Feasibility Study of a New Magnetic Resonance Imaging Mini-capsule Device to Measure Whole Gut Transit Time in Paediatric Constipation.

OBJECTIVE: In England, 27,500 children are referred annually to hospital with constipation. An objective measure of whole gut transit time (WGTT) could aid management. The current standard WGTT assessment, the x-ray radiopaque marker (ROM) test, gives poor definition of colonic anatomy and the radiation dose required is undesirable in children. Our objective was to develop an alternative magnetic resonance imaging (MRI) WGTT measure to the x-ray ROM test and to demonstrate its initial feasibility in paediatric constipation. METHODS: With the Nottingham Young Person's Advisory Group we developed a small (8 × 4 mm), inert polypropylene capsule shell filled with MRI-visible fat emulsion. The capsule can be imaged using MRI fat and water in-phase and out-of-phase imaging. Sixteen patients with constipation and 19 healthy participants aged 7 to 18 years old were recruited. Following a common ROM protocol, the participants swallowed 24 mini-capsules each day for 3 days and were imaged on days 4 and 7 using MRI. The number of successful studies (feasibility) and WGTT were assessed. Participants' EuroQoL Visual Analogue Scale were also collected and compared between the day before the taking the first set of mini-capsules to the day after the last MRI study day. RESULTS: The mini-capsules were imaged successfully in the colon of all participants. The WGTT was 78 ±â€Š35 hours (mean ±â€Šstandard deviation) for patients, and 36 ±â€Š16 hours, P < 0.0001 for healthy controls. Carrying out the procedures did not change the EuroQoL Visual Analogue Scale scores before and after the procedures. CONCLUSIONS: Magnetic Resonance Imaging in Paediatric Constipation was a first-in-child feasibility study of a new medical device to measure WGTT in paediatric constipation using MRI. The study showed that the new method is feasible and is well tolerated.

A Multimodality Hybrid Gamma-Optical Camera for Intraoperative Imaging.

The development of low profile gamma-ray detectors has encouraged the production of small field of view (SFOV) hand-held imaging devices for use at the patient bedside and in operating theatres. Early development of these SFOV cameras was focussed on a single modality-gamma ray imaging. Recently, a hybrid system-gamma plus optical imaging-has been developed. This combination of optical and gamma cameras enables high spatial resolution multi-modal imaging, giving a superimposed scintigraphic and optical image. Hybrid imaging offers new possibilities for assisting clinicians and surgeons in localising the site of uptake in procedures such as sentinel node detection. The hybrid camera concept can be extended to a multimodal detector design which can offer stereoscopic images, depth estimation of gamma-emitting sources, and simultaneous gamma and fluorescence imaging. Recent improvements to the hybrid camera have been used to produce dual-modality images in both laboratory simulations and in the clinic. Hybrid imaging of a patient who underwent thyroid scintigraphy is reported. In addition, we present data which shows that the hybrid camera concept can be extended to estimate the position and depth of radionuclide distribution within an object and also report the first combined gamma and Near-Infrared (NIR) fluorescence images.

(18)F-FDG PET/CT quantification in head and neck squamous cell cancer: principles, technical issues and clinical applications.

(18)F-FDG PET/CT plays a crucial role in the diagnosis and management of patients with head and neck squamous cell cancer (HNSCC). The major clinical applications of this method include diagnosing an unknown primary tumour, identifying regional lymph node involvement and distant metastases, and providing prognostic information. (18)F-FDG PET/CT is also used for precise delineation of the tumour volume for radiation therapy planning and dose painting, and for treatment response monitoring, by detecting residual or recurrent disease. Most of these applications would benefit from a quantitative approach to the disease, but the quantitative capability of (18)F-FDG PET/CT is still underused in HNSCC. Innovations in PET/CT technology promise to overcome the issues that until now have hindered the employment of dynamic procedures in clinical practice and have limited "quantification" to the evaluation of standardized uptake values (SUV), de facto a semiquantitative parameter, the limits of which are well known to the nuclear medicine community. In this paper the principles of quantitative imaging and the related technical issues are reviewed so that professionals involved in HNSCC management can reflect on the advantages of "true" quantification. A discussion is then presented on how semiquantitative information is currently used in clinical (18)F-FDG PET/CT applications in HNSCC, by discussing the improvements that could be obtained with more advanced and "personalized" quantification techniques.

