In vitro immunomodulation of splenocytes from DO11.10 mice by the food colouring agent amaranth.

The chemical amaranth (AM) is permitted as a colouring agent in a variety of foods. Safety was established based on chronic rodent studies. AM and its metabolite naphthionic acid (NA) can be absorbed through the intestine, exposing circulating immune cells including splenocytes. An AM feeding study in rats demonstrated an increase in blood lymphocytes. Yet, in contrast, AM inhibited the delayed-type hypersensitivity reaction to antigen. DO11.10 mice express a T Cell Receptor specific for ovalbumin323-339 peptide (OVAp) presented by I-Ad MHCII. DO11.10 splenocytes were cultured to evaluate mechanisms by which AM and NA modulate immune cell function in vitro. Exposure to OVAp alone for 72 h induced cell proliferation, and combination with 2 or 20 µg/mL AM increased IFN-γ. Cytotoxicity was evident at higher concentrations of AM (200 and 2000 µg/mL) and NA (2000 µg/mL) in combination with OVAp, as both cell number and cytokine secretion decreased. At 200 µg/mL AM with OVAp, immunotoxicity gene expression was modified and OVAp-specific KJ1-26+ CD28+ cells became enriched. The equivalent dose of NA did not modify those parameters. Using an antigen-specific model in vitro, lower concentrations of AM potentiated pro-inflammatory cytokine production, and higher concentrations of AM and NA demonstrated cytotoxicity.

Review on production of 89Zr in a medical cyclotron for PET radiopharmaceuticals.

UNLABELLED: This article is intended to provide an overview of the production and application of (89)Zr for the professional development of nuclear medicine technologists. It outlines the cyclotron targeting, separation and labeling options, and techniques for the preparation of the radionuclide (89)Zr (half-life, 78.4 h [3.3 d]) used in PET. Unlike the commonly used (18)F-FDG, with a 109.7-min half-life, the longer half-life of (89)Zr makes it possible to use high-resolution PET/CT to localize and image tumors with monoclonal antibody radiopharmaceuticals and thus potentially expand the use of PET. METHODS: This paper briefly reviews the cyclotron technique of (89)Zr production and outlines the range and preparation techniques available for making (89)Y targets as a starting material. It then discusses how cyclotron-produced (89)Zr can be separated, purified, and labeled to monoclonal antibodies for PET/CT of specific tumors. RESULTS: We argue that knowledge and understanding of this long-lived PET radionuclide should be part of the professional development of nuclear medicine technologists because it will lead to better patient outcomes and potentially increase the pool of collaborators in this field of research.

Quasi-cubic magnetite/silica core-shell nanoparticles as enhanced MRI contrast agents for cancer imaging.

Development of magnetic resonance imaging (MRI) contrast agents that can be readily applied for imaging of biological tissues under clinical settings is a challenging task. This is predominantly due to the expectation of an ideal MR agent being able to be synthesized in large quantities, possessing longer shelf life, reasonable biocompatibility, tolerance against its aggregation in biological fluids, and high relaxivity, resulting in better contrast during biological imaging. Although a repertoire of reports address various aforementioned issues, the previously reported results are far from optimal, which necessitates further efforts in this area. In this study, we demonstrate facile large-scale synthesis of sub-100 nm quasi-cubic magnetite and magnetite/silica core-shell (Mag@SiO2) nanoparticles and their applicability as a biocompatible T2 contrast agent for MRI of biological tissues. Our study suggests that silica-coated magnetite nanoparticles reported in this study can potentially act as improved MR contrast agents by addressing a number of aforementioned issues, including longer shelf life and stability in biological fluids. Additionally, our in vitro and in vivo studies clearly demonstrate the importance of silica coating towards improved applicability of T2 contrast agents for cancer imaging.

Effects of lactone derivatives on aromatase (CYP19) activity in H295R human adrenocortical and (anti)androgenicity in transfected LNCaP human prostate cancer cells.

