Purpose To assess the ability of fast-kilovolt-peak switching dual-energy computed tomography (CT) by using the multimaterial decomposition (MMD) algorithm to quantify liver fat. Materials and Methods Fifteen syringes that contained various proportions of swine liver obtained from an abattoir, lard in food products, and iron (saccharated ferric oxide) were prepared. Approval of this study by the animal care and use committee was not required. Solid cylindrical phantoms that consisted of a polyurethane epoxy resin 20 and 30 cm in diameter that held the syringes were scanned with dual- and single-energy 64-section multidetector CT. CT attenuation on single-energy CT images (in Hounsfield units) and MMD-derived fat volume fraction (FVF; dual-energy CT FVF) were obtained for each syringe, as were magnetic resonance (MR) spectroscopy measurements by using a 1.5-T imager (fat fraction [FF] of MR spectroscopy). Reference values of FVF (FVFref) were determined by using the Soxhlet method. Iron concentrations were determined by inductively coupled plasma optical emission spectroscopy and divided into three ranges (0 mg per 100 g, 48.1-55.9 mg per 100 g, and 92.6-103.0 mg per 100 g). Statistical analysis included Spearman rank correlation and analysis of covariance. Results Both dual-energy CT FVF (ρ = 0.97; P < .001) and CT attenuation on single-energy CT images (ρ = -0.97; P < .001) correlated significantly with FVFref for phantoms without iron. Phantom size had a significant effect on dual-energy CT FVF after controlling for FVFref (P < .001). The regression slopes for CT attenuation on single-energy CT images in 20- and 30-cm-diameter phantoms differed significantly (P = .015). In sections with higher iron concentrations, the linear coefficients of dual-energy CT FVF decreased and those of MR spectroscopy FF increased (P < .001). Conclusion Dual-energy CT FVF allows for direct quantification of fat content in units of volume percent. Dual-energy CT FVF was larger in 30-cm than in 20-cm phantoms, though the effect of object size on fat estimation was less than that of CT attenuation on single-energy CT images. In the presence of iron, dual-energy CT FVF led to underestimateion of FVFref to a lesser degree than FF of MR spectroscopy led to overestimation of FVFref. © RSNA, 2016 Online supplemental material is available for this article.

Assessing the severity of liver fibrosis has direct clinical implications for patient diagnosis and treatment. Liver biopsy, typically considered the gold standard, has limited clinical utility due to its invasiveness. Therefore, several imaging-based techniques for staging liver fibrosis have emerged, such as magnetic resonance elastography (MRE) and ultrasound elastography (USE), but they face challenges that include limited availability, high cost, poor patient compliance, low repeatability, and inaccuracy. Computed tomography (CT) can address many of these limitations, but is still hampered by inaccuracy in the presence of confounding factors, such as liver fat. Dual-energy CT (DECT), with its ability to discriminate between different tissue types, may offer a viable alternative to these methods. By combining the "multi-material decomposition" (MMD) algorithm with a biologically driven hypothesis we developed a method for assessing liver fibrosis from DECT images. On a twelve-patient cohort the method produced quantitative maps showing the spatial distribution of liver fibrosis, as well as a fibrosis score for each patient with statistically significant correlation with the severity of fibrosis across a wide range of disease severities. A preliminary comparison of the proposed algorithm against MRE showed good agreement between the two methods. Finally, the application of the algorithm to longitudinal DECT scans of the cohort produced highly repeatable results. We conclude that our algorithm can successfully stratify patients with liver fibrosis and can serve to supplement and augment current clinical practice and the role of DECT imaging in staging liver fibrosis.

Image shading in high-field magnetic resonance imaging (MRI) due to radio-frequency (RF) wave propagation effects in biological tissue can be used to measure the electrical conductivity and relative permittivity of tissue in vivo. We describe a method to extract electrical properties of biological tissue from RF-shaded MR images without an explicit RF field mapping. The method is demonstrated on a meat sample and in the brain of a normal volunteer.

