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Targeted Imaging of Colonic Tumors in Smad3−/− Mice Discriminates Cancer and Inflammation
Natasha G. Deane, H. Charles Manning, A. Coe Foutch, M. Kay Washington, Bruce A. Aronow, Darryl J. Bornhop and Robert J. Coffey
Natasha G. Deane
H. Charles Manning
A. Coe Foutch
M. Kay Washington
Bruce A. Aronow
Darryl J. Bornhop
Robert J. Coffey
DOI: 10.1158/1541-7786.MCR-06-0225 Published April 2007
Correction: Article on Optical Imaging of Intestinal Neoplasia - May 17, 2007
The peripheral benzodiazepine receptor (PBR) is a trans-mitochondrial membrane protein that modulates steroid biosynthesis. Recently, up-regulation and nuclear localization of PBR has been shown to be associated with colon, prostate, and breast cancer. PBR has been targeted by the exogenous synthetic ligand, PK11195, for various purposes including imaging. To capitalize on these observations, we developed a high-throughput, noninvasive, in vivo imaging approach to detect spontaneously arising colonic tumors in mice using a novel PBR-targeted molecular imaging agent (NIR-conPK11195). NIR-conPK11195 localized and was retained in colonic adenomas and carcinomas in Smad3−/− mice but not in non-neoplastic hamartomas or chronically inflamed colonic tissue. Using a fluorescence signal-to-noise ratio of ≥4-fold 13 h after injection of the agent, we detected colonic tumors with a sensitivity of 67% and a specificity of 86% in a cohort of 37 Smad3−/− mice and control littermates. Furthermore, using oral administration of dextran sulfate to induce colonic inflammation, we showed that the clearance profile of NIR-conPK11195 distinguished transient uptake in inflammatory tissue from longer term retention in tumors. Taken together, these results indicate that NIR-conPK11195 is a promising optical molecular imaging tool to rapidly screen for colonic tumors in mice and to discriminate inflammation from cancer. (Mol Cancer Res 2007;5(4):341–9)
Genetically engineered mouse models of human cancer represent a significant advance over conventional nude mouse xenograft models because it is possible to mimic features of human cancer development and progression by discrete spatial and temporal targeting of genetic events to distinct organs in the mouse. Adding to the relevance of these models, tumors from genetically engineered mouse models arise in immunocompetent hosts and are exposed to local factors of disease such as gut flora in the case of intestinal tumors. Among such models, Smad3tm1par−/− (hereafter referred to as Smad3−/− mice; ref. 1) have been shown to develop colonic tumors, including carcinomas, that exhibit a marked inflammatory component. In a recent advance, a single dose of azoxymethane has been coupled with the administration of dextran sulfate (DSS), which results in colonic inflammation (2) and then cancer. This combined approach produces cancers within the context of an inflammatory microenvironment, which has been shown to promote carcinogenesis in the gut (3, 4).
Preclinical assessment of tumor development and progression, as well as response to therapeutic intervention, in intestinal tumor models is currently limited by the lack of noninvasive methodologies suitable for evaluating the tumor. Thus, direct tumor assessment in these models requires sacrificing the animals, which complicates experimental protocols and significantly increases the number of animals required. Recently, others have reported advancement in the imaging of colonic tumors by contrast-enhanced computed tomography (CT) (5, 6) and by contrast-enhanced magnetic resonance imaging (MRI) (6). These techniques, while useful, remain low throughput and inherently invasive due to the necessity for purging, refilling, and suturing of the bowel to provide adequate contrast between the lumen of the bowel and the bowel wall. The development of accurate, low-cost, high-throughput, noninvasive imaging strategies capable of identifying tumor onset and progression, as well as response to treatment, remains an important goal toward rapid translation of innovative diagnostics and therapeutics.
The recent influx of low-cost instrumentation and novel molecular imaging reagents (7, 8) designed to operate within the tissue-transparent near-IR (NIR) window has enabled rapid, systemic, deep tissue targeting of tumors in small animals. In this study, we developed a novel NIR imaging agent, NIR-conPK11195, to target the peripheral benzodiazepine receptor (PBR), which is up-regulated in late-stage colon cancer (9). PBR is primarily associated with mitochondrial steroidogenesis and has been shown to be up-regulated in the epithelial component of cancers of the colon, breast, and prostate (10), as well as in activated macrophages in the brain (11, 12). The PBR synthetic ligand, PK11195, has been used clinically to image inflammation associated with several neurologic diseases (13-15). Con-PK11195, an analogue of the widely used PBR ligand PK11195, was recently prepared (16) and shown to be useful as a targeting agent for fluorescent probes as well as bimodal lanthanide chelate-imaging agents (17).
Here, we prepared a NIR fluorophore-labeled version of the ligand, NIR-conPK11195, and tested it as a targeted imaging agent for colonic tumors in Smad3−/− mice. The accuracy of detecting colonic tumors was assessed by imaging a total of 37 mice [Smad3−/− (n = 25), Smad3+/− (n = 7), and Smad3+/+ (n = 5) littermates]. Using fluorescence signal-to-noise ratio of ≥4-fold 13 h after injection of labeled ligand, the sensitivity and specificity of detecting adenomas and carcinomas were 67% and 86%, respectively. By this operationally defined criterion, small, flat lesions with invasive properties were detected but not benign tumors, chronically inflamed colon, or experimentally induced colonic inflammation. Overall, the imaging strategy we present provides a widely applicable, rapid, and inexpensive means of detecting colonic adenomas and carcinomas in the background of benign tumors and/or inflammation.
Given the putative clinical relevance of PBR expression in human colon cancer (9), we queried PBR gene expression data from 39 colonic tumors derived from four distinct mouse models of intestinal neoplasia, including Smad3−/− (n = 13), azoxymethane-induced (n = 14), APCMin+/− (n = 9), and transforming growth factor β−;Rag2−/− tumors (n = 3). Expression values for 28,000 genes of known function were compared with those from wild-type (WT) adult C57BL6/J colons (n = 3). We found up-regulation of PBR expression in Smad3−/− tumors (mean log fold increase over adult WT colon = 3.6; SD, ±0.9), azoxymethane-induced tumors (mean log fold increase over adult WT colon = 3.0; SD, ±1.6), APCMin/+ tumors (mean log fold increase over adult WT colon = 4.8; SD, ±3.3), and transforming growth factor β−/− × Rag2−/− tumors (mean log fold increase over adult WT colon = 4.3; SD, ±0.8; Supplementary Fig. S1A). Network analysis of gene expression changes clustering with respect to PBR up-regulation was conducted. This analysis indicated that PBR is coordinately regulated with genes that have emerged as master regulatory nodes in colon cancer such as p53, CEBP/β, and signal transducers and activators of transcription 3, and that it links to these nodes directly downstream of Myc (Supplementary Fig. S1B).
To develop an optical imaging agent capable of rapid and high-throughput imaging of deep-tissue PBR-expressing tumors, we labeled our novel analogue of the PBR ligand, con-PK11195 (16, 17), with a NIR fluorophore yielding the molecular imaging agent NIR-conPK11195 (Fig. 1A ). The aqueous media spectroscopic properties of the resulting agent are shown in Fig. 1B, with excitation (λmax = 780 nm) and emission (λmax = 800 nm) centered within the tissue transparency window.
Structural and spectral characteristics of NIR-con-PK11195. A. Chemical structure of NIR-con-PK11195, an isoquinoline carboximide (bottom left), showing conjugation with LI-COR 800 W (top right) through a six-carbon linker. B. Spectral properties of NIR-con-PK11195 conjugate showing characteristic light absorbance (•) at 780 nm and emission (▪) at 830 nm.
We next tested NIR-conPK11195 for specific retention in colonic tumors using 37 Smad3−/−, Smad3+/−, and Smad3+/+ littermates between 2 and 5 months of age. For these experiments, we empirically selected a signal-to-noise ratio of ≥4-fold at 13 h after injection of labeled ligand as a cutoff for the prediction of the presence of tumor in the Smad3−/− mice. Using this operationally defined criterion, we evaluated NIR-conPK11195 signal retention in this cohort of mice. The results of this analysis are summarized in Table 1 . Of the 37 animals tested, 15 harbored tumors, and 10 of these retained foci of NIR-conPK11195 fluorescent signal, thus producing 67% sensitivity (10/15) for tumor detection. Among the 22 non–tumor-bearing mice, only 3 retained foci of NIR-conPK11195 fluorescent signal 4-fold or higher above background, thus producing 86% specificity (19/22) for tumor detection.
