maximum observed difference between recovery coefficients was found to be ± 0.02. Furthermore, dead-time coefficients measured on two Siemens Intevo systems agreed well with previously published dead-time values. Conclusions: Results presented here provide additional support for the proposal to use global calibration parameters for cameras of the same make and model. This could potentially facilitate the extension of the imaging network for further dosimetry-based studies

"First pain" in humans: convergent and specific forebrain responses

<p>Abstract</p> <p>Background</p> <p>Brief heat stimuli that excite nociceptors innervated by finely myelinated (Aδ) fibers evoke an initial, sharp, well-localized pain ("first pain") that is distinguishable from the delayed, less intense, more prolonged dull pain attributed to nociceptors innervated by unmyelinated (C) fibers ("second pain"). In the present study, we address the question of whether a brief, noxious heat stimulus that excites cutaneous Aδ fibers activates a distinct set of forebrain structures preferentially in addition to those with similar responses to converging input from C fibers. Heat stimuli at two temperatures were applied to the dorsum of the left hand of healthy volunteers in a functional brain imaging (fMRI) paradigm and responses analyzed in a set of volumes of interest (VOI).</p> <p>Results</p> <p>Brief 41°C stimuli were painless and evoked only C fiber responses, but 51°C stimuli were at pain threshold and preferentially evoked Aδ fiber responses. Most VOI responded to both intensities of stimulation. However, within volumes of interest, a contrast analysis and comparison of BOLD response latencies showed that the bilateral anterior insulae, the contralateral hippocampus, and the ipsilateral posterior insula were preferentially activated by painful heat stimulation that excited Aδ fibers.</p> <p>Conclusions</p> <p>These findings show that two sets of forebrain structures mediate the initial sharp pain evoked by brief cutaneous heat stimulation: those responding preferentially to the brief stimulation of Aδ heat nociceptors and those with similar responses to converging inputs from the painless stimulation of C fibers. Our results suggest a unique and specific physiological basis, at the forebrain level, for the "first pain" sensation that has long been attributed to Aδ fiber stimulation and support the concept that both specific and convergent mechanisms act concurrently to mediate pain.</p

TGF-β Induces Surface LAP Expression on Murine CD4 T Cells Independent of Foxp3 Induction

It has been reported that human FOXP3(+) CD4 Tregs express GARP-anchored surface latency-associated peptide (LAP) after activation, based on the use of an anti-human LAP mAb. Murine CD4 Foxp3(+) Tregs have also been reported to express surface LAP, but these studies have been hampered by the lack of suitable anti-mouse LAP mAbs.We generated anti-mouse LAP mAbs by immunizing TGF-β(-/-) animals with a mouse Tgfb1-transduced P3U1 cell line. Using these antibodies, we demonstrated that murine Foxp3(+) CD4 Tregs express LAP on their surface. In addition, retroviral transduction of Foxp3 into mouse CD4(+)CD25(-) T cells induced surface LAP expression. We then examined surface LAP expression after treating CD4(+)CD25(-) T cells with TGF-β and found that TGF-β induced surface LAP not only on T cells that became Foxp3(+) but also on T cells that remained Foxp3(-) after TGF-β treatment. GARP expression correlated with the surface LAP expression, suggesting that surface LAP is GARP-anchored also in murine T cells.Unlike human CD4 T cells, surface LAP expression on mouse CD4 T cells is controlled by Foxp3 and TGF-β. Our newly described anti-mouse LAP mAbs will provide a useful tool for the investigation and functional analysis of T cells that express LAP on their surface

Evolution in the Cluster Early-type Galaxy Size-Surface Brightness Relation at z =~ 1