The ability of dual-energy computed-tomographic (CT) systems to determine the concentration of constituent materials in a mixture, known as material decomposition, is the basis for many of dual-energy CT's clinical applications. However, the complex composition of tissues and organs in the human body poses a challenge for many material decomposition methods, which assume the presence of only two, or at most three, materials in the mixture. We developed a flexible, model-based method that extends dual-energy CT's core material decomposition capability to handle more complex situations, in which it is necessary to disambiguate among and quantify the concentration of a larger number of materials. The proposed method, named multi-material decomposition (MMD), was used to develop two image analysis algorithms. The first was virtual unenhancement (VUE), which digitally removes the effect of contrast agents from contrast-enhanced dual-energy CT exams. VUE has the ability to reduce patient dose and improve clinical workflow, and can be used in a number of clinical applications such as CT urography and CT angiography. The second algorithm developed was liver-fat quantification (LFQ), which accurately quantifies the fat concentration in the liver from dual-energy CT exams. LFQ can form the basis of a clinical application targeting the diagnosis and treatment of fatty liver disease. Using image data collected from a cohort consisting of 50 patients and from phantoms, the application of MMD to VUE and LFQ yielded quantitatively accurate results when compared against gold standards. Furthermore, consistent results were obtained across all phases of imaging (contrast-free and contrast-enhanced). This is of particular importance since most clinical protocols for abdominal imaging with CT call for multi-phase imaging. We conclude that MMD can successfully form the basis of a number of dual-energy CT image analysis algorithms, and has the potential to improve the clinical utility of dual-energy CT in disease management.

The diagnosis and treatment of fatty liver disease requires accurate quantification of the amount of fat in the liver. Image-based methods for quantification of liver fat are of increasing interest due to the high sampling error and invasiveness associated with liver biopsy, which despite these difficulties remains the gold standard. Current computed tomography (CT) methods for liver-fat quantification are only semi-quantitative and infer the concentration of liver fat heuristically. Furthermore, these techniques are only applicable to images acquired without the use of contrast agent, even though contrast-enhanced CT imaging is more prevalent in clinical practice. In this paper, we introduce a method that allows for direct quantification of liver fat for both contrast-free and contrast- enhanced CT images. Phantom and patient data are used for validation, and we conclude that our algorithm allows for highly accurate and repeatable quantification of liver fat for spectral CT.

Spectral CT’s ability to determine material concentration drives its clinical application, but the complex make up of the human body poses a challenge. We developed methods for quantifying N > 3 materials, expanding spectral CT’s utility.

Positron Emission Tomography (PET) is a powerful tool for patient diagnosis and assessment of therapy response, which is carried out through comparison of PET measurements from longitudinal scans. However, as with any measurement tool, an estimate of error or uncertainty is required for meaningful comparison of such measurements. We have developed a bootstrap-based method for estimating uncertainty in respiratory-gated PET images. First, we independently reconstruct a set of gated images, each corresponding to a different stage in the respiratory cycle. We then apply a Bayesian framework to estimate parameters of the underlying posterior probability distribution of radioactivity concentration at each voxel, using a Gaussian model with non-negative mean, and considering the variance of the Gaussian model as a nuisance parameter with an asymptotically locally invariant prior. Once the posterior distribution of the radioactivity concentration at each voxel is determined, relevant image statistics are obtained at each voxel, either in closed-form (for the mean and standard deviation), or through numerical methods (for confidence intervals). The mean of the estimated distribution is shown to be a quantitatively better image than that obtained by averaging the set of gated reconstructions, yielding tighter confidence intervals for the values measured at each voxel. The procedure was successfully tested on real PET data.

The feasibility and utility of creating virtual un-enhanced images from contrast enhanced data acquired using a fast switching dual energy CT acquisition, is explored. Utilizing projection based material decomposition data, monochromatic images are generated and a Multi-material decomposition technique is applied. Quantitative and qualitative evaluation is performed to assess the equivalence of Virtual Un-Enhanced (VUE) and True Un-enhanced (TUE) for multiple tissue types and different organs in the abdomen. Ten patient cases were analyzed where a TUE and a subsequent Contrast Enhanced (CE) acquisition were obtained using fast kVp-switching dual energy CT utilizing Gemstone Spectral Imaging. Quantitative measurements were made by placing multiple Regions of Interest on the different tissues and organs in both the TUE and the VUE images. The absolute Hounsfield Unit (HU) differences in the mean values between TUE & VUE were calculated as well as the differences of the standard deviations. Qualitative analysis was done by two radiologists for overall image quality, presence of residual contrast, appearance of pathology, appearance and contrast of normal tissues and organs in comparison to the TUE. There is a very strong correlation between the TUE and VUE images.

