Reagents for astatination of biomolecules. 2. Conjugation of anionic boron cage pendant groups to a protein provides a method for direct labeling that is stable to in vivo deastatination.

PubMed

Wilbur, D Scott; Chyan, Ming-Kuan; Hamlin, Donald K; Vessella, Robert L; Wedge, Timothy J; Hawthorne, M Frederick

2007-01-01

Cancer-targeting biomolecules labeled with 211At must be stable to in vivo deastatination, as control of the 211At distribution is critical due to the highly toxic nature of alpha-particle emission. Unfortunately, no astatinated aryl conjugates have shown in vivo stability toward deastatination when (relatively) rapidly metabolized proteins, such as monoclonal antibody Fab' fragments, are labeled. As a means of increasing the in vivo stability of 211At-labeled proteins, we have been investigating antibody conjugates of boron cage moieties. In this investigation, protein-reactive derivatives containing a nido-carborane (2), a bis-nido-carborane derivative (Venus Flytrap Complex, 3), and four 2-nonahydro-closo-decaborate(2-) derivatives (4-7) were prepared and conjugated with an antibody Fab' fragment such that subsequent astatination and in vivo tissue distributions could be obtained. To aid in determination of stability toward in vivo deastatination, the Fab'-borane conjugates were also labeled with 125I, and that material was coinjected with the 211At-labeled Fab'. For comparison, direct labeling of the Fab' with 125I and 211At was conducted. Direct labeling with Na[125I]I and Chloramine-T gave an 89% radiochemical yield. However, direct labeling of the Fab' with Na[211At]At and Chloramine-T resulted in a yield of <1% after quenching with NaS2O5. As another comparison, the same Fab' was conjugated with p-[211At]astatobenzoate NHS ester, [211At]1c-Fab', and (separately) with p-[125I]iodobenzoate NHS ester, [125I]1b-Fab'. An evaluation in athymic mice demonstrated that [211At]1c-Fab' underwent deastatination. In contrast, the high in vivo stability of [125I]1b-Fab' allowed it to be used as a tracer control for the natural distribution of Fab'. Although found to be much more stable in vivo than [211At]1c-Fab', the biodistributions of nido-carborane conjugated Fab' ([125I]2-Fab'/ [211At]2-Fab') and the bis-nido-carborane (VFC) ([125I]3-Fab'/[211At]3-Fab') had very different in vivo distributions than the control [125I]1b-Fab'. Biodistributions of closo-decaborate(2-) conjugates ([125I]4-Fab'/[211At]4-Fab', [125I]6-Fab'/[211At]6-Fab', and [125I]7-Fab'/[211At]7-Fab') demonstrated that they were stable to in vivo deastatination and had distributions similar to that of the control [125I]1b-Fab'. In contrast, a benzyl-modified closo-decaborate(2-) derivative evaluated in vivo ([125I]5-Fab'/[211At]5-Fab') had a very different tissue distribution from the control. This study has shown that astatinated protein conjugates of closo-decaborate(2-) are quite stable to in vivo deastatination and that some derivatives have little effect on the distribution of Fab'. Additionally, direct 211At labeling of Fab' conjugated with closo-decaborate(2-) derivatives provide very high (e.g., 58-75%) radiochemical yields. However, in vivo data also indicate that the closo-decaborate(2-) may cause some retention of radioactivity in the liver. Studies to optimize the closo-decaborate(2-) conjugates for protein labeling are underway.

Synthesis and preliminary biological evaluations of fluorescent or 149Promethium labeled Trastuzumab-polyethylenimine

DOE PAGES

Fitzsimmons, Jonathan; Nayak, Tapan; Cutler, Cathy; ...

2015-12-30

Radioimmunotherapy utilize a targeting antibody coupled to a therapeutic isotope to target and treat a tumor or disease. In this study we examine the synthesis and cell binding of a polymer scaffold containing a radiotherapeutic isotope and a targeting antibody. Methods: The multistep synthesis of a fluorescent or 149Promethium-labeled Trastuzumab-polyethyleneimine (PEI), Trastuzumab, or PEI is described. In vitro uptake, internalization and/or the binding affinity to the Her2/neu expressing human breast adenocarcinoma SKBr3 cells was investigated with the labeled compounds. Fluorescent-labeled Trastuzumab-PEI was internalized more into cells at 2 and 18 h than fluorescent-labeled Trastuzumab or PEI. The fluorescent-labeled Trastuzumab wasmore » concentrated on the cell surface at 2 and 18 h and the labeled PEI had minimal uptake. DOTA-PEI was prepared and contained an average of 16 chelates per PEI; the compound was radio-labeled with 149Promethium and conjugated to Trastuzumab. The purified 149Pm-DOTA-PEI-Trastuzumab had a radiochemical purity of 96.7% and a specific activity of 0.118 TBq/g. The compound demonstrated a dissociation constant for the Her2/neu receptor of 20.30 ± 6.91 nM. In conclusion, the results indicate the DOTA-PEI-Trastuzumab compound has potential as a targeted therapeutic carrier, and future in vivo studies should be performed.« less

Radiosensitivity of Prostate Cancer Cell Lines for Irradiation from Beta Particle-emitting Radionuclide ¹⁷⁷Lu Compared to Alpha Particles and Gamma Rays.

PubMed

Elgqvist, Jörgen; Timmermand, Oskar Vilhelmsson; Larsson, Erik; Strand, Sven-Erik

2016-01-01

The purpose of the present study was to investigate the radiosensitivity of the prostate cancer cell lines LNCaP, DU145, and PC3 when irradiated with beta particles emitted from (177)Lu, and to compare the effect with irradiation using alpha particles or gamma rays. Cells were irradiated with beta particles emitted from (177)Lu, alpha particles from (241)Am, or gamma rays from (137)Cs. A non-specific polyclonal antibody was labeled with (177)Lu and used to irradiate cells in suspension with beta particles. A previously described in-house developed alpha-particle irradiator based on a (241)Am source was used to irradiate cells with alpha particles. External gamma-ray irradiation was achieved using a standard (137)Cs irradiator. Cells were irradiated to absorbed doses equal to 0, 0.5, 1, 2, 4, 6, 8, or 10 Gy. The absorbed doses were calculated as mean absorbed doses. For evaluation of cell survival, the tetrazolium-based WST-1 assay was used. After irradiation, WST-1 was added to the cell solutions, incubated, and then measured for level of absorbance at 450 nm, indicating the live and viable cells. LNCaP, DU145, and PC3 cell lines all had similar patterns of survival for the different radiation types. No significant difference in surviving fractions were observed between cells treated with beta-particle and gamma-ray irradiation, represented for example by the surviving fraction values (mean±SD) at 2, 6, and 10 Gy (SF2, SF6, and SF10) for DU145 after beta-particle irradiation: 0.700±0.090, 0.186±0.050 and 0.056±0.010, respectively. A strong radiosensitivity to alpha particles was observed, with SF2 values of 0.048±0.008, 0.018±0.006 and 0.015±0.005 for LNCaP, DU145, and PC3, respectively. The surviving fractions after irradiation using beta particles or gamma rays did not differ significantly at the absorbed dose levels and dose rates used. Irradiation using alpha particles led to a high level of cell killing. The results show that the beta-particle emitter (177)Lu as well as alpha-particles are both good candidates for radionuclide-therapy applications in the treatment of prostate cancer. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shen, S; Meredith, R; Azure, M

Purpose: To support the phase I trial for toxicity, biodistribution and pharmacokinetics of intra-peritoneal (IP) 212Pb-TCMC-trastuzumab in patients with HER-2 expressing malignancy. A whole body gamma camera imaging method was developed for estimating amount of 212Pb-TCMC-trastuzumab left in the peritoneal cavity. Methods: {sup 212}Pb decays to {sup 212}Bi via beta emission. {sup 212}Bi emits an alpha particle at an average of 6.1 MeV. The 238.6 keV gamma ray with a 43.6% yield can be exploited for imaging. Initial phantom was made of saline bags with 212Pb. Images were collected for 238.6 keV with a medium energy general purpose collimator. Theremore » are other high energy gamma emissions (e.g. 511keV, 8%; 583 keV, 31%) that penetrate the septae of the collimator and contribute scatter into 238.6 keV. An upper scatter window was used for scatter correction for these high energy gammas. Results: A small source containing 212Pb can be easily visualized. Scatter correction on images of a small 212Pb source resulted in a ∼50% reduction in the full width at tenth maximum (FWTM), while change in full width at half maximum (FWHM) was <10%. For photopeak images, substantial scatter around phantom source extended to > 5 cm outside; scatter correction improved image contrast by removing this scatter around the sources. Patient imaging, in the 1st cohort (n=3) showed little redistribution of 212Pb-TCMC-trastuzumab out of the peritoneal cavity. Compared to the early post-treatment images, the 18-hour post-injection images illustrated the shift to more uniform anterior/posterior abdominal distribution and the loss of intensity due to radioactive decay. Conclusion: Use of medium energy collimator, 15% width of 238.6 keV photopeak, and a 7.5% upper scatter window is adequate for quantification of 212Pb radioactivity inside peritoneal cavity for alpha radioimmunotherapy of ovarian cancer. Research Support: AREVA Med, NIH 1UL1RR025777-01.« less

[(64) Cu]-labelled trastuzumab: optimisation of labelling by DOTA and NODAGA conjugation and initial evaluation in mice.

PubMed

Schjoeth-Eskesen, Christina; Nielsen, Carsten Haagen; Heissel, Søren; Højrup, Peter; Hansen, Paul Robert; Gillings, Nic; Kjaer, Andreas

2015-05-30

The human epidermal growth factor receptor-2 (HER2) is overexpressed in 20-30% of all breast cancer cases, leading to increased cell proliferation, growth and migration. The monoclonal antibody, trastuzumab, binds to HER2 and is used for treatment of HER2-positive breast cancer. Trastuzumab has previously been labelled with copper-64 by conjugation of a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator. The aim of this study was to optimise the (64) Cu-labelling of DOTA-trastuzumab and as the first to produce and compare with its 1,4,7-triazacyclononane, 1-glutaric acid-5,7 acetic acid (NODAGA) analogue in a preliminary HER2 tumour mouse model. The chelators were conjugated to trastuzumab using the activated esters DOTA mono-N-hydroxysuccinimide (NHS) and NODAGA-NHS. (64) Cu-labelling of DOTA-trastuzumab was studied by varying the amount of DOTA-trastuzumab used, reaction temperature and time. Full (64) Cu incorporation could be achieved using a minimum of 10-µg DOTA-trastuzumab, but the fastest labelling was obtained after 15 min at room temperature using 25 µg of DOTA-trastuzumab. In comparison, 80% incorporation was achieved for (64) Cu-labelling of NODAGA-trastuzumab. Both [(64) Cu]DOTA-trastuzumab and [(64) Cu]NODAGA-trastuzumab were produced after purification with radiochemical purities of >97%. The tracers were injected into mice with HER2 expressing tumours. The mice were imaged by positron emission tomography and showed high tumour uptake of 3-9% ID/g for both tracers. © 2015 The Authors Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons Ltd.

Modifications in Dynamic Contrast-Enhanced Magnetic Resonance Imaging Parameters After α-Particle-Emitting {sup 227}Th-trastuzumab Therapy of HER2-Expressing Ovarian Cancer Xenografts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heyerdahl, Helen, E-mail: Helen.Heyerdahl@rr-research.no; Røe, Kathrine; Brevik, Ellen Mengshoel

2013-09-01

Purpose: The purpose of this study was to investigate the effect of α-particle-emitting {sup 227}Th-trastuzumab radioimmunotherapy on tumor vasculature to increase the knowledge about the mechanisms of action of {sup 227}Th-trastuzumab. Methods and Materials: Human HER2-expressing SKOV-3 ovarian cancer xenografts were grown bilaterally in athymic nude mice. Mice with tumor volumes 253 ± 36 mm{sup 3} (mean ± SEM) were treated with a single injection of either {sup 227}Th-trastuzumab at a dose of 1000 kBq/kg body weight (treated group, n=14 tumors) or 0.9% NaCl (control group, n=10 tumors). Dynamic T1-weighted contrast-enhanced magnetic resonance imaging (DCEMRI) was used to study themore » effect of {sup 227}Th-trastuzumab on tumor vasculature. DCEMRI was performed before treatment and 1, 2, and 3 weeks after therapy. Tumor contrast-enhancement curves were extracted voxel by voxel and fitted to the Brix pharmacokinetic model. Pharmacokinetic parameters for the tumors that underwent radioimmunotherapy were compared with the corresponding parameters of control tumors. Results: Significant increases of k{sub ep}, the rate constant of diffusion from the extravascular extracellular space to the plasma (P<.05), and k{sub el,} the rate of clearance of contrast agent from the plasma (P<.01), were seen in the radioimmunotherapy group 2 and 3 weeks after injection, compared with the control group. The product of k{sub ep} and the amplitude parameter A, associated with increased vessel permeability and perfusion, was also significantly increased in the radioimmunotherapy group 2 and 3 weeks after injection (P<.01). Conclusions: Pharmacokinetic modeling of MRI contrast-enhancement curves evidenced significant alterations in parameters associated with increased tumor vessel permeability and tumor perfusion after {sup 227}Th-trastuzumab treatment of HER2-expressing ovarian cancer xenografts.« less

Modifications in dynamic contrast-enhanced magnetic resonance imaging parameters after α-particle-emitting ²²⁷Th-trastuzumab therapy of HER2-expressing ovarian cancer xenografts.

PubMed

Heyerdahl, Helen; Røe, Kathrine; Brevik, Ellen Mengshoel; Dahle, Jostein

2013-09-01

The purpose of this study was to investigate the effect of α-particle-emitting (227)Th-trastuzumab radioimmunotherapy on tumor vasculature to increase the knowledge about the mechanisms of action of (227)Th-trastuzumab. Human HER2-expressing SKOV-3 ovarian cancer xenografts were grown bilaterally in athymic nude mice. Mice with tumor volumes 253 ± 36 mm(3) (mean ± SEM) were treated with a single injection of either (227)Th-trastuzumab at a dose of 1000 kBq/kg body weight (treated group, n=14 tumors) or 0.9% NaCl (control group, n=10 tumors). Dynamic T1-weighted contrast-enhanced magnetic resonance imaging (DCEMRI) was used to study the effect of (227)Th-trastuzumab on tumor vasculature. DCEMRI was performed before treatment and 1, 2, and 3 weeks after therapy. Tumor contrast-enhancement curves were extracted voxel by voxel and fitted to the Brix pharmacokinetic model. Pharmacokinetic parameters for the tumors that underwent radioimmunotherapy were compared with the corresponding parameters of control tumors. Significant increases of kep, the rate constant of diffusion from the extravascular extracellular space to the plasma (P<.05), and kel, the rate of clearance of contrast agent from the plasma (P<.01), were seen in the radioimmunotherapy group 2 and 3 weeks after injection, compared with the control group. The product of kep and the amplitude parameter A, associated with increased vessel permeability and perfusion, was also significantly increased in the radioimmunotherapy group 2 and 3 weeks after injection (P<.01). Pharmacokinetic modeling of MRI contrast-enhancement curves evidenced significant alterations in parameters associated with increased tumor vessel permeability and tumor perfusion after (227)Th-trastuzumab treatment of HER2-expressing ovarian cancer xenografts. Copyright © 2013 Elsevier Inc. All rights reserved.

Reagents for Astatination of Biomolecules. 5. Evaluation of hydrazone linkers in 211At- and 125I-labeled closo-decaborate(2-) conjugates of Fab′ as a means of decreasing kidney retention

PubMed Central

Wilbur, D. Scott; Chyan, Ming-Kuan; Hamlin, Donald K.; Nguyen, Holly; Vessella, Robert L.

2011-01-01

Evaluation of monoclonal antibody (MAb) fragments (e.g. Fab′, Fab or engineered fragments) as cancer-targeting reagents for therapy with the α-particle emitting radionuclide astatine-211 (211At) has been hampered by low in vivo stability of the label and a propensity of these proteins localize to kidneys. Fortunately, our group has shown that the low stability of the 211At label, generally a meta- or para-[211At]astatobenzoyl conjugate, on MAb Fab′ fragments can be dramatically improved by use of closo-decaborate(2-) conjugates. However, the higher stability of radiolabeled MAb Fab′ conjugates appears to result in retention of the radioactivity in kidneys. This investigation was conducted to evaluate whether the retention of radioactivity in kidney might be decreased by the use of acid-cleavable hydrazone between the Fab′ and the radiolabeled closo-decaborate(2-) moiety. Five conjugation reagents containing sulfhydryl-reactive maleimide groups, a hydrazone functionality and a closo-decaborate(2-) moiety were prepared. In four of the five conjugation reagents, a discrete polyethylene glycol (PEG) linker was used, and one substituent adjacent to the hydrazone was varied (phenyl, benzoate, anisole or methyl) to provide varying acid-sensitivity. In the initial studies, the five maleimido-closo-decaborate(2-) conjugation reagents were radioiodinated (125I or 131I), then conjugated with an anti-PSMA Fab′ (107-1A4 Fab′). Biodistributions of the five radioiodinated Fab′ conjugates were obtained in nude mice at 1, 4 and 24 h post injection (pi). In contrast to closo-decaborate(2-) conjugated to 107-1A4 Fab′ through a non-cleavable linker, two conjugates containing either a benzoate or a methyl substituent on the hydrazone functionality displayed clearance rates from kidney, liver and spleen that were similar to those obtained with directly radioiodinated Fab′ (i.e. no conjugate). The maleimido-closo-decaborate(2-) conjugation reagent containing a benzoate substituent on the hydrazone was chosen for study with 211At. That reagent was conjugated with 107-1A4 Fab′, then labeled (separately) with 125I and 211At. The radiolabeled Fab′ conjugates were coinjected into nude mice bearing LNCaP human tumor xenografts, and biodistribution data was obtained at 1, 4 and 24 h pi. Tumor targeting was achieved with both 125I- and 211At-labeled Fab′, but the 211At-labeled Fab′ reached a higher concentration (25.56 ± 11.20 vs. 11.97 ± 1.31 %ID/g). Surprisingly, while the 125I-labeled Fab′ was cleared from kidney similar to earlier studies, the 211At-labeled Fab′ was not (i.e. kidney conc. for 125I vs. 211At; 4h: 13.14 ± 2.03 ID/g vs. 42.28 ± 16.38 %D/g, 24h: 4.23 ± 1.57 ID/g vs. 39.52 ± 15.87 %ID/g). Since the Fab′ conjugate is identical in both cases except for the radionuclide, it seems likely that the difference in tissue clearance seen is due to an effect that 211At has on either the hydrazone cleavage or on the retention of a metabolite. Results from other studies in our laboratory suggest that the latter case is most likely. The hydrazone linkers tested do not provide the tissue clearance sought for 211At, so additional hydrazones linkers will be evaluated. However, the results support the use of hydrazone linkers when Fab′ conjugated with closo-decaborate(2-) reagents are radioiodinated. PMID:21513347

Evaluating 99mTc Auger electrons for targeted tumor radiotherapy by computational methods.

PubMed

Tavares, Adriana Alexandre S; Tavares, João Manuel R S

2010-07-01

Technetium-99m (99mTc) has been widely used as an imaging agent but only recently has been considered for therapeutic applications. This study aims to analyze the potential use of 99mTc Auger electrons for targeted tumor radiotherapy by evaluating the DNA damage and its probability of correct repair and by studying the cellular kinetics, following 99mTc Auger electron irradiation in comparison to iodine-131 (131I) beta minus particles and astatine-211 (211At) alpha particle irradiation. Computational models were used to estimate the yield of DNA damage (fast Monte Carlo damage algorithm), the probability of correct repair (Monte Carlo excision repair algorithm), and cell kinetic effects (virtual cell radiobiology algorithm) after irradiation with the selected particles. The results obtained with the algorithms used suggested that 99mTc CKMMX (all M-shell Coster-Kroning--CK--and super-CK transitions) electrons and Auger MXY (all M-shell Auger transitions) have a therapeutic potential comparable to high linear energy transfer 211At alpha particles and higher than 131I beta minus particles. All the other 99mTc electrons had a therapeutic potential similar to 131I beta minus particles. 99mTc CKMMX electrons and Auger MXY presented a higher probability to induce apoptosis than 131I beta minus particles and a probability similar to 211At alpha particles. Based on the results here, 99mTc CKMMX electrons and Auger MXY are useful electrons for targeted tumor radiotherapy.

(2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy

PubMed Central

Kiess, Ana P.; Minn, Il; Vaidyanathan, Ganesan; Hobbs, Robert F.; Josefsson, Anders; Shen, Colette; Brummet, Mary; Chen, Ying; Choi, Jaeyeon; Koumarianou, Eftychia; Baidoo, Kwamena; Brechbiel, Martin W.; Mease, Ronnie C.; Sgouros, George; Zalutsky, Michael R.

