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PubMed1997

Imaging of boron in tissue at the cellular level for boron neutron capture therapy.

Glioblastoma multiforme, and other tumors involving the brain, are undergoing experimental treatment with a promising new technique: boron neutron capture therapy (BNCT). BNCT relies on the capture of thermal neutrons by boron deposited biochemically in the tumor and the subsequent fission of the boron into energetic lithium ions and alpha particles. An important requirement for improved BNCT is the development of more selective boron delivery mechanisms. The ability to image the boron concentration in tissue sections and even inside individual cells would be an important aid in the development of these delivery mechanisms. We have compared both sputter-initiated resonance ionization microprobe (SIRIMP), which combines resonance ionization with a high-energy pulsed focused sputter ion beam and mass spectrometric detection of ions, with laser atomization resonance ionization microprobe (LARIMP), which uses a laser pulse instead of an ion pulse for the atomization process, to determine their characteristics in locating and quantifying boron concentrations as a function of position in tissues obtained from a rat which had been infused with a BNCT drug. The data show that the SIRIMP/LARIMP techniques are well suited for quantitative and ultrasensitive imaging of boron trace element concentrations in biological tissue sections. The LARIMP mode could be used to quickly determine the spatial boron concentration with intercellular resolution over large areas down to the low nanograms-per-gram level, while the SIRIMP mode could be used to determine the spatial boron concentration and its variability in intracellular areas.

Animals↗

PubMed2000

Charge reduction electrospray mass spectrometry.

A new mass spectrometric technique, charge reduction electrospray mass spectrometry (CREMS), allowing the analysis of complex mixtures of biological molecules is described. The charge state of ions produced by electrospray ionization may be reduced in a controlled manner to yield predominantly singly charged ions through reactions with bipolar (i.e., both positively and negatively charged) ions generated using a 210Po alpha particle source. The electrospray-generated multiply charged ions undergo charge reduction in a "neutralization chamber" positioned before the entrance nozzle to the mass spectrometer. The ions are detected using a commercial orthogonal electrospray time-of-flight mass spectrometer, although the neutralization chamber can be adapted to virtually any mass analyzer. The CREMS results obtained exhibit a signal intensity drop-off with increasing oligonucleotide size similar to that observed with matrix-assisted laser desorption/ionization mass spectrometry. Proton-transfer reactions were found to be responsible for reducing charge on proteins and oligonucleotides in both positive and negative ion mode.

DNA↗

PubMedDate not supplied

Influence of the linker on the biodistribution and catabolism of actinium-225 self-immolative tumor-targeted isotope generators.

Current limitations to applications of monoclonal antibody (mAb) targeted isotope generators in radioimmunotherapy include the low mAb labeling yields and the nonspecific radiation of normal tissues by nontargeted radioimmunoconjugates (RIC). Radiotoxicity occurs in normal organs that metabolize radiolabeled proteins and peptides, primarily liver and kidneys, or in radiosensitive organs with prolonged exposure to the isotope from the blood, such as the bone marrow. Actinium-225 nanogenerators also have the problem of released agar-emitting daughters. We developed two new bifunctional chelating agents (BCA) in order to address these issues. Thiol-maleimide conjugation chemistry was employed to increase the efficiency of the mAb radiolabelings by up to 8-fold. In addition, one bifunctional chelating agent incorporated a cleavable linker to alter the catabolism of the alpha-particle-emitting mAb conjugate. This linker was designed to be sensitive to cathepsins to allow release and clearance of the chelated radiometal after internalization of the radioimmunoconjugate into the cell. We compared the properties of the cleavable conjugate (mAb-DOTA-G3FC) to noncleavable constructs (mAb-DOTA-NCS and mAb-DOTA-SH). The cleavable RIC was able to release 80% of its radioactive payload when incubated with purified cathepsin B. The catabolism of the constructs mAb-DOTA-G3FC and mAb-DOTA-NCS was investigated in vitro and in vivo. RIC integrity was retained at 85% over a period of 136 h in mouse serum in vivo. Both conjugates were degraded over time inside HL-60 cells after internalization and in mouse liver in vivo. While we found that the rates of degradation of the two RICs in those conditions were similar, the amounts of the radiolabeled product residues were different. The cleavable mAb-DOTA-G3FC conjugate yielded a larger proportion of fragments below 6kDa in size in mouse liver in vivo after 12 h than the DOTA-NCS conjugate. Biodistribution studies in mice showed that the mAb-DOTA-G3FC construct yielded a higher liver dose and prolonged liver retention of radioactivity compared to the mAb-DOTA-NCS conjugate. The accumulation in the liver seemed to be in part caused by the maleimide functionalization of the antibody, since the noncleavable mAb-DOTA-SH maleimide-functionalized control conjugate displayed the same biodistribution pattern. These results provide an insight into the catabolism of RICs, by demonstrating that the release of the radioisotope from a RIC is not a sufficient condition to allow the radioactive moiety to clear from the body. The excretion mechanisms of radiolabeled fragments seem to constitute a major limiting step in the chain of events leading to their clearance.