Thermal imaging to assess age-related changes of skin temperature within the supraclavicular region co-locating with brown adipose tissue in healthy children.

OBJECTIVE: To establish the feasibility of infrared thermal imaging as a reproducible, noninvasive method for assessing changes in skin temperature within the supraclavicular region in vivo. STUDY DESIGN: Thermal imaging was used to assess the effect of a standard cool challenge (by placement of the participant's feet or hand in water at 20°C) on the temperature of the supraclavicular region in healthy volunteer participants of normal body mass index in 3 age groups, 3-8, 13-18, and 35-58 years of age. RESULTS: We demonstrated a highly localized increase in temperature within the supraclavicular region together with a significant age-related decline under both baseline and stimulated conditions. CONCLUSION: Thermogenesis within the supraclavicular region can be readily quantified by thermal imaging. This noninvasive imaging technique now has the potential to be used to assess brown adipose tissue function alone, or in combination with other techniques, in order to determine the roles of thermogenesis in energy balance and, therefore, obesity prevention.

PEGylation and biodistribution of an anti-MUC1 aptamer in MCF-7 tumor-bearing mice.

Aptamers are characterized by a rapid renal clearance leading to a short in vivo circulating half-life. In order to use aptamers as anticancer therapeutic agents, their exposure time to the tumor has to be enhanced via increasing residency in the bloodstream. A way to achieve this goal is by conjugating the aptamer to poly(ethylene glycol) (PEG). Herein, we present the conjugation of a bifunctionalized anti-MUC1 aptamer (NH(2)-AptA-SR) with the (99m)Tc coordinating moiety MAG2 and either a conventional branched PEG or the comb-shaped PolyPEG via a two-step synthesis. The isolated products were radiolabeled with (99m)Tc and their biodistribution and tumor-targeting properties in MCF-7 tumor bearing mice were analyzed and compared.

Simultaneous Measurement of Gastric Emptying of a Soup Test Meal Using MRI and Gamma Scintigraphy.

Measurement of gastric emptying is of clinical value for a range of conditions. Gamma scintigraphy (GS) has an established role, but the use of magnetic resonance imaging (MRI) has recently increased. Previous comparison studies between MRI and GS showed good correlation, but were performed on separate study days. In this study, the modalities were alternated rapidly allowing direct comparison with no intra-individual variability confounds. Twelve healthy participants consumed 400 g of Technetium-99m (99mTc)-labelled soup test meal (204 kcal) and were imaged at intervals for 150 min, alternating between MRI and GS. The time to empty half of the stomach contents (T1/2) and retention rate (RR) were calculated and data correlated. The average T1/2 was similar for MRI (44 ± 6 min) and GS (35 ± 4 min) with a moderate but significant difference between the two modalities (p < 0.004). The individual T1/2 values were measured, and MRI and GS showed a good positive correlation (r = 0.95, p < 0.0001), as well as all the RRs at each time point up to 120 min. Gastric emptying was measured for the first time by MRI and GS on the same day. This may help with translating the use of this simple meal, known to elicit reliable, physiological, and pathological gastrointestinal motor, peptide, and appetite responses.