2016-01-01

Alpha-particle emitters have a high linear energy transfer and short range, offering the potential for treating micrometastases while sparing normal tissues. We developed a urea-based, 211At-labeled small molecule targeting prostate-specific membrane antigen (PSMA) for the treatment of micrometastases due to prostate cancer (PC). Methods: PSMA-targeted (2S)-2-(3-(1-carboxy-5-(4-211At-astatobenzamido)pentyl)ureido)-pentanedioic acid (211At-6) was synthesized. Cellular uptake and clonogenic survival were tested in PSMA-positive (PSMA+) PC3 PIP and PSMA-negative (PSMA−) PC3 flu human PC cells after 211At-6 treatment. The antitumor efficacy of 211At-6 was evaluated in mice bearing PSMA+ PC3 PIP and PSMA– PC3 flu flank xenografts at a 740-kBq dose and in mice bearing PSMA+, luciferase-expressing PC3-ML micrometastases. Biodistribution was determined in mice bearing PSMA+ PC3 PIP and PSMA– PC3 flu flank xenografts. Suborgan distribution was evaluated using α-camera images, and microscale dosimetry was modeled. Long-term toxicity was assessed in mice for 12 mo. Results: 211At-6 treatment resulted in PSMA-specific cellular uptake and decreased clonogenic survival in PSMA+ PC3 PIP cells and caused significant tumor growth delay in PSMA+ PC3 PIP flank tumors. Significantly improved survival was achieved in the newly developed PSMA+ micrometastatic PC model. Biodistribution showed uptake of 211At-6 in PSMA+ PC3 PIP tumors and in kidneys. Microscale kidney dosimetry based on α-camera images and a nephron model revealed hot spots in the proximal renal tubules. Long-term toxicity studies confirmed that the dose-limiting toxicity was late radiation nephropathy. Conclusion: PSMA-targeted 211At-6 α-particle radiotherapy yielded significantly improved survival in mice bearing PC micrometastases after systemic administration. 211At-6 also showed uptake in renal proximal tubules resulting in late nephrotoxicity, highlighting the importance of long-term toxicity studies and microscale dosimetry. PMID:27230930

Modeling Cell and Tumor-Metastasis Dosimetry with the Particle and Heavy Ion Transport Code System (PHITS) Software for Targeted Alpha-Particle Radionuclide Therapy.

PubMed

Lee, Dongyoul; Li, Mengshi; Bednarz, Bryan; Schultz, Michael K

2018-06-26

The use of targeted radionuclide therapy for cancer is on the rise. While beta-particle-emitting radionuclides have been extensively explored for targeted radionuclide therapy, alpha-particle-emitting radionuclides are emerging as effective alternatives. In this context, fundamental understanding of the interactions and dosimetry of these emitted particles with cells in the tumor microenvironment is critical to ascertaining the potential of alpha-particle-emitting radionuclides. One important parameter that can be used to assess these metrics is the S-value. In this study, we characterized several alpha-particle-emitting radionuclides (and their associated radionuclide progeny) regarding S-values in the cellular and tumor-metastasis environments. The Particle and Heavy Ion Transport code System (PHITS) was used to obtain S-values via Monte Carlo simulation for cell and tumor metastasis resulting from interactions with the alpha-particle-emitting radionuclides, lead-212 ( 212 Pb), actinium-225 ( 225 Ac) and bismuth-213 ( 213 Bi); these values were compared to the beta-particle-emitting radionuclides yttrium-90 ( 90 Y) and lutetium-177 ( 177 Lu) and an Auger-electron-emitting radionuclide indium-111 ( 111 In). The effect of cellular internalization on S-value was explored at increasing degree of internalization for each radionuclide. This aspect of S-value determination was further explored in a cell line-specific fashion for six different cancer cell lines based on the cell dimensions obtained by confocal microscopy. S-values from PHITS were in good agreement with MIRDcell S-values (cellular S-values) and the values found by Hindié et al. (tumor S-values). In the cellular model, 212 Pb and 213 Bi decay series produced S-values that were 50- to 120-fold higher than 177 Lu, while 225 Ac decay series analysis suggested S-values that were 240- to 520-fold higher than 177 Lu. S-values arising with 100% cellular internalization were two- to sixfold higher for the nucleus when compared to 0% internalization. The tumor dosimetry model defines the relative merit of radionuclides and suggests alpha particles may be effective for large tumors as well as small tumor metastases. These results from PHITS modeling substantiate emerging evidence that alpha-particle-emitting radionuclides may be an effective alternative to beta-particle-emitting radionuclides for targeted radionuclide therapy due to preferred dose-deposition profiles in the cellular and tumor metastasis context. These results further suggest that internalization of alpha-particle-emitting radionuclides via radiolabeled ligands may increase the relative biological effectiveness of radiotherapeutics.

A small-scale anatomical dosimetry model of the liver

NASA Astrophysics Data System (ADS)

Stenvall, Anna; Larsson, Erik; Strand, Sven-Erik; Jönsson, Bo-Anders

2014-07-01

Radionuclide therapy is a growing and promising approach for treating and prolonging the lives of patients with cancer. For therapies where high activities are administered, the liver can become a dose-limiting organ; often with a complex, non-uniform activity distribution and resulting non-uniform absorbed-dose distribution. This paper therefore presents a small-scale dosimetry model for various source-target combinations within the human liver microarchitecture. Using Monte Carlo simulations, Medical Internal Radiation Dose formalism-compatible specific absorbed fractions were calculated for monoenergetic electrons; photons; alpha particles; and 125I, 90Y, 211At, 99mTc, 111In, 177Lu, 131I and 18F. S values and the ratio of local absorbed dose to the whole-organ average absorbed dose was calculated, enabling a transformation of dosimetry calculations from macro- to microstructure level. For heterogeneous activity distributions, for example uptake in Kupffer cells of radionuclides emitting low-energy electrons (125I) or high-LET alpha particles (211At) the target absorbed dose for the part of the space of Disse, closest to the source, was more than eight- and five-fold the average absorbed dose to the liver, respectively. With the increasing interest in radionuclide therapy of the liver, the presented model is an applicable tool for small-scale liver dosimetry in order to study detailed dose-effect relationships in the liver.

Targeted alpha therapy using short-lived alpha-particles and the promise of nanobodies as targeting vehicle

PubMed Central

Dekempeneer, Yana; Keyaerts, Marleen; Krasniqi, Ahmet; Puttemans, Janik; Muyldermans, Serge; Lahoutte, Tony; D’huyvetter, Matthias; Devoogdt, Nick

2016-01-01

ABSTRACT Introduction: The combination of a targeted biomolecule that specifically defines the target and a radionuclide that delivers a cytotoxic payload offers a specific way to destroy cancer cells. Targeted radionuclide therapy (TRNT) aims to deliver cytotoxic radiation to cancer cells and causes minimal toxicity to surrounding healthy tissues. Recent advances using α-particle radiation emphasizes their potential to generate radiation in a highly localized and toxic manner because of their high level of ionization and short range in tissue. Areas covered: We review the importance of targeted alpha therapy (TAT) and focus on nanobodies as potential beneficial vehicles. In recent years, nanobodies have been evaluated intensively as unique antigen-specific vehicles for molecular imaging and TRNT. Expert opinion: We expect that the efficient targeting capacity and fast clearance of nanobodies offer a high potential for TAT. More particularly, we argue that the nanobodies’ pharmacokinetic properties match perfectly with the interesting decay properties of the short-lived α-particle emitting radionuclides Astatine-211 and Bismuth-213 and offer an interesting treatment option particularly for micrometastatic cancer and residual disease. PMID:27145158

Spatial resolution properties of digital autoradiography systems for pre-clinical alpha particle imaging (Conference Presentation)

NASA Astrophysics Data System (ADS)

Tanguay, Jesse; Benard, Francois; Celler, Anna; Ruth, Thomas; Schaffer, Paul

2017-03-01

Attaching alpha-emitting radionuclides to cancer-targeting agents increases the anti-tumor effects of targeted cancer therapies. The success of alpha therapy for treating bone metastases has increased interest in using targeted alpha therapy (TAT) to treat a broad spectrum of metastatic cancers. Estimating radiation doses to targeted tumors, including small (<250 μm) clusters of cancer cells, and to non-targeted tissues is critical in the pre-clinical development of TATs. However, accurate quantification of heterogeneous distributions of alpha-emitters in small metastases is not possible with existing pre-clinical in-vivo imaging systems. Ex-vivo digital autoradiography using a scintillator in combination with an image intensifier and a charged coupled device (CCD) has gained interest for pre-clinical ex-vivo alpha particle imaging. We present a simulation-based analysis of the fundamental spatial resolution limits of digital autoradiography systems. Spatial resolution was quantified in terms of the modulation transfer function (MTF) and Wagner's equivalent aperture. We modeled systems operating in either particle-counting (PC) or energy-integrating (EI) mode using a cascaded systems approach that accounts for: 1) the stopping power of alpha particles; 2) the distance alpha particles travel within the scintillator; 3) optical blur, and; 4) binning in detector elements. We applied our analysis to imaging of astatine-211 using an LYSO scintillator with thickness ranging from 10 μm to 20 μm. Our analysis demonstrates that when these systems are operated in particle-counting mode with a centroid-calculation algorithm, the effective apertures of 35 μm can be achieved, which suggests that digital autoradiography may enable quantifying the uptake of alpha emitters in tumors consisting of a few cancer cells. Future work will investigate the image noise and energy-resolution properties of digital autoradiography systems.

Development of a three-layer phoswich alpha-beta-gamma imaging detector

NASA Astrophysics Data System (ADS)

Yamamoto, Seiichi; Ishibashi, Hiroyuki

2015-06-01

For radiation monitoring at the sites of such nuclear power plant accidents as Fukushima Daiichi, radiation detectors are needed not only for gamma photons but also for alpha and beta particles because some nuclear fission products emit beta particles and gamma photons and some nuclear fuels contain plutonium that emits alpha particles. In some applications, imaging detectors are required to detect the distribution of plutonium particles that emit alpha particles and radiocesium in foods that emits beta particles and gamma photons. To solve these requirements, we developed an imaging detector that can measure the distribution of alpha and beta particles as well as gamma photons. The imaging detector consists of three-layer scintillators optically coupled to each other and to a position sensitive photomultiplier tube (PSPMT). The first layer, which is made of a thin plastic scintillator (decay time: 5 ns), detects alpha particles. The second layer, which is made of a thin Gd2SiO5 (GSO) scintillator with 1.5 mol% Ce (decay time: 35 ns), detects beta particles. The third layer made of a thin GSO scintillator with 0.4 mol% Ce (decay time: 70 ns) detects gamma photons. Using pulse shape discrimination, the images of these layers can be separated. The position information is calculated by the Anger principle from 8×8 anode signals from the PSPMT. The images for the alpha and beta particles and the gamma photons are individually formed by the pulse shape discriminations for each layer. We detected alpha particle images in the first layer and beta particle images in the second layer. Gamma photon images were detected in the second and third layers. The spatial resolution for the alpha and beta particles was 1.25 mm FWHM and less than 2 mm FWHM for the gamma photons. We conclude that our developed alpha-beta-gamma imaging detector is promising for imaging applications not only for the environmental monitoring of radionuclides but also for medical and molecular imaging.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elgqvist, Joergen; Andersson, Hakan; Bernhardt, Peter

Purpose: To elucidate the therapeutic efficacy of {alpha}-radioimmunotherapy of ovarian cancer in mice. This study: (i) estimated the minimum required activity (MRA), giving a reasonable high therapeutic efficacy; and (ii) calculated the specific energy to tumor cell nuclei and the metastatic cure probability (MCP) using various assumptions regarding monoclonal-antibody (mAb) distribution in measured tumors. The study was performed using the {alpha}-particle emitter Astatine-211 ({sup 211}At) labeled to the mAb MX35 F(ab'){sub 2}. Methods and Materials: Animals were inoculated intraperitoneally with {approx}1 x 10{sup 7} cells of the cell line NIH:OVCAR-3. Four weeks later animals were treated with 25, 50, 100,more » or 200 kBq {sup 211}At-MX35 F(ab'){sub 2} (n = 74). Another group of animals was treated with a nonspecific mAb: 100 kBq {sup 211}At-Rituximab F(ab'){sub 2} (n = 18). Eight weeks after treatment the animals were sacrificed and presence of macro- and microscopic tumors and ascites was determined. An MCP model was developed and compared with the experimentally determined tumor-free fraction (TFF). Results: When treatment was given 4 weeks after cell inoculation, the TFFs were 25%, 22%, 50%, and 61% after treatment with 25, 50, 100, or 200 kBq {sup 211}At-MX35 F(ab'){sub 2}, respectively, the specific energy to irradiated cell nuclei varying between {approx}2 and {approx}400 Gy. Conclusion: As a significant increase in the therapeutic efficacy was observed between the activity levels of 50 and 100 kBq (TFF increase from 22% to 50%), the conclusion was that the MRA is {approx}100 kBq {sup 211}At-MX35 F(ab'){sub 2}. MCP was most consistent with the TFF when assuming a diffusion depth of 30 {mu}m of the mAbs in the tumors.« less

Hit rates and radiation doses to nuclei of bone lining cells from alpha-particle-emitting radionuclides

NASA Technical Reports Server (NTRS)

Polig, E.; Jee, W. S.; Kruglikov, I. L.

1992-01-01

Factors relating the local concentration of a bone-seeking alpha-particle emitter to the mean hit rate have been determined for nuclei of bone lining cells using a Monte Carlo procedure. Cell nuclei were approximated by oblate spheroids with dimensions and location taken from a previous histomorphometric study. The Monte Carlo simulation is applicable for planar and diffuse labels at plane or cylindrical bone surfaces. Additionally, the mean nuclear dose per hit, the dose mean per hit, the mean track segment length and its second moment, the percentage of stoppers, and the frequency distribution of the dose have been determined. Some basic features of the hit statistics for bone lining cells have been outlined, and the consequences of existing standards of radiation protection with regard to the hit frequency to cell nuclei are discussed.

Development of 64Cu-NOTA-Trastuzumab for HER2 targeting: radiopharmaceutical with improved pharmacokinetics for human study.

PubMed

Woo, Sang-Keun; Jang, Su Jin; Seo, Min-Jung; Park, Ju Hui; Kim, Byoung Soo; Kim, Eun Jung; Lee, Yong Jin; Lee, Tae Sup; An, Gwang Il; Song, In Ho; Seo, Youngho; Kim, Kwang Il; Kang, Joo Hyun

2018-05-18

Purpose The purpose of this study was to develop 64 Cu-labeled trastuzumab with improved pharmacokinetics for human epidermal growth factor receptor 2. Methods Trastuzumab was conjugated with SCN-Bn-NOTA and radiolabeled with 64 Cu. Serum stability and immunoreactivity of 64 Cu-NOTA-trastuzumab were tested. Small animal PET imaging and biodistribution study were performed in HER2-positive breast cancer xenograft model (BT-474). Internal dosimetry of experimental animals was performed using the image-based approach with the Monte Carlo N-Particle Code. Results 64 Cu-NOTA-trastuzumab was prepared with high radiolabel yield and radiochemical purity (>98%) and showed high stability in serum and good immunoreactivity. Uptake of 64 Cu-NOTA-trastuzumab was highest at 48 h after injection determined by PET imaging and biodistribution results in BT-474 tumors. The blood radioactivity concentrations of 64 Cu-NOTA-trastuzumab decreased bi-exponentially with time in both mice with and without BT-474 tumor xenografts. The calculated absorbed dose of 64 Cu-NOTA-trastuzumab was 0.048 mGy/MBq for the heart, 0.079 for the liver and 0.047 for the spleen. Conclusion 64 Cu-NOTA-trastuzumab was effectively targeted to the HER2-expressing tumor in vitro and in vivo , and it exhibited relatively low absorbed dose due to short residence time. Therefore, 64 Cu-NOTA-trastuzumab could be applied to select the right patients/right timing for HER2 therapy, to monitor the treatment response after HER2-targeted therapy, and to detect distal or metastatic spread. Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Realizing the potential of the Actinium-225 radionuclide generator in targeted alpha-particle therapy applications

PubMed Central

Miederer, Matthias; Scheinberg, David A.; McDevitt, Michael R.

2013-01-01

Alpha particle-emitting isotopes have been proposed as novel cytotoxic agents for augmenting targeted therapy. Properties of alpha particle radiation such as their limited range in tissue of a few cell diameters and their high linear energy transfer leading to dense radiation damage along each alpha track are promising in the treatment of cancer, especially when single cells or clusters of tumor cells are targeted. Actinium-225 (225Ac) is an alpha particle-emitting radionuclide that generates 4 net alpha particle isotopes in a short decay chain to stable 209Bi, and as such can be described as an alpha particle nanogenerator. This article reviews the literature pertaining to the research, development, and utilization of targeted 225Ac to potently and specifically affect cancer. PMID:18514364

A new method for evaluating radon and thoron alpha-activities per unit volume inside and outside various natural material samples by calculating SSNTD detection efficiencies for the emitted alpha-particles and measuring the resulting track densities.

PubMed

Misdaq, M A; Aitnouh, F; Khajmi, H; Ezzahery, H; Berrazzouk, S

2001-08-01

A Monte Carlo computer code for determining detection efficiencies of the CR-39 and LR-115 II solid-state nuclear track detectors (SSNTD) for alpha-particles emitted by the uranium and thorium series inside different natural material samples was developed. The influence of the alpha-particle initial energy on the SSNTD detection efficiencies was investigated. Radon (222Rn) and thoron (220Rn) alpha-activities per unit volume were evaluated inside and outside the natural material samples by exploiting data obtained for the detection efficiencies of the SSNTD utilized for the emitted alpha-particles, and measuring the resulting track densities. Results obtained were compared to those obtained by other methods. Radon emanation coefficients have been determined for some of the considered material samples.

Production of Astatine-211 at the Duke University Medical Center for its regional distribution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zalutsky, Michael

Systemic targeted radiation therapy and radioimmunotherapy continue to be important tools in the treatment of certain cancers. Because of their high energy and short path length, alpha particle emitters such as 211At are more effective than either external beam x- ray or in vivo beta radiation in delivering potentially curative doses of radiation. The limited clinical trials that have been conducted to date have yielded encouraging responses in some patients, e.g., malignant brain tumors. In order to escalate the additional necessary research and development in radiochemistry, radiobiology and efficacy evaluation of alpha particle radiotherapeutics, it is universally agreed that accessmore » to an affordable, reliable supply of 211At is warranted. In conjunction with the Department of Energy's intent to enhance stable and radioactive isotope availability for research applications, it is the primary objective of this project to improve 211At production and purification capabilities at Duke so that this radionuclide can be supplied to researchers at other institutions throughout the US.The most widely used 211At production method involves the α,2n reaction on Bismuth using a cyclotron with beams ≤ 28 MeV. Yields can be enhanced with use of an internal target that allows for a higher alpha fluence plus efficient heat dissipation in the target. Both of these items are in place at Duke; however, in order to support production for multi-institutional use, irradiation campaigns in excess of 50 µAp and four hours duration will be needed. Further, post-irradiation processing equipment is lacking that will enable the distribution process. Financial support is sought for i) a shielded, ventilated processing/containment hood; ii) development of a post-irradiation target retrieval system; iii) fabrication of a 211At distillation and recovery module and iv) a performance review and, where needed, an enhancement of seven major subsystems that comprise the CS-30 Cyclotron. With these modifications in place, routine production of ≥200 mCi of At-211 should be readily achievable, given our methodological development of At-211 target preparation, internal target irradiation and dry distillation to recover the radionuclide.« less

Development of an alpha/beta/gamma detector for radiation monitoring

NASA Astrophysics Data System (ADS)

Yamamoto, Seiichi; Hatazawa, Jun

2011-11-01

For radiation monitoring at the site of nuclear power plant accidents such as Fukushima Daiichi, radiation detectors not only for gamma photons but also for alpha and beta particles are needed because some nuclear fission products emit beta particles and gamma photons and some nuclear fuels contain plutonium that emits alpha particles. We developed a radiation detector that can simultaneously monitor alpha and beta particles and gamma photons for radiation monitoring. The detector consists of three-layered scintillators optically coupled to each other and coupled to a photomultiplier tube. The first layer, which is made of a thin plastic scintillator (decay time: 2.4 ns), detects alpha particles. The second layer, which is made of a thin Gd2SiO5 (GSO) scintillator with 1.5 mol.% Ce (decay time: 35 ns), detects beta particles. The third layer made of a thin GSO scintillator with 0.4 mol.% Ce (decay time: 70 ns) detects gamma photons. By using pulse shape discrimination, the count rates of these layers can be separated. With individual irradiation of alpha and beta particles and gamma photons, the count rate of the first layer represented the alpha particles, the second layer represented the beta particles, and the third layer represented the gamma photons. Even with simultaneous irradiation of the alpha and beta particles and the gamma photons, these three types of radiation can be individually monitored using correction for the gamma detection efficiency of the second and third layers. Our developed alpha, beta, and gamma detector is simple and will be useful for radiation monitoring, especially at nuclear power plant accident sites or other applications where the simultaneous measurements of alpha and beta particles and gamma photons are required.

Development of an alpha/beta/gamma detector for radiation monitoring.