The FIP1-like-1 (FIP1L1)-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFR- α ) fusion kinase causes hypereosinophilic syndrome (HES) in a defined subset of patients. Imatinib mesylate is a potent inhibitor of ABL but also of PDGFR- α , and has been associated with durable hematologic responses in patients with HES. However, development of mutations in the tyrosine kinase domain may hamper the activity of tyrosine kinase inhibitors (TKIs), which suggests that novel agents are warranted to prevent or overcome resistance. We evaluated the efficacy of the novel TKI EXEL-0862 in FIP1L1-PDGFR- α -expressing cell lines and in cells from a patient with HES harboring the FIP1L1-PDGFR- α gene. EXEL-0862 inhibited the proliferation of EOL-1 and imatinib-resistant T674I FIP1L1-PDGFR- α -expressing cells and resulted in potent inhibition of the phosphorylation of PDGFR- α and downstream proteins STAT3 and Erk1/2, both in vitro and ex vivo . Moreover, EXEL-0862 induced apoptotic death in EOL-1 cells and imatinib-resistant T674I FIP1L1-PDGFR- α -expressing cells, and resulted in significant downregulation of the antiapoptotic protein Mcl-1 through a caspase-dependent mechanism. Our data establish EXEL-0862 as a solid candidate for the targeted treatment of patients with FIP1L1-PDGFR- α -positive HES.

PurposeThe purpose of the study is to examine the influence of multiple factors on the green purchase intention of customers in Australia.Design/methodology/approachA conceptual model is proposed and was subjected to empirical verification with the use of a survey of metropolitan and regional households in Victoria, Australia. The data were analyzed using both descriptive measures and exploratory factor analysis to identify and validate the items contributing to each component in the model. AMOS structural modeling was used to estimate the measure of respondents' overall perception of green products and their intention to purchase.FindingsThe results indicate that customers' corporate perception with respect to companies placing higher priority on profitability than on reducing pollution and regulatory protection were the significant predictors of customers' negative overall perception toward green products. The only positive contribution to customers' perception was their past experience with the product. Other factors including the perception of green products, product labels, packaging, and product ingredients did not appear to influence customers' perception. The results also indicate that customers are not tolerant of lower quality and higher prices of green products.Research limitations/implicationsThe knowledge of the overall perception formation about green products and its predictors provides management with the facility to identify and implement strategies that may better influence the change of attitude by customers. Corporations can also benefit from the identification of the types of information required to enable management to influence this process of perception formation.Originality/valueThe present findings contributes to an understanding of the antecedents of green purchasing and highlight that green customers rely more on personal experience with the product than the information provided by the marketer.

In this short position paper, we describe our approach to developing a system for delivering remote services to people suffering from depression and similar mental illnesses. Our initial system architecture has two key components: a tool for helping the consumer and their carers develop and manage her care plan, and .a consumercontrolled consent control and management tool. We believe that the former will give the consumer much-needed control over their long-term care, and that the latter will support the development of the user’s trust in the system. Author

The recent recognition of Plasmodium falciparum Hsp90 (PfHsp90) as a promising anti-malaria drug target has sparked interest in identifying factors that regulate its function and drug-interaction. Co-chaperones are well-known regulators of Hsp90's chaperone function, and certain members have been implicated in conferring protection against lethal cellular effects of Hsp90-specific inhibitors. In this context, studies on PfHsp90's co-chaperones are imperative to gain insight into the regulation of the chaperone in the malaria parasite. In this study, a putative co-chaperone P. falciparum Aha1 (PfAha1) was identified and investigated for its interaction and regulation of PfHsp90. A previous genome-wide yeast two-hybrid study failed to identify PfAha1's association with PfHsp90, which prompted us to use a directed assay to investigate their interaction. PfAha1 was shown to interact with PfHsp90 via the in vivo split-ubiquitin assay and the association was confirmed in vitro by GST pull-down experiments. The GST pull-down assay further revealed PfAha1's interaction with PfHsp90 to be dependent on MgCl2 and ATP, and was competed by co-chaperone Pfp23 that binds PfHsp90 under the same condition. In addition, the PfHsp90–PfAha1 complex was found to be sensitive to disruption by high salt, indicating a polar interaction between them. Using bio-computational modelling coupled with site-directed mutagenesis, the polar residue N108 in PfAha1 was found to be strategically located and essential for PfHsp90 interaction. The functional significance of PfAha1's interaction was clearly that of exerting a stimulatory effect on the ATPase activity of PfHsp90, likely to be essential for promoting the activation of PfHsp90's client proteins.