Whole-body and adipose tissue-specific mechanisms underlying the metabolic effects of fibroblast growth factor 21 in the Siberian hamster.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) has been shown to rapidly lower body weight in the Siberian hamster, a preclinical model of adiposity. This induced negative energy balance mediated by FGF21 is associated with both lowered caloric intake and increased energy expenditure. Previous research demonstrated that adipose tissue (AT) is one of the primary sites of FGF21 action and may be responsible for its ability to increase the whole-body metabolic rate. The present study sought to determine the relative importance of white (subcutaneous AT [sWAT] and visceral AT [vWAT]), and brown (interscapular brown AT [iBAT]) in governing FGF21-mediated metabolic improvements using the tissue-specific uptake of glucose and lipids as a proxy for metabolic activity. METHODS: We used positron emission tomography-computed tomography (PET-CT) imaging in combination with both glucose (18F-fluorodeoxyglucose) and lipid (18F-4-thiapalmitate) tracers to assess the effect of FGF21 on the tissue-specific uptake of these metabolites and compared responses to a control group pair-fed to match the food intake of the FGF21-treated group. In vivo imaging was combined with ex vivo tissue-specific functional, biochemical, and molecular analyses of the nutrient uptake and signaling pathways. RESULTS: Consistent with previous findings, FGF21 reduced body weight via reduced caloric intake and increased energy expenditure in the Siberian hamster. PET-CT studies demonstrated that FGF21 increased the uptake of glucose in BAT and WAT independently of reduced food intake and body weight as demonstrated by imaging of the pair-fed group. Furthermore, FGF21 increased glucose uptake in the primary adipocytes, confirming that these in vivo effects may be due to a direct action of FGF21 at the level of the adipocytes. Mechanistically, the effects of FGF21 are associated with activation of the ERK signaling pathway and upregulation of GLUT4 protein content in all fat depots. In response to treatment with FGF21, we observed an increase in the markers of lipolysis and lipogenesis in both the subcutaneous and visceral WAT depots. In contrast, FGF21 was only able to directly increase the uptake of lipid into BAT. CONCLUSIONS: These data identify brown and white fat depots as primary peripheral sites of action of FGF21 in promoting glucose uptake and also indicate that FGF21 selectively stimulates lipid uptake in brown fat, which may fuel thermogenesis.

Assessing a small field of view hybrid gamma camera for perioperative iodine-125 seed localisation.

OBJECTIVE: To examine the imaging capability of a novel small field of view hybrid gamma camera (HGC) using 125I seeds prior to surgical use. METHODS: The imaging performance of the camera system was assessed quantitatively and qualitatively at different source depths, source to collimator distances (SCD), activity levels, acquisition times and source separations, utilising bespoke phantoms. RESULTS: The system sensitivity and spatial resolution of the HGC for 125I were 0.41 cps/MBq (at SCD 48 mm) and 1.53 ± 0.23 mm (at SCD 10 mm) respectively. The camera was able to detect the 125I seed at a SCD of 63 mm (with no scattering material in place) in images recorded within a 1-min acquisition time. The detection of the seeds beneath scattering material (simulating deep-seated tumours) was limited to depths of less than 20 mm beneath the skin surface with a SCD of 63 mm and seed activity of 2.43 MBq. Subjective assessments of the hybrid images acquired showed the capability of the HGC for localising the 125I seeds. CONCLUSION: This preliminary ex vivo study demonstrates that the HGC is capable of detecting 125I seeds and could be a useful tool in radioactive seed localisation with the added benefit of providing hybrid optical γ images for guiding breast conserving surgery. ADVANCES IN KNOWLEDGE: The SFOV HGC could provide high resolution fused optical-gamma images of 125I radioactive seeds indicating the potential use in intraoperative surgical procedure such as RSL.

Hypoxia imaging with [18F]HX4 PET in squamous cell head and neck cancers: a pilot study for integration into treatment planning.

BACKGROUND: Radical chemoradiotherapy is the primary treatment for head and neck cancers in many hospitals. Tumour hypoxia causes radiotherapy resistance and is an indicator of poor prognosis for patients. Identifying hypoxia to select patients for intensified or hypoxia-modified treatment regimens is therefore of high clinical importance. PATIENTS AND METHODS: We evaluated hypoxia in a group of patients with newly diagnosed squamous cell head and neck cancer using the hypoxia-selective radiotracer [F]HX4. Patients underwent a single [F]HX4 PET/computed tomography scan prior to beginning chemoradiotherapy. RESULTS: Three out of eight patients recruited were scanned with [F]HX4. Two out of three had pretreatment [F]FDG PET/computed tomography scans available for review. [F]HX4 tumour uptake varied between patients, with tumour to mediastinal ratios ranging from 1 to 3.5. CONCLUSION: The spectrum of [F]HX4 uptake in this small series of patients exemplifies the difference in oxygenation profiles between histologically similar tumours. Performing an additional PET scan with [F]HX4 prior to chemoradiotherapy treatment was logistically challenging in a routine setting, and therefore validation of its clinical impact should be the focus of future studies [EudraCT number 2013-003563-58].