PubMed

Yamamoto, Seiichi; Hatazawa, Jun

2011-11-01

For radiation monitoring at the site of nuclear power plant accidents such as Fukushima Daiichi, radiation detectors not only for gamma photons but also for alpha and beta particles are needed because some nuclear fission products emit beta particles and gamma photons and some nuclear fuels contain plutonium that emits alpha particles. We developed a radiation detector that can simultaneously monitor alpha and beta particles and gamma photons for radiation monitoring. The detector consists of three-layered scintillators optically coupled to each other and coupled to a photomultiplier tube. The first layer, which is made of a thin plastic scintillator (decay time: 2.4 ns), detects alpha particles. The second layer, which is made of a thin Gd(2)SiO(5) (GSO) scintillator with 1.5 mol.% Ce (decay time: 35 ns), detects beta particles. The third layer made of a thin GSO scintillator with 0.4 mol.% Ce (decay time: 70 ns) detects gamma photons. By using pulse shape discrimination, the count rates of these layers can be separated. With individual irradiation of alpha and beta particles and gamma photons, the count rate of the first layer represented the alpha particles, the second layer represented the beta particles, and the third layer represented the gamma photons. Even with simultaneous irradiation of the alpha and beta particles and the gamma photons, these three types of radiation can be individually monitored using correction for the gamma detection efficiency of the second and third layers. Our developed alpha, beta, and gamma detector is simple and will be useful for radiation monitoring, especially at nuclear power plant accident sites or other applications where the simultaneous measurements of alpha and beta particles and gamma photons are required. © 2011 American Institute of Physics

Monte Carlo N-Particle (MCNP) Modeling of the Cellular Dosimetry of 64Cu: Comparison with MIRDcell S Values and Implications for Studies of Its Cytotoxic Effects.

PubMed

Cai, Zhongli; Kwon, Yongkyu Luke; Reilly, Raymond M

2017-02-01

64 Cu emits positrons as well as β - particles and Auger and internal conversion electrons useful for radiotherapy. Our objective was to model the cellular dosimetry of 64 Cu under different geometries commonly used to study the cytotoxic effects of 64 Cu. Monte Carlo N-Particle (MCNP) was used to simulate the transport of all particles emitted by 64 Cu from the cell surface (CS), cytoplasm (Cy), or nucleus (N) of a single cell; monolayer in a well (radius = 0.32-1.74 cm); or a sphere (radius = 50-6,000 μm) of cells to calculate S values. The radius of the cell and N ranged from 5 to 12 μm and 2 to 11 μm, respectively. S values were obtained by MIRDcell for comparison. MCF7/HER2-18 cells were exposed in vitro to 64 Cu-labeled trastuzumab. The subcellular distribution of 64 Cu was measured by cell fractionation. The surviving fraction was determined in a clonogenic assay. The relative differences of MCNP versus MIRDcell self-dose S values (S self ) for 64 Cu ranged from -0.2% to 3.6% for N to N (S N←N ), 2.3% to 8.6% for Cy to N (S N←Cy ), and -12.0% to 7.3% for CS to N (S N←CS ). The relative differences of MCNP versus MIRDcell cross-dose S values were 25.8%-30.6% for a monolayer and 30%-34% for a sphere, respectively. The ratios of S N←N versus S N←Cy and S N←Cy versus S N←CS decreased with increasing ratio of the N of the cell versus radius of the cell and the size of the monolayer or sphere. The surviving fraction of MCF7 /: HER2-18 cells treated with 64 Cu-labeled trastuzumab (0.016-0.368 MBq/μg, 67 nM) for 18 h versus the absorbed dose followed a linear survival curve with α = 0.51 ± 0.05 Gy -1 and R 2 = 0.8838. This is significantly different from the linear quadratic survival curve of MCF7 /: HER2-18 cells exposed to γ-rays. MCNP- and MIRDcell-calculated S values agreed well. 64 Cu in the N increases the dose to the N in isolated single cells but has less effect in a cell monolayer or small cluster of cells simulating a micrometastasis, and little effect in a sphere analogous to a tumor xenograft compared with 64 Cu in the Cy or on the CS. The dose deposited by 64 Cu is less effective for cell killing than γ-rays. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

SU-E-J-03: A Comprehensive Comparison Between Alpha and Beta Emitters for Cancer Radioimmunotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, C.Y.; Guatelli, S; Oborn, B

2014-06-01

Purpose: The purpose of this study is to perform a comprehensive comparison of the therapeutic efficacy and cytotoxicity of alpha and beta emitters for Radioimmunotherapy (RIT). For each stage of cancer development, specific models were built for the separate objectives of RIT to be addressed:a) kill isolated cancer cells in transit in the lymphatic and vascular circulation,b) regress avascular cell clusters,c) regress tumor vasculature and tumors. Methods: Because of the nature of short range, high LET alpha and long energy beta radiation and heterogeneous antigen expression among cancer cells, the microdosimetric approach is essential for the RIT assessment. Geant4 basedmore » microdosimetric models are developed for the three different stages of cancer progression: cancer cells, cell clusters and tumors. The energy deposition, specific energy resulted from different source distribution in the three models was calculated separately for 4 alpha emitting radioisotopes ({sup 211}At, {sup 213}Bi, {sup 223}Ra and {sup 225}Ac) and 6 beta emitters ({sup 32}P, {sup 33}P, {sup 67}Cu, {sup 90}Y, {sup 131}I and {sup 177}Lu). The cell survival, therapeutic efficacy and cytotoxicity are determined and compared between alpha and beta emitters. Results: We show that internal targeted alpha radiation has advantages over beta radiation for killing isolated cancer cells, regressing small cell clusters and also solid tumors. Alpha particles have much higher dose specificity and potency than beta particles. They can deposit 3 logs more dose than beta emitters to single cells and solid tumor. Tumor control probability relies on deep penetration of radioisotopes to cancer cell clusters and solid tumors. Conclusion: The results of this study provide a quantitative understanding of the efficacy and cytotoxicity of RIT for each stage of cancer development.« less

Actinium-225 in targeted alpha-particle therapeutic applications

PubMed Central

Scheinberg, David A.; McDevit, Michael R.

2017-01-01

Alpha particle-emitting isotopes are being investigated in radioimmunotherapeutic applications because of their unparalleled cytotoxicity when targeted to cancer and their relative lack of toxicity towards untargeted normal tissue. Actinium-225 has been developed into potent targeting drug constructs and is in clinical use against acute myelogenous leukemia. The key properties of the alpha particles generated by 225Ac are the following: i) limited range in tissue of a few cell diameters; ii) high linear energy transfer leading to dense radiation damage along each alpha track; iii) a 10 day half-life; and iv) four net alpha particles emitted per decay. Targeting 225Ac-drug constructs have potential in the treatment of cancer. PMID:22202153

Method of and apparatus for measuring the mean concentration of thoron and/or radon in a gas mixture

DOEpatents

Lucas, Henry

1990-01-01

A method of and an apparatus for detecting and accurately measuring the mean concentrations of .sup.222 Rn and .sup.220 Tn in a gas mixture, such as the ambient atmosphere in a mine, is provided. The apparatus includes an alpha target member which defines at least one operative target surface and which is preferably fabricated from a single piece of an alpha particle sensitive material. At least one portion of the operative target surface is covered with an alpha particle filter. The uncovered and filter covered operative surface is exposed to the gas mixture containing the .sup.222 Rn and .sup.220 Tn. In the radioactive decay series of these isotopes the maximum kinetic energy emitted by the alpha decay of .sup.222 Rn is about 1.1 MeV less than the maximum kinetic energy emitted by the alpha decay of a .sup.220 Tn. The alpha particle filter has a predetermined mass per unit area of the covered portion of the operative target surface that prevents penetration of alpha particles which originate from .sup.222 Rn decay, but which allows passage therethrough of the maximum kinetic energy alpha particles from .sup.220 Tn decay. Thus, a count of the alpha particle tracks in the uncovered portion of the target member is proportional to the mean concentration of sum of .sup.222 Rn and .sup.220 Tn in the gas mixture, while the count of alpha tracks in the target member under the filter is proportional to the concentration of only the .sup.220 Tn in the gas mixture.

Intense alpha-particle emitting crystallites in uranium mill wastes

USGS Publications Warehouse

Landa, E.R.; Stieff, L.R.; Germani, M.S.; Tanner, A.B.; Evans, J.R.

1994-01-01

Nuclear emulsion microscopy has demonstrated the presence of small, intense ??-particle emitting crystallites in laboratory-produced tailings derived from the sulfuric acid milling of uranium ores. The ??-particle activity is associated with the isotope pair 210Pb 210Po, and the host mineral appears to be PbSO4 occurring as inclusions in gypsum laths. These particles represent potential inhalation hazards at uranium mill tailings disposal areas. ?? 1994.

Evidence of the photosynthetic origin of monoterpenes emitted by quercus ilex L. leaves by {sup 13}C labeling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Loreto, F.; Ciccioli, P.; Cecinato, A.

1996-04-01

The carbon of the four main monoterpenes emitted by Quercus ilex L. leaves was completely labeled with {sup 13}C after a 20-min feeding with 99% {sup 13}CO{sub 2}. This labeling time course is comparable with the labeling time course of isoprene, the terpenoid emitted by other Quercus species and synthesized in leaf chloroplasts. It is also comparable with that of phosphoglyceric acid. Our experiment therefore provides evidence that monoterpenes emitted by Q. ilex are formed photosynthesis intermediates and may share the same synthetic pathway with isoprene. By analyzing the rate and the distribution of labeling in the different fragments, wemore » looked for evidence of differential carbon labeling in the {alpha}-pinene emitted. However, the labeling pattern was quite uniform in the different fragments, suggesting that the carbon skeleton of the emitted monoterpenes comes from a unique carbon source. 16 refs., 3 figs., 1 tab.« less

Labeling and Biological Evaluation of (99m)Tc-HYNIC-Trastuzumab as a Potential Radiopharmaceutical for In Vivo Evaluation of HER2 Expression in Breast Cancer.

PubMed

Calzada, Victoria; Garcia, Fernanda; Fernández, Marcelo; Porcal, Williams; Quinn, Thomas; Alonso, Omar; Gambini, Juan Pablo; Cabral, Pablo

2013-01-01

The amplification of HER2 gene has been described in several tumor types, mainly breast cancer with a subsequent increase in HER2 protein expression. Trastuzumab is a humanized monoclonal antibody that recognizes selectively the HER2 extracellular domain. The objective of the present work was to standardize the conjugation of Trastuzumab with Succinimidyl-hydrazinonicotinamide (HYNIC) and labeling with (99m)Tc to obtain (99m)Tc-HYNIC-Trastuzumab for use as in vivo tracer of the HER2 expression in breast cancer. The labeling procedure involved derivatization of 0.067 μmol of Trastuzumab with 0.33 μmols of HYNIC in dimethyl sulfoxide (DMSO). The mixture was incubated for 30 min. A mixture of Tricine and SnCl2.2H2O was prepared by add a solution of 44.6 μmols Tricine in 0.05 mL HCl 2.0 M and a similar volume of another solution containing 44.3 μmols SnCl2.2H2O in 0.5 mL HCl 2.0 M. Then, 0.05 mL of this mixed was added to the conjugated with 296 MBq of 99mTcO-4. The final mixture was incubated at room temperature (18-25°C) for 30 min. Radiochemical purity of the labeled solution was studied by chromatography, to evaluate (99m)Tc-Tricine, (99m)TcO2.H2O, and free (99m)TcO4 (-). Radiochemical purity was also evaluated by HPLC. Stability studies were tested in solution at 4°C and lyophilized at 4°C. Biodistribution studies were performed in healthy CD-1 female mice at 2, 5, and 24 h (n = 3) and CD-1 female mice spontaneous breast adenocarcinoma (n = 3). Scintigraphic images of spontaneous breast adenocarcinoma in female CD-1 mice were acquired in a gamma camera at 2, 5, and 24 h post-injection. Labeling was easily performed with high yields (>90%) and radiopharmaceutical stability for 24 h post-labeling. Stability studies revealed that antibody derivative must be lyophilized for undamaged storage. Biodistribution studies and imaging revealed excellent uptake in the tumor. Based on the results it was concluded that (99m)Tc-HYNIC-Trastuzumab could be a promising radiopharmaceutical for in vivo diagnosis of the HER2 status in breast with impact on treatment planning.

Low-energy neutron detector based upon lithium lanthanide borate scintillators

DOEpatents

Czirr, John B.

1998-01-01

An apparatus for detecting neutrons includes a cerium activated scintillation crystal containing .sup.10 B, with the scintillation crystal emitting light in response to .alpha. particles emitted from the .sup.10 B(n,.alpha.)Li* reaction. The apparatus also includes a gamma scintillator positioned adjacent the crystal and which generates light in response to gamma rays emitted from the decay of Li*. The apparatus further includes a first and a second light-to-electronic signal converter each positioned to respectively receive light from the crystal and the gamma scintillator, and each respectively outputting first and second electronic signals representative of .alpha. particles from the .sup.10 B(n,.alpha.)Li* reaction and gamma rays from the .sup.10 B(n,.alpha.)Li* reaction. The apparatus includes a coincidence circuit connected to receive the first and second signals and which generates a coincidence signal when the first and second signals coincide. The apparatus also includes a data analyzer for receiving an additional signal from at least one of the first and second converters, and for operating in response to the coincidence signal.

A CAM (continuous air monitor) sampler for collecting and assessing alpha-emitting aerosol particles

DOE Office of Scientific and Technical Information (OSTI.GOV)

McFarland, A.R.; Bethel, E.L.; Ortiz, C.A.

1991-07-01

A new continuous air monitor (CAM) sampler for assessing alpha-emitting transuranic aerosol particles has been developed. The system has been designed to permit collection of particles that can potentially penetrate into the thoracic region of the human respiratory system. Wind tunnel testing of the sampler has been used to characterize the penetration of aerosol to the collection filter. Results show that greater than or equal to 50% of 10-micrograms aerodynamic equivalent diameter (AED) particles are collected by the filter at wind speeds of 0.3 to 2 m s-1 and at sampling flow rates of 28 to 113 L min-1 (1more » to 4 cfm). The deposition of 10-microns AED particles takes place primarily in the center of the filter, where the counting efficiency of the detector is highest.« less

Development and preclinical studies of 64Cu-NOTA-pertuzumab F(ab′)2 for imaging changes in tumor HER2 expression associated with response to trastuzumab by PET/CT

PubMed Central

Lam, Karen; Chan, Conrad; Reilly, Raymond M.

2017-01-01

ABSTRACT We previously reported that microSPECT/CT imaging with 111In-labeled pertuzumab detected decreased HER2 expression in human breast cancer (BC) xenografts in athymic mice associated with response to treatment with trastuzumab (Herceptin). Our aim was to extend these results to PET/CT by constructing F(ab′)2 of pertuzumab modified with NOTA chelators for complexing 64Cu. The effect of the administered mass (5–200 µg) of 64Cu-NOTA-pertuzumab F(ab′)2 was studied in NOD/SCID mice engrafted with HER2-positive SK-OV-3 human ovarian cancer xenografts. Biodistribution studies were performed in non-tumor bearing Balb/c mice to predict radiation doses to normal organs in humans. Serial PET/CT imaging was conducted on mice engrafted with HER2-positive and trastuzumab-sensitive BT-474 or trastuzumab-insensitive SK-OV-3 xenografted mice treated with weekly doses of trastuzumab. There were no significant effects of the administered mass of 64Cu-NOTA-pertuzumab F(ab′)2 on tumor or normal tissue uptake. The predicted total body dose in humans was 0.015 mSv/MBq, a 3.3-fold reduction compared to 111In-labeled pertuzumab. MicroPET/CT images revealed specific tumor uptake of 64Cu-NOTA-pertuzumab F(ab′)2 at 24 or 48 h post-injection in mice with SK-OV-3 tumors. Image analysis of mice treated with trastuzumab showed 2-fold reduced uptake of 64Cu-NOTA-pertuzumab F(ab′)2 in BT-474 tumors after 1 week of trastuzumab normalized to baseline, and 1.9-fold increased uptake in SK-OV-3 tumors after 3 weeks of trastuzumab, consistent with tumor response and resistance, respectively. We conclude that PET/CT imaging with 64Cu-NOTA-pertuzumab F(ab′)2 detected changes in HER2 expression in response to trastuzumab while delivering a lower total body radiation dose compared to 111In-labeled pertuzumab. PMID:27813707

Monte Carlo based dosimetry for neutron capture therapy of brain tumors

NASA Astrophysics Data System (ADS)

Zaidi, Lilia; Belgaid, Mohamed; Khelifi, Rachid

2016-11-01

Boron Neutron Capture Therapy (BNCT) is a biologically targeted, radiation therapy for cancer which combines neutron irradiation with a tumor targeting agent labeled with a boron10 having a high thermal neutron capture cross section. The tumor area is subjected to the neutron irradiation. After a thermal neutron capture, the excited 11B nucleus fissions into an alpha particle and lithium recoil nucleus. The high Linear Energy Transfer (LET) emitted particles deposit their energy in a range of about 10μm, which is of the same order of cell diameter [1], at the same time other reactions due to neutron activation with body component are produced. In-phantom measurement of physical dose distribution is very important for BNCT planning validation. Determination of total absorbed dose requires complex calculations which were carried out using the Monte Carlo MCNP code [2].

Development of optical monitor of alpha radiations based on CR-39.

PubMed

Joshirao, Pranav M; Shin, Jae Won; Vyas, Chirag K; Kulkarni, Atul D; Kim, Hojoong; Kim, Taesung; Hong, Seung-Woo; Manchanda, Vijay K

2013-11-01

Fukushima accident has highlighted the need to intensify efforts to develop sensitive detectors to monitor the release of alpha emitting radionuclides in the environment caused by the meltdown of the discharged spent fuel. Conventionally, proportional counting, scintillation counting and alpha spectrometry are employed to assay the alpha emitting radionuclides but these techniques are difficult to be configured for online operations. Solid State Nuclear Track Detectors (SSNTDs) offer an alternative off line sensitive technique to measure alpha emitters as well as fissile radionuclides at ultra-trace level in the environment. Recently, our group has reported the first ever attempt to use reflectance based fiber optic sensor (FOS) to quantify the alpha radiations emitted from (232)Th. In the present work, an effort has been made to develop an online FOS to monitor alpha radiations emitted from (241)Am source employing CR-39 as detector. Here, we report the optical response of CR-39 (on exposure to alpha radiations) employing techniques such as Atomic Force Microscopy (AFM) and Reflectance Spectroscopy. In the present work GEANT4 simulation of transport of alpha particles in the detector has also been carried out. Simulation includes validation test wherein the projected ranges of alpha particles in the air, polystyrene and CR-39 were calculated and were found to agree with the literature values. An attempt has been further made to compute the fluence as a function of the incidence angle and incidence energy of alphas. There was an excellent correlation in experimentally observed track density with the simulated fluence. The present work offers a novel approach to design an online CR-39 based fiber optic sensor (CRFOS) to measure the release of nanogram quantity of (241)Am in the environment. © 2013 Elsevier Ltd. All rights reserved.

Visualization of Radioisotope Detectability Over Time.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huynh, Brady

A radioactive isotope is an atom that has an unstable nucleus. The isotope can undergo radioactive decay, the process in which excessive nuclear energy is emitted from the nucleus in many different forms, such as gamma radiation, alpha particles, or beta particles. The important thing to note is that these emissions act as a signature for the isotope. Each radioisotope has a particular emission spectrum, emitting radiation at different energies and at different rates.

Radiation-induced biologic bystander effect elicited in vitro by targeted radiopharmaceuticals labeled with alpha-, beta-, and auger electron-emitting radionuclides.

PubMed

Boyd, Marie; Ross, Susan C; Dorrens, Jennifer; Fullerton, Natasha E; Tan, Ker Wei; Zalutsky, Michael R; Mairs, Robert J

2006-06-01

Recent studies have shown that indirect effects of ionizing radiation may contribute significantly to the effectiveness of radiotherapy by sterilizing malignant cells that are not directly hit by the radiation. However, there have been few investigations of the importance of indirect effects in targeted radionuclide treatment. Our purpose was to compare the induction of bystander effects by external beam gamma-radiation with those resultant from exposure to 3 radiohaloanalogs of metaiodobenzylguanidine (MIBG): (131)I-MIBG (low-linear-energy-transfer [LET] beta-emitter), (123)I-MIBG (potentially high-LET Auger electron emitter), and meta-(211)At-astatobenzylguanidine ((211)At-MABG) (high-LET alpha-emitter). Two human tumor cell lines-UVW (glioma) and EJ138 (transitional cell carcinoma of bladder)-were transfected with the noradrenaline transporter (NAT) gene to enable active uptake of MIBG. Medium from cells that accumulated the radiopharmaceuticals or were treated with external beam radiation was transferred to cells that had not been exposed to radioactivity, and clonogenic survival was determined in donor and recipient cultures. Over the dose range 0-9 Gy of external beam radiation of donor cells, 2 Gy caused 30%-40% clonogenic cell kill in recipient cultures. This potency was maintained but not increased by higher dosage. In contrast, no corresponding saturation of bystander cell kill was observed after treatment with a range of activity concentrations of (131)I-MIBG, which resulted in up to 97% death of donor cells. Cellular uptake of (123)I-MIBG and (211)At-MABG induced increasing recipient cell kill up to levels that resulted in direct kill of 35%-70% of clonogens. Thereafter, the administration of higher activity concentrations of these high-LET emitters was inversely related to the kill of recipient cells. Over the range of activity concentrations examined, neither direct nor indirect kill was observed in cultures of cells not expressing the NAT and, thus, incapable of active uptake of MIBG. Potent toxins are generated specifically by cells that concentrate radiohalogenated MIBG. These may be LET dependent and distinct from those elicited by conventional radiotherapy.