Actinium↗

PubMed2002

Use of ICP/MS with ultrasonic nebulizer for routine determination of uranium activity ratios in natural water.

A method is described that allows precise determination of 234U/238U activity ratios (UAR) in most natural waters using commonly available inductively coupled plasma/mass spectrometry (ICP/MS) instrumentation and accessories. The precision achieved by this technique (+/- 0.5% RSD, 1 sigma) is intermediate between thermal ionization mass spectrometry (+/- 0.25% RSD, 1 sigma) and alpha particle spectrometry (+/- 5% RSD, 1 sigma). It is precise and rapid enough to allow analysis of a large number of samples in a short period of time at low cost using standard, commercially available quadrupole instrumentation with ultrasonic nebulizer and desolvator accessories. UARs have been analyzed successfully in fresh to moderately saline waters with U concentrations of from less than 1 microg/L to nearly 100 microg/L. An example of the uses of these data is shown for a study of surface-water mixing in the North Platte River in western Nebraska. This rapid and easy technique should encourage the wider use of uranium isotopes in surface-water and groundwater investigations, both for qualitative (e.g. identifying sources of water) and quantitative (e.g. determining end-member mixing ratios purposes.

Environmental Monitoring↗

PubMed1999

Radiotoxicity of plutonium in NTA-degrading Chelatobacter heintzii cell suspensions.

The radiotoxicity of plutonium in NTA-degrading Chelatobacter heintzii cell suspensions was investigated as part of a more general study to establish the key interactions between actinide-organic complexes and microorganisms in the subsurface. The radiation tolerance of C. heintzii, based on 60Co gamma irradiation experiments, was 165 +/- 30 Gy. No bacteria survived irradiation doses greater than 500 Gy. In the presence of plutonium, where alpha particle decay was the primary source of ionizing radiation, the observed toxicity was predominantly radiolytic rather than chemical. This was evident by the greater effect of activity, rather than concentration, on the toxicity noted. Bioassociation of plutonium with C. heintzii was postulated to be an important and necessary step in the observed loss of cell viability since this was the best way to account for the observed death rate. The radiotoxicity of plutonium towards bacteria is a potentially important consideration in the bioremediation of sites contaminated with radionuclide-organic mixtures and the bioprocessing of nuclear waste.

Gram-Negative Aerobic Bacteria↗

PubMed1994

Analysis of the therapeutic gain in the treatment of human osteosarcoma microcolonies in vitro with 211At-labelled monoclonal antibody.

Microcolonies were obtained by culturing cells of two human osteosarcoma lines (OHS and KPDX) and one human melanoma line (WIX-c) for either 24 or 72 h. The microcolonies were treated with either alpha-particle radiation emitted by the 211At-labelled monoclonal antibody (MAb) TP-3 or external beam X-rays. Survival of microcolonies was assayed by colony formation. Therapeutic gain factor (TGF) values were calculated for two survival levels, 50% and 20% microcolony regeneration (i.e. at least one cell in 50% or 20% of the colonies survived the treatments). The TGF values were affected by the specific activity of the 211At-MAb conjugate, the antigen expression of the cells and the size and growth pattern of the microcolonies. Treatment with 211At-TP-3 gave TGF values that varied from 1.3 +/- 0.4 to 4.5 +/- 0.7 (mean +/- s.e.). The antigen-rich OHS cell line had on average 1.6 times higher TGF than the antigen-poor KPDX cell line. The TGF increased significantly with colony size for the densely packed colonies of the KPDX cell line but not for the OHS cell line, which had colonies with cells growing in a more scattered pattern. Control experiments with the two non-specific 211At forms, free 211At and 211At-labelled bovine serum albumin, gave TGF values from 0.6 +/- 0.1 to 1.0 +/- 0.3. This study suggests that in vivo evaluation of 211At-MAbs using relevant tumour models is desirable.