Nasal Administration and Plasma Pharmacokinetics of Parathyroid Hormone Peptide PTH 1-34 for the Treatment of Osteoporosis.

Nasal delivery of large peptides such as parathyroid 1-34 (PTH 1-34) can benefit from a permeation enhancer to promote absorption across the nasal mucosa into the bloodstream. Previously, we have published an encouraging bioavailability (78%), relative to subcutaneous injection in a small animal preclinical model, for a liquid nasal spray formulation containing the permeation enhancer polyethylene glycol (15)-hydroxystearate (Solutol® HS15). We report here the plasma pharmacokinetics of PTH 1-34 in healthy human volunteers receiving the liquid nasal spray formulation containing Solutol® HS15. For comparison, data for a commercially manufactured teriparatide formulation delivered via subcutaneous injection pen are also presented. Tc-99m-DTPA gamma scintigraphy monitored the deposition of the nasal spray in the nasal cavity and clearance via the inferior meatus and nasopharynx. The 50% clearance time was 17.8 min (minimum 10.9, maximum 74.3 min). For PTH 1-34, mean plasma Cmax of 5 pg/mL and 253 pg/mL were obtained for the nasal spray and subcutaneous injection respectively; relative bioavailability of the nasal spray was ≤1%. Subsequently, we investigated the pharmacokinetics of the liquid nasal spray formulation as well as a dry powder nasal formulation also containing Solutol® HS15 in a crossover study in an established ovine model. In this preclinical model, the relative bioavailability of liquid and powder nasal formulations was 1.4% and 1.0% respectively. The absolute bioavailability of subcutaneously administered PTH 1-34 (mean 77%, range 55-108%) in sheep was in agreement with published human data for teriparatide (up to 95%). These findings have important implications in the search for alternative routes of administration of peptides for the treatment of osteoporosis, and in terms of improving translation from animal models to humans.

Esophageal transit and in vivo disintegration of branded risedronate sodium tablets and two generic formulations of alendronic acid tablets: a single-center, single-blind, six-period crossover study in healthy female subjects.

BACKGROUND: Delayed esophageal transit or disintegration of oral bisphosphonate tablets before they enter the stomach may be of concern with respect to iatrogenic complications among patients receiving longterm treatment. Different formulations of generic bisphosphonate tablets meeting regulatory requirements may have substantial differences in pharmaceutical attributes from the branded product that may result in different characteristics during esophageal transit. OBJECTIVE: The primary objective of this study was to evaluate and compare esophageal transit times and in vivo disintegration of 3 bisphosphonate formulations, one branded and the others generic, that are commercially available in Canada and the United Kingdom. METHODS: This was a single-center, randomized, singleblind, 6-period crossover study in healthy postmenopausal women aged >50 years. Each subject received a single oral dose of a branded risedronate sodium 35-mg tablet and 2 generic formulations of alendronic acid 70-mg tablets (Novopharm Limited, Toronto, Canada, and Teva UK Limited, Morley, United Kingdom) in both the erect and semisupine (45 degrees ) positions. Although the products are labeled to be taken in the erect position, the semisupine position was included to simulate dosing in bedridden patients. Subjects took tablets with 30 mL of water in the morning after an overnight fast. The tablets were radiolabeled with technetium-99m ion-exchange resins to enable visualization and measurement of esophageal transit time and disintegration using a gamma camera. Dynamic scintigraphic images were obtained for a total of 10 minutes: 2 images per second for the first 30 seconds and 1 image every 15 seconds for 9.5 minutes. This was a mechanistic study and tolerability was not assessed. RESULTS: The study was conducted in 20 healthy white female subjects with a mean age of 62 years (range, 51-77 years). The effect of body position was statistically significant (P = 0.043), with the estimated hazard ratio (HR) of 0.74 indicating longer transit time in the semisupine position relative to the erect position. There was a statistically significant difference in transit time among the 3 types of tablets (P = 0.007), with the Novopharm tablet (HR = 0.59; P < 0.001) and Teva tablet (HR = 0.71; P = 0.042) having longer transit times compared with the risedronate tablet. In 4 instances, the Novopharm tablet disintegrated and dispersed in the esophagus, once in the erect position and 3 times in the semisupine position. CONCLUSIONS: In these healthy female subjects, esophageal transit was delayed when the tablets were given in the semisupine position. The branded risedronate tablet had a significantly faster transit time than the 2 generic formulations of alendronate tested.