Radioimmunotherapy of nude mice with intraperitoneally growing ovarian cancer xenograft utilizing 211At-labelled monoclonal antibody MOv18.

PubMed

Andersson, H; Lindegren, S; Back, T; Jacobsson, L; Leser, G; Horvath, G

2000-01-01

The aim of this study was to investigate the therapeutic efficacy of 211At-labelled monoclonal antibody given intraperitoneally to nude mice with intraperitoneal growth of a human ovarian cancer cell line. Female nude mice were inoculated intraperitoneally with 1 x 10(7) cells of the human ovarian cancer cell line NIH:OVCAR 3. After about two weeks they were injected with the 211At-labelled specific monoclonal antibody MOv18 intraperitoneally. For comparison, other groups of mice were given the same labelled antibody intravenously, 211At-labelled unspecific antibody C242 intraperitoneally or unalbelled MOv18 intraperitoneally. Six weeks later the animals were sacrificed and the occurrence of tumour and ascites was determined. When the mice were treated with 211At-labelled MOv18 intraperitoneally 9 out of 10 were apparently free of both ascites and tumour compared to none of the mice given unlabelled antibody. 211At-labelled MOv18 given intravenously or 211At-labelled unspecific antibody given intraperitoneally were less effective. Regional radioimmunotherapy with the alpa-emitter 211Astatine seems to be an effective treatment of nude mice with intraperitoneally growing human ovarian cancer. Hopefully this treatment can be given in an adjuvant setting to women with minimal residual ovarian cancer in the future.

64Cu-DOTA-trastuzumab PET Imaging in Women with HER2 Overexpressing Breast Cancer

DTIC Science & Technology

2011-10-01

AD_________________ Award Number: W81XWH-10-1-0824 TITLE: 64Cu- DOTA -trastuzumab PET imaging in...September 2011 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER 64Cu- DOTA -trastuzumab PET imaging in women with HER2 overexpressing breast cancer 5b...synthesized 64Cu- DOTA -trastuzumab and tested it in model systems. Relative to the 111In-labeled antibody, positron emission tomography (PET) with 64Cu

Luminescence imaging of water during alpha particle irradiation

NASA Astrophysics Data System (ADS)

Yamamoto, Seiichi; Komori, Masataka; Koyama, Shuji; Toshito, Toshiyuki

2016-05-01

The luminescence imaging of water using the alpha particle irradiation of several MeV energy range is thought to be impossible because this alpha particle energy is far below the Cerenkov-light threshold and the secondary electrons produced in this energy range do not emit Cerenkov-light. Contrary to this consensus, we found that the luminescence imaging of water was possible with 5.5 MeV alpha particle irradiation. We placed a 2 MBq of 241Am alpha source in water, and luminescence images of the source were conducted with a high-sensitivity, cooled charge-coupled device (CCD) camera. We also carried out such imaging of the alpha source in three different conditions to compare the photon productions with that of water, in air, with a plastic scintillator, and an acrylic plate. The luminescence imaging of water was observed from 10 to 20 s acquisition, and the intensity was linearly increased with time. The intensity of the luminescence with the alpha irradiation of water was 0.05% of that with the plastic scintillator, 4% with air, and 15% with the acrylic plate. The resolution of the luminescence image of water was better than 0.25 mm FWHM. Alpha particles of 5.5 MeV energy emit luminescence in water. Although the intensity of the luminescence was smaller than that in air, it was clearly observable. The luminescence of water with alpha particles would be a new method for alpha particle detection and distribution measurements in water.

Astatine-211 conjugated to an anti-CD20 monoclonal antibody eradicates disseminated B-cell lymphoma in a mouse model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Green, Damian J.; Shadman, Mazyar; Jones, Jon C.

Alpha emitting radionuclides release a large amount of energy within a few cell diameters and may be particularly effective for radioimmunotherapy targeting minimal residual disease (MRD) conditions in which micrometastatic disease satellites are broadly distributed. To evaluate this hypothesis, 211At conjugated 1F5 mAb (anti-CD20) was studied in both bulky lymphoma tumor xenograft and MRD animal models. Superior treatment responses to 211At conjugated 1F5 mAb were evident in the MRD setting. Lymphoma xenograft tumor bearing animals treated with doses of up to 48µCi of anti-CD20 211At-decaborate [211At-B10-1F5] experienced modest responses (0% cures but 2-3-fold prolongation of survival compared to negative controls).more » In contrast, 70% of animals in the MRD lymphoma model demonstrated complete eradication of disease when treated with 211At-B10-1F5 at a radiation dose that was less than one-third (15 µCi) of the highest dose given to xenograft animals. Tumor progression among untreated control animals in both models was uniformly lethal. After 130 days, no significant renal or hepatic toxicity is observed in the cured animals receiving 15 µCi of 211At-B10-1F5. These findings suggest that in a MRD lymphoma model, where isolated cells and tumor microclusters prevail, α-emitters may be uniquely efficacious.« less

A new mechanism for DNA alterations induced by alpha particles such as those emitted by radon and radon progeny.

PubMed Central

Lehnert, B E; Goodwin, E H

1997-01-01

The mechanism(s) by which alpha (alpha) particles like those emitted from inhaled radon and radon progeny cause their carcinogenic effects in the lung remains unclear. Although direct nuclear traversals by alpha-particles may be involved in mediating these outcomes, increasing evidence indicates that a particles can cause alterations in DNA in the absence of direct hits to cell nuclei. Using the occurrence of excessive sister chromatid exchanges (SCE) as an index of DNA damage in human lung fibroblasts, we investigated the hypothesis that alpha-particles may induce DNA damage through the generation of extracellular factors. We have found that a relatively low dose of alpha-particles can result in the generation of extracellular factors, which, upon transfer to unexposed normal human cells, can cause excessive SCE to an extent equivalent to that observed when the cells are directly irradiated with the same irradiation dose. A short-lived, SCE-inducing factor(s) is generated in alpha-irradiated culture medium containing serum in the absence of cells. A more persistent SCE-inducing factor(s), which can survive freeze-thaw and is heat labile is produced by fibroblasts after exposure to the alpha-particles. These results indicate that the initiating target for alpha-particle-induced genetic changes can be larger than a cell's nucleus or even a whole cell. How transmissible factors like those observed here in vitro may extend to the in vivo condition in the context of a-particle-induced carcinogenesis in the respiratory tract remains to be determined. PMID:9400706

Modelling and Dosimetry for Alpha-Particle Therapy

PubMed Central

Sgouros, George; Hobbs, Robert F.; Song, Hong

2015-01-01

As a consequence of the high potency and short range of alpha-particles, radiopharmaceutical therapy with alpha-particle emitting radionuclides is a promising treatment approach that is under active pre-clinical and clinical investigation. To understand and predict the biological effects of alpha-particle radiopharmaceuticals, dosimetry is required at the micro or multi-cellular scale level. At such a scale, highly non-uniform irradiation of the target volume may be expected and the utility of a single absorbed dose value to predict biological effects comes into question. It is not currently possible to measure the pharmacokinetic input required for micro scale dosimetry in humans. Accordingly, pre-clinical studies are required to provide the pharmacokinetic data for dosimetry calculations. The translation of animal data to the human requires a pharmacokinetic model that links macro- and micro-scale pharmacokinetics thereby enabling the extrapolation of micro-scale kinetics from macroscopic measurements. These considerations along with a discussion of the appropriate physical quantity and related units for alpha-particle radiopharmaceutical therapy are examined in this review. PMID:22201712

delta 9-(16 alpha-/sup 125/I)iodo-19-nortestosterone: a gamma-emitting photoaffinity label for the progesterone receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lamb, D.J.; Bullock, D.W.; Hoyte, R.M.

1988-05-01

We have synthesized 16 alpha-iodo-4,9-estradien-17 beta-ol-3-one (delta 9-16 alpha-iodo-19-nortestosterone (delta 9-INT)) labeled with 125I (delta 9-(16 alpha-125I)INT) to provide a new gamma-emitting photoaffinity ligand for the progesterone receptor that has many advantages over the currently available (3H)R5020. We have characterized the interaction of delta 9-(16 alpha-125I)INT with the rabbit uterine progesterone receptor and have demonstrated the usefulness of this compound for studies of receptor structure. The binding of 2 nM (3H)progesterone to receptor in rabbit uterine cytosol was specifically competed for by 19-nortestosterone, 16 alpha-iodo-19-nortestosterone, and delta 9-INT. Scatchard analysis demonstrated that delta 9-(16 alpha-125I)INT and (3H)progesterone estimated the samemore » number of binding sites in rabbit uterine cytosol, with a Kd for delta 9-(16 alpha-125I)INT of about 2.7 nM. The binding of delta 9-(16 alpha-125I)INT was inhibited by both progesterone and R5020, whereas testosterone, estradiol, and 5 alpha-dihydrotestosterone were ineffective. In cytosol, delta 9-(16 alpha-125I)INT covalently labeled the same mol wt receptor forms as (3H)R5020. Although the efficiency of cross-linking was similar for (3H)R5020 (3%) and delta 9-(16 alpha-125I)INT (4%), the radioactivity was 10-fold greater due to the higher specific activity of delta 9-(16 alpha-125I)INT and the lack of sample quench. The use of delta 9-(16 alpha-125I)INT greatly increases the sensitivity and efficiency of the photoaffinity labeling technique; it will provide a valuable tool for further studies of the progesterone receptor, allowing the detection of receptor in dilute cytosol after gel electrophoresis under denaturing conditions.« less

In vitro cell irradiation systems based on 210Po alpha source: construction and characterisation

NASA Technical Reports Server (NTRS)

Szabo, J.; Feher, I.; Palfalvi, J.; Balashazy, I.; Dam, A. M.; Polonyi, I.; Bogdandi, E. N.

2002-01-01

One way of studying the risk to human health of low-level radiation exposure is to make biological experiments on living cell cultures. Two 210Po alpha-particle emitting devices, with 0.5 and 100 MBq activity, were designed and constructed to perform such experiments irradiating monolayers of cells. Estimates of dose rate at the cell surface were obtained from measurements by a PIPS alpha-particle spectrometer and from calculations by the SRIM 2000, Monte Carlo charged particle transport code. Particle fluence area distributions were measured by solid state nuclear track detectors. The design and dosimetric characterisation of the devices are discussed. c2002 Elsevier Science Ltd. All rights reserved.

Lyman alpha radiation in external galaxies

NASA Technical Reports Server (NTRS)

Neufeld, David A.; Mckee, Christopher F.

1990-01-01

The Ly alpha line of atomic hydrogen is often a luminous component of the radiation emitted by distant galaxies. Except for those galaxies which have a substantial central source of non-stellar ionizing radiation, most of the Ly alpha radiation emitted by galaxies is generated within regions of the interstellar medium which are photoionized by starlight. Conversely, much of the energy radiated by photoionized regions is carried by the Ly alpha line. Only hot, massive stars are capable of ionizing hydrogen in the interstellar medium which surrounds them, and because such stars are necessarily short-lived, Ly alpha emission traces regions of active star formation. Researchers argue that the strength of the Ly alpha emission observed from external galaxies may be used to estimate quantitatively the dust content of the emitting region, while the Ly alpha line profile is sensitive to the presence of shock waves. Interstellar dust particles and shock waves are intimately associated with the process of star formation in two senses. First, both dust particles and shock waves owe their existence to stellar activity; second, they may both serve as agents which facilitate the formation of stars, shocks by triggering gravitational instabilities in the interstellar gas that they compress, and dust by shielding star-forming molecular clouds from the ionizing and dissociative effects of external UV radiation. By using Ly alpha observations as a probe of the dust content in diffuse gas at high redshift, we might hope to learn about the earliest epochs of star formation.

The BetaCage: Ultrasensitive Screener for Radioactive Backgrounds

NASA Astrophysics Data System (ADS)

Thompson, Michael; BetaCage Collaboration

2017-09-01

Rare event searches, such as dark matter detection and neutrinoless double beta decay, require screening of materials for backgrounds such as beta emission and alpha decaying isotopes. The BetaCage is a proposed ultra-sensitive time-projection chamber to screen for alpha-emitting and low energy beta-emitting (10-200 keV) contaminants. The expected sensitivity is 0.1 beta particles (perkeV -m2 - day) and 0.1 alpha particles (perm2 - day) , where the former will be limited by Compton scattering of external photons in the screening samples and the latter is expected to be signal-limited. The prototype BetaCage under commissioning at South Dakota School of Mines & Technology is filled with P10 gas (10% methane, 90% argon) in place of neon and is 40×40×20 cm in size. Details on design, construction and characterization will be presented.

Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET) Radiation Originating from 177Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts

PubMed Central

Yong, Kwon Joong; Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.

2016-01-01

Radiolabeled antibodies (mAbs) provide efficient tools for cancer therapy. The combination of low energy β−-emissions (500 keVmax; 130 keVave) along with a γ-emission for imaging makes 177Lu (T1/2 = 6.7 day) a suitable radionuclide for radioimmunotherapy (RIT) of tumor burdens possibly too large to treat with α-particle radiation. RIT with 177Lu-trastuzumab has proven to be effective for treatment of disseminated HER2 positive peritoneal disease in a pre-clinical model. To elucidate mechanisms originating from this RIT therapy at the molecular level, tumor bearing mice (LS-174T intraperitoneal xenografts) were treated with 177Lu-trastuzumab comparatively to animals treated with a non-specific control, 177Lu-HuIgG, and then to prior published results obtained using 212Pb-trastuzumab, an α-particle RIT agent. 177Lu-trastuzumab induced cell death via DNA double strand breaks (DSB), caspase-3 apoptosis, and interfered with DNA-PK expression, which is associated with the repair of DNA non-homologous end joining damage. This contrasts to prior results, wherein 212Pb-trastuzumab was found to down-regulate RAD51, which is involved with homologous recombination DNA damage repair. 177Lu-trastuzumab therapy was associated with significant chromosomal disruption and up-regulation of genes in the apoptotic process. These results suggest an inhibition of the repair mechanism specific to the type of radiation damage being inflicted by either high or low linear energy transfer radiation. Understanding the mechanisms of action of β−- and α-particle RIT comparatively through an in vivo tumor environment offers real information suitable to enhance combination therapy regimens involving α- and β−-particle RIT for the management of intraperitoneal disease. PMID:27196891

Production of [211At]-Astatinated Radiopharmaceuticals and Applications in Targeted α-Particle Therapy

PubMed Central

Guérard, François; Gestin, Jean-François

2013-01-01

Abstract 211At is a promising radionuclide for α-particle therapy of cancers. Its physical characteristics make this radionuclide particularly interesting to consider when bound to cancer-targeting biomolecules for the treatment of microscopic tumors. 211At is produced by cyclotron irradiation of 209Bi with α-particles accelerated at ∼28 MeV and can be obtained in high radionuclidic purity after isolation from the target. Its chemistry resembles iodine, but there is also a tendency to behave as a metalloid. However, the chemical behavior of astatine has not yet been clearly established, primarily due to the lack of any stable isotopes of this element, which precludes the use of conventional analytical techniques for its characterization. There are also only a limited number of research centers that have been able to produce this element in sufficient amounts to carry out extensive investigations. Despite these difficulties, chemical reactions typically used with iodine can be performed, and a number of biomolecules of interest have been labeled with 211At. However, most of these compounds exhibit unacceptable instability in vivo due to the weakness of the astatine–biomolecule bond. Nonetheless, several compounds have shown high potential for the treatment of cancers in vitro and in several animal models, thus providing a promising basis that has allowed initiation of the first two clinical studies. PMID:23075373

Dynamic radioactive particle source

DOEpatents

Moore, Murray E; Gauss, Adam Benjamin; Justus, Alan Lawrence

2012-06-26

A method and apparatus for providing a timed, synchronized dynamic alpha or beta particle source for testing the response of continuous air monitors (CAMs) for airborne alpha or beta emitters is provided. The method includes providing a radioactive source; placing the radioactive source inside the detection volume of a CAM; and introducing an alpha or beta-emitting isotope while the CAM is in a normal functioning mode.

Nanozeolite bioconjugates labeled with 223Ra for targeted alpha therapy.

PubMed

Piotrowska, Agata; Męczyńska-Wielgosz, Sylwia; Majkowska-Pilip, Agnieszka; Koźmiński, Przemysław; Wójciuk, Grzegorz; Cędrowska, Edyta; Bruchertseifer, Frank; Morgenstern, Alfred; Kruszewski, Marcin; Bilewicz, Aleksander

2017-04-01

Alpha particle emitting isotopes are of considerable interest for radionuclide therapy because of their high cytotoxicity and short path length. Among the many α emitters, 223 Ra exhibits very attractive nuclear properties for application in radionuclide therapy. The decay of this radioisotope and its daughters is accompanied by the emission of four α-particles, releasing 27.9MeV of cumulative energy. Unfortunately the lack of an appropriate bifunctional ligand for radium has so far been a main obstacle for the application of 223 Ra in receptor targeted therapy. In our studies we investigated the use of nanozeolite-Substance P bioconjugates as vehicles for 223 Ra radionuclides for targeted α therapy. The sodium form of an A-type of nanozeolite (NaA) was synthesized using the template method. Next, the nanozeolite particles were conjugated to the Substance P (5-11) peptide fragment, which targets NK-1 receptors on glioma cells. The obtained bioconjugate was characterized by transmission emission spectroscopy, thermogravimetric analysis and dynamic light scattering analysis. The NaA-silane-PEG-SP(5-11) bioconjugates were labeled with 223 Ra by exchange of the Na + cation and the stability, receptor affinity and cytotoxicity of the obtained radiobioconjugates were tested. The 223 Ra-labeled nanozeolite bioconjugate almost quantitatively retains 223 Ra in vitro after 6days, while the retention of decay products varies from 90 to 95%. The synthesized 223 RaA-silane-PEG-SP(5-11) showed high receptor affinity toward NK-1 receptor expressing glioma cells and exhibited a high cytotoxic effect in vitro. Substance P functionalized nanozeolite-A represents a viable solution for the use of the 223 Ra in vivo generator as a therapeutic construct for targeting glioma cells. Copyright © 2016 Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adelstein, S.J.; Kassis, A.I.

This report describes many factors that need to be considered if radioimmunotherapy is to become a commonplace reality. For beta-emitting radionuclides, two physical features of importance are half-life and energy, with the latter determining the range. These features must be matched to the pharmacokinetics of the carrier and the distribution of the radionuclide, both macroscopically and microscopically. Alpha-particle emitters could be considered for cells that are readily accessible to the labeled antibody and for populations that uniformly and constantly display the targeted antigen or idiotype, e.g., trafficking cells such as T or B lymphocytes. For cells that concentrate the radioactivemore » label, the use of low-energy electrons should be examined. If the radionuclide is translocated to the nucleus, the Auger effect can be particularly lethal because of the high LET-like biological response. 15 refs., 3 figs., 2 tabs.« less

64Cu-Labeled Trastuzumab Fab-PEG24-EGF Radioimmunoconjugates Bispecific for HER2 and EGFR: Pharmacokinetics, Biodistribution, and Tumor Imaging by PET in Comparison to Monospecific Agents.