Accuracy of NIR-conPK11195 Tumor Detection
To determine the kinetics of NIR-conPK11195 in live animals, we conducted clearance profile analyses upon the full set of animals. For these experiments, 10 nmol of the agent was given i.v., and images were recorded before administration and at timed intervals up to 20 h postadministration (Fig. 2A ). In Fig. 2B, we show a plot of the clearance profiles for age-matched Smad3+/+ (left mouse) and Smad3−/− (right mouse) mice shown in Fig. 2A, using a uniform region of interest (ROI) to collect photon counts in the abdomen at locations avoiding the gall bladder where high focal background occurs (see ROI depicted in Fig. 2A). As can be seen, we observed little difference in focal fluorescent retention between control and Smad3−/− mice at early time points postadministration (<4 h) of NIR-conPK11195. However, between 4 and 7 h postadministration, the agent accumulated rapidly in the Smad3−/− mice and exhibited localized abdominal retention (≥4-fold over background per uniform ROI). Subsequently, the fluorescence intensity in both Smad3−/− and control animals gradually decreased, returning to background levels by 20 h postadministration. The presence or absence of colonic tumors in H&E-stained slides of intestinal "Swiss Rolls" was assessed by a pathologist (M.K. Washington), and PBR expression in the tumors was confirmed by immunohistochemistry. Here, strong nuclear staining of PBR can be seen in the epithelial component of intestinal tumors (Fig. 2D), consistent with published results (18). In contrast, there was weaker and more heterogeneous staining for PBR in normal colonic mucosa taken from control littermates (Fig. 2C).
NIR-con-PK11195 accumulates and is retained in colonic cancers of Smad3−/− mice. A. Smad3+/+ (left mouse in each picture) and Smad3−/− (right mouse in each picture) mice were imaged and fluorescent signal quantified within a specified ROI (last picture) before and after administration of NIR-con-PK11195. B. Dynamic time-intensity curves for signal obtained from previous panels for tumor-bearing Smad3−/− (•) and their tumor-free Smad+/+ (▾) siblings. C. PBR stain of normal colonic mucosa from Smad3+/+ mouse imaged in A-M. D. Nuclear PBR staining in Smad3−/− tumor (magnification, 200×).
To further examine the specificity of NIR-conPK11195 for tumors, the retention of free (unconjugated) NIR dye (LI-COR 800CW) was compared with the targeted chemistry (NIR-conPK11195) in Smad3−/− tumor-bearing animals. Images shown in Fig. 3 illustrate that free dye does not accumulate in the colons of tumor-bearing Smad3−/− mice following i.v. administration, nor does it produce signal at either low or high resolution (Fig. 3A and B, bottom). Furthermore, fluorescence of the free dye is comparable to control mice (Fig. 3A and B, top) signals. We also found that the free dye is rapidly cleared through the urinary tract and not through the hepatobiliary system, as is NIR-conPK11195 (data not shown). As seen in Fig. 3, high-resolution fluorescent imaging of excised colonic tissues following in vivo administration of the free dye or NIR-conPK11195 indicate ligand-specific focal retention in colonic cancer lesions intestinal at 13 h postadministration (Fig. 3B and E, top and bottom). Unconjugated LI-COR 800CW did not accumulate to a significant extent or colocalize with colonic tumors, nor did it accumulate in non–tumor-bearing animals (Fig. 3A-C, top and bottom). A clearance profile for representative tumor-bearing mice, shown in Fig. 3G, illustrates the relative photon flux per uniform ROI over time and shows ligand-specific retention of the agent. Therefore, accumulation and colocalization of NIR-conPK11195 is ligand dependent and is not due to nonspecific association with biological properties related to the tumor such as leaky vasculature.
NIR-conPK11105 retention and colocalization with tumors is ligand dependent. Images of Smad3+/+ (top) and Smad3−/− (bottom) mice injected with 10 nmol of unconjugated LI-Cor 800CW (A, top and bottom) or NIR-conPK11195 (D, top and bottom; signal intensity indicated by photon flux per second). B and E. High-resolution images (matched to A and D) of excised intestinal tissue show focal retention of NIR-conPK11195 in tumor-bearing mouse only (E, bottom). C and F. Matched H&E-stained slides at 50× magnification demonstrating normal mucosa from Smad3+/+ mouse (top) and carcinoma from Smad3−/− mice (bottom). G. Clearance profiles of free dye versus NIR-conPK11195 in Smad3−/− tumor-bearing mice.
To compare the optical imaging strategy with a more conventional imaging methodology, we imaged a set of Smad3+/+ and Smad3−/− animals using 18F-fluorodeoxyglucose (18FDG)-positron emission tomography (PET) coregistered with CT and NIR-conPK11195. Representative images are shown in Fig. 4 . We observed a good correlation between optical imaging using NIR-conPK11195 and PET imaging with 18FDG for tumor detection in Smad3−/− mice. The presence of tumors could be detected using either imaging strategy at comparable resolution.
Compared resolution of NIR-con-PK11195 imaging with 18FDG-PET/CT imaging of colonic cancer in Smad3−/− mouse. Five-month-old WT (A and B, left) and Smad3−/− (A and B, right) mice were imaged sequentially. First, optically using NIR-con-PK11195 (A) and then by 18FDG-PET coregistered with contrast-enhanced CT (B). WT mice accumulate 18FDG in the bladder (dashed line), whereas Smad3−/− mice have additional 18FDG activity in areas corresponding to colonic tumors (solid lines) found at autopsy. H&E stain of colonic mucosa from animals imaged in (A) and (B) shown at 100× magnification. C. Smad3−/− mucosa demonstrating cancer characterized by laterally invasive epithelial cells (arrows).
Upon close examination, we found variation in histopathology of tumors between Smad3−/− and Smad3+/− mice. This variation had apparent effects on the quantification of retained NIR-conPK11195 in these mice. Figure 5 shows a representative imaging experiment of Smad3−/− and Smad3+/− mice with accompanying histopathologic findings. As expected, we found adenomas and carcinomas in the Smad3−/− mice. In addition, benign lesions, such as hamartomas (Fig. 5B, top), and cystic lesions were identified only in Smad3 heterozygous mice. In live animal imaging, the NIR-conPK11195 fluorescent signature suggested varying degrees of labeling intensity among these mice. Representative examples show that benign hamartomas retained signal in the range of 1 to 2 × 108 photon flux per second (fps) (Fig. 5A, top), adenomas retained intermediate signal in the range of 2 to 3 × 108 fps (Fig. 5A, middle), and carcinomas retained signal above 3.5 × 108 fps (Fig. 5A, bottom). It is important to note that Smad3−/− animals with heavy tumor burden exhibited runting, resulting in a shorter path length for light to travel from the tumor through tissue, thus increasing the relative photon flux impinging onto the detector and complicating signal quantification between genotypes. Strategies to normalize signal to animal size should improve the quality of the information derived from deep tissue tumors and are currently under investigation.
NIR-con-PK11195 is retained proportionately to tumor stage. A. Representative optical imaging of Smad3+/− (top row) and Smad3−/− (middle and bottom row) mice (fluorescence intensity indicated by photon flux per second). B. Matching H&E stains demonstrating hamartoma (top row; magnification, 100×), adenoma (middle row; magnification, 100×; arrows, uninterrupted muscularis mucosa), and carcinoma (bottom row; magnification, 50×; arrows, invasive component).