PurposeDespite research studies indicating strong support for labelling information, uncertainty remains with respect to how labels influence consumers. This paper attempts to empirically investigate how consumers who differ in terms of environmentalism respond to labels.Design/methodology/approachThe data were collected on an Australian sample using a structured questionnaire administered on the phone using quantum research (CATI) data collection services. A total of 155 questionnaires were completed and used for data analysis. The data were analysed using both descriptive measures and correlations between variables.FindingsThere appears to be a proportion of consumers that find product labels hard to understand. The research found that there are consumers who will buy green products even if they are lower in quality in comparison to alternative products, but would look for environmental information on labels. With respect to price sensitive green consumers, there appears to be a relationship between price sensitivity and “always” reading labels as well as indicating that there is “sufficient” information on product labels to make informed purchase decisions.Research limitations/implicationsIt was beyond the scope of the research to account for some of the utilitarian approaches to interpretation or in‐depth comprehension of label information. The sample size of 155, although selected using a probability method, may, to some extent, limit the overall accuracy of the results.Practical implicationsThe research offers some important information on different green consumer segments that would alert managers on how best to position environmental labels. Findings such as “Satisfied with labels” correlates with “Labels are accurate”, which suggests that businesses need to provide a clear, accurate and easily legible label design to encourage satisfaction with the accuracy of content and the communication aspects of a label.Originality/valueThe paper contributes to better understanding of green customers purchase intentions and the usefulness of ecological product labels. It offers some insights and assistance to businesses in planning their green product/labelling strategies.

AbstractThis research examined the demographic profiles of Australian green consumers in relation to their satisfaction of environmental labelling. It examined consumers’ understanding of labelling and empirically investigated the association of demographic profile of consumers with their attitudes towards such labels. The results indicated that some of the demographic variables were significant, which is largely consistent with earlier findings by other researchers in this area. Label dissatisfaction was higher in the older and middle age respondents. However, some respondents disagreed that labels were accurate while commenting that labels were easy to understand. The key issue arising from the findings is that in order to provide perception of accuracy in labels, it is an option to use Type I or Type III labelling on products. These labels are, arguably, more credible because they are endorsed by third party labelling experts. This would come at a cost and for green products that use third party labelling, they will also have to bear in mind to keep the prices competitive.

2565 SB-497115 is an orally bioavailable, non-peptidyl, small molecule thrombopoietin receptor (TpoR) agonist under development for treatment of thrombocytopenia. SB-497115 requires TpoR to activate the JAK/STAT signalling pathway and stimulates transcription through STAT based and megakaryocyte specific (gpIIb) promoters. SB-497115 did not have activity on cell lines that expressed cytokine receptors other than TpoR (i.e., G-CSF, Epo, IL-3, Interferon -alpha or Interferon-gamma). To characterize the kinetics and specificity of SB-497115 in cells, multiple molecular markers for Tpo activity were measured. Western blot analysis for activation of the JAK2, STAT and MAPK pathways was performed using phospho-specific antibodies on lysates of UT7-Tpo cells treated with SB-497115. The kinetics and level of induction for pathway phosphorylation events were similar to those seen with Tpo. A proliferative response in the human Tpo-dependent cell line, UT7-Tpo, induced by SB-497115 was assayed by thymidine incorporation with an EC50 of 30 nM. SB-497115 was shown to be equivalent to rhTpo in the ability to induce differentiation of normal human bone marrow progenitors (CD34) into CD41+ cells of the megakaryocyte lineage, with an EC50 of 100 nM. SB-497115 specifically induced activity on cells expressing only human or chimpanzee TpoR. In a randomized, single blind, placebo-controlled, parallel group, phase I study conducted in 72 healthy male subjects, SB-497115 was administered as oral capsules once daily for 1 day and, after a 1 week washout, for 10 days at doses of 5 to 75 mg. Subjects were randomized into six groups of 12 subjects to receive either active or placebo medication in a ratio of 9:3. The study was conducted according to Good Clinical Practice and all subjects gave their written informed consent to participate in the study. SB-497115 was well tolerated in the study, there were no serious adverse events, no significant changes in laboratory or cardiovascular safety parameters and there was no observed relationship between the incidence or severity of adverse events and dose. Most adverse events were mild in intensity and self-limiting. SB-497115 was shown to be orally bioavailable in humans with a linear pharmacokinetic profile suitable for a once daily oral medication. When administered at oral doses of 30mg and above for 10 days a dose dependent increase in the platelet count was observed, maximum platelet count was observed on days 14 to 16 following initiation of dosing. In conclusion, SB-497115 is the first non-peptide small molecule TpoR agonist to demonstrate activity in human in vitro bone marrow assays and demonstrate pharmacological activity in humans.