Certain lactone-containing secondary plant metabolites display potent biological effects, including anti-tumor activities. This is of particular interest as these compounds appear effective against hormone-dependent cancers, such as those of breast and prostate, of which the incidence is on the rise. The mechanisms of anti-tumor action of these compounds are largely unknown. Thirteen synthetic lactone derivatives were evaluated for effects on aromatase activity and mRNA expression in H295R human adrenocortical carcinoma cells. Aromatase (CYP19) is a key enzyme in the synthesis of estrogens from androgens. Over-expression has been associated with increased risk of developing estrogen-dependent mammary tumors, and aromatase inhibitors are effective in their treatment. The androgen receptor is implicated in mediating hormone-dependent prostate tumor growth, and androgen antagonists are effective in the treatment of these cancers. Thus the (anti)androgenic effects of the lactones were also assessed in LNCaP human prostate cancer cells transfected with human androgen receptor and an androgen receptor-responsive luciferase reporter gene. Cells were exposed to lactones (0.1-100 microM) dissolved in dimethyl sulfoxide (0.1% in medium) for 24 h prior to measurement of aromatase activity using a tritiated water-release assay. Three (competitive) inhibitors of aromatase activity were identified (potencies in decreasing order): 3-(3,4-dimethoxy-phenyl)-4-(4-methoxy-phenyl)-5H-furan-2-one (CRI-7; IC(50)=1 microM; K(i)=1.0 microM), 3,4-bis-(3,4-dimethoxy-phenyl)-5H-furan-2-one (CRI-8; IC(50)=2 microM; K(i)=1.2 microM) and 3-(3,4-dimethoxy-phenyl)-4-(3,4,5-trimethoxy-phenyl)-5H-furan-2-one (CRI-9; IC(50)=3 microM; K(i)=6.8 microM). Several concentration-dependent inducers of aromatase (>2fold) were also identified (CRI-1, CRI-4 or Vioxx, CRI-11 and CRI-13). These lactones also induced pII promoter-specific CYP19 transcripts. In transfected LNCaP cells, the three aromatase inhibitors CRI-7, 8 and 9 demonstrated concentration-dependent anti-androgenicity above 0.1 microM in the presence of either 0.1 nM of dihydrotestosterone or the synthetic androgen R1881. The other lactones showed no consistent pro- or anti-androgenic effects in these LNCaP cells. Lactone moiety-containing molecules may form the structural basis for the development of potent drugs effective against hormone-dependent cancers.

Position affects distribution of ventilation in the lungs of older people: an experimental study.

QUESTION: What is the effect of sitting and side-lying on the distribution of ventilation during tidal breathing in healthy older people? DESIGN: Randomised, within-participant, experimental study. PARTICIPANTS: Ten healthy people more than 65 years old. INTERVENTION: Tidal breathing during sitting and right side-lying. OUTCOME MEASURES: Distribution of ventilation as a percentage of total counts using Technetium-99m Technegas lung ventilation imaging. RESULTS: In sitting, the ratio of the distribution of ventilation to apical: middle: basal regions was 1: 3.5: 3.3 in the right lung, and 1: 2.9: 2.3 in the left lung. In right side-lying, 32% (95% CI 22 to 43) more ventilation was distributed to the right lung than to the left lung. The ratio of the distribution of ventilation to apical: middle: basal regions was 1: 2.8: 2.2 in the right lung, and 1: 2.4: 1.9 in the left lung. CONCLUSIONS: In both sitting and right side-lying, ventilation was distributed more to the middle than to the basal region, which may be related to age-associated changes in the respiratory system.

Lycopene differentially induces quiescence and apoptosis in androgen-responsive and -independent prostate cancer cell lines.

BACKGROUND & AIMS: Lycopene has been credited with a number of health benefits including a decrease in prostate cancer risk. Our study investigates the molecular mechanism underlying anti-cancer activity of lycopene-based products in androgen-responsive (LNCaP) and androgen-independent (PC3) cells. METHODS: The effect of lycopene-based agents on prostate cancer growth and survival were examined using proliferation assays, bromodeoxyuridine incorporation and flow cytometric analysis of cellular DNA content. Biochemical effects of lycopene treatment were investigated by immunoblotting for changes in the absolute levels and phosphorylation states of cell cycle regulatory and signalling proteins. RESULTS: LNCaP and PC3 cells treated with the lycopene-based agents undergo mitotic arrest, accumulating in G0/G1 phase. Immunoblot screening indicated that lycopene's antiproliferative effects are likely achieved through a block in G1/S transition mediated by decreased levels of cyclins D1 and E and cyclin dependent kinase 4 and suppressed Retinoblastoma phosphorylation. These responses correlated with decreased insulin-like growth factor-I receptor expression and activation, increased insulin-like growth factor binding protein 2 expression and decreased AKT activation. Exposure to lycopene at doses as low as 10 nM for 48 h induced a profound apoptotic response in LNCaP cells. In contrast PC3 cells were resistant to apoptosis at doses up to 1 microM. CONCLUSIONS: Lycopene exposure can suppress phosphatidylinositol 3-kinase-dependent proliferative and survival signalling in androgen-responsive LNCaP and androgen-independent PC3 cells suggesting that the molecular mechanisms for the cytostatic and cytotoxic actions of lycopene involve induction of G0/G1 cell cycle arrest. This study supports further examination of lycopene as a potential agent for both the prevention and treatment of prostate cancer.

pH modulation using CsCl enhances therapeutic effects of vitamin D in LNCaP tumor bearing mice.