In an effort to determine the effectiveness of detecting early lesions by NIR-conPK11195 imaging, we screened a panel of young Smad3−/− mice (aged 2 to 4 months). Because carcinomas in Smad3−/− mice are preceded by inflammation and dysplasia, these analyses allowed us to determine whether NIR-conPK11195 distinguished inflammation and dysplasia from cancer. As shown in Fig. 6A , NIR-conPK11195 was not retained in young Smad3−/− animals harboring significant inflammation, associated mucosal thickening, or dysplasia. One 4-month-old mouse in this group retained significant ≥4-fold (over background) NIR-conPK11195. Although initially overlooked by gross inspection, a single flat (sessile) adenocarcinoma was detected histologically in the excised tissue from this mouse (Fig. 6B, right, boundaries of tumor outlined by arrows). The invasive properties of this lesion were subsequently confirmed by our pathologist (M.K. Washington). This result suggests enhanced specificity of NIR-conPK11195 for invasive lesions, as suggested in Fig. 5 and will serve as the basis for further study on the role of PBR expression in tumor cell behavior.
NIR-conPK11195 is not retained in dysplastic or inflammatory lesions of 2- to 3-month-old Smad3−/− mice. A. Smad3−/− mice (1-4, 6-7) and Smad3+/+ control mice (5, 8), aged 9 to 16 wks as indicated, imaged optically using NIR-con-PK11195, show no focal accumulation of the imaging agent with the exception of mouse 7. B. Matching H&E-stained slides from select mice shown in (A), each at 100× magnification. Thickened colonic mucosa with inflammation and epithelial cell dysplasia taken from 9-week-old Smad3−/− mouse (left, taken from mouse 1 in A). Image of normal colonic mucosa (middle) was taken from mouse 5. Image of invasive flat lesion was taken from 16-week-old Smad3−/− mouse (7 in A). Solid arrows, outline of the lesion. Dashed arrow, tumor invasion into the muscularis mucosa.
Expression of PBR protein has been shown to be up-regulated in activated macrophages of the brain (11, 12). To determine whether NIR-conPK11195 would be retained by intestinal inflammation, we administered NIR-conPK11195 to WT mice with colonic inflammation induced by a 7-day course of DSS in their drinking water according to the method of Cooper et al. (19). In these experiments, DSS-treated WT mice were imaged alongside untreated Smad3−/− mice. We found that significant NIR signal appeared abdominally at 4 and 8 h postadministration of NIR-conPK11195 in both tumor-bearing Smad3−/− and in DSS-treated WT animals. However, that fluorescent signal was retained at 13 h postadministration only in tumor-bearing animals (Fig. 7A ). Strikingly, a rapid clearance of NIR signal occurred in the DSS-treated mice beginning between 4 and 8 h postadministration, as can be seen in the clearance profile (Fig. 7C). By 12 h postadministration, NIR signal returned to background levels in the DSS-treated mice, but not in the tumor-bearing Smad3−/− mice (Fig. 7A and B, top and bottom). Figure 7C depicts the mean fluorescence profile for DSS-treated and tumor-bearing mice between NIR-conPK11195 administration and 12 h thereafter. As can be seen in this profile, a 6-fold difference in signal was observed between Smad3−/− and DSS-treated WT mice. Upon tissue resection, we found patchy acute inflammation in sections from all DSS-treated animals accompanied by significant crypt degeneration, attenuated crypts, and significant loss of epithelium (Fig. 7B, bottom). Carcinomas were confirmed histologically for all Smad3−/− mice (Fig. 7B, top). Collectively, these data indicate that temporal behavior of NIR-conPK11195 retention can be used to discriminate neoplastic tissue from inflammation in Smad3−/− mice.
NIR-con-PK11195 retention by inflammation is distinguishable from retention by tumor at late time points. A. Representative imaging of a 5-month-old Smad3−/− mouse (top row) and a 5-month-old WT mouse treated with DSS (bottom row). Optical images acquired at 13 h postadministration of NIR-conPK11195. B. Matched H&E-stained sections demonstrating invasive adenocarcinoma with inflammation in intestinal tissue taken from 5-month-old Smad3−/− mouse (top) and patchy crypt loss with a mixed acute and chronic inflammatory infiltrate in the lamina propria (magnification, 400×) in colonic tissue taken from WT DSS-treated mouse imaged in (bottom). Clearance curve for NIR-PK-11195 retention in tumor-bearing (solid line; n = 7), DSS-treated (dotted line; n = 11), and control (dashed line; n = 4) mice. bars, SE at each time point.
We tested the effectiveness of a NIR-conPK11195–targeted imaging strategy in the Smad3−/− mouse model of intestinal cancer (for a review of the histopathology of these tumors as well as those from other experimental models of intestinal neoplasia, see ref. 20). Smad3−/− mice develop mucinous invasive carcinomas of the colon with a strong inflammatory component. We queried global tumor expression profiles from four mouse models of intestinal neoplasia for PBR expression. We found that PBR overexpression was uniformly up-regulated in mouse colonic tumors from all four mouse models. We did network analysis on a cluster of 11 genes that were coordinately regulated with PBR and found that 10 of these genes organized into a single network (Supplementary Fig. S1). This network analysis shows that PBR expression is regulated downstream of c-myc, and that its overexpression may serve as a broad marker for neoplasia and, thus, as a widely applicable imaging target. Therefore, we decided to use a NIR conjugate of the PBR ligand, PK11195, to test a targeted optical imaging strategy for colonic tumor detection in Smad3−/− mice. This strategy was sensitive and specific for colonic tumors and allowed us to rapidly screen a large cohort of mice for the presence of tumors on a background of colonic inflammation.
As illustrated in Fig. 2, we found by immunohistochemistry that overexpression of PBR in colonic tumors from Smad3−/− mice associates with nuclear accumulation of the protein. This is a novel finding for this protein in neoplastic colonic epithelium but is consistent with data from others (18, 21) who have observed this phenomenon in both breast and in liver cancer cells. Although the role of nuclear PBR has not been precisely defined, it has been shown to exert an effect upon cellular proliferation in MDA-231 breast cancer cells (18).
Multiple methods for noninvasive assessment of intestinal tumors in mouse models have emerged over the past several years (5, 6, 22). The method presented here based on targeting PBR expression combines the low-cost, high-throughput advantages of optical methods based on bioluminescence, yet avoids the requirement for a reporter transgene enhancing the potential for translational usefulness. Although optical strategies have drawbacks in terms of spatial resolution and signal quantitation, we found these limitations to be comparable to those encountered with 18FDG-PET/CT imaging (Fig. 4). Notably, however, the high-throughput nature of the optical screening strategy enabled high-throughput screening (up to 60 animals per hour is possible), whereas only a few animals could be screened by PET/CT imaging in a comparable time frame. Furthermore, screening the animals with optical imaging was accomplished at a fraction of the cost of PET/CT imaging, without the added complications of lengthy anesthesia or for the introduction of ionizing radiation. The advantage of this strategy lies in the fact that large populations of mice can be taken through an inexpensive and noninvasive screen, and more invasive and costly contrast-enhanced methods (PET, CT, or MRI) would be reserved for the subset of animals harboring tumors when appropriate. With respect to screening for the presence of colorectal cancer, the specificity (86%) and sensitivity (67%) reported here compares favorably with that obtained with comparable 18FDG-PET data in humans reported at 91% to 93% sensitivity and 63% to 83% specificity (refs. 23, 24; considering the relative experience of trained radiologists versus laboratory scientists). No data exist to date regarding the detection specificity or sensitivity for intestinal lesion by 18FDG-PET in mouse models.
The role of inflammation in cancer development is an area of intense investigation (2, 3). Previous studies have shown a high level of PBR expression in activated macrophages associated with inflammation (13, 25), so it was important for us to rule out nonspecific retention of the targeted agent related to tumor-associated inflammatory processes. We found that retention profiles of NIR-conPK11195 discriminated between mice treated with DSS and tumor-bearing mice at times between 8 and 13 h postadministration (Fig. 7C). Furthermore, we found that young mice exhibiting precancerous inflammation and associated epithelial dysplasia did not retain a NIR-conPK11195 (Fig. 6); however, in one animal from this group of younger animals, the presence of an invasive lesion correlated with significant NIR retention. Thus, NIR-conPK11195 represents an imaging agent that could be used to screen cohorts of mice during tumor development, even on the background of accompanying or experimentally induced inflammation.