Antibodies, Monoclonal↗

PubMed2005

Observation of nuclear fusion driven by a pyroelectric crystal.

While progress in fusion research continues with magnetic and inertial confinement, alternative approaches--such as Coulomb explosions of deuterium clusters and ultrafast laser-plasma interactions--also provide insight into basic processes and technological applications. However, attempts to produce fusion in a room temperature solid-state setting, including 'cold' fusion and 'bubble' fusion, have met with deep scepticism. Here we report that gently heating a pyroelectric crystal in a deuterated atmosphere can generate fusion under desktop conditions. The electrostatic field of the crystal is used to generate and accelerate a deuteron beam (> 100 keV and >4 nA), which, upon striking a deuterated target, produces a neutron flux over 400 times the background level. The presence of neutrons from the reaction D + D --> 3He (820 keV) + n (2.45 MeV) within the target is confirmed by pulse shape analysis and proton recoil spectroscopy. As further evidence for this fusion reaction, we use a novel time-of-flight technique to demonstrate the delayed coincidence between the outgoing alpha-particle and the neutron. Although the reported fusion is not useful in the power-producing sense, we anticipate that the system will find application as a simple palm-sized neutron generator.

Journal Article↗

PubMed2002

213Bi-PAI2 conjugate selectively induces apoptosis in PC3 metastatic prostate cancer cell line and shows anti-cancer activity in a xenograft animal model.

A novel alpha-particle emitting ((213)Bi) plasminogen activator inhibitor type 2 construct, which targets the membrane-bound urokinase plasminogen activator on prostate cancer cells, was prepared and evaluated in vitro and in a xenograft animal model. The PC3 prostate cancer cell line expresses urokinase plasminogen activator which binds to its receptor on the cell membrane; plasminogen activator inhibitor type 2 is bound to urokinase plasminogen activator/urokinase plasminogen activator receptor to form stable complexes. In vitro, the cytotoxicity of (213)Bi-plasminogen activator inhibitor type 2 against prostate cancer cells was tested using the MTS assay and apoptosis was documented using terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick end-labelling (TUNEL) assay. In vivo, antiproliferative effects for tumours and prostate cancer lymph node metastasis were carried out in an athymic nude mouse model with a subcutaneous xenograft of PC3 cells. (213)Bi-plasminogen activator inhibitor type 2 was specifically cytotoxic to PC3 cells in a concentration-dependent fashion, causing the cells to undergo apoptosis. A single local or i.p. injection of (213)Bi-plasminogen activator inhibitor type 2 was able to completely regress the growth of tumours and lymph node metastases 2 days post subcutaneous inoculation, and obvious tumour regression was achieved in the therapy groups compared with control groups with (213)Bi-plasminogen activator inhibitor type 2 when the tumours measured 30-40 mm(3) and 85-100 mm(3). All control animals and one of five (20%) mice treated with 3 mCi kg(-1) (213)Bi-plasminogen activator inhibitor type 2 developed metastases in the lymph nodes while no lymphatic spread of cancer was found in the 6 mCi kg(-1) treated groups at 2 days and 2 weeks post-cell inoculation. These results demonstrate that this novel (213)Bi-plasminogen activator inhibitor type 2 conjugate selectively targets prostate cancer in vitro and in vivo, and could be considered for further development for the therapy of prostate cancer, especially for the control of micro-metastases or in minimal residual disease.

Animals↗

PubMed2003

Clinical implications of radiation-induced genomic instability.