PubMed

Kwon, Luke Yongkyu; Scollard, Deborah A; Reilly, Raymond M

2017-02-06

Heterodimerization of EGFR with HER2 coexpressed in breast cancer (BC) promotes tumor growth, and increased EGFR expression is associated with trastuzumab resistance. Our aim was to construct 64 Cu-labeled bispecific radioimmunoconjugates (bsRIC) composed of trastuzumab Fab, which binds HER2 linked through a polyethylene glycol (PEG 24 ) spacer to EGF, and to compare their pharmacokinetic, biodistribution, and tumor imaging characteristics by positron-emission tomography (PET). bsRICs were generated by linking maleimide modified trastuzumab Fab with thiolated EGF through a thioether bond. HER2 and EGFR binding were assessed in vitro in MDA-MB-231 (EGFR mod /HER2 low ), MDA-MB-468 (EGFR high /HER2 neg ), MDA-MB-231-H2N (EGFR mod /HER2 mod ), and SKOV3 (EGFR low /HER2 high ) cells by competition and saturation cell binding assays to estimate the dissociation constant (K d ). The elimination of the 64 Cu-NOTA-trastuzumab Fab-PEG 24 -EGF bsRICs from the blood of Balb/c mice was compared to monospecific 64 Cu-NOTA-trastuzumab Fab and 64 Cu-NOTA-EGF. MicroPET/CT imaging was performed in NOD/SCID mice bearing subcutaneous MDA-MB-468, MDA-MB-231/H2N, or SKOV3 human BC xenografts at 24 and 48 h postinjection (p.i.) of bsRICs. Tumor and normal tissue uptake were quantified by biodistribution studies and compared to monospecific agents. The binding of bsRICs to MDA-MB-231 cells was decreased to 24.5 ± 5.2% by excess EGF, while the binding of bsRICs to SKOV3 cells was decreased to 38.6 ± 5.4% by excess trastuzumab Fab, demonstrating specific binding to both EGFR and HER2. 64 Cu-labeled bsRICs incorporating the PEG 24 spacer were eliminated more slowly from the blood than 64 Cu-bsRICs without the PEG spacer and were cleared much more slowly than 64 Cu-NOTA-Fab or 64 Cu-NOTA-EGF. All three tumor xenografts were visualized by microPET/CT at 24 and 48 h p.i. of bsRICs. Biodistribution studies at 48 h p.i. in NOD/SCID mice with MDA-MB-231/H2N tumors demonstrated significantly greater tumor uptake of 64 Cu-NOTA-Fab-PEG 24 -EGF (4.9 ± 0.4%ID/g) than 64 Cu-NOTA-Fab (1.9 ± 0.3%ID/g; P < 0.0001) and 64 Cu-NOTA-EGF (0.7 ± 0.2%ID/g; P < 0.0001). Furthermore, preadministration of an excess of trastuzumab Fab or trastuzumab Fab-PEG 24 -EGF significantly decreased the tumor uptake of 64 Cu-NOTA-Fab-PEG 24 -EGF in SK-OV-3 and MDA-MB-468 xenografts by 4.4-fold (P = 0.0012) and 1.8-fold (P = 0.0031), respectively. 64 Cu-labeled bsRICs bound HER2 or EGFR and were taken up specifically in vivo in tumor xenografts expressing one or both receptors. The PEG 24 linker prolonged the blood residence time contributing to the higher tumor uptake of the bsRICs than monospecific agents.

Multidetector system for nanosecond tagged neutron technology based on hardware selection of events

NASA Astrophysics Data System (ADS)

Karetnikov, M. D.; Korotkov, S. A.; Khasaev, T. O.

2016-09-01

At the T( d, n)He4 reaction a neutron is accompanied by an associated alpha-particle emitted in the opposite direction. A time and a direction of the neutron escape can be determined by measuring a time and coordinates of the alpha particle at the position-sensitive alpha-detector. The nanosecond tagged neutron technology (NTNT) based on this principle has great potentialities for various applications, e.g., for remote detection of explosives. A spectrum of gamma-rays emitted at the interaction of tagged neutrons with nuclei of chemical elements allows identify a chemical composition of an irradiated object. For practical realization of NTNT, a time resolution of recording the alpha-gamma coincidences should be close to 1 ns. The total intensity of signals can exceed 1 × 106 1/s from all gamma-detectors and 7 × 106 1/s from the alpha-detector. The processing of such stream of data without losses and distortion of information is one of challenging problems of NTNT. Several models of analog DAQ system based on hardware selection of events were devised and their characteristics are examined. The comparison with the digital DAQ systems demonstrated that the analog DAQ provides better timing parameters, lower power consumption, and higher maximum rate of useful events.

Inclusive and exclusive measurements of alpha particle production mechanisms in the 7Li + 144Sm system

NASA Astrophysics Data System (ADS)

Carnelli, P. F. F.; Martinez Heimann, D.; Pacheco, A. J.; Arazi, A.; Capurro, O. A.; Fernández Niello, J. O.; Cardona, M. A.; de Barbará, E.; Figueira, J. M.; Hojman, D. L.; Martí, G. V.; Negri, A. E.

2018-01-01

In this work we have studied the production of alpha particles emitted as a consequence of different reactions in the 7Li + 144Sm system at near-barrier energies. We have obtained absolute cross sections of the total yield at backward angles and at bombarding energies of 24 and 30 MeV. We have also performed complementary exclusive measurements of non-capture breakup processes at 30 MeV. In particular, the neutron transfer followed by non-capture breakup of the 6Li ejectile, which was found to be the dominant process in the studied region, could be accounted for by estimations of a classical dynamical model. This contribution, together with estimations for the incomplete fusion and alpha particle evaporation following compound-nucleus formation, are compared to the experimental inclusive angular distributions obtained in this work.

Derivation of Soil Screening Guidelines for Gross Alpha/Beta Radioactivity for United States Air Force Deployment Sites

DTIC Science & Technology

2007-04-19

These levels are provided to assist in making decisions in case of a large accident. Assessment can be made based on what health effects can be...a beta particle to become polonium -214 (99.98% of decays), or it can emit an alpha particle to become thallium- 210 (0.02% of decays). Bismuth-214...lead- 210 , and polonium - 210 . A decay of bismuth-214 will eventually yield 5 alpha particles and 4 beta particles. Four radionuclides that occur in

Development of a transmission alpha particle dosimetry technique using A549 cells and a Ra-223 source for targeted alpha therapy.

PubMed

Al Darwish, R; Staudacher, A H; Li, Y; Brown, M P; Bezak, E

2016-11-01

In targeted radionuclide therapy, regional tumors are targeted with radionuclides delivering therapeutic radiation doses. Targeted alpha therapy (TAT) is of particular interest due to its ability to deliver alpha particles of high linear energy transfer within the confines of the tumor. However, there is a lack of data related to alpha particle distribution in TAT. These data are required to more accurately estimate the absorbed dose on a cellular level. As a result, there is a need for a dosimeter that can estimate, or better yet determine the absorbed dose deposited by alpha particles in cells. In this study, as an initial step, the authors present a transmission dosimetry design for alpha particles using A549 lung carcinoma cells, an external alpha particle emitting source (radium 223; Ra-223) and a Timepix pixelated semiconductor detector. The dose delivery to the A549 lung carcinoma cell line from a Ra-223 source, considered to be an attractive radionuclide for alpha therapy, was investigated in the current work. A549 cells were either unirradiated (control) or irradiated for 12, 1, 2, or 3 h with alpha particles emitted from a Ra-223 source positioned below a monolayer of A549 cells. The Timepix detector was used to determine the number of transmitted alpha particles passing through the A549 cells and DNA double strand breaks (DSBs) in the form of γ-H2AX foci were examined by fluorescence microscopy. The number of transmitted alpha particles was correlated with the observed DNA DSBs and the delivered radiation dose was estimated. Additionally, the dose deposited was calculated using Monte Carlo code SRIM. Approximately 20% of alpha particles were transmitted and detected by Timepix. The frequency and number of γ-H2AX foci increased significantly following alpha particle irradiation as compared to unirradiated controls. The equivalent dose delivered to A549 cells was estimated to be approximately 0.66, 1.32, 2.53, and 3.96 Gy after 12, 1, 2, and 3 h irradiation, respectively, considering a relative biological effectiveness of alpha particles of 5.5. The study confirmed that the Timepix detector can be used for transmission alpha particle dosimetry. If cross-calibrated using biological dosimetry, this method will give a good indication of the biological effects of alpha particles without the need for repeated biological dosimetry which is costly, time consuming, and not readily available.

Phase 1B/2 study of the HSP90 inhibitor AUY922 plus trastuzumab in metastatic HER2-positive breast cancer patients who have progressed on trastuzumab-based regimen.

PubMed

Kong, Anthony; Rea, Daniel; Ahmed, Samreen; Beck, J Thaddeus; López López, Rafael; Biganzoli, Laura; Armstrong, Anne C; Aglietta, Massimo; Alba, Emilio; Campone, Mario; Hsu Schmitz, Shu-Fang; Lefebvre, Caroline; Akimov, Mikhail; Lee, Soo-Chin

2016-06-21

This open-label, multicenter, phase 1B/2 trial assessed AUY922 plus trastuzumab in patients with locally advanced or metastatic HER2-positive breast cancer previously treated with chemotherapy and anti-HER2 therapy. This study was composed of a dose-escalation part with AUY922 administered weekly at escalating doses with trastuzumab 2 mg/kg/week (phase 1B), followed by a phase 2 part using the same regimen at recommended phase 2 dose (RP2D). The primary objectives were to determine the maximum tolerated dose (MTD) and/or RP2D (phase 1B), and to evaluate preliminary antitumor activity (phase 2) of AUY922 plus trastuzumab at MTD/RP2D. Forty-five patients were treated with AUY922 plus trastuzumab (4 in phase 1B with AUY922 at 55 mg/m2 and 41 in phase 1B/2 with AUY922 at 70 mg/m2 [7 in phase 1B and 34 in phase 2]). One patient in phase 1B (70 mg/m2) experienced a dose-limiting toxicity (grade 3 diarrhea); the RP2D was weekly AUY922 70 mg/m2 plus trastuzumab. Of the 41 patients in the 70 mg/m2 cohort, the overall response rate (complete or partial responses) was 22.0% and 48.8% patients had stable disease. Study treatment-related adverse events occurred in 97.8% of patients; of these, 31.1% were grade 3 or 4. Forty-one patients (91.1%) reported ocular events (82.3% had grade 1 or 2 events). Two patients (4.4%) had ocular events leading to the permanent discontinuation of study treatment. AUY922 at 70 mg/m2 plus trastuzumab standard therapy is well tolerated and active in patients with HER2-positive metastatic breast cancer who progressed on trastuzumab-based therapy.

A comparison of 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT.

PubMed

Chan, Conrad; Scollard, Deborah A; McLarty, Kristin; Smith, Serena; Reilly, Raymond M

2011-08-17

Our objective was to compare 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging small or large s.c. tumor xenografts in athymic mice that display a wide range of human epidermal growth factor receptor-2 (HER2) expression using microSPECT/CT or microPET/CT. Trastuzumab Fab were labeled with 111In or 64Cu by conjugation to 1,4,7,10-tetraazacyclododecane N, N', N'', N'''-tetraacetic acid (DOTA). The purity of 111In- and 64Cu-DOTA-trastuzumab Fab was measured by SDS-PAGE and HPLC. HER2 binding affinity was determined in saturation radioligand binding assays using SKBR-3 cells (1.3 × 106 HER2/cell). MicroSPECT/CT and microPET/CT were performed in athymic mice bearing s.c. BT-20 and MDA-MB-231 xenografts with low (0.5 to 1.6 × 105 receptors/cell), MDA-MB-361 tumors with intermediate (5.1 × 105 receptors/cell) or SKOV-3 xenografts with high HER2 expression (1.2 × 106 receptors/cell) at 24 h p.i. of 70 MBq (10 μg) of 111In-DOTA-trastuzumab Fab or 22 MBq (10 μg) of 64Cu-DOTA-trastuzumab Fab or irrelevant 111In- or 64Cu-DOTA-rituximab Fab. Tumor and normal tissue uptake were quantified in biodistribution studies. 111In- and 64Cu-DOTA-trastuzumab were > 98% radiochemically pure and bound HER2 with high affinity (Kd = 20.4 ± 2.5 nM and 40.8 ± 3.5 nM, respectively). MDA-MB-361 and SKOV-3 tumors were most clearly imaged using 111In- and 64Cu-DOTA-trastuzumab Fab. Significantly higher tumor/blood (T/B) ratios were found for 111In-DOTA-trastuzumab Fab than 111In-DOTA-rituximab Fab for BT-20, MDA-MB-231 and MDA-MB-361 xenografts, and there was a direct association between T/B ratios and HER2 expression. In contrast, tumor uptake of 64Cu-DOTA-trastuzumab Fab was significantly higher than 64Cu-DOTA-rituximab Fab in MDA-MB-361 tumors but no direct association with HER2 expression was found. Both 111In- and 64Cu-DOTA-trastuzumab Fab imaged small (5 to 10 mm) or larger (10 to 15 mm) MDA-MB-361 tumors. Higher blood, liver, and spleen radioactivity were observed for 64Cu-DOTA-trastuzumab Fab than 111In-DOTA-trastuzumab Fab. We conclude that 111In-DOTA-trastuzumab Fab was more specific than 64Cu-DOTA-trastuzumab Fab for imaging HER2-positive tumors, especially those with low receptor density. This was due to higher levels of circulating radioactivity for 64Cu-DOTA-trastuzumab Fab which disrupted the relationship between HER2 density and T/B ratios. Use of alternative chelators that more stably bind 64Cu may improve the association between T/B ratios and HER2 density for 64Cu-labeled trastuzumab Fab.

A comparison of 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT

PubMed Central

2011-01-01

Background Our objective was to compare 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging small or large s.c. tumor xenografts in athymic mice that display a wide range of human epidermal growth factor receptor-2 (HER2) expression using microSPECT/CT or microPET/CT. Methods Trastuzumab Fab were labeled with 111In or 64Cu by conjugation to 1,4,7,10-tetraazacyclododecane N, N', N'', N'''-tetraacetic acid (DOTA). The purity of 111In- and 64Cu-DOTA-trastuzumab Fab was measured by SDS-PAGE and HPLC. HER2 binding affinity was determined in saturation radioligand binding assays using SKBR-3 cells (1.3 × 106 HER2/cell). MicroSPECT/CT and microPET/CT were performed in athymic mice bearing s.c. BT-20 and MDA-MB-231 xenografts with low (0.5 to 1.6 × 105 receptors/cell), MDA-MB-361 tumors with intermediate (5.1 × 105 receptors/cell) or SKOV-3 xenografts with high HER2 expression (1.2 × 106 receptors/cell) at 24 h p.i. of 70 MBq (10 μg) of 111In-DOTA-trastuzumab Fab or 22 MBq (10 μg) of 64Cu-DOTA-trastuzumab Fab or irrelevant 111In- or 64Cu-DOTA-rituximab Fab. Tumor and normal tissue uptake were quantified in biodistribution studies. Results 111In- and 64Cu-DOTA-trastuzumab were > 98% radiochemically pure and bound HER2 with high affinity (Kd = 20.4 ± 2.5 nM and 40.8 ± 3.5 nM, respectively). MDA-MB-361 and SKOV-3 tumors were most clearly imaged using 111In- and 64Cu-DOTA-trastuzumab Fab. Significantly higher tumor/blood (T/B) ratios were found for 111In-DOTA-trastuzumab Fab than 111In-DOTA-rituximab Fab for BT-20, MDA-MB-231 and MDA-MB-361 xenografts, and there was a direct association between T/B ratios and HER2 expression. In contrast, tumor uptake of 64Cu-DOTA-trastuzumab Fab was significantly higher than 64Cu-DOTA-rituximab Fab in MDA-MB-361 tumors but no direct association with HER2 expression was found. Both 111In- and 64Cu-DOTA-trastuzumab Fab imaged small (5 to 10 mm) or larger (10 to 15 mm) MDA-MB-361 tumors. Higher blood, liver, and spleen radioactivity were observed for 64Cu-DOTA-trastuzumab Fab than 111In-DOTA-trastuzumab Fab. Conclusions We conclude that 111In-DOTA-trastuzumab Fab was more specific than 64Cu-DOTA-trastuzumab Fab for imaging HER2-positive tumors, especially those with low receptor density. This was due to higher levels of circulating radioactivity for 64Cu-DOTA-trastuzumab Fab which disrupted the relationship between HER2 density and T/B ratios. Use of alternative chelators that more stably bind 64Cu may improve the association between T/B ratios and HER2 density for 64Cu-labeled trastuzumab Fab. PMID:22214307

Charged-particle emission tomography

NASA Astrophysics Data System (ADS)

Ding, Yijun

Conventional charged-particle imaging techniques--such as autoradiography-- provide only two-dimensional (2D) images of thin tissue slices. To get volumetric information, images of multiple thin slices are stacked. This process is time consuming and prone to distortions, as registration of 2D images is required. We propose a direct three-dimensional (3D) autoradiography technique, which we call charged-particle emission tomography (CPET). This 3D imaging technique enables imaging of thick sections, thus increasing laboratory throughput and eliminating distortions due to registration. In CPET, molecules or cells of interest are labeled so that they emit charged particles without significant alteration of their biological function. Therefore, by imaging the source of the charged particles, one can gain information about the distribution of the molecules or cells of interest. Two special case of CPET include beta emission tomography (BET) and alpha emission tomography (alphaET), where the charged particles employed are fast electrons and alpha particles, respectively. A crucial component of CPET is the charged-particle detector. Conventional charged-particle detectors are sensitive only to the 2-D positions of the detected particles. We propose a new detector concept, which we call particle-processing detector (PPD). A PPD measures attributes of each detected particle, including location, direction of propagation, and/or the energy deposited in the detector. Reconstruction algorithms for CPET are developed, and reconstruction results from simulated data are presented for both BET and alphaET. The results show that, in addition to position, direction and energy provide valuable information for 3D reconstruction of CPET. Several designs of particle-processing detectors are described. Experimental results for one detector are discussed. With appropriate detector design and careful data analysis, it is possible to measure direction and energy, as well as position of each detected particle. The null functions of CPET with PPDs that measure different combinations of attributes are calculated through singular-value decomposition. In general, the more particle attributes are measured from each detection event, the smaller the null space of CPET is. In other words, the higher dimension the data space is, the more information about an object can be recovered from CPET.

Effects of alpha-particles on survival and chromosomal aberrations in human mammary epithelial cells

NASA Technical Reports Server (NTRS)

Durante, M.; Grossi, G. F.; Gialanella, G.; Pugliese, M.; Nappo, M.; Yang, T. C.

1995-01-01

We have studied the radiation responses of a human mammary epithelial cell line, H184B5 F5-1 M/10. This cell line was derived from primary mammary cells after treatment with chemicals and heavy ions. The F5-1 M/10 cells are immortal, density-inhibited in growth, and non-tumorigenic in athymic nude mice and represent an in vitro model of the human epithelium for radiation studies. Because epithelial cells are the target of alpha-particles emitted from radon daughters, we concentrated our studies on the efficiency of alpha-particles. Confluent cultures of M/10 cells were exposed to accelerated alpha-particles [beam energy incident at the cell monolayer = 3.85 MeV, incident linear energy transfer (LET) in cell = 109 keV/microns] and, for comparison, to 80 kVp x-rays. The following endpoints were studied: (1) survival, (2) chromosome aberrations at the first postirradiation mitosis, and (3) chromosome alterations at later passages following irradiation. The survival curve was exponential for alpha-particles (D0 = 0.73 +/- 0.04 Gy), while a shoulder was observed for x-rays (alpha/beta = 2.9 Gy; D0 = 2.5 Gy, extrapolation number 1.6). The relative biological effectiveness (RBE) of high-LET alpha-particles for human epithelial cell killing was 3.3 at 37% survival. Dose-response curves for the induction of chromosome aberrations were linear for alpha-particles and linearquadratic for x-rays. The RBE for the induction of chromosome aberrations varied with the type of aberration scored and was high (about 5) for chromosome breaks and low (about 2) for chromosome exchanges.(ABSTRACT TRUNCATED AT 250 WORDS).

Effects of alpha-particles on survival and chromosomal aberrations in human mammary epithelial cells.

PubMed

Durante, M; Grossi, G F; Gialanella, G; Pugliese, M; Nappo, M; Yang, T C

1995-08-01

We have studied the radiation responses of a human mammary epithelial cell line, H184B5 F5-1 M/10. This cell line was derived from primary mammary cells after treatment with chemicals and heavy ions. The F5-1 M/10 cells are immortal, density-inhibited in growth, and non-tumorigenic in athymic nude mice and represent an in vitro model of the human epithelium for radiation studies. Because epithelial cells are the target of alpha-particles emitted from radon daughters, we concentrated our studies on the efficiency of alpha-particles. Confluent cultures of M/10 cells were exposed to accelerated alpha-particles [beam energy incident at the cell monolayer = 3.85 MeV, incident linear energy transfer (LET) in cell = 109 keV/microns] and, for comparison, to 80 kVp x-rays. The following endpoints were studied: (1) survival, (2) chromosome aberrations at the first postirradiation mitosis, and (3) chromosome alterations at later passages following irradiation. The survival curve was exponential for alpha-particles (D0 = 0.73 +/- 0.04 Gy), while a shoulder was observed for x-rays (alpha/beta = 2.9 Gy; D0 = 2.5 Gy, extrapolation number 1.6). The relative biological effectiveness (RBE) of high-LET alpha-particles for human epithelial cell killing was 3.3 at 37% survival. Dose-response curves for the induction of chromosome aberrations were linear for alpha-particles and linearquadratic for x-rays. The RBE for the induction of chromosome aberrations varied with the type of aberration scored and was high (about 5) for chromosome breaks and low (about 2) for chromosome exchanges.(ABSTRACT TRUNCATED AT 250 WORDS)

[The application of Doppler broadening and Doppler shift to spectral analysis].

PubMed

Xu, Wei; Fang, Zi-shen

2002-08-01

The distinction between Doppler broadening and Doppler shift has analyzed, Doppler broadening locally results from the distribution of velocities of the emitting particles, the line width gives the information on temperature of emitting particles. Doppler shift results when the emitting particles have a bulk non random flow velocity in a particular direction, the drift of central wavelength gives the information on flow velocity of emitting particles, and the Doppler shift only drifts the profile of line without changing the width. The difference between Gaussian fitting and the distribution of chord-integral line shape have also been discussed. The distribution of H alpha spectral line shape has been derived from the surface of limiter in HT-6M Tokamak with optical spectroscope multichannel analysis (OSMA), the result by double Gaussian fitting shows that the line shape make up of two port, the emitting of reflect particles with higher energy and the release particle from the limiter surface. Ion temperature and recycling particle flow velocity have been obtained from Doppler broadening and Doppler shift.