The ability to follow molecular events in vivo represents a paradigm shift for medical science. A critically important goal of molecular imaging studies is to detect spontaneously arising tumors in the context of the host/tumor microenvironment (4). Smad3−/− mice exhibit many of the features of the tumor microenvironment of human colon cancer and, thus, represent an opportunity to study molecular features of disease progression and to assess therapeutic efficacy in preclinical trials. In a step toward these goals, we have shown an inexpensive, high-throughput strategy for in vivo molecular imaging of spontaneous intestinal neoplasia. Our ongoing efforts are directed toward preparing con-PK11195 analogues containing 99Tc or 64Cu to facilitate PBR targeting in clinically relevant imaging modalities, such as single-photon emission computed tomography (SPECT) and PET with the long-term goal of improving the early diagnosis of colon cancer. Additionally, we expect these agents to be useful for noninvasive monitoring of therapeutic efficacy that should be useful in improving clinical outcomes. These agents would be expected to achieve greater sensitivity and specificity than seen in this study when used in conjunction with detectors that have tomographic capability such as PET or SPECT.
Data for PBR gene expression were obtained from a mouse colon tumor gene expression database composed of mouse tumors collected through the Mouse Models of Human Cancers Consortium.10 Individual colonic tumors from individually excised tumors in various experimental strains were analyzed for PBR expression relative to normal C57BL6/J adult intestinal mucosa. The specific probe element for PBR was H3039E04 from a custom chip spotted at the Vanderbilt Microarray Core Facility representing 22,000 elements from the National Institute of Aging mouse cDNA library, 5,000 clones from Research Genetics, and 1,000 custom clones (28,000 cDNA elements total). Briefly, individual RNA samples were labeled with Cy5 as described by Park (26), and a universal reference RNA (day E17.5 whole mouse) was labeled with Cy3, hybridized to individual microarrays. Individual arrays were normalized by the Lowess intensity-dependent correction, and relative gene expression levels were estimated by dividing individual gene signal ratios by that of the average of adult mouse colon samples. Gene network analysis was done using Ingenuity Pathway Analysis (Ingenuity Systems, Inc., Redwood City, CA).
Con-PK11195 was synthesized as described previously (16). LI-COR-800CW was purchased from LI-COR Biosciences (Lincoln, NE). Briefly, the dye and the conPK11195 derivative were dissolved by stirring in dry DMSO in an argon-flushed vessel. The reaction was protected from room light and allowed to proceed at room temperature overnight. Reaction progress was followed with reverse-phase HPLC using a C18 column and acetonitrile/water as the eluent. NIR-conPK11195 was purified on an open, alumina column eluting with acetonitrile/water, followed by an ion-exchange column eluting with water. Pure fractions were then concentrated using rotary evaporation and further concentrated with lyopholization. The imaging agent was characterized by nuclear magnetic resonance and electrospray ionization mass spectrometry calculated (found): 1364.01 (M2+ 681.95). Spectroscopic characterization in both water and DMSO consisted of both UV–visible light and fluorometry.
Mouse Models
Smad3−/− mice were maintained according to institutional guidelines. Induction of inflammation in mice was obtained according to the method of Cooper et al. (19). Briefly, adult mice were fed DSS (MW 40-50 kDa; U.S. Biochemical Co., Cleveland, OH) at 2.5% in the drinking water for 7 days at which time consumption of normal drinking water was resumed. Mice were imaged at days 9, 13, and 16 after commencement of the DSS treatment and sacrificed thereafter. Excised tissues were imaged on the Odyssey NIR imaging system (LI-COR Biosciences) using an 800-nm filter. Following ex vivo imaging, tissues were fixed in 4% paraformaldehyde for 8 to 12 h before dehydration in 70% ethanol and then paraffin embedded. H&E-stained slides were prepared, and pathology was ascertained by an experienced gastrointestinal pathologist (M.K. Washington).
Following i.v. administration of 10 nmol of NIR-conPK11195, in vivo imaging was carried out in a Xenogen IVIS 200 imaging system (Alameda, CA), equipped with a ventilator. Animals were anesthetized for imaging using 1.2% isoflurane (Baxter Pharmaceuticals, Deerfield, IL) in O2 at 2 L/min. Body temperature was maintained using a thermostat-controlled heating pad. The Odyssey imaging system (see above) was used to image excised tissues using the 800-nm channel and 1-mm focus offset. Resolution and laser intensity were conserved during quantitative experiments.
For quantification of optical signal, uniform ROIs were created using the Xenogen software package. ROI area was conserved for each experiment, and the total photon flux was determined for individual ROIs. Signal-to-noise ratio was determined by dividing the ROI intensity for an experimental animal by the ROI intensity for the control animal.
For contrast-enhanced CT, 250 μL of 350 mg/mL organically bound iodine (Optiray 350, Mallinckrodt, Inc., St. Louis, MO) was injected i.p. immediately before imaging. Images were acquired with an 8-min exposure time at 80 kV with 360 projections over 360°, (125-μm isotropic voxel size). For micro-PET imaging, animals were injected i.p. with 120 to 180 μCi of 18FDG. One hour later, the animal was anesthetized and positioned in the imaging cradle. For coregistration of CT and PET images, injections of iodinated triglyceride (Advanced Research Technologies Inc., Saint Laurent, Quebec, Canada) and FDG were timed such that imaging with the PET system immediately followed imaging with the CT system. A single imaging cradle, interchangeable with the CT and PET, was used such that mice could be imaged by both systems sequentially with minimal change in positioning. This imaging cradle had four fiducial markers that could be identified in both the PET and CT images. Image registration based on rigid-body alignment of these fiducials was achieved using the software package, Amide (27).
Histologic Analysis
Intestinal tissue was examined in situ for evidence of macroscopic tumors (>1 mm diameter). Sections of intestine were washed and prepared as a Swiss roll before preservation in 4% paraformaldehyde and subsequently paraffin embedded and sectioned for H&E staining. Five-micrometer tissue sections for immunohistochemistry were prepared as previously described (28). Primary rabbit anti-PBR polyclonal antibody (a generous gift from V. Papadopoulos, Georgetown University, Washington, DC) or anti-bromodeoxyuridine antibody (Accurate Chemical and Scientific Co., Westbury, NY) were used to stain sections using the Vectastin Elite ABC kit (Vector Laboratories, Burlingame, CA).
↵10 http://emice.nci.nih.gov/
Grant support: NCI Mouse Models of Human Cancer Consortium (CA84239), NCI GI Special Program of Research Excellence (SPORE; CA95103), the Vanderbilt Ingram Cancer Center (CA68485) and the Vanderbilt Institute for Chemical Biology. H. C. Manning is supported by the Vanderbilt University Institute of Imaging Science, N. Deane is supported by NCI CA84239 and NIH DK52334. The Vanderbilt Microarray Shared Resource is supported by NIH CA68485 and by the Vanderbilt Diabetes Research and Training Center (DK20593), the Vanderbilt Digestive Disease Center (DK58404), the Genomics of Inflammation Program Project Grant (HL6744), and the Vanderbilt Vision Center (EY08126). The Mouse Metabolic and Phenotyping Core is supported by NCI DK59637. LI-COR Inc. is acknowledged for donating a portion of the dye employed.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).
Accepted January 31, 2007.
Received July 25, 2006.
Revision received December 21, 2006.
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Mol Cancer Res April 1 2007 (5) (4) 341-349; DOI: 10.1158/1541-7786.MCR-06-0225
Molecular Mechanisms of Liver Carcinogenesis in the Mdr2-Knockout Mice
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The US Environmental Protection Agency's (EPA) annual report "Light-Duty Automotive Technology, Carbon Dioxide Emissions, and Fuel Economy Trends" (earlier post) has, in its past editions since its inception in 1975, treated alternative fuel vehicles—electric vehicles (EVs), plug-in hybrid vehicles (PHEVs), and compressed natural gas (CNG) vehicles—separately from gasoline and diesel vehicles, with the vast majority of its analysis limited to gasoline and diesel vehicles only.