Radiation-induced genomic instability encompasses a range of measurable end points such as chromosome destabilization, sister chromatid exchanges, gene mutation and amplification, late cell death and aneuploidy, all of which may be causative factors in the development of clinical disease, including carcinoma. Clinical implications of genomic instability can be broadly grouped into two main areas: as a marker for increased cancer risk/early detection, and as a consequence of radiation therapy (IR) that may be causative of, or a strong marker for, the induction of a therapy-induced second malignancy. Research in human populations has been limited, but broadly encompasses three populations: those exposed to alpha-particle irradiation, those with a cancer diagnosis who were examined for lymphocyte sensitivity to IR as a biomarker for risk of cancer induction, and those who successfully completed radiation therapy for an index cancer and who were examined for the induction of a second malignancy. This review examines each of those populations in turn and offers some potential future research directions to better elucidate the role of radiation-induced genomic instability in clinical disease.

DNA Damage↗

PubMed2005

Medium-mediated intercellular communication is involved in bystander responses of X-ray-irradiated normal human fibroblasts.

Although radiation-induced bystander effects have been demonstrated in a number of cell types, the studies have largely been performed using high linear energy transfer (LET) radiation, such as alpha-particles. The literature is contradictory on whether fibroblasts show bystander responses, especially after low LET radiation such as X- or gamma-rays and whether the same signal transmission pathways are involved. Herein, a novel transwell insert culture dish method is used to show that X-irradiation induces medium-mediated bystander effects in AGO1522 normal human fibroblasts. The frequency of micronuclei formation in unirradiated bystander cells increases from a background of about 6.5% to about 9-13% at all doses from 0.1 to 10 Gy to the irradiated cells. Induction of p21Waf1 protein and foci of gamma-H2AX in bystander cells is also independent of dose to the irradiated cells above 0.1 Gy. In addition, levels of reactive oxygen species (ROS) were increased persistently in directly irradiated cells up to 60 h after irradiation and in bystander cells for 30 h. Adding Cu-Zn superoxide dismutase (SOD) and catalase to the medium decreases the formation of micronuclei and induction of p21Waf1 and gamma-H2AX foci in bystander cells, suggesting oxidative metabolism plays a role in the signaling pathways in bystander cells. The results of clonogenic assay of bystander cells showed that survival of bystander cells decreases from 0 to 0.5 Gy, and then is independent of the dose to irradiated cells from 0.5 to 10 Gy. Unlike the response with p21Waf1 expression, gamma-H2AX foci and micronuclei, adding SOD and catalase has no effect on the survival of bystander cells. The data suggest that irradiated cells release toxic factors other than ROS into the medium.

Bystander Effect↗

PubMed2005

Ionizing radiation induces DNA double-strand breaks in bystander primary human fibroblasts.

That irradiated cells affect their unirradiated 'bystander' neighbors is evidenced by reports of increased clonogenic mortality, genomic instability, and expression of DNA-repair genes in the bystander cell populations. The mechanisms underlying the bystander effect are obscure, but genomic instability suggests DNA double-strand breaks (DSBs) may be involved. Formation of DSBs induces the phosphorylation of the tumor suppressor protein, histone H2AX and this phosphorylated form, named gamma-H2AX, forms foci at DSB sites. Here we report that irradiation of target cells induces gamma-H2AX focus formation in bystander cell populations. The effect is manifested by increases in the fraction of cells in a population that contains multiple gamma-H2AX foci. After 18 h coculture with cells irradiated with 20 alpha-particles, the fraction of bystander cells with multiple foci increased 3.7-fold. Similar changes occurred in bystander populations mixed and grown with cells irradiated with gamma-rays, and in cultures containing media conditioned on gamma-irradiated cells. DNA DSB repair proteins accumulated at gamma-H2AX foci, indicating that they are sites of DNA DSB repair. Lindane, which blocks gap-junctions, prevented the bystander effect in mixing but not in media transfer protocols, while c-PTIO and aminoguanidine, which lower nitric oxide levels, prevented the bystander effect in both protocols. Thus, multiple mechanisms may be involved in transmitting bystander effects. These studies show that H2AX phosphorylation is an early step in the bystander effect and that the DNA DSBs underlying gamma-H2AX focus formation may be responsible for its downstream manifestations.

Bystander Effect↗

PubMed1983

The alpha particulate liver glycogen. A morphometric approach to the kinetics of its synthesis and degradation.