Mobile PET in the UK: legislative, regulatory and cost-effectiveness considerations.

Mobile PET/CT or mobile stand alone PET, is becoming more widely available throughout the developed world, allowing many small and medium-sized hospitals that do not have the scale or financial resources to purchase the static diagnostic equipment, to benefit from this imaging technology. Before embarking on such a service, a number of legislative, logistical and administrative issues have to be addressed to ensure that a mobile PET/CT service is run with optimal efficiency and safety and in compliance with the regulations governing the use of radioactive substances. Some of these issues are similar to those encountered in operating a mobile magnetic resonance imaging scanner but there are important differences owing to the use of both sealed and open radioactive sources. This article highlights the legislative, administrative and practical issues relevant to the UK and also discusses some of the practical issues that need to be addressed to ensure the operation of a safe and effective PET service.

In vitro and preclinical assessment of an intranasal spray formulation of parathyroid hormone PTH 1-34 for the treatment of osteoporosis.

Osteoporosis treatment with PTH 1-34 injections significantly reduces the incidence of bone fracture. Potential further reductions in fracture rate should be observed through nasal spray delivery to address the poor compliance associated with patient dislike of repeated PTH 1-34 subcutaneous injections. In vitro human osteoblast-like Saos-2 cell intracellular cAMP levels were used to define PTH 1-34 nasal spray formulation bioactivity. The chemically synthesised PTH 1-34 had an EC50 of 0.76nM. Absorption enhancers polyethylene glycol (15)-hydroxystearate (Solutol® HS15), poloxamer 407, chitosan or sodium hyaluronate did not diminish the bioactivity of PTH 1-34 within an in vitro cell culture model (p >0.05). We also demonstrated the effectiveness of the transmucosal absorption enhancer Solutol® HS15 in a nasal spray formulation using a preclinical pharmacokinetic model. In Sprague-Dawley rats without the absorption enhancer the uptake of PTH 1-34 into the blood via intranasal delivery produced a Cmax of 2.1±0.5ng/ml compared to 13.7±1.6ng/ml with Solutol® HS15 enhancer (p=0.016) and a Cmax14.8±8ng/ml in subcutaneous injections. Together these data illustrate that the nasal spray formulation bioactivity in vitro is not affected by the nasal spray absorption enhancers investigated, and the Solutol® HS15 nasal spray formulation had an equivalent pharmacokinetic profile to subcutaneous injection in the rat model. The Solutol® HS15 formulation therefore demonstrated potential as a PTH 1-34 nasal spray formulation for the treatment of osteoporosis.

Design and implementation of a prototype head and neck phantom for the performance evaluation of gamma imaging systems.