The agency's reasoning was that since alternative fuel vehicle production has generally been less than 0.1% of total vehicle production until very recently, the impact of excluding alternative fuel vehicles was negligible. With alternative fuel vehicles now approaching 1% of new vehicle production, however, they are in fact beginning to have a "measurable and meaningful impact" on overall new vehicle fuel economy and CO2 emissions.
The EPA report is an authoritative reference for CO2emissions, fuel economy, and powertrain technology trends for new personal vehicles in the United States.
EPA obtains the detailed data supporting the report directly from automobile manufacturers; the agency has been collecting and maintaining these data since 1975. They comprise the most comprehensive database of its kind.
The Trends report has been published annually since 1975 and covers all passenger cars, sport utility vehicles, minivans, and all but the largest pickup trucks and vans.
Thus, for the first time, in the newly released 2014 edition of the Trends report, EPA presents a brief analysis of the impact of alternative fuel vehicles on overall new vehicle fuel economy and CCO2O2 emissions. In the analysis, EPA uses overall fuel economy in mpg equivalent (mpge) and tailpipe CO2 emission values. Including net upstream CO2 emissions for vehicles operating on electricity would reduce the positive impact of alternative fuel vehicles on fleet-wide CO2 emissions, the agency noted.
In MY 2013, there were 11 EVs and 4 PHEVs available in the market; MY 2014 has 12 (counting the Tesla Model S 60 and 80 as one) EVs on the market and 10 PHEVs, along with the lone CNG car, the Honda Civic. (In this tally, the BMW i3 counts as an EV in its battery-only configuration and as a PHEV when equipped with a range extender.) More are coming to the US market, such as the Audi A3 e-tron plug-in hybrid and Volkswagen e-Golf BEV.
The combined production of alternative fueled vehicles has increased from under 1,200 in MY 2010, to nearly 105,000 in MY 2013. While alternative fueled vehicles still represent a very limited portion of overall new vehicle production (0.7% of overall light-duty vehicle production in MY 2013), this increase by a factor of about 100 in three years is both notable and significant.
Overall fuel economy (miles per gallon gasoline equivalent) and average tailpipe + net upstream CO2 emissions for EVs and PHEVs in 2014 Trends report. Fuel economy average for the US fleet, per the Trends report, is 24.1 mpg. Data: EPA. Click to enlarge.
Alt fuel vehicle impact on OEMs. Alternative fuel vehicles represented 0.7% of new vehicle production in MY 2013, according to EPA. Including mpge and tailpipe CO2—i.e., not full well-to-wheels CO2—emissions from alternative fuel vehicles (AFV) increases the overall MY 2013 new vehicle fuel economy by 0.1 mpg, and reduces the overall CO2 emissions by 3 g/mi.
Of the major manufacturers (production above 100,000 vehicles), Nissan had the highest concentration of AFV production at 2.0%, followed by GM at 1.2%. Including AFVs improves Nissan's performance the most, increasing MY 2013 fuel economy by 0.4 mpge overall, and decreasing Nissan's MY 2013 CO2 emissions by 7 g/mi.
Fuel economy and range for BEVs (as well as the BMW i3 with range extender, which performs better than some BEVs). The first number in the data labels is mpge, the second, alternative fuel range. Again, with the exception of the i3 REX, this is the full range of the vehicle. Data: EPA. Click to enlarge.
The impact of AFVs on overall manufacturer numbers is still relatively small, and does not change the manufacturer rankings, for either adjusted fuel economy or adjusted CO2 emissions… This report will continue to track alternative fuel vehicles and may show more analysis including alternative fuel vehicles in future reports. This will be especially important if sales of alternative fuel vehicles continue to increase at the rapid rate of the last three years.
1. Improved batteries and BEVs flood the market.
2. REs start to replace fossil fuel power plants.
The post 2020 era will see major changes in the fleet composition, fossil fuel consumption and GHG emission from vehicles.
I would not bet on that battery breakthrough real soon, Tesla does not seem concerned at all. I would say FFV hybrids running cellulose E85 is the way to go. Make the 15% gasoline from bio synthetic cellulose and you are there.
Sooner or latter we will have to stop burning fuels for vehicles, tools, machinery, power plants, heating, cooking etc.
Current 1B ICEVs (and rising) and CPPs, NGPPs will pollute the atmosphere, lakes, rivers and oceans beyond acceptable level.
I am all for reducing combustion, what is why I favor reforming methanol, ethanol, gasoline or diesel on the car and using a fuel cell.
We will have internal combustion for at least the next 30 years all over the planet, that is a safe prediction. NO WAY are you going to convert ONE BILLION engine vehicles to EV in that time.
Sadly, the use of fossil fuels is growing, not shrinking. Renewable energy (wind, solar) is too expensive and unreliable for new generation in the Third World, which is where the big increases in power generation are happening--mostly via new coal-fired power plants. If you look at the big picture, the global picture, you will see that there is more coal, oil and natural gas in the ground than we can afford to burn. But we, as a species, don't seem to have any serious plan to slow down consumption.
Cheap, carbon-free nuclear power is the only technology that has a chance to persuade us to keep those hydrocarbons in the ground.
Molten salt fast breeder reactors will use the 700,000 tons of deplete uranium as fuel while producing no long term waste problems. We have enough depleted uranium to power the U.S. for hundreds of years.
The scientist who invented and developed the light water reactor was also the one who invented and developed the molten salt reactor. He told the U.S. government that the light water reactor was inherently unsafe...they fired him.
The BEV makes the most sense from any POV and it will replace the ICE in time. What you read and hear from critics is based on biases for ICE cars and the capitalistic system we have that places monetary consideration as the top parameter, well above the health and welfare of the American and the World's people.
The way to make the transition to mass BEVs is to work within the capitalistic system and offer BEVs that are fairly-priced and truly meet the needs of the people; so far that hasn't occurred and I'm afraid that won't happen until a company like Tesla can build the car. I though Nissan had a march on everyone; but, they chose to count beans, to march in place and use PR instead of engineering innovation to advance EV sales. History will prove they made a very bad mistake by not "going all in."
GE-Hitachi have the PRISM reactor that is sodium cooled, uses waste uranium and plutonium and can power the U.K. for 500 years just from waste without producing long term radioactivity.
Britain has lots of plutonium from reprocessing fuel rods over the decades, they debate what to do with that plutonium. The U.K. may install two PRISM reactors soon and we may also at Savannah River. This has been a viable option for 50 years, but Hyman Rickover the naval commander in charge of civilian reactors said no.
SJC - will the resulting electricity be cheap enough to afford?
If so, where do the cost cuts come from compared to a reactor like is being built in Georgia where the price will be $0.11/kWh or higher?
When you use waste for fuel, you have a chance to reduce costs. Uranium U235 can only go up in price over time, creating more light water reactors builds in that price increase.
The cost of fuel is insignificant for a nuclear reactor.
"The average fuel cost at a nuclear power plant in 2013 was 0.79 cents / kWh." NEI That's the nuclear energy industry reporting.
Fuel could be free and the cost of electricity from a new reactor would still be well over $0.10/kWh. And that's simply not competitive. If fuel cost were an issue the industry would have moved to thorium.
You have to replace fuel in light water reactors every two years. PRISM is every six years and traveling wave every 20. There are more costs than plant and fuel, but you seem to think you have the whole picture and your opinion is the only relevant one.
1. Build new type reactor.
6. Nuclear electricity becomes cheap enough to compete.
I want you to fill in the missing steps of how nuclear gets from >$0.11/kWh to ~0.05/kWh. If you can adequately do that then I'll have some more of the picture.
I'm pretty sure cost of fuel is not the answer. And if by not having to refuel for 20 years meant an almost 100% CF that wouldn't do it. Moving from 90% CF to 100% CF would drop the price only a penny or so.
Uranium U235 actually can only go *down* in price. Raw uranium is only a portion of fuel cost - there's also fabrication and enrichment.
SILEX laser enrichment makes it so the cost of "regular" fuel bundles can only go *down* for light water reactors.
Uranium is so cheap right now the new SILEX plant is on hold.
Fresh uranium will remain cheap for basically forever because the fabrication and enrichment technology improvements always exceed any increase in raw uranium cost.
And raw uranium cost isn't going up. Its going down.