Electron micrographs of rat hepatocytes with a glycogen content between 0.36 and 2.55% (w/w) were submitted to morphometrical analysis. From the number and size of glycogen profiles, the distribution of radius and volume of glycogen alpha particles were computed. The 7-fold difference in glycogen content was accompanied by an only 1.8-fold increase in the mean volume of the particles while their number increased by a factor of 4. On the basis of these observations, it is proposed that the population of glycogen particles can be divided in two groups. The first one is made of growing particles, still associated with glycogen synthase; they are the only particles present at low glycogen concentration and their number is limited. Application of a simple mathematical model allows to estimate their number in hepatocytes as 49 X 10(12) particles . ml-1. The second group is made of glycogen particles which have reached their maximal size and the number of which is in principle unlimited. The maximal particle size is estimated to be 0.36 X 10(-15) ml, corresponding to an average molecular weight of 178 X 10(6). The average molecular weight of glycogen, as measured from the actual size of the particles, varied from 89 X 10(6) to 161 X 10(6).

Animals↗

PubMed1999

Effect of biocides commonly used in the hospital environment on the transfer of antibiotic-resistance genes in Staphylococcus aureus.

The effect of sub-minimal inhibitory concentrations of biocides, commonly used in the hospital environment, on the conjugation and transduction of plasmid pWG613 was investigated in three strains of Staphylococcus aureus. The highest transfer frequency was obtained in the conjugation experiments. A low concentration of povidone-iodine was found to significantly reduce transfer frequency by 10-fold in S. aureus SAU3/13136 mating, while other biocides had no effect at low concentrations. Cetrimide (0.0001%) was found to increase significantly transduction efficiency in S. aureus RF2 when the biocide was included in the recovery media. A low concentration of chlorhexidine or povidone-iodine reduced transduction efficiency in the same recipient. This study showed that reduction in transduction efficiency was caused by the direct effect of biocides on the recipient strains rather than on the phage 80 alpha particles.

Analysis of Variance↗

PubMed2000

Analysis of radon-associated squamous cell carcinomas of the lung for a p53 gene hotspot mutation.

Squamous cell lung carcinomas (SCC) from former employees of the Wismut uranium mining company (Saxony, Germany) were obtained from the Stollberg Archive in order to screen for p53 tumour suppressor gene codon 249 arg-->met hotspot mutations, a putative molecular bio-dosimeter of alpha-particle (radon) exposure (Taylor et al (1994) Lancet 343: 86-87; McDonald et al (1995) Cancer Epidemiol Biomarkers Prevent 4: 791-793). Of the 29 archived samples of SCC meeting quality criteria for DNA analysis by polymerase chain reaction (PCR) and Haelll restriction enzyme digestion, two tumours were found that harboured this mutation. DNA sequencing confirmed the presence of a G to T base substitution within the Haelll site spanning codons 249 and 250 of the p53 gene that results in replacement of arginine (wild-type) by methionine at residue 249. When these data are combined with those from our previous study of tumours from the Stollberg Archive in which 50 lung tumours were examined, (including nine SCCs), we conclude that the G-->T (arg-->met) codon 249 mutation prevalence in the Wismut miner cohort is not sharply elevated in lung cancers in general (two mutations/79 tumours), or specifically in SCCs of the lung (two mutations/38 SCC) when compared to data from lung cancer patients with no reported occupational exposure to radon gas.

Carcinoma, Squamous Cell↗

PubMed1981

Radiation-induced myelomatosis.

It is well known that radiation can cause myeloid leukemia. However, no excess of chronic lymphocytic leukemia has been observed. Myelomatosis, like chronic lymphocytic leukemia, is a tumor of B lymphocytes. To determine whether this disease has a radiogenic origin, we surveyed all cohorts of persons exposed to radiation for which data on cancer-related mortality are available. An excess of myeloma was found in most cohorts. However, a striking deficit was found in two groups irradiated intensely for uterine neoplasms (three cases observed, 10.71 expected; P = 0.012). All other groups combined had a highly significant excess (50 observed, 22.21 expected; P = 2 X 10(-7)). The largest relative risk appeared among persons receiving internal doses of alpha-particles (14 observed, 3.24 expected; P = 2 X 10(-5)), but a significant excess (13 observed, 6.33 expected; P = 0.026) was also found in patients receiving only therapeutic or diagnostic gamma-rays or x-rays. Most cases occurred 15 to 25 years after exposure.

