Multivalent metal-induced iron acquisition from transferrin and lactoferrin by myeloid cells.
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We previously described a unique, high-capacity, ATP-independent mechanism through which myeloid cells acquire Fe from low-m.w. chelates. The rate of this Fe acquisition is markedly increased by cellular exposure to multivalent metal cations. Because most Fe in vivo is bound to transferrin or lactoferrin, we examined whether this mechanism also contributes to myeloid cell acquisition of Fe from transferrin and/or lactoferrin. Using HL-60 cells as a model system, we show cellular acquisition of (59)Fe from both lactoferrin and transferrin that was unaffected by conditions that depleted the cells of ATP or disrupted their cytoskeleton. Fe acquisition was dramatically increased by cell exposure to various metals including Ga(3+), Gd(3+), Al(3+), Fe(3+), La(3+), Zr(4+), Sn(4+), Cu(2+), and Zn(2+) by a process that was reversible. Exposure to these same metals also increased binding of both transferrin and lactoferrin to the cell surface by a process that does not appear to involve the well-described plasma membrane receptor for transferrin. Approximately 60% of the Fe acquired by the cells from transferrin and lactoferrin remained cell associated 18 h later. HL-60 cells possess a high-capacity multivalent metal-inducible mechanism for Fe acquisition from transferrin and lactoferrin that bears many similarities to the process previously described that allows these and other cell types to acquire Fe from low-m.w. Fe chelates. The biologic importance of this mechanism may relate to its high Fe acquisition capacity and the speed with which it is able to rapidly adapt to the level of extracellular Fe. (+info)
Systemic vascular disease in male B6C3F1 mice exposed to particulate matter by inhalation: studies conducted by the National Toxicology Program.
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Epidemiological studies suggest an association between ambient particulate matter and cardiopulmonary diseases in humans. The mechanisms underlying these health effects are poorly understood. To better understand the potential relationship between particulate-matter-induced inflammation and vascular disease, a 2-phase retrospective study was conducted. Phase one included the review of heart, lung, and kidney tissues from high-dose and control male B6C3F1 mice exposed by inhalation to 9 particulate compounds for a 2-year period. The results showed that high-dose males developed significantly increased incidences of coronary and renal arteritis over controls in 2 of the 9 studies (indium phosphide and cobalt sulfate heptahydrate), while marginal increases in arteritis incidence was detected in 2 additional studies (vanadium pentoxide and gallium arsenide). In contrast, arteritis of the muscular arteries of the lung was not observed. Morphological features of arteritis in these studies included an influx of mixed inflammatory cells including neutrophils, lymphocytes, and macrophages. Partial and complete effacement of the normal vascular wall architecture, often with extension of the inflammatory process into the periarterial connective tissue, was observed. Phase 2 evaluated the heart, lung, kidney, and mesentery of male and female B6C3F1 mice from the 90-day studies of the 4 compounds demonstrating arteritis after a 2-year period. The results showed arteritis did not develop in the 90-day studies, suggesting that long-term chronic exposure to lower-dose metallic particulate matter may be necessary to induce or exacerbate arteritis. (+info)
Tumor model studies of 131I-tetracycline and other compounds.
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Iodine-131-tetracycline (131I-TET) was prepared by allowing tetracycline hydrochloride to react with radioiodide in acidic methanol (labeling efficiency greater than 85%). This preparation was found to be stable at--4 degrees C for at least 72 hr. Some minimal in vivo breakdown did occur. The 131I-TET, 67Ga, and several 99mTc compounds were studied in a rat hepatoma model. The incorporation of the radiopharmaceuticals into the tumor occurred rapidly, with peak levels at 0.5 and 24 hr after injection for 131I-TET and 67Ga, respectively. The clearnace of the radiopharmaceutical from nonviable tumor was slower than for viable tumor, and by 72 hr after injection the greatest concentration of radioactivity appeared in the nonviable fraction. All normal tissues showed faster clearance than did tumor tissue, regardless of viability. Decreasing the quantity of 131I-TET injected increased the percent of uptake in the nonviable tumor tissue but had no effect on the viable tumor uptake. Of the 99mTc compounds studied, the phosphates developed the highest tumor-to-background ratios. Unfortunately these ratios were not as high as those achieved for 67Ga or 131I-TET. (+info)
The concentration of 67Ga and 45Ca in the lactating mammary gland and its relevance to the tumor uptake of 67Ga citrate.