BACKGROUND: A prototype anthropomorphic head and neck phantom has been designed to simulate the adult head and neck anatomy including some internal organs and tissues of interest, such as thyroid gland and sentinel lymph nodes (SLNs). The design of the head and neck phantom includes an inner jig holding the simulated SLNs and thyroid gland. The thyroid gland structure was manufactured using three-dimensional (3D) printing taking into consideration the morphology and shape of a healthy adult thyroid gland. RESULT: The head and neck phantom was employed to simulate a situation where there are four SLNs distributed at two different vertical levels and at two depths within the neck. Contrast to noise ratio (CNR) calculations were performed for the detected SLNs at an 80 mm distance between both pinhole collimators (0.5 and 1.0 mm diameters) and the surface of the head and neck phantom with a 100 s acquisition time. The recorded CNR values for the simulated SLNs are higher when the hybrid gamma camera (HGC) was fitted with the 1.0 mm diameter pinhole collimator. For instance, the recorded CNR values for the superficially simulated SLN (15 mm depth) containing 0.1 MBq of 99mTc using 0.5 and 1.0 mm diameter pinhole collimators are 6.48 and 16.42, respectively (~87% difference). Gamma and hybrid optical images were acquired using the HGC for the simulated thyroid gland. The count profiles through the middle of the simulated thyroid gland images provided by both pinhole collimators were obtained. The HGC could clearly differentiate the individual peaks of both thyroid lobes in the gamma image produced by the 0.5-mm pinhole collimator. In contrast, the recorded count profile for the acquired image using the 1.0-mm-diameter pinhole collimator showed broader peaks for both lobes, reflecting the degradation of the spatial resolution with increasing the diameter of the pinhole collimator. CONCLUSIONS: This anthropomorphic head and neck phantom provides a valuable tool for assessing the imaging ability of gamma cameras used for imaging the head and neck region. The standardisation of test phantoms for SFOV gamma systems will provide an opportunity to collect data across various medical centres. The phantom described is cost effective, reproducible, flexible and anatomically representative.

A novel compact small field of view hybrid gamma camera: first clinical results.

INTRODUCTION: Hybrid imaging has proven to be a major innovation in nuclear medicine, allowing the fusion of functional information with anatomical detail. In the past, the use of hybrid imaging such as PET-CT, PET-MRI and SPECT-CT has been of great clinical benefit; however, these scanners are relatively large and bulky. We have developed and investigated the clinical application of a compact small field of view hybrid gamma camera (HGC) that is suitable for small-organ imaging at the patient bedside. PATIENTS AND METHODS: The HGC - consisting of a CsI(Tl) scintillation crystal coupled to an electron-multiplying charge-coupled device and an optical camera - was used in this study. Eligible patients attending the nuclear medicine clinic at Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK, were invited to take part in this study. Following the standard injection of either a Tc-labelled or I-labelled radiopharmaceutical, images of the patient were acquired using the HGC and presented in a fused optical-gamma display. RESULTS: There were 24 patients enrolled in the study (age range between 30 and 83 years, mean: 58.6 years), images of 18 of whom were successfully acquired. These included patients who were undergoing bone, thyroid, lacrimal drainage, DaTscan and lymphatic imaging. In general, the small field of view system was well suited to small-organ imaging. The uptake could be clearly seen in relation to the patient surface anatomy and showed particular promise for lymphatic, thyroid and lacrimal drainage studies. CONCLUSION: This pilot study has demonstrated the first clinical results of hybrid optical-gamma imaging in patients. The use of this system has raised new possibilities for small-organ imaging, in which the localization of radiopharmaceutical uptake can be presented in an anatomical context using optical imaging. The compact nature of the hybrid system offers the potential for bedside investigations and intraoperative use.

Reduced adiposity attenuates FGF21 mediated metabolic improvements in the Siberian hamster.

FGF21 exerts profound metabolic effects in Siberian hamsters exposed to long day (LD) photoperiods that increase appetite and adiposity, however these effects are attenuated in short day (SD) animals that display hypophagia and reduced adiposity. The aim of this study was to investigate whether the beneficial effects of a novel mimetic of FGF21 in the LD state are a consequence of increased adiposity or of the central photoperiodic state. This was achieved by investigating effects of FGF21 in aged hamsters, which is associated with reduced adiposity. In LD hamsters with increased adiposity, FGF21 lowered body weight as a result of both reduced daily food intake and increased caloric expenditure, driven by an increase in whole-body fat oxidation. However, in LD animals with reduced adiposity, the effect of FGF21 on body weight, caloric intake and fat oxidation were significantly attenuated or absent when compared to those with increased adiposity. These attenuated/absent effects were underpinned by the inability of FGF21 to increase the expression of key thermogenic genes in interscapular and visceral WAT. Our study demonstrates the efficacy of a novel FGF21 mimetic in hamsters, but reveals attenuated effects in the animal model where adiposity is reduced naturally independent of photoperiod.

