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Purpose To develop an MR-compatible resistive heater for temperature maintenance of anaesthetized animals. Materials and Methods An MR-compatible resistive electrical heater was formed from a tightly-wound twisted pair wire, interfaced to a homeothermic maintenance controller. Fat-suppressed images and localized spectra were acquired with the twisted pair heater and a near-identical single strand heater during operation at maximum power. Data were also acquired in the absence of heating to demonstrate the insensitivity of MR to distortions arising from the passage of current through the heater elements. The efficacy of temperature maintenance was examined by measuring rectal temperature immediately following induction of general anesthesia and throughout and after the acquisition of a heater artifact-prone image series. Results Images and spectra acquired in the presence and absence of DC current through the twisted pair heater were identical whereas the passage of current through the single strand wire created field shifts and lineshape distortions. Temperature that is lost during anesthesia induction was recovered within approximately 10–20 minutes of induction, and a stable temperature is reached as the animal's temperature approaches the set target. Conclusion The twisted pair wire heater does not interfere with MR image quality and maintains adequate thermal input to the animal to maintain body temperature.

Commercial mouse chow is designed to provide a complete, nutrient-rich diet, and it can contain upwards of 100 mg/kg manganese, an essential mineral. Manganese acts as a relaxation time-shortening contrast agent for both T1 and T2, and where standard chow is hydrated in the gastrointestinal tract, bright signals are produced when using T1-weighted imaging (T1WI). As a result of peristalsis, gastrointestinal hyperintensities result in temporally unstable signals, leading to image ghosting and decreased resolution from that prescribed. To avoid the problem, various methods of gastrointestinal tract modulation, including the use of intestinal cleansing with laxatives and dietary modulation, have been reported. Here, dietary modulation has been extended to the use of a biologically innocuous, long-term change of diet. In this study, we report on the use of a commercially available manganese-free chow to improve the image quality of the gastrointestinal tract. This manganese-free chow, apart from the omitted manganese which is available in tap water, is a complete diet and readily available. We investigated the time-dependent, diet-related gastrointestinal intensities on short-TR T1WI magnetic resonance imaging; monitored body mass, food and water consumption and standard blood biochemistry analysis following diet change; and determined manganese concentration in blood plasma following a five-day change to manganese-free chow. We show that the manganese-free chow presents a refinement to other gastrointestinal tract modulation, as it avoids the need for invasive procedures for gut voiding and can be provided ad libitum so that animals can be maintained with no need for prescribed diet change before imaging.

A magnetic resonance (MR)-, computed tomography (CT)-, single-photon emission computed tomography (SPECT)-, and positron emission tomography (PET)-compatible carbon-fiber sheet resistor for temperature maintenance in small animals where space limitations prevent the use of circulating fluids was developed. A 250 Ω carbon-fiber sheet resistor was mounted to the underside of an imaging cradle. Alternating current, operating at 99 kHz, and with a power of 1-2 W, was applied to the resistor providing a cradle base temperature of ∼37°C. Temperature control was implemented with a proportional–integral–derivative controller, and temperature maintenance was demonstrated in 4 mice positioned in both MR and PET/SPECT/CT scanners. MR and CT compatibility were also shown, and multimodal MR-CT-PET-SPECT imaging of the mouse abdomen was performed in vivo. Core temperature was maintained at 35.5°C ± 0.2°C. No line-shape, frequency, or image distortions attributable to the current flow through the heater were observed on MR. Upon CT imaging, no heater-related artifacts were observed when carbon-fiber was used. Multimodal imaging was performed and images could be easily coregistered, displayed, analyzed, and presented. Carbon fiber sheet resistors powered with high-frequency alternating current allow homeothermic maintenance that is compatible with multimodal imaging. The heater is small, and it is easy to produce and integrate into multimodal imaging cradles.