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67Ga is known to concentrate in the breasts of pregnant and postpartum women, and a case is now described in which 67Ga uptake was seen in the breasts of a woman who was neither pregnant nor postpartum, but was receiving chemotherapy for Hodgkin's disease. Comparative studies of the uptake of 67Ga and 45Ca in lactating dogs have shown that both nuclides are secreted in the milk in similar amounts and in protein-bound form. The concentration of 67Ga in mammary tissue is about one-half of that found in the milk at 5 hr postinjection but, by 48 hr, the concentrations are approximately equal. There were similarities in the subcellular distributions of 67Ga and 45Ca in the lactating mammary gland at 5 and 48 hr. Although there was a correlation between 67Ga and 45Ca in individual pieces of a lactating mammary gland at 5 hr after injection, no such correlation was seen between the two nuclides in multiple samples of a transmissible venereal tumor measured at various time intervals. The rate of dispersion of 67Ga and 45Ca from the lactating mammary gland was similar but, in the tumor, 67Ga was present in very much greater amounts than 45Ca and was retained longer. It is concluded that, although there may be similarities in the metabolic pathways of gallium and calcium in the lactating mammary gland, there is no similarity in the mechanism of uptake of these two elements into tumors. (+info)
Effects of Ga addition on the mechanical properties of 35Ag-30Pd-20Au-15Cu alloy.
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Ten 35Ag-30Pd-20Au-15Cu alloys containing 0.00, 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 4.00, or 6.00% Ga were experimentally prepared to investigate the effect of Ga on their mechanical properties in addition to their use for denture frameworks, connectors and clasps. The effect of Ga addition on the mechanical properties was marked with a significant increase in the tensile strength, 0.2% off-set proof stress (proof stress) and Vickers hardness observed at low Ga contents (0.25-2.00%). On the other hand, the elongation significantly decreased with the addition of Ga at all contents used in this study. The tensile strength, proof stress and Vickers hardness of the 35Ag-30Pd-20Au-15Cu alloys containing 0.25-2.00% Ga were in the range of 809-957 MPa, 669-857 MPa and 260-301 MPa, respectively. These values are similar to those of Co-Cr alloys, suggesting that 0.25-2.00% Ga alloys can be used for denture frameworks, clasps and connectors. (+info)
Prognostic value of FDG-PET in malignant lymphoma.
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Lymphomas have represented an indication for nuclear medicine investigations for 30 years. Gallium-67 scintigraphy has been shown to be a valuable complementary method in Hodgkin's disease and non-Hodgkin lymphoma for detecting viable residual lesions after chemotherapy and for diagnosis of a relapse. Thallium-201 is of interest in differentiating cerebral lymphomas from infectious lesions in AIDS patients but less useful in extra-cerebral lymphomas. PET with fluorine-18-FDG is more accurate than 67Ga in lymphoma. In patients with a positive PET scan after chemotherapy an early relapse occurs in up to 100%, while more than 80% of patients with a negative PET will have a long-term remission. Most studies show that FDG-PET is significantly correlated with patient outcome whereas there is much weaker or even no correlation for CT. The main reason is that PET is not bound to morphological criteria like lymph node size while CT is often not able to differentiate between residual tumour and post-therapeutic fibrosis. Therefore, based on a considerable number of clinical studies, FDG-PET gains increasing significance for staging, restaging and therapy monitoring in malignant lymphomas. (+info)
Gallium scan in adolescents and children with Hodgkin's disease (HD). Treatment response assessment and prognostic value.