The world spends only a few million dollars a year on uranium prospecting yet we keep finding enormous quantities of it that are economic to mine/process/leach.
I never said "affordable nuclear" you are the one going on about that. Nuclear is about the same cost as coal.
Now you will have a stable fuel price, uranium went from $20 per pound to $113 per pound back down to $59 per pound from 2005-2010. With waste plutonium and depleted uranium the cost is known.
I want to use up the depleted uranium and plutonium. We can power this country without importing any more uranium, we import 85%. You can talk about "energy independence" but as long as we import oil and uranium we are NOT.
"a 3-percentage point increase in the cost of capital is added when evaluating investments in greenhouse gas (GHG) intensive technologies like coal-fired power and coal-to-liquids (CTL) plants without carbon control and sequestration (CCS). While the 3-percentage point adjustment is somewhat arbitrary, in levelized cost terms its impact is similar to that of a $15 per metric ton of carbon dioxide (CO2) emissions fee. ... As a result, the levelized capital costs of coal-fired plants without CCS are higher than would otherwise be expected."
It further imputes a $7 mmBTU price of natural gas, when prices are about half that. So not only did the natural gas capital cost get shoved upwards, the fuel price is too high.
On top of that, advanced nuclear quotes are coming in at 13 cents per kilowatt-hour. Higher than this eia.gov projection.
Germany's newest Hamburg/Moorburg coal plant was $2.5 per nameplate watt (45% of nuclear) and has a 46.5% thermal efficiency and can cleanly burn cheap lignite coal. Its cost is much less than nuclear.
Even if nuclear can match new coal plants (and an AP1000 cannot right now) its irrelevant as natural gas is at around 5 cents per kilowatt-hour, and where wind and solar is ideally sited (e.g. Texas) the levelized cost is 7 cents per kilowatt-hour, *without* subsidy.
A $50 per tonne carbon price only adds 2 cents per kilowatt-hour to natural gas LCOE. And at that carbon price, you could force coal out and offset the entire rest of the worlds emissions with planting projects.
So until nuclear is within 2 cents per kilowatt-hour of natural gas, it is too expensive to be a solution right now in the USA.
PRISM emits NO carbon, uses waste and produces small amounts of short lived products. If you want to reduce carbon emissions, this is one way.
Making and distributing clean electricity for 1+B BEVs is not a major challenge (in most places). Lower cost REs are around the corner and the per kWh cost is going down every year.
Of course, nuclear (at $0.16/kWh and rising) is also a clean, almost limitless solution for countries with a lot of $$$$$.
Reducing battery price by 5X (to under $100/kWh at the pack level) and increasing their energy storage density by 5X (to between 600 Wh/Kg and 1,000 Wh/Kg at the pack level) may need more time and efforts. The first 50% step may be around by 2020 or so.
An acquaintance living in NY City says that they are paying $0.32/kWh for electricity. That's almost 5 times what we pay.
Why local enterpreneurs do not built half a dozen Nuke Plants nearby?. They could make a fortune?
Alternatively, the same enterpreneurs could buy clean electricity fronm New Found Land and Québec and rake it ($$$)in every day.
The last suggestion may not please the local and national climato-septics.


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Grandma arrested after deputy finds child playing in road
According to the deputy, the child had been found in the street multiple times that day.
Grandma arrested after deputy finds child playing in road According to the deputy, the child had been found in the street multiple times that day. Check out this story on thenewsstar.com: https://www.thenewsstar.com/story/news/crime/2018/03/12/grandma-arrested-after-deputy-finds-child-playing-road/417044002/
Bonnie Bolden, bbolden@thenewsstar.com Published 12:33 p.m. CT March 12, 2018 | Updated 3:15 p.m. CT March 12, 2018
Here's a look at today's weather, courtesy of NBC 10 News.
Martha Lucas Kaplan(Photo: Courtesy OCC)
A grandmother was arrested Saturday morning after a deputy found a child playing in the middle of Wellerman Road in West Monroe.
According to the arrest report, the Ouachita Parish deputy was on routine patrol when he noticed a small child playing in the middle of the 1900 block of Wellerman with no supervision. He grabbed the child before the boy could be struck by traffic, which was coming to a complete stop.
A passerby told the deputy where the child lived.
At the residence, Martha Lucas Kaplan, 58, of 110 Willow Branch, Unit A, West Monroe, told the deputy that she was watching the child.
Before the deputy could say anything else, she reportedly said "please don't take me to jail." The deputy read her Miranda rights.
She reportedly told the deputy that she lets the child play outside unattended. Earlier that day, an unknown woman brought the boy back to the residence because he was about a quarter-mile down Willow Branch, playing in the roadway.
When told he was about a mile down Wellerman, she reportedly said "he was only outside by himself five minutes this time."
The deputy noted in his arrest report that Kaplan seemed unconcerned about the boys' welfare. She never asked where he was. When asked to sit with the child in the back of the patrol unit, she replied, "Well, if you want me to."
Kaplan was charged with child desertion and booked into Ouachita Correctional Center. Bond has not yet been set.
Read or Share this story: https://www.thenewsstar.com/story/news/crime/2018/03/12/grandma-arrested-after-deputy-finds-child-playing-road/417044002/
New Wossman High School principal named
Reed resigns from police jury, lives in wrong district
Abraham backs Trump's attack on minority congresswomen
Swartz, Sterlington, Columbia and Ruston Fred's stores closing

redpajama_set_name: RedPajamaCommonCrawl


The property lies on the east side of Pasture Road between Fourth and Fifth Avenues, on the northern edge of the towns central retail area, along the main road link between the town centre and Goole rail station in a mixed retail and residential area.
The property dates from 1992, with the premises comprising a development of seven retail units and eight residential units.
We details below the following approx. floor areas which have been taken from the VOA website: Unit 1:	102 sq m	(1,097 sq ft) Unit 2:	87 sq m	(940 sq ft) Unit 3:	95 sq m	(1,025 sq ft) Unit 4:	87 sq m	(941 sq ft) Unit 5:	94 sq m	(1,015 sq ft) Unit 6 & 7:	199 sq m	(2,141 sq ft) 8 residential flats.
Parking area to the rear.


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Home > Research > Researchers > Elena Semino
Corpus stylistics, Literary stylistics, Non-literary stylistics, Stylistics, Metaphor, Cognitive linguistics, Medical humanities
Research Group in Cognitive Linguistics
ISF Fellows
Elena Semino supervises 5 postgraduate research students. If these students have produced research profiles, these are listed below:
Noor Adnan
Professor Elena Semino
My research interests are in health communication, medical humanities, stylistics, and metaphor theory and analysis. In my work I combine qualitative analysis with corpus linguistic methods.
Health communication/medical humanities: representations of autism and mental illness in fictional and non-fictional narratives; metaphor, cancer and the end of life; (figurative) language, creativity and chronic pain.
Stylistics: cognitive stylistics; corpus stylistics; mind style in fiction.
Metaphor theory and analysis: metaphor in literature, politics, science, health communication, end-of-life care; metaphor and embodied simulation; corpus approaches to the study of metaphor.
Metaphor in discourse: study of metaphor in literature, politics, science and health communication; corpus-based approaches to the study of metaphor. Health communication/Medical Humanities: language use in communication about health and illness, including particularly metaphors and narratives. Cognitive stylistics: integration of linguistic analysis with theories of cognition (e.g. Schema theory, Blending theory) in order to study literary texts; the linguistic construction of fictional text worlds; the linguistic construction of minds in fictional and non-fictional narratives. Corpus stylistics: application of corpus methods to the study of literary texts.
LING 102: English Language
LING 210: Stylistics
LING 439: Cognitive Linguistics
I am Director of the ESRC Centre for Corpus Approaches to Social Science.
I hold a Visiting Professorship in the Faculty of Foreign Languages at Fuzhou University in China.
I was Head of the Department of Linguistics and English Language at Lancaster in the periods 2011-14 and 2015-18.
Before joining the Department, I taught Italian as a foreign language at Napier Polytechnic (Edinburgh) and Lancaster University.