Purpose Multi-slice scanning in the abdomen and thorax of small animals is compromised by the effects of respiration unless imaging and respiration are synchronised. To avoid the signal modulations that result from respiration motion and a variable TR, blocks of fully relaxed slices are typically acquired during inter-breath periods, at the cost of scan efficiency. This paper reports a conceptually simple yet effective prospective gating acquisition mode for multi-slice scanning in free breathing small animals at any fixed TR of choice with reduced sensitivity to respiratory motion. Methods Multi-slice scan modes have been implemented in which each slice has its own specific projection or phase encode loop index counter. When a breath is registered RF pulses continue to be applied but data are not acquired, and the corresponding counters remain fixed so that the data are acquired one TR later, providing it coincides with an inter-breath period. The approach is refined to reacquire the slice data that are acquired immediately before each breath is detected. Only the data with reduced motion artefact are used in image reconstruction. The efficacy of the method is demonstrated in the RARE scan mode which is well known to be particularly useful for tumour visualization. Results Validation in mice with RARE demonstrates improved stability with respect to ungated scanning where signal averaging is often used to reduce artefacts. SNR enhancement maps demonstrate the improved efficiency of the proposed method that is equivalent to at least a 2.5 fold reduction in scan time with respect to ungated signal averaging. A steady-state magnetisation transfer contrast prepared gradient echo implementation is observed to highlight tumour structure. Supplementary simulations demonstrate that only small variations in respiration rate are required to enable efficient sampling with the proposed method. Conclusions The proposed prospective gating acquisition scheme enables efficient multi-slice scanning in small animals at the optimum TR with reduced sensitivity to respiratory motion. The method is compatible with a wide range of complementary methods including non-Cartesian scan modes, partially parallel imaging, and compressed sensing. In particular, the proposed scheme reduces the need for continual close monitoring to effect operator intervention in response to respiratory rate changes, which is both difficult to maintain and precludes high throughput.

Because metastasis is associated with the majority of cancer-related deaths, its prevention is a clinical aspiration. Prostanoids are a large family of bioactive lipids derived from the activity of cyclooxygenase-1 (COX-1) and COX-2. Aspirin impairs the biosynthesis of all prostanoids through the irreversible inhibition of both COX isoforms. Long-term administration of aspirin leads to reduced distant metastases in murine models and clinical trials, but the COX isoform, downstream prostanoid, and cell compartment responsible for this effect are yet to be determined. Here, we have shown that aspirin dramatically reduced lung metastasis through inhibition of COX-1 while the cancer cells remained intravascular and that inhibition of platelet COX-1 alone was sufficient to impair metastasis. Thromboxane A2 (TXA2) was the prostanoid product of COX-1 responsible for this antimetastatic effect. Inhibition of the COX-1/TXA2 pathway in platelets decreased aggregation of platelets on tumor cells, endothelial activation, tumor cell adhesion to the endothelium, and recruitment of metastasis-promoting monocytes/macrophages, and diminished the formation of a premetastatic niche. Thus, platelet-derived TXA2 orchestrates the generation of a favorable intravascular metastatic niche that promotes tumor cell seeding and identifies COX-1/TXA2 signaling as a target for the prevention of metastasis.

IntroductionPreclinical in vivo CT is commonly used to visualise vessels at a macroscopic scale. However, it is prone to many artefacts which can degrade the quality of CT images significantly. Although some artefacts can be partially corrected for during image processing, they are best avoided during acquisition. Here, a novel imaging cradle and tumour holder was designed to maximise CT resolution. This approach was used to improve preclinical in vivo imaging of the tumour vasculature.ProceduresA custom built cradle containing a tumour holder was developed and fix-mounted to the CT system gantry to avoid artefacts arising from scanner vibrations and out-of-field sample positioning. The tumour holder separated the tumour from bones along the axis of rotation of the CT scanner to avoid bone-streaking. It also kept the tumour stationary and insensitive to respiratory motion. System performance was evaluated in terms of tumour immobilisation and reduction of motion and bone artefacts. Pre- and post-contrast CT followed by sequential DCE-MRI of the tumour vasculature in xenograft transplanted mice was performed to confirm vessel patency and demonstrate the multimodal capacity of the new cradle. Vessel characteristics such as diameter, and branching were quantified.ResultsImage artefacts originating from bones and out-of-field sample positioning were avoided whilst those resulting from motions were reduced significantly, thereby maximising the resolution that can be achieved with CT imaging in vivo. Tumour vessels >= 77 mu m could be resolved and blood flow to the tumour remained functional. The diameter of each tumour vessel was determined and plotted as histograms and vessel branching maps were created. Multimodal imaging using this cradle assembly was preserved and demonstrated.ConclusionsThe presented imaging workflow minimised image artefacts arising from scanner induced vibrations, respiratory motion and radiopaque structures and enabled in vivo CT imaging and quantitative analysis of the tumour vasculature at higher resolution than was possible before. Moreover, it can be applied in a multimodal setting, therefore combining anatomical and dynamic information.