Durable donor engraftment after radioimmunotherapy using α-emitter astatine-211–labeled anti-CD45 antibody for conditioning in allogeneic hematopoietic cell transplantation

PubMed Central

Chen, Yun; Kornblit, Brian; Hamlin, Donald K.; Sale, George E.; Santos, Erlinda B.; Wilbur, D. Scott; Storer, Barry E.; Storb, Rainer

2012-01-01

To reduce toxicity associated with external γ-beam radiation, we investigated radioimmunotherapy with an anti-CD45 mAb labeled with the α-emitter, astatine-211 (211At), as a conditioning regimen in dog leukocyte antigen-identical hematopoietic cell transplantation (HCT). Dose-finding studies in 6 dogs treated with 100 to 618 μCi/kg 211At-labeled anti-CD45 mAb (0.5 mg/kg) without HCT rescue demonstrated dose-dependent myelosuppression with subsequent autologous recovery, and transient liver toxicity in dogs treated with 211At doses less than or equal to 405 μCi/kg. Higher doses of 211At induced clinical liver failure. Subsequently, 8 dogs were conditioned with 155 to 625 μCi/kg 211At-labeled anti-CD45 mAb (0.5 mg/kg) before HCT with dog leukocyte antigen-identical bone marrow followed by a short course of cyclosporine and mycophenolate mofetil immunosuppression. Neutropenia (1-146 cells/μL), lymphopenia (0-270 cells/μL), and thrombocytopenia (1500-6560 platelets/μL) with prompt recovery was observed. Seven dogs had long-term donor mononuclear cell chimerism (19%-58%), whereas 1 dog treated with the lowest 211At dose (155 μCi/kg) had low donor mononuclear cell chimerism (5%). At the end of follow-up (18-53 weeks), only transient liver toxicity and no renal toxicity had been observed. In conclusion, conditioning with 211At-labeled anti-CD45 mAb is safe and efficacious and provides a platform for future clinical trials of nonmyeloablative transplantation with radioimmunotherapy-based conditioning. PMID:22134165

Investigation of the Possibility of Using Nuclear Magnetic Spin Alignment

NASA Technical Reports Server (NTRS)

Dent, William V., Jr.

1998-01-01

The goal of the program to investigate a "Gasdynamic fusion propulsion system for space exploration" is to develop a fusion propulsion system for a manned mission to the planet mars. A study using Deuterium and Tritium atoms are currently in progress. When these atoms under-go fusion, the resulting neutrons and alpha particles are emitted in random directions (isotropically). The probable direction of emission is equal for all directions, thus resulting in wasted energy, massive shielding and cooling requirements, and serious problems with the physics of achieving fusion. If the nuclear magnetic spin moments of the deuterium and tritium nuclei could be precisely aligned at the moment of fusion, the stream of emitted neutrons could be directed out the rear of the spacecraft for thrust and the alpha particles directed forward into an electromagnet ot produce electricity to continue operating the fusion engine. The following supporting topics are discussed: nuclear magnetic moments and spin precession in magnetic field, nuclear spin quantum mechanics, kinematics of nuclear reactions, and angular distribution of particles.

Plutonium radiation surrogate

DOEpatents

Frank, Michael I [Dublin, CA

2010-02-02

A self-contained source of gamma-ray and neutron radiation suitable for use as a radiation surrogate for weapons-grade plutonium is described. The source generates a radiation spectrum similar to that of weapons-grade plutonium at 5% energy resolution between 59 and 2614 keV, but contains no special nuclear material and emits little .alpha.-particle radiation. The weapons-grade plutonium radiation surrogate also emits neutrons having fluxes commensurate with the gamma-radiation intensities employed.

Monte Carlo calculations of the cellular S-values for α-particle-emitting radionuclides incorporated into the nuclei of cancer cells of the MDA-MB231, MCF7 and PC3 lines.

PubMed

Rojas-Calderón, E L; Ávila, O; Ferro-Flores, G

2018-05-01

S-values (dose per unit of cumulated activity) for alpha particle-emitting radionuclides and monoenergetic alpha sources placed in the nuclei of three cancer cell models (MCF7, MDA-MB231 breast cancer cells and PC3 prostate cancer cells) were obtained by Monte Carlo simulation. The MCNPX code was used to calculate the fraction of energy deposited in the subcellular compartments due to the alpha sources in order to obtain the S-values. A comparison with internationally accepted S-values reported by the MIRD Cellular Committee for alpha sources in three sizes of spherical cells was also performed leading to an agreement within 4% when an alpha extended source uniformly distributed in the nucleus is simulated. This result allowed to apply the Monte Carlo Methodology to evaluate S-values for alpha particles in cancer cells. The calculation of S-values for nucleus, cytoplasm and membrane of cancer cells considering their particular geometry, distribution of the radionuclide source and chemical composition by means of Monte Carlo simulation provides a good approach for dosimetry assessment of alpha emitters inside cancer cells. Results from this work provide information and tools that may help researchers in the selection of appropriate radiopharmaceuticals in alpha-targeted cancer therapy and improve its dosimetry evaluation. Copyright © 2018 Elsevier Ltd. All rights reserved.

Fluorescence-Assisted Gamma Spectrometry for Surface Contamination Analysis

NASA Astrophysics Data System (ADS)

Ihantola, Sakari; Sand, Johan; Perajarvi, Kari; Toivonen, Juha; Toivonen, Harri

2013-02-01

A fluorescence-based alpha-gamma coincidence spectrometry approach has been developed for the analysis of alpha-emitting radionuclides. The thermalization of alpha particles in air produces UV light, which in turn can be detected over long distances. The simultaneous detection of UV and gamma photons allows detailed gamma analyses of a single spot of interest even in highly active surroundings. Alpha particles can also be detected indirectly from samples inside sealed plastic bags, which minimizes the risk of cross-contamination. The position-sensitive alpha-UV-gamma coincidence technique reveals the presence of alpha emitters and identifies the nuclides ten times faster than conventional gamma spectrometry.

Targeted radionuclide therapy with astatine-211: Oxidative dehalogenation of astatobenzoate conjugates.

PubMed

Teze, David; Sergentu, Dumitru-Claudiu; Kalichuk, Valentina; Barbet, Jacques; Deniaud, David; Galland, Nicolas; Maurice, Rémi; Montavon, Gilles

2017-05-31

211 At is a most promising radionuclide for targeted alpha therapy. However, its limited availability and poorly known basic chemistry hamper its use. Based on the analogy with iodine, labelling is performed via astatobenzoate conjugates, but in vivo deastatination occurs, particularly when the conjugates are internalized in cells. Actually, the chemical or biological mechanism responsible for deastatination is unknown. In this work, we show that the C-At "organometalloid" bond can be cleaved by oxidative dehalogenation induced by oxidants such as permanganates, peroxides or hydroxyl radicals. Quantum mechanical calculations demonstrate that astatobenzoates are more sensitive to oxidation than iodobenzoates, and the oxidative deastatination rate is estimated to be about 6 × 10 6 faster at 37 °C than the oxidative deiodination one. Therefore, we attribute the "internal" deastatination mechanism to oxidative dehalogenation in biological compartments, in particular lysosomes.

Utilization of the CS-30 cyclotron at the Duke University Medical Center

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wieland, B.W.; McKinney, C.J.; Dailey, M.F.

1994-12-31

Present routine radionuclide production includes {sup 18}F fluoride from protons on {sup 18}O water, {sup 13}N ammonia from protons on {sup 13}C slurry, {sup 15}O water from deuterons on nitrogen gas, and {sup 211}At from alphas on bismuth metal. Clinical PET using two tomographs (GE 4096 and Advance) is done Tuesday through Friday, typically 4 to 11 patients per day using {sup 15}O water, {sup 13}N ammonia, and {sup 18}F FDG synthesized with a GE Microlab. Clinical patient studies are 50% neurology using FDG, 45% body using FDG, and 5% cardiology using ammonia and FDG (oncology in these three areasmore » totals 60%). {sup 15}O water for clinical research patients (THC and cognitive) is produced twice a week. {sup 211}At is produced about twice a week for monoclonal antibody labelling.« less

Microdistribution of fluorescently-labeled monoclonal antibody in a peritoneal dissemination model of ovarian cancer

NASA Astrophysics Data System (ADS)

Kosaka, Nobuyuki; Ogawa, Mikako; Paik, David S.; Paik, Chang H.; Choyke, Peter L.; Kobayashi, Hisataka

2010-02-01

The microdistribution of therapeutic monoclonal antibodies within a tumor is important for determining clinical response. Nonuniform microdistribution predicts therapy failure. Herein, we developed a semiquantitative method for measuring microdistribution of an antibody within a tumor using in situ fluorescence microscopy and sought to modulate the microdistribution by altering the route and timing of antibody dosing. The microdistribution of a fluorescently-labeled antibody, trastuzumab (50-μg and 150-μg intraperitoneal injection (i.p.), and 100-μg intravenous injection (i.v.)) was evaluated in a peritoneal dissemination mouse model of ovarian cancer. In addition, we evaluated the microdistribution of concurrently-injected (30-μg i.p. and 100-μg i.v.) or serial (two doses of 30-μg i.p.) trastuzumab using in situ multicolor fluorescence microscopy. After the administration of 50-μg i.p. and 100-μg i.v. trastuzumab fluorescence imaging showed no significant difference in the central to peripheral signal ratio (C/P ratio) and demonstrated a peripheral-dominant accumulation, whereas administration of 150-μg i.p. trastuzumab showed relatively uniform, central dominant accumulation. With concurrent-i.p.-i.v. injections trastuzumab showed slightly higher C/P ratio than concurrently-injected i.p. trastuzumab. Moreover, in the serial injection study, the second injection of trastuzumab distributed more centrally than the first injection, while no difference was observed in the control group. Our results suggest that injection routes do not affect the microdistribution pattern of antibody in small peritoneal disseminations. However, increasing the dose results in a more uniform antibody distribution within peritoneal nodules. Furthermore, the serial i.p. injection of antibody can modify the microdistribution within tumor nodules. This work has implications for the optimal delivery of antibody based cancer therapies.

Functionalized NaA nanozeolites labeled with 224,225Ra for targeted alpha therapy.

PubMed

Piotrowska, Agata; Leszczuk, Edyta; Bruchertseifer, Frank; Morgenstern, Alfred; Bilewicz, Aleksander

2013-01-01

The 223 Ra, 224 Ra, and 225 Ra radioisotopes exhibit very attractive nuclear properties for application in radionuclide therapy. Unfortunately the lack of appropriate bifunctional ligand for radium is the reason why these radionuclides have not found application in receptor-targeted therapy. In the present work, the potential usefulness of the NaA nanozeolite as a carrier for radium radionuclides has been studied. 224 Ra and 225 Ra, α-particle emitting radionuclides, have been absorbed in the nanometer-sized NaA zeolite (30-70 nm) through simple ion exchange. 224,225 Ra-nanozeolites exhibited very high stability in solutions containing physiological salt, EDTA, amino acids, and human serum. To make NaA nanozeolite particles dispersed in water their surface was modified with a silane coupling agent containing poly(ethylene glycol) molecules. This functionalization approach let us covalently attach a biomolecule to the NaA nanozeolite surface.

Molecular radiotheragnostics in prostate cancer.

PubMed

Du, Yong; Dizdarevic, Sabina

2017-10-01

Two different molecular radio-theragnostic principles are applied in prostate cancer, providing a personalised management for those patients. Firstly, radiopharmaceuticals with the same or similar mechanism of action but different energy (gamma-γ, eg 99m Tc-diphosphonates or positron-β+, eg 18F-NaF emitting isotopes) can be used to identify patients with osteoblastic metastases for a treatment with bone seeking beta (β-) or alpha (α-) emitting radionuclides to deliver targeted molecular radiotherapy. A number of such β- emitting molecules have been used for bone palliation. More recently, an alpha emitting 223 Ra-dicholoride demonstrated not only symptomatic relief but also significantly improved overall survival in castration-resistant prostate cancer with predominant bone metastases. The second principle involves utilisation of the same prostatic specific membrane antigen (PSMA) or similar compound (eg PSMA-11, PSMA-617), but different label with either β+ ( 68 Ga) or γ ( 99m Tc) emitting radioisotope for imaging and subsequently β- ( 177 Lu) or α ( 225 Ac) emitting radionuclide for treatment. © Royal College of Physicians 2017. All rights reserved.

Induction of mutations by bismuth-212 alpha particles at two genetic loci in human B-lymphoblasts.

PubMed

Metting, N F; Palayoor, S T; Macklis, R M; Atcher, R W; Liber, H L; Little, J B

1992-12-01

The human lymphoblast cell line TK6 was exposed to the alpha-particle-emitting radon daughter 212Bi by adding DTPA-chelated 212Bi directly to the cell suspension. Cytotoxicity and mutagenicity at two genetic loci were measured, and the molecular nature of mutant clones was studied by Southern blot analysis. Induced mutant fractions were 2.5 x 10(-5)/Gy at the hprt locus and 3.75 x 10(-5)/Gy at the tk locus. Molecular analysis of HPRT- mutant DNAs showed a high frequency (69%) of clones with partial or full deletions of the hprt gene among radiation-induced mutants compared with spontaneous mutants (31%). Chi-squared analyses of mutational spectra show a significant difference (P < or = 0.005) between spontaneous mutants and alpha-particle-induced mutants. Comparison with published studies of accelerator-produced heavy-ion exposures of TK6 cells indicates that the induction of mutations at the hprt locus, and perhaps a subset of mutations at the tk locus, is a simple linear function of particle fluence regardless of the ion species or its LET.

Angular distributions of the protons in the reaction. pi. /sup +/+Xe. -->. p+xxx at 2. 34 GeV/c as a background for the shock-wave effect

DOE Office of Scientific and Technical Information (OSTI.GOV)

Slowinski, B.; Strugalski, Z.

1977-02-20

Results are presented of an analysis of the angular distributions of protons with E/sub p/> or =30 MeV emitted with different numbers of secondary charged particles in ..pi../sup +/+Xe interactions at 2.34 GeV/c. The obtained distributions are compared with the analogous characteristics of the protons emitted in collisions of protons or ..cap alpha.. particles with heavy emulsion nuclei and with lead at 70 and 17 GeV/c. It is concluded that the investigated distributions reveal no irregularities capable of attesting to a noticable role of the shock-wave mechanism in the target nuclei.

Rationalization of the solvation effects on the AtO+ ground-state change.

PubMed

Ayed, Tahra; Réal, Florent; Montavon, Gilles; Galland, Nicolas

2013-09-12

(211)At radionuclide is of considerable interest as a radiotherapeutic agent for targeted alpha therapy in nuclear medicine, but major obstacles remain because the basic chemistry of astatine (At) is not well understood. The AtO(+) cationic form might be currently used for (211)At-labeling protocols in aqueous solution and has proved to readily react with inorganic/organic ligands. But AtO(+) reactivity must be hindered at first glance by spin restriction quantum rules: the ground state of the free cation has a dominant triplet character. Investigating AtO(+) clustered with an increasing number of water molecules and using various flavors of relativistic quantum methods, we found that AtO(+) adopts in solution a Kramers restricted closed-shell configuration resembling a scalar-relativistic singlet. The ground-state change was traced back to strong interactions, namely, attractive electrostatic interactions and charge transfer, with water molecules of the first solvation shell that lift up the degeneracy of the frontier π* molecular orbitals (MOs). This peculiarity brings an alternative explanation to the highly variable reproducibility reported for some astatine reactions: depending on the production protocols (with distillation in gas-phase or "wet chemistry" extraction), (211)At may or may not readily react.

The Apollo Alpha Spectrometer.

NASA Technical Reports Server (NTRS)

Jagoda, N.; Kubierschky, K.; Frank, R.; Carroll, J.

1973-01-01

Located in the Science Instrument Module of Apollo 15 and 16, the Alpha Particle Spectrometer was designed to detect and measure the energy of alpha particles emitted by the radon isotopes and their daughter products. The spectrometer sensor consisted of an array of totally depleted silicon surface barrier detectors. Biased amplifier and linear gate techniques were utilized to reduce resolution degradation, thereby permitting the use of a single 512 channel PHA. Sensor identification and in-flight radioactive calibration were incorporated to enhance data reduction.

Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer (EORTC 75111-10114): an open-label, randomised, phase 2 trial from the Elderly Task Force/Breast Cancer Group.

PubMed

Wildiers, Hans; Tryfonidis, Konstantinos; Dal Lago, Lissandra; Vuylsteke, Peter; Curigliano, Giuseppe; Waters, Simon; Brouwers, Barbara; Altintas, Sevilay; Touati, Nathan; Cardoso, Fatima; Brain, Etienne

2018-03-01

Despite the high incidence of metastatic breast cancer and its related mortality in the elderly population, our knowledge about optimal treatment for older patients with cancer is far from adequate. We aimed to evaluate the efficacy of dual anti-HER2 treatment with or without metronomic chemotherapy in older patients with HER2-positive metastatic breast cancer. We did a multicentre, open-label, randomised, phase 2 trial in 30 centres from eight countries in Europe, in patients with histologically proven, HER2-positive metastatic breast cancer, without previous chemotherapy for metastatic disease, who were 70 years or older, or 60 years or older with confirmed functional restrictions defined by protocol, and had a life expectancy of more than 12 weeks and a performance status according to WHO scale of 0-3. Eligible patients were randomly assigned (1:1) by an online randomisation system based on the minimisation method to receive metronomic oral cyclophosphamide 50 mg per day plus trastuzumab and pertuzumab, or trastuzumab and pertuzumab alone. Trastuzumab was given intravenously with a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Pertuzumab was given intravenously with a loading dose of 840 mg, followed by 420 mg every 3 weeks. Patients were stratified by hormone receptor positivity, previous HER2 treatment, and baseline geriatric screening. The primary endpoint was investigator-assessed progression-free survival at 6 months as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A difference of 10% or greater between the two groups was sought. Efficacy analyses were by intention to treat; safety was assessed in all patients who received at least one dose of study treatment. In case of progression, all patients were offered trastuzumab emtansine. This trial is registered with ClinicalTrials.gov, number NCT01597414, and is completed. Between July 2, 2013, and May 10, 2016, 80 patients, of whom 56 (70%) had a potential frailty profile according to the geriatric screening G8 score (≤14), were randomly assigned to receive trastuzumab and pertuzumab (n=39) or trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (n=41). Estimated progression-free survival at 6 months was 46·2% (95% CI 30·2-60·7) with trastuzumab and pertuzumab versus 73·4% (56·6-84·6) with trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (hazard ratio [HR] 0·65 [95% CI 0·37-1·12], p=0·12). At a median follow-up of 20·7 months (IQR 12·5-30·4), the median progression-free survival was 5·6 months (95% CI 3·6-16·8) with trastuzumab and pertuzumab versus 12·7 months (6·7-24·8) with the addition of metronomic oral cyclophosphamide. The most frequent grade 3-4 adverse events were hypertension (in six [15%] of 39 patients in the trastuzumab and pertuzumab group vs five [12%] of 41 in the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group), diarrhoea (four [10%] vs five [12%]), dyspnoea (two [5%] vs four [10%]), fatigue (three [8%] vs two [5%]), pain (two [5%] vs two [5%]), and a thromboembolic event (0 [0%] vs four [10%]). Severe cardiac toxicities were occasionally observed in both groups. In the trastuzumab and pertuzumab group four patients died without progression, due to cardiac arrest during treatment (n=1), peritoneal infection (n=1), respiratory failure (n=1), and sudden death without a specified cause (n=1). In the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group, one patient died from heart failure. Addition of metronomic oral cyclophosphamide to trastuzumab plus pertuzumab in older and frail patients with HER2-positive metastatic breast cancer increased median progression-free survival by 7 months compared with dual HER2 blockade alone, with an acceptable safety profile. Trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, followed by trastuzumab emtansine after disease progression, might delay or supersede the need for taxane chemotherapy in this population. F Hoffmann-La Roche. Copyright © 2018 Elsevier Ltd. All rights reserved.

40 CFR 211.104 - Label content.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 26 2012-07-01 2011-07-01 true Label content. 211.104 Section 211.104 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING General Provisions § 211.104 Label content. The following data and information must be on the label of all products for which...

40 CFR 211.104 - Label content.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 26 2013-07-01 2013-07-01 false Label content. 211.104 Section 211.104 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING General Provisions § 211.104 Label content. The following data and information must be on the label of all products for which...

40 CFR 211.104 - Label content.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 25 2014-07-01 2014-07-01 false Label content. 211.104 Section 211.104 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING General Provisions § 211.104 Label content. The following data and information must be on the label of all products for which...

40 CFR 211.104 - Label content.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Label content. 211.104 Section 211.104 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING General Provisions § 211.104 Label content. The following data and information must be on the label of all products for which...

40 CFR 211.104 - Label content.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 25 2011-07-01 2011-07-01 false Label content. 211.104 Section 211.104 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING General Provisions § 211.104 Label content. The following data and information must be on the label of all products for which...