We investigate the evolution in the distribution of surface brightness, as a function of size, for elliptical and S0 galaxies in the two clusters RDCS J1252.9-2927, z=1.237 and RX J0152.7-1357, z=0.837. We use multi-color imaging with the Advanced Camera for Surveys on the Hubble Space Telescope to determine these sizes and surface brightnesses. Using three different estimates of the surface brightnesses, we find that we reliably estimate the surface brightness for the galaxies in our sample with a scatter of < 0.2 mag and with systematic shifts of \lesssim 0.05 mag. We construct samples of galaxies with early-type morphologies in both clusters. For each cluster, we use a magnitude limit in a band which closely corresponds to the rest-frame B, to magnitude limit of M_B = -18.8 at z=0, and select only those galaxies within the color-magnitude sequence of the cluster or by using our spectroscopic redshifts. We measure evolution in the rest-frame B surface brightness, and find -1.41 \+/- 0.14 mag from the Coma cluster of galaxies for RDCS J1252.9-2927 and -0.90 \+/- 0.12 mag of evolution for RX J0152.7-1357, or an average evolution of (-1.13 \+/- 0.15) z mag. Our statistical errors are dominated by the observed scatter in the size-surface brightness relation, sigma = 0.42 \+/- 0.05 mag for RX J0152.7-1357 and sigma = 0.76 \+/- 0.10 mag for RDCS J1252.9-2927. We find no statistically significant evolution in this scatter, though an increase in the scatter could be expected. Overall, the pace of luminosity evolution we measure agrees with that of the Fundamental Plane of early-type galaxies, implying that the majority of massive early-type galaxies observed at z =~ 1 formed at high redshifts.Comment: Accepted in ApJ, 16 pages in emulateapj format with 15 eps figures, 6 in colo

A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: a role for monocarboxylate transporters as metabolic targets for therapy.

Metabolic adaptation is considered an emerging hallmark of cancer, whereby cancer cells exhibit high rates of glucose consumption with consequent lactate production. To ensure rapid efflux of lactate, most cancer cells express high levels of monocarboxylate transporters (MCTs), which therefore may constitute suitable therapeutic targets. The impact of MCT inhibition, along with the clinical impact of altered cellular metabolism during prostate cancer (PCa) initiation and progression, has not been described. Using a large cohort of human prostate tissues of different grades, in silico data, in vitro and ex vivo studies, we demonstrate the metabolic heterogeneity of PCa and its clinical relevance. We show an increased glycolytic phenotype in advanced stages of PCa and its correlation with poor prognosis. Finally, we present evidence supporting MCTs as suitable targets in PCa, affecting not only cancer cell proliferation and survival but also the expression of a number of hypoxia-inducible factor target genes associated with poor prognosis. Herein, we suggest that patients with highly glycolytic tumours have poorer outcome, supporting the notion of targeting glycolytic tumour cells in prostate cancer through the use of MCT inhibitors.Pertega-Gomes N. and Sousa S. received fellowships from the Portuguese Foundation for Science and Technology (FCT), refs. SFRH/BD/61027/2009, and PTDC/SAU-MET/113415/2009, respectively. Felisbino S. received a fellowship from the Sao Paulo Research Foundation (FAPESP) ref. 2013/08830-2 and 2013/06802-1. We thank the core facilities at the Cancer Research UK Cambridge Institute led by James Hadfield (Genomics), Matt Eldridge (Bioinformatics) and Allen Hazelhurst (BRU). We also thank the support and critical advice on the project given by Christian Frezza and Marco Sciacovelli from The MRC Cancer Cell Unit and Professor Rui Henrique from Portuguese Institute of Oncology for providing samples from patients with metastatic prostate cancer.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/path.454

Abnormalities in autonomic function in obese boys at-risk for insulin resistance and obstructive sleep apnea.

Study objectivesCurrent evidence in adults suggests that, independent of obesity, obstructive sleep apnea (OSA) can lead to autonomic dysfunction and impaired glucose metabolism, but these relationships are less clear in children. The purpose of this study was to investigate the associations among OSA, glucose metabolism, and daytime autonomic function in obese pediatric subjects.MethodsTwenty-three obese boys participated in: overnight polysomnography; a frequently sampled intravenous glucose tolerance test; and recordings of spontaneous cardiorespiratory data in both the supine (baseline) and standing (sympathetic stimulus) postures.ResultsBaseline systolic blood pressure and reactivity of low-frequency heart rate variability to postural stress correlated with insulin resistance, increased fasting glucose, and reduced beta-cell function, but not OSA severity. Baroreflex sensitivity reactivity was reduced with sleep fragmentation, but only for subjects with low insulin sensitivity and/or low first-phase insulin response to glucose.ConclusionsThese findings suggest that vascular sympathetic activity impairment is more strongly affected by metabolic dysfunction than by OSA severity, while blunted vagal autonomic function associated with sleep fragmentation in OSA is enhanced when metabolic dysfunction is also present