Antibody-Mediated Targeting of the FGFR1c Isoform Increases Glucose Uptake in White and Brown Adipose Tissue in Male Mice.

The increased prevalence of obesity and its cardiometabolic implications demonstrates the imperative to identify novel therapeutic targets able to effect meaningful metabolic changes in this population. Antibody-mediated targeting of fibroblast growth factor receptor 1c isoform (FGFR1c) has been shown to ameliorate hyperglycemia and protect from diet- and genetically-induced obesity in rodents and nonhuman primates. However, it is currently unknown which tissue(s) contribute to this glucose-lowering effect. Thus, to elucidate this effect, we treated euglycemic mice with H7, a monoclonal antibody that selectively targets FGFR1c, and used whole-body positron emission computed tomography with a glucose tracer (18F-fluorodeoxyglucose). Treatment with H7 increased basal glucose uptake in white adipose tissue (WAT), brown adipose tissue (BAT), the brain, and liver but reduced it in the quadriceps muscles. Consequentially, blood glucose was significantly reduced in response to treatment. Under insulin-stimulated conditions, the effects of H7 were maintained in WAT, BAT, liver, and muscle. Treatment with H7 decreased triglyceride (TG) content and increased adipose TG lipase content in white adipose tissue, while increasing activation of acetyl coenzyme A carboxylase, suggesting futile cycling of TGs, albeit favoring net hydrolysis. We demonstrated, in vitro, this is a direct effect of treatment in adipose tissue, as basal cellular respiration and glucose uptake were increased in response to treatment. Taken together, these data suggest that antibody-mediated targeting of FGFR1c exerts its powerful glucose-lowering efficacy primarily due to increased glucose uptake in adipose tissue.

Cytotoxicity of PAI2, C595 and Herceptin vectors labeled with the alpha-emitting radioisotope Bismuth-213 for ovarian cancer cell monolayers and clusters.

The vectors PAI2, C595 and Herceptin target the membrane-bound uPA, MUC1 and HER2 antigens expressed by cancer cells, respectively. The expression of these receptors was tested in the ovarian cancer cell line OVCAR-3; MUC-1 was strongly expressed (3+), uPA moderately expressed (2+), but HER2 was negative (-). The alpha-emitting radionuclide Bismuth-213 was chelated with these targeting vectors to form alpha conjugates (ACs), the cytotoxicity of which were tested with OVCAR-3 cells. The PAI2 and C595 ACs are highly cytotoxic to the ovarian monolayer cancer cells and cell clusters in a concentration-dependent fashion and cause morphological changes of treated cancer cells, inducing apoptosis. These ACs are potential candidates for the control of ovarian cancer at the minimum residual disease (MRD) stage.

Esophageal transit of the weekly film-coated risedronate (Actonel) placebo tablet in subjects with Kyphosis.

Risedronate sodium is a pyridinyl bisphosphonate of proven effectiveness for the treatment and prevention of osteoporosis and Paget's disease of the bone. The aim of this study was to compare the esophageal transit and gastric emptying of the placebo film-coated risedronate tablet when taken with 50 or 120 mL of water in subjects with Kyphosis. A total of 23 patients with radiologically documented osteoporosis participated in a single-center, open-label, crossover gamma scintigraphy study. The mean esophageal transit times were 15.6 s (50 mL) and 12.0 s (120 mL) and the mean gastric emptying half-times were 20.5 min (50 mL) and 14.3 min (120 mL). There was no relationship between the degree of Kyphosis measured from lateral standing radiographs and the esophageal transit time. This study demonstrated that even when taken with a minimal volume of water the esophageal transit and gastric emptying of the film-coated 35 mg weekly risedronate placebo tablet was similar in kyphotic subjects to previously obtained results from healthy control subjects.