¹¹¹In-Bn-DTPA-nimotuzumab with/without modification with nuclear translocation sequence (NLS) peptides: an Auger electron-emitting radioimmunotherapeutic agent for EGFR-positive and trastuzumab (Herceptin)-resistant breast cancer.

PubMed

Fasih, Aisha; Fonge, Humphrey; Cai, Zhongli; Leyton, Jeffrey V; Tikhomirov, Ilia; Done, Susan J; Reilly, Raymond M

2012-08-01

Increased expression of epidermal growth factor receptors (EGFR) in breast cancer (BC) is often associated with trastuzumab (Herceptin)-resistant forms of the disease and represents an attractive target for novel therapies. Nimotuzumab is a humanized IgG(1) monoclonal antibody that is in clinical trials for treatment of EGFR-overexpressing malignancies. We show here that nimotuzumab derivatized with benzylisothiocyanate diethylenetriaminepentaacetic acid for labelling with the subcellular range Auger electron-emitter, (111)In and modified with nuclear translocation sequence (NLS) peptides ((111)In-NLS-Bn-DTPA-nimotuzumab) was bound, internalized and transported to the nucleus of EGFR-positive BC cells. Emission of Auger electrons in close proximity to the nucleus caused multiple DNA double-strand breaks which diminished the clonogenic survival (CS) of MDA-MB-468 cells that have high EGFR density (2.4 × 10(6) receptors/cell) to less than 3 %. (111)In-Bn-DTPA-nimotuzumab without NLS peptide modification was sevenfold less effective for killing MDA-MB-468 cells. (111)In-Bn-DTPA-nimotuzumab with/without NLS peptide modification were equivalently cytotoxic to MDA-MB-231 and TrR1 BC cells that have moderate EGFR density (5.4 × 10(5) or 4.2 × 10(5) receptors/cell, respectively) reducing their CS by twofold. MDA-MB-231 cells have intrinsic trastuzumab resistance due to low HER2 density, whereas TrR1 cells have acquired resistance despite HER2 overexpression. Biodistribution and microSPECT/CT imaging revealed that (111)In-NLS-Bn-DTPA-nimotuzumab exhibited more rapid elimination from the blood and lower tumour uptake than (111)In-Bn-DTPA-nimotuzumab. Tumour uptake of the radioimmunoconjugates in mice with MDA-MB-468 xenografts was high (8-16 % injected dose/g) and was blocked by administration of an excess of unlabelled nimotuzumab, demonstrating EGFR specificity. We conclude that (111)In-Bn-DTPA-nimotuzumab with/without NLS peptide modification are promising Auger electron-emitting radioimmunotherapeutic agents for EGFR-positive BC, but (111)In-Bn-DTPA-nimotuzumab may be preferred due to its higher tumour uptake in vivo.

40 CFR 211.211 - Compliance with labeling requirement.

Code of Federal Regulations, 2010 CFR

2010-07-01

... ABATEMENT PROGRAMS PRODUCT NOISE LABELING Hearing Protective Devices § 211.211 Compliance with labeling requirement. (a) All hearing protective devices manufactured after the effective date of this regulation, and... comply with the Labeled Values of mean attenuation. (b) A manufacturer must take into account both...

Dosimetry of radium-223 and progeny

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fisher, D.R.; Sgouros, G.

Radium-223 is a short-lived (11.4 d) alpha emitter with potential applications in radioimmunotherapy of cancer. Radium-223 can be complexed and linked to protein delivery molecules for specific tumor-cell targeting. It decays through a cascade of short-lived alpha- and beta-emitting daughters with emission of about 28 MeV of energy through complete decay. The first three alpha particles are essentially instantaneous. Photons associated with Ra-223 and progeny provide the means for tumor and normal-organ imaging and dosimetry. Two beta particles provide additional therapeutic value. Radium-223 may be produced economically and in sufficient amounts for widescale application. Many aspects of the chemistry ofmore » carrier-free isotope preparation, complexation, and linkage to the antibody have been developed and are being tested. The radiation dosimetry of a Ra-223-labeled antibody shows favorable tumor to normal tissue dose ratios for therapy. The 11.4-d half-life of Ra-223 allows sufficient time for immunoconjugate preparation, administration, and tumor localization by carrier antibodies before significant radiological decay takes place. If 0.01 percent of a 37 MBq (1 mCi) injection deposits in a one gram tumor mass, and if the activity is retained with a typical effective half-time (75 h), the absorbed dose will be 163 mGy MBq{sup {minus}1} (600 rad mCi{sup {minus}1}) administered. 49 refs., 5 figs., 2 tabs.« less

Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer.

PubMed

Burstein, Harold J; Sun, Yan; Dirix, Luc Y; Jiang, Zefei; Paridaens, Robert; Tan, Antoinette R; Awada, Ahmad; Ranade, Anantbhushan; Jiao, Shunchang; Schwartz, Gary; Abbas, Richat; Powell, Christine; Turnbull, Kathleen; Vermette, Jennifer; Zacharchuk, Charles; Badwe, Rajendra

2010-03-10

Neratinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor. The efficacy and safety of neratinib were evaluated in two cohorts of patients with advanced ErbB2-positive breast cancer-those with and those without prior trastuzumab treatment-in an open-label, multicenter, phase II trial. Patients in the two cohorts (prior trastuzumab, n = 66; no prior trastuzumab, n = 70) received oral neratinib 240 mg once daily. The primary end point was the 16-week progression-free survival (PFS) rate for the evaluable population (prior trastuzumab, n = 63; no prior trastuzumab, n = 64), as assessed by independent review. The 16-week PFS rates were 59% for patients with prior trastuzumab treatment and 78% for patients with no prior trastuzumab treatment. Median PFS was 22.3 and 39.6 weeks, respectively. Objective response rates were 24% among patients with prior trastuzumab treatment and 56% in the trastuzumab-naïve cohort. The most common adverse events were diarrhea, nausea, vomiting, and fatigue. Diarrhea was the most frequent grades 3 to 4 adverse event, occurring in 30% of patients with prior trastuzumab treatment and in 13% of patients with no prior trastuzumab treatment, which prompted dose reductions in 29% and 4% of patients, respectively, but treatment discontinuation in only one patient. No neratinib-related, grades 3 or 4 cardiotoxicity was reported. Oral neratinib showed substantial clinical activity and was reasonably well tolerated among both heavily pretreated and trastuzumab-naïve patients who had advanced, ErbB2-positive breast cancer. Diarrhea was the most common adverse effect but was manageable with antidiarrheal agents and dose modification.

Recombinant anti-tenascin antibody constructs

DOE Office of Scientific and Technical Information (OSTI.GOV)

ZALUTSKY, MICHAEL R

2006-08-29

The general objective of this research is to combine genetically derived molecular constructs reactive with tenascin, with appropriate radionuclides and labeling methods in order to generate more effective diagnostic and therapeutic reagents for oncologic nuclear medicine. Tenascin, a polymorphic extracellular matrix glycoprotein, is of interest because of its high expression on glioma, melanoma, as well as prostate and breast carcinoma. Recently, we have also documented high levels of tenascin in lymphomas, particularly those of higher grade, making the potential clinical impact of tenascin-specific radiodiagnostics and therapeutics even greater. An essential feature of our work plan is the ability to exploitmore » our extensive clinical experience in order to design second-generation constructs with properties which could improve clinical efficacy. To date, we have treated over 150 brain tumor patients with 131I-labeled murine 81C6, an antibody which binds specifically to the alternatively spliced fibronectin type III repeats CD of the tenascin molecule. During the current grant period, we have made several observations which form the basis for our proposed specific aims. First, tissue distribution and catabolism experiments in animal models have demonstrated enhanced stability for a chimeric construct composed of murine variable regions and human IgG2 constant domains. Furthermore, pharmacokinetic studies in patients with 131I-labeled chimeric 81C6 have shown significantly longer retention in glioma tumor resection cavities compared with its murine parent. Second, we have initiated the first clinical trial of an endoradiotherapeutic labeled with the 7.2-hr -particle emitter 211At. Twelve glioma patients have received 211At-labeled chimeric 81C6 directly into their brain tumor resection cavity, and very encouraging results have been obtained. Now that the feasibility of human studies with 211At, has been demonstrated, the development and evaluation of anti-tenascin constructs with optimized properties for use in tandem with short half life radionuclides such as 211At ( as well as 1.8-hr 18F for PET imaging) is warranted. Our specific aims are: 1) to construct a bivalent, anti-tenascin molecule containing murine 81C6 variable regions and the human IgG2 hinge region. Both the CH2 domain deletion construct (CH2) and F(ab’)2 will be investigated; 2) to construct a single-chain Fv dimer or multimer with adequate stability, affinity and immunoreactivity for use in tandem with 211At for therapy and 18F for imaging; 3) to generate higher affinity scFv constructs reactive with the alternatively spliced fibronectin type III repeats CD of the tenascin molecule via phage display technology and site-directed mutagenesis; 4) to label promising anti-tenascin constructs with radioiodine, 211At, and 18F and evaluate their potential as radiodiagnostic and radiotherapeutic agents. The proposed studies include: characterization of affinity and immunoreactivity after labeling; evaluation of tissue distribution and projected dosimetry in normal mice, and athymic rodents with subcutaneous, intracranial and neoplastic meningitis xenografts; investigation of the nature of low and high molecular weight labeled catabolites generated in mice; and assessment of cytotoxicity in vitro and in vivo models of human glioma, and possibly, other tenascin expressing tumors; and 5) to investigate strategies for labeling scFv monomers and dimers which will minimize retention of the radiohalogen in the kidneys through the use of negatively charged templates.« less

Baseline Immunoglobulin E Levels as a Marker of Doxorubicin and Trastuzumab-Associated Cardiac Dysfunction

PubMed Central

Beer, Lynn A.; Kossenkov, Andrew V.; Liu, Qin; Luning Prak, Eline; Domchek, Susan; Speicher, David W.; Ky, Bonnie

2016-01-01

Rationale There is a critical need to develop robust, mechanistic strategies to identify patients at increased risk of cancer therapeutics-related cardiac dysfunction (CTRCD). Objective We aimed to discover new biomarkers associated with doxorubicin and trastuzumab-induced CTRCD using high-throughput proteomic profiling. Methods and Results Plasma, echocardiograms, and clinical outcomes were collected at standardized intervals in breast cancer patients undergoing doxorubicin and trastuzumab cancer therapy. Thirty-one longitudinal plasma samples from three cases with CTRCD and four age- and cancer-matched controls without CTRCD were processed and analyzed using label-free liquid chromatography- mass spectrometry (LC-MS). From these analyses, 862 proteins were identified from case/control pairs 1 and 2, and 1,360 proteins from case/control pair 3. Proteins with a greater than 1.5-fold change in cases compared to controls with a p<0.05 either at the time of CTRCD diagnosis or across all timepoints were considered candidate diagnostic or predictive biomarkers, respectively. The protein that demonstrated the largest differences between cases and controls was immunoglobulin E (IgE), with higher levels detected at baseline and across all timepoints in controls without CTRCD as compared to matched CTRCD cases (p<0.05). Similarly, in a validation study of 35 participants treated with doxorubicin and trastuzumab, high baseline IgE levels were associated with a significantly lower risk of CTRCD (p=0.018). Conclusions In patients receiving doxorubicin and trastuzumab, high baseline IgE levels are associated with a lower risk of CTRCD. These novel findings suggest a new paradigm in cardio-oncology, implicating the immune system as a potential mediator of doxorubicin and trastuzumab-induced cardiac dysfunction. PMID:27582370

Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial

PubMed Central

Baselga, José; Bradbury, Ian; Eidtmann, Holger; Di Cosimo, Serena; de Azambuja, Evandro; Aura, Claudia; Gómez, Henry; Dinh, Phuong; Fauria, Karine; Van Dooren, Veerle; Aktan, Gursel; Goldhirsch, Aron; Chang, Tsai-Wang; Horváth, Zsolt; Coccia-Portugal, Maria; Domont, Julien; Tseng, Ling-Min; Kunz, Georg; Sohn, Joo Hyuk; Semiglazov, Vladimir; Lerzo, Guillermo; Palacova, Marketa; Probachai, Volodymyr; Pusztai, Lajos; Untch, Michael; Gelber, Richard D; Piccart-Gebhart, Martine

2017-01-01

Summary Background The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer. We argue that the two anti-HER2 agents given together would be better than single-agent therapy. Methods In this parallel groups, randomised, open-label, phase 3 study undertaken between Jan 5, 2008, and May 27, 2010, women from 23 countries with HER2-positive primary breast cancer with tumours greater than 2 cm in diameter were randomly assigned to oral lapatinib (1500 mg), intravenous trastuzumab (loading dose 4 mg/kg, subsequent doses 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab. Treatment allocation was by stratified, permuted blocks randomisation, with four stratification factors. Anti-HER2 therapy alone was given for the first 6 weeks; weekly paclitaxel (80 mg/m2) was then added to the regimen for a further 12 weeks, before definitive surgery was undertaken. After surgery, patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks. The primary endpoint was the rate of pathological complete response (pCR), analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00553358. Findings 154 patients received lapatinib, 149 trastuzumab, and 152 the combination. pCR rate was significantly higher in the group given lapatinib and trastuzumab (78 of 152 patients [51·3%; 95% CI 43·1–59·5]) than in the group given trastuzumab alone (44 of 149 patients [29·5%; 22·4–37·5]; difference 21·1%, 9·1–34·2, p=0·0001). We recorded no significant difference in pCR between the lapatinib (38 of 154 patients [24·7%, 18·1–32·3]) and the trastuzumab (difference −4·8%, −17·6 to 8·2, p=0·34) groups. No major cardiac dysfunctions occurred. Frequency of grade 3 diarrhoea was higher with lapatinib (36 patients [23·4%]) and lapatinib plus trastuzumab (32 [21·1%]) than with trastuzumab (three [2·0%]). Similarly, grade 3 liver-enzyme alterations were more frequent with lapatinib (27 [17·5%]) and lapatinib plus trastuzumab (15 [9·9%]) than with trastuzumab (11 [7·4%]). Interpretation Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting. Funding GlaxoSmithKline. PMID:22257673

Controlling alpha tracks registration in Makrofol DE 1-1 detector

NASA Astrophysics Data System (ADS)

Hassan, N. M.; Hanafy, M. S.; Naguib, A.; El-Saftawy, A. A.

2017-09-01

Makrofol DE 1-1 is a recent type of solid state nuclear track detectors could be used to measure radon concentration in the environment throughout the detection of α-particles emitted from radon decay. Thus, studying the physical parameters that control the formation of alpha tracks is vital for environmental radiation protection. Makrofol DE 1-1 polycarbonate detector was irradiated by α-particles of energies varied from 2 to 5 MeV emitted from the 241Am source of α-particle energy of 5.5 MeV. Then, the detector was etched in an optimum etching solution of mixed ethyl alcohol in KOH aqueous solution of (85% (Vol.) of 6 M KOH + 15% (Vol.) C2H5OH) at 50 °C for 3 h. Afterward, the bulk etch rate, etching sensitivity, and the registration efficiency of the detector, which control the tracks registration, were measured. The bulk etch rate of Makrofol detector was found to be 3.71 ± 0.71 μm h-1. The etching sensitivity and the detector registration efficiency were decreased exponentially with α-particles' energies following Bragg curve. A precise registration of α-particle was presented in this study. Therefore, Makrofol DE 1-1 can be applied as a radiation dosimeter as well as radon and thoron monitors.

Characterization of synthesis and storage of TGF-alpha in rat parotid acinar and intercalated duct cells.

PubMed

Login, G R; Yang, J; Bryan, K P; Digenis, E C; McBride, J; Elovic, A; Quissell, D O; Dvorak, A M; Wong, D T

1997-03-01

Although the expression and biological role of transforming growth factor-alpha (TGF-alpha) have been explored in a variety of normal cells in mammalian species, little is known about the storage of TGF-alpha in secretory cells of exocrine organs. Parotid glands from four rats were homogenized for RNA isolation followed by reverse transcription-polymerase chain reaction to determine the presence of TGF-alpha message. In situ hybridization using a hamster-specific TGF-alpha riboprobe was done on paraffin sections. Parotid gland and isolated acinar cells were processed for transmission electron microscopy (TEM) and postembedding immunogold labeled for TGF-alpha. Gold particles were counted on approximately 200 granules in 10 acinar cells and in 10 intercalated duct cells. Labeling density was calculated as the number of gold particles per square micrometer +/- SD. Statistical significance was calculated using one-way analysis of variance. Using multiple technologies, we have established that rat parotid acinar and intercalated duct cells synthesize TGF-alpha and store the precursor form of this cytokine in their secretory granules.

Detection of Cancer Metastases with a Dual-labeled Near-Infrared/Positron Emission Tomography Imaging Agent12

PubMed Central

Sampath, Lakshmi; Kwon, Sunkuk; Hall, Mary A; Price, Roger E; Sevick-Muraca, Eva M

2010-01-01

By dual labeling a targeting moiety with both nuclear and optical probes, the ability for noninvasive imaging and intraoperative guidance may be possible. Herein, the ability to detect metastasis in an immunocompetent animal model of human epidermal growth factor receptor 2 (HER-2)-positive cancer metastases using positron emission tomography (PET) and near-infrared (NIR) fluorescence imaging is demonstrated. METHODS: (64Cu-DOTA)n-trastuzumab-(IRDye800)m was synthesized, characterized, and administered to female Balb/c mice subcutaneously inoculated with highly metastatic 4T1.2neu/R breast cancer cells. (64Cu-DOTA)n-trastuzumab-(IRDye800)m (150 µg, 150 µCi, m = 2, n = 2) was administered through the tail vein at weeks 2 and 6 after implantation, and PET/computed tomography and NIR fluorescence imaging were performed 24 hours later. Results were compared with the detection capabilities of F-18 fluorodeoxyglucose (18FDG-PET). RESULTS: Primary tumors were visualized with 18FDG and (64Cu-DOTA)n-trastuzumab-(IRDye800)m, but resulting metastases were identified only with the dual-labeled imaging agent. 64Cu-PET imaging detected lung metastases, whereas ex vivo NIR fluorescence showed uptake in regions of lung, skin, skeletal muscle, and lymph nodes, which corresponded with the presence of cancer cells as confirmed by histologic hematoxylin and eosin stains. In addition to detecting the agent in lymph nodes, the high signal-to-noise ratio from NIR fluorescence imaging enabled visualization of channels between the primary tumor and the axillary lymph nodes, suggesting a lymphatic route for trafficking cancer cells. Because antibody clearance occurs through the liver, we could not distinguish between nonspecific uptake and liver metastases. CONCLUSION: (64Cu-DOTA)n-trastuzumab-(IRDye800)m may be an effective diagnostic imaging agent for staging HER-2-positive breast cancer patients and intraoperative resection. PMID:20885893

Testing the stand-alone microbeam at Columbia University.

PubMed

Garty, G; Ross, G J; Bigelow, A W; Randers-Pehrson, G; Brenner, D J

2006-01-01

The stand-alone microbeam at Columbia University presents a novel approach to biological microbeam irradiation studies. Foregoing a conventional accelerator as a source of energetic ions, a small, high-specific-activity, alpha emitter is used. Alpha particles emitted from this source are focused using a compound magnetic lens consisting of 24 permanent magnets arranged in two quadrupole triplets. Using a 'home made' 6.5 mCi polonium source, a 1 alpha particle s(-1), 10 microm diameter microbeam can, in principle, be realised. As the alpha source energy is constant, once the microbeam has been set up, no further adjustments are necessary apart from a periodic replacement of the source. The use of permanent magnets eliminates the need for bulky power supplies and cooling systems required by other types of ion lenses and greatly simplifies operation. It also makes the microbeam simple and cheap enough to be realised in any large lab. The Microbeam design as well as first tests of its performance, using an accelerator-based beam are presented here.

Site-Specific Antibody Labeling by Covalent Photoconjugation of Z Domains Functionalized for Alkyne-Azide Cycloaddition Reactions.

PubMed

Perols, Anna; Arcos Famme, Melina; Eriksson Karlström, Amelie

2015-11-01

Antibodies are extensively used in research, diagnostics, and therapy, and for many applications the antibodies need to be labeled. Labeling is typically performed by using amine-reactive probes that target surface-exposed lysine residues, resulting in heterogeneously labeled antibodies. An alternative labeling strategy is based on the immunoglobulin G (IgG)-binding protein domain Z, which binds to the Fc region of IgG. Introducing the photoactivable amino acid benzoylphenylalanine (BPA) into the Z domain makes it possible for a covalent bond to be be formed between the Z domain and the antibody on UV irradiation, to produce a site-specifically labeled product. Z32 BPA was synthesized by solid-phase peptide synthesis and further functionalized to give alkyne-Z32 BPA and azide-Z32 BPA for Cu(I) -catalyzed cycloaddition, as well as DBCO-Z32 BPA for Cu-free strain-promoted cycloaddition. The Z32 BPA variants were conjugated to the human IgG1 antibody trastuzumab and site-specifically labeled with biotin or fluorescein. The fluorescently labeled trastuzumab showed specific staining of the membranes of HER2-expressing cells in immunofluorescence microscopy. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cleaning Products and Air Fresheners: Emissions and ResultingConcentrations of Glycol Ethers and Terpenoids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Singer, Brett C.; Destaillat, Hugo; Hodgson, Alfred T.