I have a long-standing interest in first-person accounts of the experiences of autism and mental illness in fictional and non-fictional narratives. I am involved in a study of mind style in an autobiographical narrative of schizophrenia with Dr Zsófia Demjén (University College London). I am a collaborator on the Language of Voice-hearing project at University College London, and Principal Investigator on the corpus-based interdisciplinary project Narratives of Voice-hearing– a collaboration between the ESRC Centre for Corpus Approaches to Social Science and Hearing the Voice at Durham University.
I collaborate with Prof Joanna Zakrzewska (Eastman Dental Hospital, London) on a corpus-based study of language and the diagnosis of chronic pain. I am part of the interdisciplinary project Pain: Speaking the Threshold at University College London.
From 2012 to 2014, I led a team working on Metaphor, Cancer and the End of Life, with funding from the ESRC. I act as advisor on the project Metaphor in Palliative Cancer Care at Linnaeus University (Sweden).
I am a Co-Investigator on the AHRC-funded project Translating Science for Young People and on the ESRC-funded project Linguistic Challenges of the Transition between Primary and Secondary School – both led by Prof Alice Deignan in the School of Education at the University of Leeds.
Selected Publications and Research Outputs
Metaphor framing and distress in lived-experience accounts of voice-hearing
Demjen, Z., Marszalek, A., Semino, E. & Varese, F., 31/01/2019, In : Psychosis. 11, 1, p. 16-27 12 p.
Emotional Implications of Metaphor: Consequences of Metaphor Framing for Mindset about Cancer
Hendricks, R. K., Demjén, Z., Semino, E. & Boroditsky, L., 11/02/2019, In : Metaphor and Symbol. 33, 4, p. 267-279 13 p.
The cancer card: Metaphor, intimacy and humor in online interactions about the experience of cancer
Semino, E. & Demjen, Z., 2017, Metaphor: Embodied Cognition and Discourse. Hampe, B. (ed.). Cambridge University Press, p. 181-199 19 p.
Research output: Contribution in Book/Report/Proceedings - With ISBN/ISSN › Chapter
Metaphors of Climate Science in Three Genres: Research Articles, Educational Texts, and Secondary School Student Talk
Deignan, A., Semino, E. & Paul, S-A., 1/04/2019, In : Applied Linguistics. 40, 2, p. 379-403 25 p.
Metaphor, Cancer and the End of Life: A Corpus-based Study
Semino, E., Demjen, Z., Hardie, A., Payne, S. A. & Rayson, P. E., 2018, London: Routledge. 308 p.
The Routledge Handbook of Metaphor and Language
Semino, E. (ed.) & Demjen, Z. (ed.), 2017, London: Routledge. 544 p.
Research output: Book/Report/Proceedings › Anthology
Images and the dynamics of pain consultations
Semino, E., Zakrzewska, J. M. & Williams, A., 25/03/2017, In : The Lancet. 389, 10075, p. 1186-1187 2 p.
Healthcare professionals' online use of violence metaphors for care at the end of life in the US: a corpus-based comparison with the UK
Potts, A. & Semino, E., 04/2017, In : Corpora. 12, 1, p. 55-84 30 p.
An integrated approach to metaphor and framing in cognition, discourse and practice, with an application to metaphors for cancer
Semino, E., Demjen, Z. & Demmen, J. E., 1/10/2018, In : Applied Linguistics. 39, 5, p. 625-645 21 p.
Metaphors for 'good' and 'bad' deaths: a health professional view
Demjen, Z., Semino, E. & Koller, V., 05/2016, In : Metaphor and the Social World. 6, 1, p. 1-19 19 p.
Face attack in Italian politics: Beppe Grillo's insulting epithets for other politicians
Bortoluzzi, M. & Semino, E., 2016, In : Journal of Language Aggression and Conflict. 4, 2, p. 178-201 24 p.
The online use of Violence and Journey metaphors by patients with cancer, as compared with health professionals: a mixed methods study
Semino, E., Demjen, Z., Demmen, J., Koller, V., Payne, S., Hardie, A. & Rayson, P., 1/03/2017, In : BMJ Supportive and Palliative Care. 7, 1, p. 60-66 7 p.
A computer-assisted study of the use of violence metaphors for cancer and end of life by patients, family carers and health professionals
Demmen, J. E., Semino, E., Demjen, Z., Koller, V., Hardie, A., Rayson, P. & Payne, S., 17/08/2015, In : International Journal of Corpus Linguistics. 20, 2, p. 205-231 27 p.
Henry's voices: the representation of auditory verbal hallucinations in an autobiographical narrative
Demjen, Z. & Semino, E., 8/06/2015, In : Medical Humanities. 41, 1, p. 57-62 6 p.
'Good' and 'bad' deaths: narratives and professional identities in interviews with hospice managers
Semino, E., Demjen, Z. & Koller, V., 2014, In : Discourse Studies. 16, 5, p. 667-685 19 p.
Pragmatic failure, mind style and characterisation in fiction about autism
Semino, E., 8/05/2014, In : Language and Literature. 23, 2, p. 141-158 18 p.
Language, mind and autism in Mark Haddon's The Curious Incident of the Dog in the Night-Time
Semino, E., 15/03/2014, Linguistics and literary studies: interfaces, encounters, transfers. Fludernik, M. & Jacob, D. (eds.). Berlin: De Gruyter, p. 279-303 25 p.
Figurative language, genre and register
Deignan, A., Littlemore, J. & Semino, E., 2013, Cambridge: Cambridge University Press. 330 p. (Cambridge Applied Linguistics)
Metaphor in Discourse
Semino, E., 2008, Cambridge: Cambridge University Press. 247 p.
Corpus stylistics: speech, writing and thought presentation in a corpus of English writing.
Semino, E. & Short, M. H., 2004, London: Routledge. 256 p.
Cognitive stylistics: language and cognition in text analysis.
Semino, E. (ed.) & Culpeper, J. (ed.), 2002, Amsterdam: John Benjamins. 333 p. (Linguistic approaches to literature)
Language and world creation in poems and other texts.
Semino, E., 1997, London: Longman. 288 p. (Textual Explorations)
Poetics and Linguistics Association Conference
4th International Cognitive Poetics Conference
Keynote lecture on 'Metaphor and Narrative in Health Communication' at 4th Conference of the European Narrative Network
The 'Metaphor in End of Life Care' project is featured in a New York Times blog


This dataset contains 13679 crowdsourced science exam questions about Physics, Chemistry and Biology, among others. The questions are in multiple-choice format with 4 answer options each. For the majority of the questions, an additional paragraph with supporting evidence for the correct answer is provided.
The training, testing, and validation sets can be downloaded via the download button.


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Connecticut College The Connections Curriculum 06/13/16 $750,000 New London, CT, United States Higher Learning
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Massachusetts Institute of Technology Arts Across the Curriculum 03/15/12 $1,500,000 Cambridge, MA, United States Higher Learning
Alma College Curriculum Change 12/10/15 $100,000 Alma, MI, United States Higher Learning
City University of New York CUNY Cultural Corps 08/07/20 $2,000,000 New York, NY, United States Higher Learning
Appalachian College Association Cultural Awareness for the 21st Century 12/10/09 $300,000 Berea, KY, United States Higher Learning
American Academy of Arts and Sciences American Academic Culture 12/13/93 $120,000 Cambridge, MA, United States Higher Learning
National Academy of Sciences CSCPRC 03/28/85 $225,000 Washington, DC, United States Higher Learning
St. Olaf College Cross-College Collaboration 07/16/12 $50,000 Northfield, MN, United States Higher Learning
Middlebury College Creating Connections Consortium 12/06/12 $4,700,000 Middlebury, VT, United States Higher Learning
Middlebury College Creating Connections Consortium 03/10/16 $703,000 Middlebury, VT, United States Higher Learning
Ohio Wesleyan University Course Connections 07/19/10 $100,000 Delaware, OH, United States Higher Learning
Council of American Overseas Research Centers Administrative Costs 10/02/85 $35,000 Washington, DC, United States Higher Learning
New-York Historical Society Cataloguing Costs 03/16/83 $100,000 New York, NY, United States Higher Learning
PEN American Center, Inc. Centers Coordinator 12/29/05 $49,680 New York, NY, United States Higher Learning
Macalester College Competition and Cooperation 03/29/00 $46,000 Saint Paul, MN, United States Higher Learning
Five Colleges, Incorporated Administrative Cooperation 12/15/03 $275,000 Amherst, MA, United States Higher Learning
Recording for the Blind, Inc. Catalogue Conversion 10/08/80 $150,000 Princeton, NJ, United States Higher Learning
History of Science Society Bibliographic Control 03/22/91 $6,600 Cambridge, MA, United States Higher Learning
New York Public Library Annual Contribution 03/14/72 $25,000 New York, NY, United States Higher Learning
United Negro College Fund, Inc. Construction 09/27/74 $100,000 Washington, DC, United States Higher Learning
Historical Society of Pennsylvania Conservation Activities 06/19/84 $200,000 Philadelphia, PA, United States Higher Learning
Modern Language Association of America Alt Ac Careers - Connected Academies 09/11/14 $1,900,000 New York, NY, United States Higher Learning
National History Center, Inc. Congressional Briefings 08/25/14 $130,000 Washington, DC, United States Higher Learning


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BLOG 29 June 2016
How Ghana Set Its Rules on Interest Payment on e-Money Accounts
Buddy Buruku, Stefan Staschen
Emerging Regulatory Enablers in Digital Financial Services
Soon, customers in Ghana will earn interest on their mobile money wallets – an important provision that regulators in more and more markets are including in their regulations to provide different ways to maximize customer benefit. How did Ghana do it differently than Tanzania, the first country where a mobile money service paid out interest?