BACKGROUND: The downstream effects of pH modulation significantly impact the biological fate of chemotherapeutic agents and tumor responsiveness to therapy. We have studied the effects of cesium chloride (CsCl) on pH modulation and subsequent vitamin D treatment in vitamin D receptor (VDR) positive LNCaP tumors and VDR null MDA/LCC6 tumors in vivo. METHODS: Mice bearing LNCaP or MDA/LCC6 tumors were dosed orally with CsCl (150 mg/kg) or vitamin D (1 microg/kg) alone and in combination. Tumor volume and serum PSA (LNCaP only) were measured and intracellular pH was determined, using magnetic resonance spectroscopy (MRS), at tumor and leg muscle sites. Atomic absorption spectroscopy (AAS) was used to quantitate cesium in serum, organs, and tumor tissues. RESULTS: From day 10 onwards, statistically significant (P<0.01) differences were observed in all LNCaP treated groups as compared with control. CsCl co-administered with vitamin D, caused an apparent sensitization of efficacy in this tumor model. There were no correlating differences in serum PSA. Elevation of pH was statistically significant for all three treatment groups as compared with control. The pH measured in leg muscle was not influenced by CsCl treatment. Inhibition of tumor growth was not apparent in VDR null MDA/LCC6 tumors although intracellular tumor pH was shifted. Cesium was rapidly absorbed into serum and present in LNCaP tumors, prostates and other tissues after 1 hr, remaining for up to 24 hr. CONCLUSIONS: The data presented in this manuscript is the first report of chemosensitization by in vivo pH modulation using CsCl in mice bearing prostate or any other tumor xenograft.

Drug Insight: lycopene in the prevention and treatment of prostate cancer.

For almost a decade researchers in the field of urology have investigated lycopene and the chemopreventive potential of the tomato. A potent antioxidant found in abundance in the tomato, lycopene has repeatedly been correlated with reduced risk of prostate cancer in numerous epidemiological and population-based studies. Researchers and clinicians continue to investigate beyond the potent antioxidant properties of lycopene for other mechanisms of action and chemotherapeutic potential. This review examines the preclinical and preliminary clinical evidence surrounding the tomato and the health claims based on lycopene. We have explored recent mechanistic insights and conclude that more clinical research is warranted. The scope and extent of scientific evidence accrued on lycopene and tomato extracts, reported molecular mechanisms of action, and its potential impact on the incidence and severity of prostate cancer are discussed.

A preliminary assessment of Internet-based nuclear telecardiology to support the clinical management of cardiac disease in a remote community.

A portable nuclear medicine (NM) processing system was established in Kalgoorlie and an acute myocardial perfusion scintigraphy (MPS) service was provided for the local regional hospital. After scanning the patient, the data were processed on a laptop computer and JPEG images were transmitted to a secure Web server. A secure email message, with the URL link enclosed and a provisional indication of normal or abnormal findings, was sent to the referring clinician from the NM facility. Use of the Internet allowed for a group consultation between the NM technician, the referrer and the cardiologist in Perth. During a three-month study period, 42 patients were referred for exclusion of acute coronary syndrome. Of these, 21 (50%) demonstrated abnormal perfusion studies, two of which were classified as requiring urgent medical intervention. Seventeen studies were normal (41%) and four (10%) were designated equivocal. There was an alteration in the treatment plan for 32 patients (76%), including four for whom admission or further investigation was deemed unwarranted. The results suggest that MPS findings, distributed via the Internet, allow for earlier risk stratification and have a direct affect on clinical decision making.

Polychlorinated biphenyls interfere with androgen-induced transcriptional activation and hormone binding.

Polychlorinated biphenyls (PCBs) are ubiquitous highly persistent manufactured chemicals known to bioaccumulate in the food chain. Exposure to PCBs has been implicated in a wide range of human health effects, including altering normal endocrine processes and reproductive function. However, very little is understood regarding the specific mechanisms by which PCBs may exert their effects in biological systems. We have examined the ability of PCBs to interfere with transcriptional activation of the androgen receptor (AR) and glucocorticoid receptor (GR) in an in vitro transcription-based reporter assay system. Four Aroclor PCB mixtures were found to antagonize AR-mediated transcription in the presence of the natural AR ligand dihydrotestosterone (DHT). The antagonistic activity of Aroclor mixtures increased in the following order: 1260 < 1242 < 1254 < 1248. These Aroclor mixtures had no discernible effect on GR activity. Aroclor 1254 in the absence of DHT exhibited weak agonistic responses in a dose-dependent manner with AR. Within a series of individual congeners, congeners 42, 128, and 138 are shown to antagonize AR activity. These congeners all share a common core chlorine substitution pattern. Ligand-binding studies demonstrate that endocrine activities of PCB mixtures and congeners on AR are likely due to direct and specific binding to AR ligand-binding domain.