Detectability of colorectal neoplasia with fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (FDG-PET/CT)

The purpose of this study was to analyze the detectability of colorectal neoplasia with fluorine-18-2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG-PET/CT). Data for a total of 492 patients who had undergone both PET/CT and colonoscopy were analyzed. After the findings of PET/CT and colonoscopy were determined independently, the results were compared in each of the six colonic sites examined in all patients. The efficacy of PET/CT was determined using colonoscopic examination as the gold standard. In all, 270 colorectal lesions 5 mm or more in size, including 70 pathologically confirmed malignant lesions, were found in 172 patients by colonoscopy. The sensitivity and specificity of PET/CT for detecting any of the colorectal lesions were 36 and 98%, respectively. For detecting lesions 11 mm or larger, the sensitivity was increased to 85%, with the specificity remaining consistent (97%). Moreover, the sensitivity for tumors 21 mm or larger was 96% (48/50). Tumors with malignant or high-grade pathology were likely to be positive with PET/CT. A size of 10 mm or smaller [odds ratio (OR) 44.14, 95% confidence interval (95% CI) 11.44-221.67] and flat morphology (OR 7.78, 95% CI 1.79-36.25) were significant factors that were associated with false-negative cases on PET/CT. The sensitivity of PET/CT for detecting colorectal lesions is acceptable, showing size- and pathology-dependence, suggesting, for the most part, that clinically relevant lesions are detectable with PET/CT. However, when considering PET/CT for screening purposes caution must be exercised because there are cases of false-negative results

Mitochondrial Protein Expression in NR4A3-knockout Mice

The expression of the orphan receptor, Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3), is upregulated in response to exercise, suggesting that it could be influential in altering gene expression for skeletal muscle adaptation to exercise. Recent research has demonstrated that when NR4A3 was knocked down in skeletal muscle cells, there was decreased expression of mitochondrial proteins, including those of the oxidative phosphorylation system (OXPHOS). The effect of deficient NR4A3 expression on mitochondrial proteins in mouse skeletal muscle is unknown. PURPOSE: We tested the hypothesis that NR4A3-knockout (KO) would suppress the expression of mitochondrial proteins in mouse skeletal muscle. METHODS: To test this hypothesis, the gastrocnemius muscles of 10 global NR4A3 knockout and 10 wild-type mice were collected, homogenized, and analyzed using western blotting. The proteins examined included OXPHOS proteins, PGC1, p-ACC, p-raptor, and cytochrome C. RESULTS: Contrary to our hypothesis, there was no significant difference in protein expression between the knockout and wild-type mice for any of the measured proteins. However, a strong trend (p=0.07 - 0.14) for decreased expression of some OXPHOS components was observed in knockout mice. CONCLUSION: Our findings suggest that contrary to findings in cultured muscle, the lack of NR4A3 in vivo does not heavily impact mitochondrial content, although it may affect components of the electron transport chain, and further testing of mitochondrial function would be beneficial. The lack of effect may be related to compensation by NR4A1, a protein related to NR4A3

Ribosomal Protein S6 Phosphorylation is Elevated in NR4A3 Knockout Muscle

Exercise training produces many muscle and body adaptations that improve health and function. Many of these adaptations are driven by altered gene expression. Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3; AKA NOR-1) is an orphan nuclear receptor and transcription factor whose expression is among the most upregulated genes after exercise, suggesting that it plays a critical role in the adaptation to training. Recently, a knockdown study in cultured skeletal muscle cells showed that the silencing of NR4A3 led to impaired signaling through the mechanistic target of rapamycin (mTOR), a key molecular driver of muscle mass maintenance. PURPOSE: Determine whether NR4A3 knockout in mice suppresses anabolic signaling through mTOR in muscle tissue. METHODS: Resting gastrocnemius muscles were collected from 10 global NR4A3 knockout (KO) and 9 wild-type (WT) mice and analyzed via western blotting for phosphorylated and total mTOR, p70 ribosomal protein S6 kinase (S6k), eukaryotic initiation factor 4E-binding protein 1 (4EBP1), and ribosomal protein S6 (rpS6). RESULTS: Gastrocnemius size was not different between WT vs. KO mice. No significant differences were noted in signaling protein phosphorylation between WT and KO except for rpS6 phosphorylation, which was elevated in KO muscles by 120%, contrary to our hypothesis. RpS6 is phosphorylated by both S6k (whose phosphorylation was not affected basally) and another kinase, p90 ribosomal protein S6 kinase (p90RSK). p90RSK is regulated by mitogen-activated protein kinase (MAPK) signaling. Therefore, we also measured Erk, p38, and Jnk phosphorylation, which were not significantly affected in KO muscles. CONCLUSION: Our findings indicate that NR4A3 knockout may enhance muscle anabolic potential (via elevated rpS6 action) but not through upstream mTOR or MAPK signaling. Furthermore, this suggests that the inhibition of NR4A3 could enhance muscle growth but not in unstimulated, resting muscle

Targeting cancer metabolism: a therapeutic window opens

Genetic events in cancer activate signalling pathways that alter cell metabolism. Clinical evidence has linked cell metabolism with cancer outcomes. Together, these observations have raised interest in targeting metabolic enzymes for cancer therapy, but they have also raised concerns that these therapies would have unacceptable effects on normal cells. However, some of the first cancer therapies that were developed target the specific metabolic needs of cancer cells and remain effective agents in the clinic today. Research into how changes in cell metabolism promote tumour growth has accelerated in recent years. This has refocused efforts to target metabolic dependencies of cancer cells as a selective anticancer strategy.Burroughs Wellcome FundSmith Family FoundationStarr Cancer ConsortiumDamon Runyon Cancer Research FoundationNational Institutes of Health (U.S.