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AIM: The aim of the present paper is to describe the accuracy of gallium ((67)Ga) scintigraphy in adolescents and children with Hodgkin's disease (HD). We have studied the diagnostic value of this nuclear imaging technique at disease presentation (staging) and its prognostic value based on changes in (67)Ga uptake observed after treatment (response assessment). METHODS: From April 1985 to July 1999 74 consecutive untreated patients with a median age of 13 y underwent (67)Ga scans 48-72 h after injection of 37-111 MBq of (67)Ga-citrate. Planar whole-body scintigraphy was performed, supplemented with single photon emission tomography (SPET) of the mediastinum from 1996 onwards. Three patients did not undergo further scintigraphic examination because they were treated with radical surgery. After the 1st examination 71 of the 74 patients were monitored by 1-3 (67)Ga scans during the course of their disease. All of them had at least one (67)Ga scintigraphy at the end of the induction phase of chemotherapy, before any other therapeutic regimens were planned. RESULTS: At disease presentation (67)Ga scintigraphy was positive in all patients, detecting 285 of 335 (85.0%) lymph nodal sites of disease. The best sensitivity was observed in the mediastinum (100%; 63/63) and the laterocervical supraclavicular region (85.6%; 125/146); it was lower for axillary (72.7%; 16/22) and retroperitoneal (68.7%; 11/16) lymph node masses. In detecting visceral involvement the sensitivity of (67)Ga scintigraphy was 66.6% (8/12) for lung and 80% (4/5) for bone involvement. Among 71 patients in follow-up, 2 showed rapid progression of disease during induction therapy while 69 patients were monitored for a long period. The response to therapy has been classified according to the changes observed on nuclear medicine or radiological images as complete response (CR) or partial response (PR). On the basis of (67)Ga scans 55 patients (72.4%) were considered as having a CR, while with radiological modalities (chest X-ray, CT, MRI) CR was observed in only 29 patients (40.8%). PR or progression was found with (67)Ga scintigraphy in 16 patients (22.5%) and with radiological modalities in 42 patients (59.1%). (67)Ga scan was concordant with clinical outcome in 97% (28/29). The diagnostic effectiveness of this imaging technique has been analysed by comparing the scintigraphic or radiological changes at the 1st scintigraphic/radiological follow-up examination after induction therapy with the clinical outcome. In this population the relapse rate was 50% (8/16) in the group that did not achieve a CR according to post-treatment (67)Ga scintigraphy, while it was only 10.9% (6/55) in the group that achieved a CR on the basis of scintigraphy findings. The overall survival (OS) and disease-free survival (DFS) were calculated by means of Kaplan-Meier cumulative survival plotting. When the 2 groups of patients with complete (CR) or incomplete normalisation (PR or progression) of (67)Ga scintigraphy were compared, both OS and DFS were found to be statistically different (p=0.0001 and p=0.0004, respectively). By contrast, no statistical difference was found when the radiological findings were considered as the criterion for assessment of tumour response. On the basis of X-ray results the relapse rate was 13.7% in patients with negative post-therapy findings and 23.8% in patients with positive radiological imaging. CONCLUSION: Our data demonstrate the high value of (67)Ga scintigraphy in HD staging in paediatric patients. In addition, evaluation of the (67)Ga uptake is very useful as a prognostic parameter; changes in (67)Ga uptake after therapy indicate a favourable prognosis, whereas children still positive on post-treatment (67)Ga scintigrams should be given more aggressive treatment. (+info)
Expression of the hemochromatosis (HFE) gene modulates the cellular uptake of 67Ga.
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Recent studies have revealed that the wild-type hemochromatosis protein (HFE) interacts with the transferrin receptor (TfR) and modulates TfR-mediated iron uptake by cells. Because of similarities in the transport of gallium and iron and the use of (67)Ga scanning in lymphoid malignancies, we examined the effect of HFE expression on (67)Ga uptake. METHODS: (67)Ga and (59)Fe uptakes were measured in HeLa cells transfected with a FLAG-tagged wild-type HFE (fHFE) gene under control of a tetracycline-repressible promoter. fHFE and TfR protein levels were measured by Western blotting; cellular transferrin (Tf) binding sites were measured by (125)I-Tf binding assay. RESULTS: Induction of fHFE expression produced an increase in TfR protein that was accompanied by a decrease, rather than an increase, in cellular (67)Ga and (59)Fe uptake. The difference in (67)Ga uptake between fHFE-expressing and fHFE-nonexpressing cells was markedly increased in the presence of Tf. Although fHFE expression produced an increase in cellular TfR protein, cell surface and intracellular Tf binding sites were actually decreased in these cells. CONCLUSION: Our studies suggest that expression of wild-type HFE in cells produces a decrease in (67)Ga uptake due to a reduction in available Tf binding sites for (67)Ga-Tf on the TfR. These results imply that (67)Ga uptake by cells with wild-type HFE may differ from cells with the HFE C282Y mutation. (+info)