Bridging topological and functional information in protein interaction networks by short loops profiling

Protein-protein interaction networks (PPINs) have been employed to identify potential novel interconnections between proteins as well as crucial cellular functions. In this study we identify fundamental principles of PPIN topologies by analysing network motifs of short loops, which are small cyclic interactions of between 3 and 6 proteins. We compared 30 PPINs with corresponding randomised null models and examined the occurrence of common biological functions in loops extracted from a cross-validated high-confidence dataset of 622 human protein complexes. We demonstrate that loops are an intrinsic feature of PPINs and that specific cell functions are predominantly performed by loops of different lengths. Topologically, we find that loops are strongly related to the accuracy of PPINs and define a core of interactions with high resilience. The identification of this core and the analysis of loop composition are promising tools to assess PPIN quality and to uncover possible biases from experimental detection methods. More than 96% of loops share at least one biological function, with enrichment of cellular functions related to mRNA metabolic processing and the cell cycle. Our analyses suggest that these motifs can be used in the design of targeted experiments for functional phenotype detection.This research was supported by the Biotechnology and Biological Sciences Research Council (BB/H018409/1 to AP, ACCC and FF, and BB/J016284/1 to NSBT) and by the Leukaemia & Lymphoma Research (to NSBT and FF). SSC is funded by a Leukaemia & Lymphoma Research Gordon Piller PhD Studentship

Prospective study of serum 25(OH)-vitamin D concentration and risk of oesophageal and gastric cancers

We prospectively examined the relation between pretrial serum vitamin D status and risk of oesophageal and gastric cancers among subjects who developed cancer over 5.25 years of follow-up, including 545 oesophageal squamous cell carcinomas (ESCC), 353 gastric cardia adenocarcinomas, 81 gastric noncardia adenocarcinomas, and an age- and sex-stratified random sample of 1105 subjects. The distribution of serum 25(OH)D was calculated using the known sampling weights. For the cohort as a whole, the 25th, 50th, and 75th percentile concentrations of 25(OH)-vitamin D were 19.6, 31.9, and 48.7 nmol l−1, respectively, and we found that higher serum 25(OH)D concentrations were associated with monotonically increasing risk of ESCC in men, but not in women. Comparing men in the fourth quartile of serum 25(OH)D concentrations to those in the first, we found a hazard ratio (HR) (95% confidence interval (CI)) of 1.77 (1.16–2.70), P trend=0.0033. The same comparison in women had a HR (95% CI) of 1.06 (0.71–1.59), P trend=0.70. We found no associations for gastric cardia or noncardia adenocarcinoma. Among subjects with low vitamin D status, higher serum 25(OH)D concentrations were associated with significantly increased risk of ESCC in men, but not in women. Further refinements of the analysis did not suggest any factors, which could explain this unexpected result

Epstein–Barr virus serology and gastric cancer incidence and survival

Among 185 cases of gastric cancer and 200 controls in Linxian, China, Epstein–Barr virus (EBV) seropositivity was not associated with increased risk of gastric cancer. High EBV nuclear antigen titres were associated with longer survival in cardia cancer cases, possibly due to chance

Attitudes to smoking cessation and triggers to relapse among Chinese male smokers

BACKGROUND: Smoking is related to many diseases, and the relapse to smoking after cessation in China is noticeable. We examined the attitudes of Chinese male smokers regarding smoking cessation and reasons for relapse. METHODS: We interviewed 201 male smokers in Hangzhou City, Zhejiang province, China who had tried to quit smoking at least once in order to identify reasons for quitting and situations triggering relapse. RESULTS: The most significant reported reasons for quitting included personal health (77.1%), the cost of cigarettes (53.7%), and family pressures to quit (29.9%). The most common factors triggering relapse were social situations (34.3%), feeling negative or down (13.4%) and times of being alone (8.4%). CONCLUSION: Health and family concerns, personal factors, the influence of others and a lack of cessation resources were cited as salient factors concerning smoking cessation among male smokers in this study. Effective smoking control efforts in China will require attention to these influences if China is to curb its current smoking epidemic