England↗

PubMed2006

Three-dimensional equilibria in axially symmetric tokamaks.

The NSTAB and TRAN computer codes have been developed to study equilibrium, stability, and transport in fusion plasmas with three-dimensional (3D) geometry. The numerical method that is applied calculates islands in tokamaks like the Doublet III-D at General Atomic and the International Thermonuclear Experimental Reactor. When bifurcated 3D solutions are used in Monte Carlo computations of the energy confinement time, a realistic simulation of transport is obtained. The significance of finding many 3D magnetohydrodynamic equilibria in axially symmetric tokamaks needs attention because their cumulative effect may contribute to the prompt loss of alpha particles or to crashes and disruptions that are observed. The 3D theory predicts good performance for stellarators.

Journal Article↗

PubMed2001

DNA strand break yields after post-high LET irradiation incubation with endonuclease-III and evidence for hydroxyl radical clustering.

PURPOSE: To determine the increase in single- (SSB) and double-strand break (DSB) yields after post-high LET irradiation incubation of plasmid DNA with the endonuclease-III (endo-III) of Escherichia coli. MATERIALS AND METHODS: Plasmid DNA in aerobic aqueous solution was irradiated with one of five radiation types: 137Cs gamma-rays (LET approximately 0.3keV microm(-1)), 244Cm alpha-particles (140-190 keV microm(-1)), 4He ions (97 keV microm(-1)), 56Fe ions (143 keV microm(-1)) or 197Au ions (1,440 keV microm(-1)). The irradiated samples were then incubated with endo-III. SSB and DSB yields were quantified by agarose gel electrophoresis. RESULTS: Endo-III incubation produced an increase in the SSB and DSB yields. The increases were in general lower after the high LET irradiation than after gamma-irradiation. This may reflect inhibition of the activity of endo-III by the nearby DNA damage expected from high LET radiation. It can be shown that even if the activity of endo remains unchanged, significantly lower increases in SSB and DSB yields would still be expected. CONCLUSION: The results provide evidence for clustered DNA damage after high LET irradiation.

Cesium Radioisotopes↗

PubMed2000

Mobilization and detoxification of polonium-210 in rats by 2,3-dimercaptosuccinic acid and its derivatives.

PURPOSE: To reduce retention and toxicity of the alpha particle emitter polonium-210 in rats by newly developed chelating agents. MATERIALS AND METHODS: Repeated subcutaneous chelation was conducted after intravenous injection of 210Po nitrate. For reduction of 210Po retention the treatment with vicinal dithiols meso-and rac-2,3-dimercaptosuccinic acid (DMSA), mono-i-amylmeso-2,3-dimercapto succinate (Mi-ADMS) and mono-N-(i-butyl)-meso-2,3-dimercapto succinamide (Mi-BDMA) were used. For the reduction of toxic effects of 210Po, treatment effectiveness of Mi-BDMA was compared with that of N,N'-di(2-hydroxyethyl)ethylenediamine-N,N'-biscarbodithioate (HOEtTTC, reference compound). RESULTS: Treatment with meso-DMSA and rac-DMSA altered the main excretion route of 210Po, reduced its contents in the liver but increased its deposition in the kidneys. Treatment with Mi-ADMS or Mi-BDMA increased total excretion of 210Po, mainly via the faeces. Only Mi-BDMA decreased 210Po levels in the kidneys. The effectiveness of all chelators decreased with delay in the start of treatment. In a survival study, the lives of rats treated early with Mi-BDMA or delayed with HOEtTTC were prolonged three-fold when compared with rats receiving a lethal amount of 210Po only. CONCLUSIONS: Of the vicinal dithiols examined, Mi-BDMA was the best mobilizing chelating agent for 210Po and it reduced 210Po toxicity when the treatment started immediately. However, the detoxification efficacy of the immediate treatment with HOEtTTC, observed in our previous study, was superior to that of the present result with Mi-BDMA.

Animals↗