Dual properties of the relative belief of singletons

In this paper we prove that a recent Bayesian approximation of belief functions, the relative belief of singletons, meets a number of properties with respect to Dempster’s rule of combination which mirrors those satisfied by the relative plausibility of singletons. In particular, its operator commutes with Dempster’s sum of plausibility functions, while perfectly representing a plausibility function when combined through Dempster’s rule. This suggests a classification of all Bayesian approximations into two families according to the operator they relate to

NMR-Based Prostate Cancer Metabolomics

Author's accepted version (postprint).This is an Accepted Manuscript of an article published by Springer in Methods in Molecular Biology on 22 May 2018.Available online: https://doi.org/10.1007/978-1-4939-7845-8_14acceptedVersio

Prognostic value of metabolic response in breast cancer patients receiving neoadjuvant chemotherapy

<p>Abstract</p> <p>Background</p> <p>Today's clinical diagnostic tools are insufficient for giving accurate prognosis to breast cancer patients. The aim of our study was to examine the tumor metabolic changes in patients with locally advanced breast cancer caused by neoadjuvant chemotherapy (NAC), relating these changes to clinical treatment response and long-term survival.</p> <p>Methods</p> <p>Patients (n = 89) participating in a randomized open-label multicenter study were allocated to receive either NAC as epirubicin or paclitaxel monotherapy. Biopsies were excised pre- and post-treatment, and analyzed by high resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS). The metabolite profiles were examined by paired and unpaired multivariate methods and findings of important metabolites were confirmed by spectral integration of the metabolite peaks.</p> <p>Results</p> <p>All patients had a significant metabolic response to NAC, and pre- and post-treatment spectra could be discriminated with 87.9%/68.9% classification accuracy by paired/unpaired partial least squares discriminant analysis (PLS-DA) (<it>p </it>< 0.001). Similar metabolic responses were observed for the two chemotherapeutic agents. The metabolic responses were related to patient outcome. Non-survivors (< 5 years) had increased tumor levels of lactate (<it>p </it>= 0.004) after treatment, while survivors (≥ 5 years) experienced a decrease in the levels of glycine (<it>p </it>= 0.047) and choline-containing compounds (<it>p </it>≤ 0.013) and an increase in glucose (<it>p </it>= 0.002) levels. The metabolic responses were not related to clinical treatment response.</p> <p>Conclusions</p> <p>The differences in tumor metabolic response to NAC were associated with breast cancer survival, but not to clinical response. Monitoring metabolic responses to NAC by HR MAS MRS may provide information about tumor biology related to individual prognosis.</p

Agile software development – Do we really calculate the costs? A multivocal literature review

Agile software development methods, in their various different forms, have become the basis for most software projects in today’s world. The methodology is present in almost all organisations today. However, despite the popularity, failure rates in software projects remain high. This paper identifies why agile methodologies have become so successful. In addition, the paper discusses certain factors that may often be overlooked in organisations that have adopted agile methods, such as rework, maintainability, adoption, turnover rates and the potential costs associated with each. The research carried out was a multivocal literature review (MLR). Multiple white and grey literature which was deemed to be relevant was selected. 32 contributions from white literature were selected for use in the review as well as 8 from grey literature sources. We find that while agile has many advantages, organisations may overlook the potential downsides of using an agile methodology. If not managed or implemented correctly, organisations risk taking on more hidden and expensive costs, for example in relation to rework. It is important that organisations are sufficiently trained in agile methods in order to succeed

Quantitative In Vivo Magnetic Resonance Spectroscopy Using Synthetic Signal Injection

Accurate conversion of magnetic resonance spectra to quantitative units of concentration generally requires compensation for differences in coil loading conditions, the gains of the various receiver amplifiers, and rescaling that occurs during post-processing manipulations. This can be efficiently achieved by injecting a precalibrated, artificial reference signal, or pseudo-signal into the data. We have previously demonstrated, using in vitro measurements, that robust pseudo-signal injection can be accomplished using a second coil, called the injector coil, properly designed and oriented so that it couples inductively with the receive coil used to acquire the data. In this work, we acquired nonlocalized phosphorous magnetic resonance spectroscopy measurements from resting human tibialis anterior muscles and used pseudo-signal injection to calculate the Pi, PCr, and ATP concentrations. We compared these results to parallel estimates of concentrations obtained using the more established phantom replacement method. Our results demonstrate that pseudo-signal injection using inductive coupling provides a robust calibration factor that is immune to coil loading conditions and suitable for use in human measurements. Having benefits in terms of ease of use and quantitative accuracy, this method is feasible for clinical use. The protocol we describe could be readily translated for use in patients with mitochondrial disease, where sensitive assessment of metabolite content could improve diagnosis and treatment