The Bank of Tanzania allowed mobile network operators (MNOs) significant influence in determining how customers benefited from the income MNOs earned on float accounts held by banks. The Bank of Ghana, however, has taken a more hands-on, prescriptive approach, by issuing mandates that MNOs had to react to rather than asking MNOs to make proposals.
Between 2008 and 2015, the Ghanaian regulations were silent on whether banks should pay interest on e-money float accounts and, if they did, who should benefit from the interest. The mobile money providers unsuccessfully argued early on that they should be allowed to use it. As a result, the banks by default enjoyed the entire profits from on-lending the free funds at healthy margins. For the first several years, the amounts were small and garnered little attention. But by the time new e-Money Issuer (EMI) guidelines were issued in July 2015, the total float in the system approached US$100 million, making it a matter too significant to ignore.
After deliberations, the Bank of Ghana mandated that banks pay interest on float accounts similar to that on other account types. It was also decided that EMIs must pass through not less than 80% of the interest to their end customers. According to Elly Ohene-Adu, the recently retired Head of Banking at the Bank of Ghana who oversaw the drafting and promulgation of the guidelines, these mandates were central to the bank's mission of ensuring a win-win-win outcome in which customers, EMIs and banks all benefited.
In this construct, banks would continue to benefit from a relatively stable, large and growing deposit balance, even though they now had to pay interest on it; providers would benefit from retaining up to 20% of the interest earned (which the Bank of Ghana encouraged them to use to drive customer acquisition); and customers would benefit by earning at least 80% of the interest. This was meant to provide an incentive for all players to support the growth of mobile money.
After the EMI guidelines were issued, banks and EMIs were free to begin direct negotiations on the rate of interest to be paid. And according to Ohene-Adu, the Bank of Ghana's expectation was that these discussions would be concluded swiftly and without contention. But this could not have been further from the case.
Photo by Jay Bendixen, 2012 CGAP Photo Contest
Once the EMIs and banks began discussions on the rate of interest to be paid, banks immediately revolted. They argued that the rates requested by the providers – which used the treasury bill rate of approximately 20% as a reference point – were unworkable. The banks further maintained that paying any interest at all would increase their cost of funds and give rise to unfavorable knock-on effects by forcing them to curtail lending and/or increase their interest rates on credit. Finally, some banks voiced concern about customers switching their deposits from bank accounts to e-wallets as they sought better rates and as banks typically paid very low interest on small-value savings accounts. What ensued was a very public and often contentious debate in the industry, with the Bank of Ghana in the middle, and no interest being paid.
According to Ohene-Adu, the regulator then decided to intervene and the management determined that, given the transactional nature of mobile money and the requirement for the float to be held in liquid assets, any account holding such funds should be classified as a current account. The Bank of Ghana then instructed banks to pay interest at their own prevailing rate for current accounts. Given that current accounts generally earn 0% interest, it was then the EMIs' turn to be in an uproar. The EMIs were quick to point out that customers would essentially receive 80% of nothing and that the banks were the only ones benefiting.
The Bank of Ghana instructed banks to report how much interest they were paying on current accounts. Surprisingly, banks reported a range of 1.5%-7%. This range was ultimately set as the floor and ceiling in individual negotiations between EMIs and banks. Since then, the banks, as per the Bank of Ghana's instructions, have begun paying interest into restricted, interest-only accounts, though these funds are not currently being distributed to EMIs nor to customers.
According to the Bank of Ghana, this delay is because the various EMIs are now in the process of presenting their proposals explaining the systems they will use to pass through interest, as well as the mechanisms for interest-related dispute resolution.
There is no doubt that the central banks in Tanzania and Ghana have taken very different approaches to their supervision of mobile money and to the issue of interest payments, even if the end result might be very similar. The Bank of Tanzania has mandated that the interest must benefit customers, but remains flexible on how and allows industry to come up with ideas. The Bank of Ghana went the other way, stipulating in detail that interest must be paid out, the range of interest rate payable and who may partake in what share of it.
Studying the outcomes of the two approaches should provide useful insights on how regulators should approach the question of interest on digital finance accounts. Whichever approach, there is cause for optimism on the role that interest payments can play on driving the rapid uptake of mobile money.
Topic: Business and Markets
Tag: Ghana
Buddy Buruku
Financial Sector Specialist
Stefan Staschen
Senior Financial Sector Specialist
Blog 26 July 2016
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This Wisconsin town was ranked the coziest in America
Chelsey Lewis, Milwaukee Journal Sentinel
Shops and galleries line the streets of Stockholm.
Just in time for cuffing season, one Wisconsin town has risen in the ranks of cozy small towns to claim the top spot.
Stockholm in Pepin County was ranked the coziest small town in the country by MyDatingAdvisor.com, which rated towns based on weather, food and activities.
"With a spectacular view of Lake Pepin, Stockholm offers the right blend of shops, dining, and lodging. Antique shops, art galleries, artisan furniture, a performing arts center, and a winery/cidery are all part of Stockholm's charm," the website noted.
If you're wondering if Stockholm has a cafe to complete this Hallmark movie picture, it does — and a good one. Stockholm Pie is ripe for a big city businessperson to come in and franchise.
Stockholm Pie has been a staple in Stockholm since it opened in 2008.
More:5 Hallmark-worthy Wisconsin small towns to visit during the holidays
Stockholm beat out East Coast heavy-hitter Stowe, Vermont, to claim the top spot. Other Wisconsin towns making the list were Kohler (16), Baileys Harbor (20), Hayward (31), Mineral Point (80) and Lake Geneva (81). The only other Midwestern town to crack the top 10 was Mackinac Island, Mich., which came in at No. 8.
The website considered 10 factors in three categories (weather, food and activities) when ranking 170 "popular small towns," including average December temperature and snowfall — the only time Wisconsin might have an advantage over snowbird states in the winter — cafes, bakeries, books and parks. Towns were rated out on a 100-point scale, " with a score of 100 representing the most favorable conditions for coziness."
In addition to getting high marks for weather and food, Stockholm ranked the highest of all small towns for activities. The town is located along the Great River Road, a National Scenic Byway that follows the Mississippi River and was designated as an All American Road in 2021. Wisconsin's segment of the road is peppered with small towns, parks, wineries and more that make it a popular road trip destination.
More:Things to do along Wisconsin's Great River Road
Contact Chelsey Lewis at clewis@journalsentinel.com. Follow her on Twitter at @chelseylew and @TravelMJS and Facebook at Journal Sentinel Travel.
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This article originally appeared on Milwaukee Journal Sentinel: This Wisconsin town was ranked the coziest in America
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