A prominent feature of many human cancers is oncogene-driven activation of the DNA damage response (DDR) during early tumorigenesis. It has been shown previously that noninvasive imaging of the phosphorylated histone H2A variant H2AX, γH2AX, a DNA damage signaling protein, is possible using (111)In-labeled anti-γH2AX antibody conjugated to the cell-penetrating peptide transactivator of transcription (TAT). The purpose of this study was to investigate whether (111)In-anti-γH2AX-TAT detects the DDR during mammary oncogenesis in BALB-neuT mice.Mammary fat pads from BALB-neuT and wild-type mice (age, 40-106 d) were immunostained for γH2AX. (111)In-anti-γH2AX-TAT or a control probe was administered intravenously to BALB-neuT mice. SPECT was performed weekly and compared with tumor detection using palpation and dynamic contrast-enhanced MR imaging.γH2AX expression was elevated in hyperplastic lesions in the mammary fat pads of BALB-neuT mice aged 76-106 d, compared with normal fat pads from younger mice and carcinomas from older mice (13.5 ± 1.2 γH2AX foci/cell vs. 5.2 ± 1.5 [P < 0.05] and 3.4 ± 1.1 [P < 0.001], respectively). Serial SPECT imaging revealed a 2.5-fold increase in (111)In-anti-γH2AX-TAT accumulation in the mammary fat pads of mice aged 76-106 d, compared with control probe (P = 0.01). The median time to detection of neoplastic lesions by (111)In-anti-γH2AX-TAT (defined as >5% injected dose per gram of tissue) was 96 d, compared with 120 and 131 d for dynamic contrast-enhanced MR imaging and palpation, respectively (P < 0.001).DDR imaging using (111)In-anti-γH2AX-TAT identified mammary tumors significantly earlier than MR imaging. Imaging the DDR holds promise for the detection of preneoplasia and as a technique for screening cancer-prone individuals.

Background Preclinical imaging requires anaesthesia to reduce motion-related artefacts. For direct translational relevance, anaesthesia must not significantly alter experimental outcome. This study reports on the effects of both anaesthetic and carrier gas upon the uptake of [64Cu]-CuATSM, [99mTc]-HL91 and [18F]-FMISO in a preclinical model of tumor hypoxia. Methodology/Principal Findings The effect of carrier gas and anaesthetic was studied in 6 groups of CaNT-bearing CBA mice using [64Cu]-CuATSM, [99mTc]-HL91 or [18F]-FMISO. Mice were anaesthetised with isoflurane in air, isoflurane in pure oxygen, with ketamine/xylazine or hypnorm/hypnovel whilst breathing air, or in the awake state whilst breathing air or pure oxygen. PET or SPECT imaging was performed after which the mice were killed for organ/tumor tracer quantitation. Tumor hypoxia was confirmed. Arterial blood gas analysis was performed for the different anaesthetic regimes. The results demonstrate marked influences on tumor uptake of both carrier gas and anaesthetic, and show differences between [99mTc]-HL91, [18F]-FMISO and [64Cu]-CuATSM. [99mTc]-HL91 tumor uptake was only altered significantly by administration of 100% oxygen. The latter was not the case for [18F]-FMISO and [64Cu]-CuATSM. Tumor-to-muscle ratio (TMR) for both compounds was reduced significantly when either oxygen or anaesthetics (isoflurane in air, ketamine/xylazine or hypnorm/hypnovel) were introduced. For [18F]-FMISO no further decrease was measured when both isoflurane and oxygen were administered, [64Cu]-CuATSM did show an additional significant decrease in TMR. When using the same anaesthetic regimes, the extent of TMR reduction was less pronounced for [64Cu]-CuATSM than for [18F]-FMISO (40–60% versus 70% reduction as compared to awake animals breathing air). Conclusions/Significance The use of anaesthesia can have profound effects on the experimental outcome. More importantly, all tested anaesthetics reduced tumor-hypoxia uptake. Anaesthesia cannot be avoided in preclinical studies but great care has to be taken in preclinical models of hypoxia as anaesthesia effects cannot be generalised across applications, nor disease states.