Compounds in the diazo/hydrazino acid class require expression of Tpo receptor (TpoR) for activity. These compounds have demonstrated a remarkable species specificity in their Tpo receptor agonist activity, i.e., the activation of signalling pathways by this class of compounds has only been demonstrated in human and chimpanzee platelets. Platelets of other species demonstrate signalling in response to rhTpo, however, no signalling in response to SB-497115 is detectable by electrophoretic mobility shift assays using platelets of cynomolgus macaques, cat, mouse, mouse, rag, pig, ferret or tree shrew. Additionally, HepG2 cells transiently transfected with human TpoR, but not murine or cynomolgus monkey receptor results in STAT activated-reporter gene activity. To elucidate the mechanism by which this occurs, HepG2 cells were transiently transfected with a STAT-activated reporter gene and various chimeric and mutated receptors and treated with SKF-57626, a tool compound in this diazo class. A series of cyno and human TpoR chimeric receptors were constructed in which the complement receptor homology region 1 (CRH1), CRH2 and the transmembrane (TM) and cytoplasmic domains were interchanged. The functionality of all the chimeric receptors was confirmed by response to rhTpo. The minimal human composition of the chimeric TpoR activated by SKF-57626 was composed of human sequence within the membrane proximal region of the CRH2 domain and the TM domain. Two amino acids in this region are different between cyno and human, a Thr to Ala change in the extracellular CRH2 domain and a Leu at residue 499 in cynomolgus monkeys rather than His in humans in the TM domain. Sequencing of TpoR transmembrane domains of mice, dogs and ferrets, species in which these compounds are inactive, confirmed that the receptor contains Leu499, similar to cynomolgus macaques, while chimpanzee TpoR is similar to human with His at residue 499. To verify the requirement for His499 in the TM domain, a point mutation replacing only Leu499 with His in the cyno TpoR conferred activity when treated with compound. Replacement of His499 with Leu in the human TM domain resulted in an inactive human TpoR in response to compound, but not rhTpo. Further experiments involved mutations in the murine G-CSF receptor (mGCSFR). Human TpoR and mGCSFR have little homology in their TM domains and there is no detectable signalling, proliferation or differentiation responses following treatment of GCSFR expressing cells with either compound or rhTpo. A mGSFR point mutation was tested that contained a His residue nine amino acids into the hydrophobic TM domain of GCSFR, corresponding to His499 in the human and chimpanzee TpoR. HepG2 cells transiently transfected with this receptor and the reporter gene construct responded to compound. A double mutation in which an additional residue three amino acids N-terminal to the His was replaced with Thr, as in the hTpoR exhibited an increase in activity over the single mutation. These results suggest a model in which these TpoR agonist compounds interact with His499, in addition to Thr496, to either change conformation of TpoR or induce dimerization, resulting in activation of the signal transduction pathways of TpoR and imparting biologically relevant function.

This study examines the influence of various factors on the green purchase intention of customers in Australia. A conceptual model has been proposed and was subjected to empirical verification with the use of a survey of metropolitan and regional households in Victoria. The results indicate that corporate perception with respect of companies not placing higher priority on reducing pollution than increasing profitability was the significant predictor of customers’ negative overall perception toward environmentally safe products. The only positive contribution to customers’ perceptions was their past experience with the product. Other factors including the perception of environmentally safe products, product labels, and regulatory protection did not appear to influence customers’ perceptions. The results also suggest that customers are not tolerant of lower quality and higher prices of environmentally safe products. The present findings provide an understanding of the antecedents of green purchasing and highlight that green customers rely more on personal experience with the product rather than the information provided by the marketer.