2005-08-01

Experiments were conducted to quantify emissions and concentrations of glycol ethers and terpenoids from cleaning product and air freshener use in a 50-m{sup 3} room ventilated at {approx}0.5 h{sup -1}. Five cleaning products were applied full-strength (FS); three were additionally used in dilute solution. FS application of pine-oil cleaner (POC) yielded 1-h concentrations of 10-1300 {micro}g m{sup -3} for individual terpenoids, including {alpha}-terpinene (90-120), d-limonene (1000-1100), terpinolene (900-1300), and {alpha}-terpineol (260-700). One-hour concentrations of 2-butoxyethanol and/or dlimonene were 300-6000 {micro}g m{sup -3} after FS use of other products. During FS application including rinsing with sponge and wiping with towels, fractionalmore » emissions (mass volatilized/dispensed) of 2-butoxyethanol and d-limonene were 50-100% with towels retained, {approx}25-50% when towels were removed after cleaning. Lower fractions (2-11%) resulted from dilute use. Fractional emissions of terpenes from FS use of POC were {approx}35-70% with towels retained, 20-50% with towels removed. During floor cleaning with dilute solution of POC, 7-12% of dispensed terpenes were emitted. Terpene alcohols were emitted at lower fractions: 7-30% (FS, towels retained), 2-9% (FS, towels removed), and 2-5% (dilute). During air-freshener use, d-limonene, dihydromyrcenol, linalool, linalyl acetate, and {beta}-citronellol were emitted at 35-180 mg d{sup -1} over three days while air concentrations averaged 30-160 {micro}g m{sup -3}.« less

Radioimmunotherapy of cancer with high linear energy transfer (LET) radiation delivered by radionuclides emitting α-particles or Auger electrons.

PubMed

Aghevlian, Sadaf; Boyle, Amanda J; Reilly, Raymond M

2017-01-15

Radioimmunotherapy (RIT) aims to selectively deliver radionuclides emitting α-particles, β-particles or Auger electrons to tumors by conjugation to monoclonal antibodies (mAbs) that recognize tumor-associated antigens/receptors. The approach has been most successful for treatment of non-Hodgkin's B-cell lymphoma but challenges have been encountered in extending these promising results to the treatment of solid malignancies. These challenges include the low potency of β-particle emitters such as 131 I, 177 Lu or 90 Y which have been commonly conjugated to the mAbs, due to their low linear energy transfer (LET=0.1-1.0keV/μm). Furthermore, since the β-particles have a 2-10mm range, there has been dose-limiting non-specific toxicity to hematopoietic stem cells in the bone marrow (BM) due to the cross-fire effect. Conjugation of mAbs to α-particle-emitters (e.g. 225 Ac, 213 Bi, 212 Pb or 211 At) or Auger electron-emitters (e.g. 111 In, 67 Ga, 123 I or 125 I) would increase the potency of RIT due to their high LET (50-230keV/μm and 4 to 26keV/μm, respectively). In addition, α-particles have a range in tissues of 28-100μm and Auger electrons are nanometer in range which greatly reduces or eliminates the cross-fire effect compared to β-particles, potentially reducing their non-specific toxicity to the BM. In this review, we describe the results of preclinical and clinical studies of RIT of cancer using radioimmunoconjugates emitting α-particles or Auger electrons, and discuss the potential of these high LET forms of radiation to improve the outcome of cancer patients. Copyright © 2015 Elsevier B.V. All rights reserved.

A study of the polyethylene membrane used in diffusion chambers for radon gas concentration measurements

NASA Astrophysics Data System (ADS)

Leung, S. Y. Y.; Nikezic, D.; Leung, J. K. C.; Yu, K. N.

2007-10-01

Solid-state nuclear track detectors (SSNTDs) in diffusion chambers have been routinely used for long-term measurements of radon gas concentrations. In usual practice, a filter is added across the top of the diffusion chamber to stop the progeny from entering. Thoron can also be deterred from entering the diffusion chamber by using a polyethylene (PE) membrane. However, the thickness of the PE membrane is rarely specified in the literature. In this paper, we will present our experimental results for a radon exposure that the number of alpha-particle tracks registered by the LR 115 SSNTD in a Karlsruhe diffusion chamber covered with one layer of PE membrane is actually enhanced. This is explained by enhanced deposition of radon progeny on the outside surface of the PE membrane and the insufficient thickness of the PE membrane to stop the alpha particles emitted from these deposited radon progeny to reach the SSNTD. We will present the PE thickness which can stop the alpha particles emitted from the deposited radon or thoron progeny. For the "twin diffusion chambers method", one of the diffusion chambers is covered with PE membranes. The optimal number of thickness of PE membranes will be determined, which allows the largest amount of radon gas to diffuse into the diffusion chamber while at the same time screening out the largest amount of thoron gas.

Trastuzumab-binding peptide display by Tobacco mosaic virus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frolova, Olga Y.; Petrunia, Igor V.; Komarova, Tatiana V.

2010-11-10

Human epidermal growth factor receptor-2 (HER2/neu) is a target for the humanized monoclonal antibody trastuzumab. Recently, trastuzumab-binding peptides (TBP) of HER2/neu that inhibit proliferation of breast cancer cells were identified. We have now studied conditions of efficient assembly in vivo of Tobacco mosaic virus (TMV)-based particles displaying TBP on its surface. The system is based on an Agrobacterium-mediated co-delivery of binary vectors encoding TMV RNA and coat protein (CP) with TBP in its C-terminal extension into plant leaves. We show how the fusion of amino acid substituted TBP (sTBP) to CP via a flexible peptide linker can improve the manufacturabilitymore » of recombinant TMV (rTMV). We also reveal that rTMV particles with exposed sTBP retained trastuzumab-binding capacity but lost an anti-HER2/neu immunogenic scaffold function. Mouse antibodies against rTMV did not recognize HER2/neu on surface of human SK-BR-3 cells.« less

A continuous sampler with background suppression for monitoring alpha-emitting aerosol particles.

PubMed

McFarland, A R; Rodgers, J C; Ortiz, C A; Moore, M E

1992-05-01

A continuous air monitor has been developed that includes provisions for improving the detection of alpha-emitting aerosol particles in the presence of radon/thoron progeny that are unattached to ambient aerosol particles. Wind tunnel tests show that 80% of 10-microns aerodynamic equivalent diameter particles penetrate the flow system from the ambient air to the collection filter when the flow rate is 57 L min-1 (2 cfm) and the wind speed is 1 m s-1. Uniformity of aerosol collection on the filter, as characterized by the coefficient of variation of the areal density deposits, is less than 15% for 10-microns aerodynamic-equivalent-diameter aerosol particles. Tests with unattached radon daughters in a flow-through chamber showed that approximately 99% of the 218Po was removed by an inlet screen that is designed to collect radon daughters that are in the size range of molecular clusters. The inlet screen offers the opportunity to improve the signal-to-noise ratio of energy spectra in the regions of interest (subranges of the energy spectrum) of transuranic elements and thereby enhance the performance of background compensation algorithms.

Measurement of (222)Rn by absorption in plastic scintillators and alpha/beta pulse shape discrimination.

PubMed

Mitev, Krasimir K

2016-04-01

This work demonstrates that common plastic scintillators like BC-400, EJ-200 and SCSF-81 absorb radon and their scintillation pulse decay times are different for alpha- and beta-particles. This allows the application of pulse shape analysis for separation of the pulses of alpha- and beta-particles emitted by the absorbed radon and its progeny. It is shown that after pulse shape discrimination of beta-particles' pulses, the energy resolution of BC-400 and EJ-200 alpha spectra is sufficient to separate the peaks of (222)Rn, (218)Po and (214)Po and allows (222)Rn measurements that are unaffected by the presence of thoron ((220)Rn) in the environment. The alpha energy resolution of SCSF-81 in the experiments degrades due to imperfect collection of the light emitted inside the scintillating fibers. The experiments with plastic scintillation microspheres (PSM) confirm previous findings of other researchers that PSM have alpha-/beta-discrimination properties and show suitability for radon measurements. The diffusion length of radon in BC-400 and EJ-200 is determined. The pilot experiments show that the plastic scintillators are suitable for radon-in-soil-gas measurements. Overall, the results of this work suggest that it is possible to develop a new type of radon measurement instruments which employ absorption in plastic scintillators, pulse-shape discrimination and analysis of the alpha spectra. Such instruments can be very compact and can perform continuous, real-time radon measurements and thoron detection. They can find applications in various fields from radiation protection to earth sciences. Copyright © 2016 Elsevier Ltd. All rights reserved.

40 CFR 211.204-3 - Label location and type.

Code of Federal Regulations, 2010 CFR

2010-07-01

... packaging if the label complying with § 211.204-3(a)(1) is not visible at the point of ultimate purchase or...) If the protector is individually packaged and so displayed at the point of ultimate purchase or... the protector is displayed at the point of ultimate purchase or distribution to prospective users in a...

The curative and palliative potential of the monoclonal antibody MOv18 labelled with 211At in nude mice with intraperitoneally growing ovarian cancer xenografts--a long-term study.

PubMed

Andersson, H; Lindegren, S; Bäck, T; Jacobsson, L; Leser, G; Horvath, G

2000-01-01

The purpose of the present study was to investigate the therapeutic efficacy of 211At-labelled specific monoclonal antibody MOv18 in nude mice with intraperitoneal growth of the human ovarian cancer cell line OVCAR3. In the first part of the study the antibody was injected intraperitoneally when the cancer growth was microscopic. The injected activity was 485-555 kBq. The median survival for treated mice was 213 days compared to 138 days for untreated mice (p < 0.014, log-rank test). No obvious toxicity was seen. Thirty-three percent of the mice were apparently free of cancer after 7 months and were probably cured. In the second part of the study mice with macroscopic cancer and signs of ascites were injected intraperitoneally with the same 211At-labelled antibody (377-389 kBq). This treatment possibly delayed the production of ascites. Hopefully radioimmunotherapy with regionally administered 211At-labelled antibody will be of value in women with ovarian cancer as well.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eremenko, D. O.; Fotina, O. V.; Platonov, S. Yu.

The functional fitness of the alpha-emitter At-211 for radiotherapy of the thyroid gland cancer is evaluated. Radiation doses are calculated using the MIRD method and previously obtained pharmacokinetic data for At-211 in isotonic solution.

11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial.

PubMed

Cameron, David; Piccart-Gebhart, Martine J; Gelber, Richard D; Procter, Marion; Goldhirsch, Aron; de Azambuja, Evandro; Castro, Gilberto; Untch, Michael; Smith, Ian; Gianni, Luca; Baselga, Jose; Al-Sakaff, Nedal; Lauer, Sabine; McFadden, Eleanor; Leyland-Jones, Brian; Bell, Richard; Dowsett, Mitch; Jackisch, Christian

2017-03-25

Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial. HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1:1:1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov (NCT00045032). Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10·09-11·53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0·76, 95% CI 0·68-0·86) and death (0·74, 0·64-0·86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1·02, 95% CI 0·89-1·17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7·3%) in the 2-years trastuzumab group, 74 (4·4%) in the 1-year trastuzumab group, and 15 (0·9%) in the observation group. 1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit. F Hoffmann-La Roche (Roche). Copyright © 2017 Elsevier Ltd. All rights reserved.

Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial.

PubMed

Diéras, Véronique; Miles, David; Verma, Sunil; Pegram, Mark; Welslau, Manfred; Baselga, José; Krop, Ian E; Blackwell, Kim; Hoersch, Silke; Xu, Jin; Green, Marjorie; Gianni, Luca

2017-06-01

The antibody-drug conjugate trastuzumab emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial. EMILIA was a randomised, international, open-label, phase 3 study of men and women aged 18 years or older with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane. Enrolled patients were randomly assigned (1:1) via a hierarchical, dynamic randomisation scheme and an interactive voice response system to trastuzumab emtansine (3·6 mg/kg intravenously every 3 weeks) or control (capecitabine 1000 mg/m 2 self-administered orally twice daily on days 1-14 on each 21-day cycle, plus lapatinib 1250 mg orally once daily on days 1-21). Randomisation was stratified by world region (USA vs western Europe vs or other), number of previous chemotherapy regimens for unresectable, locally advanced, or metastatic disease (0 or 1 vs >1), and disease involvement (visceral vs non-visceral). The coprimary efficacy endpoints were progression-free survival (per independent review committee assessment) and overall survival. Efficacy was analysed in the intention-to-treat population; safety was analysed in all patients who received at least one dose of study treatment, with patients analysed according to the treatment actually received. On May 30, 2012, the study protocol was amended to allow crossover from control to trastuzumab emtansine after the second interim overall survival analysis crossed the prespecified overall survival efficacy boundary. This study is registered with ClinicalTrials.gov, number NCT00829166. Between Feb 23, 2009, and Oct 13, 2011, 991 eligible patients were enrolled and randomly assigned to either trastuzumab emtansine (n=495) or capecitabine and lapatinib (control; n=496). In this final descriptive analysis, median overall survival was longer with trastuzumab emtansine than with control (29·9 months [95% CI 26·3-34·1] vs 25·9 months [95% CI 22·7-28·3]; hazard ratio 0·75 [95% CI 0·64-0·88]). 136 (27%) of 496 patients crossed over from control to trastuzumab emtansine after the second interim overall survival analysis (median follow-up duration 24·1 months [IQR 19·5-26·1]). Of those patients originally randomly assigned to trastuzumab emtansine, 254 (51%) of 495 received capecitabine and 241 [49%] of 495 received lapatinib (separately or in combination) after study drug discontinuation. In the safety population (488 patients treated with capecitabine plus lapatinib, 490 patients treated with trastuzumab emtansine), fewer grade 3 or worse adverse events occurred with trastuzumab emtansine (233 [48%] of 490) than with capecitabine plus lapatinib control treatment (291 [60%] of 488). In the control group, the most frequently reported grade 3 or worse adverse events were diarrhoea (103 [21%] of 488 patients) followed by palmar-plantar erythrodysaesthesia syndrome (87 [18%]), and vomiting (24 [5%]). The safety profile of trastuzumab emtansine was similar to that reported previously; the most frequently reported grade 3 or worse adverse events in the trastuzumab emtansine group were thrombocytopenia (70 [14%] of 490), increased aspartate aminotransferase levels (22 [5%]), and anaemia (19 [4%]). Nine patients died from adverse events; five of these deaths were judged to be related to treatment (two in the control group [coronary artery disease and multiorgan failure] and three in the trastuzumab emtansine group [metabolic encephalopathy, neutropenic sepsis, and acute myeloid leukaemia]). This descriptive analysis of final overall survival in the EMILIA trial shows that trastuzumab emtansine improved overall survival in patients with previously treated HER2-positive metastatic breast cancer even in the presence of crossover treatment. The safety profile was similar to that reported in previous analyses, reaffirming trastuzumab emtansine as an efficacious and tolerable treatment in this patient population. F Hoffmann-La Roche/Genentech. Copyright © 2017 Elsevier Ltd. All rights reserved.

Late-occurring pulmonary pathologies following inhalation of mixed oxide (uranium + plutonium oxide) aerosol in the rat.

PubMed

Griffiths, N M; Van der Meeren, A; Fritsch, P; Abram, M-C; Bernaudin, J-F; Poncy, J L

2010-09-01

Accidental exposure by inhalation to alpha-emitting particles from mixed oxide (MOX: uranium and plutonium oxide) fuels is a potential long-term health risk to workers in nuclear fuel fabrication plants. For MOX fuels, the risk of lung cancer development may be different from that assigned to individual components (plutonium, uranium) given different physico-chemical characteristics. The objective of this study was to investigate late effects in rat lungs following inhalation of MOX aerosols of similar particle size containing 2.5 or 7.1% plutonium. Conscious rats were exposed to MOX aerosols and kept for their entire lifespan. Different initial lung burdens (ILBs) were obtained using different amounts of MOX. Lung total alpha activity was determined by external counting and at autopsy for total lung dose calculation. Fixed lung tissue was used for anatomopathological, autoradiographical, and immunohistochemical analyses. Inhalation of MOX at ILBs ranging from 1-20 kBq resulted in lung pathologies (90% of rats) including fibrosis (70%) and malignant lung tumors (45%). High ILBs (4-20 kBq) resulted in reduced survival time (N = 102; p < 0.05) frequently associated with lung fibrosis. Malignant tumor incidence increased linearly with dose (up to 60 Gy) with a risk of 1-1.6% Gy for MOX, similar to results for industrial plutonium oxide alone (1.9% Gy). Staining with antibodies against Surfactant Protein-C, Thyroid Transcription Factor-1, or Oct-4 showed differential labeling of tumor types. In conclusion, late effects following MOX inhalation result in similar risk for development of lung tumors as compared with industrial plutonium oxide.

Colloid labelled with radionuclide and method

DOEpatents

Atcher, R.W.; Hines, J.J.

1990-11-13

A ferric hydroxide colloid having an alpha-emitting radionuclide essentially on the outer surfaces and a method of forming same. The method includes oxidizing a ferrous hydroxide to ferric hydroxide in the presence of a preselected radionuclide to form a colloid having the radionuclide on the outer surface thereof, and thereafter washing the colloid, and suspending the washed colloid in a suitable solution. The labelled colloid is useful in cancer therapy and for the treatment of inflamed joints. No Drawings

Method of making colloid labeled with radionuclide

DOEpatents

Atcher, Robert W.; Hines, John J.

1991-01-01

A ferric hydroxide colloid having an alpha-emitting radionuclide essentially on the outer surfaces and a method of forming same. The method includes oxidizing a ferrous hydroxide to ferric hydroxide in the presence of a preselected radionuclide to form a colloid having the radionuclide on the outer surface thereof, and thereafter washing the colloid, and suspending the washed colloid in a suitable solution. The labelled colloid is useful in cancer therapy and for the treatment of inflamed joints.

Colloid labelled with radionuclide and method

DOEpatents

Atcher, Robert W.; Hines, John J.

1990-01-01

A ferric hydroxide colloid having an alpha-emitting radionuclide essentially on the outer surfaces and a method of forming same. The method includes oxidizing a ferrous hydroxide to ferric hydroxide in the presence of a preselected radionuclide to form a colloid having the radionuclide on the outer surface thereof, and thereafter washing the colloid, and suspending the washed colloid in a suitable solution. The labelled colloid is useful in cancer therapy and for the treatment of inflamed joints.

The measurement of alpha particle emissions from semiconductor memory materials

NASA Astrophysics Data System (ADS)

Bouldin, D. P.

1981-07-01

With the increasing concern for the affects of alpha particles on the reliability of semiconductor memories, an interest has arisen in characterizing semiconductor manufacturing materials for extremely low-level alpha-emitting contaminants. It is shown that four elements are of primary concern: uranium, thorium, radium, and polonium. Measurement of contamination levels are given relevance by first correlating them with alpha flux emission levels and then corre1ating these flux values with device soft error rates. Measurement techniques involve either measurements of elemental concentrations-applicable to only uranium and thorium - or direct measurements of alpha emission fluxes. Alpha fluxes are most usefully measured by means of ZnS scintillation counting, practical details of which are discussed. Materials measurements are reported for ceramics, solder, silicon, quartz, and various metals and organic materials. Ceramics and most metals have contamination levels of concern, but the high temperature processing normally used in semiconductor manufacturing and low total amounts reduce problems, at least for metals. Silicon, silicon compounds, and organic materials have been found to have no detectable alpha emitters. Finally, a brief discussion of the calibration of alpha sources for accelerated device testing is given, including practical details on the affects of source/chip separation and alignment variations.

A modified Trastuzumab antibody for the immunohistochemical detection of HER-2 overexpression in breast cancer

PubMed Central

Bussolati, G; Montemurro, F; Righi, L; Donadio, M; Aglietta, M; Sapino, A

2005-01-01

The immunohistochemical determination of HER-2 to identify patients with advanced breast cancer candidates for Trastuzumab treatment proved neither accurate nor fully reliable, possibly because none of the current reagents detects the specific antigenic site target of Trastuzumab. To circumvent this problem, we conjugated the NH2 groups of Trastuzumab with biotin, and the compound obtained, designated BiotHER, was added directly to tissue sections. Biotin-labelling was revealed with horseradish peroxidase-conjugated streptavidin. Specificity and sensitivity of BiotHER immunostaining with respect to HER-2 amplification were tested on 164 breast carcinoma samples. BiotHER staining was detected on the tumour cell membrane of 12% of all specimens and in 49% specimens with gene amplification, while absent in nonamplified tumours. Predictivity of BiotHER status with respect to the clinical outcome was analysed in 54 patients with HER-2 amplified advanced breast cancer treated with Trastuzumab plus chemotherapy. BiotHER staining, detected in 50% of tumours with HER-2 amplification, was an independent predictor of clinical outcome. In fact, BiotHER positivity was independently associated with increased likelihood of tumour response and reduced risk of tumour progression and death. Biotinylated Trastuzumab can thus be used for immunohistochemical detection of HER-2 overexpression in breast cancer, and has the potential to identify patients likely to benefit from Trastuzumab treatment. PMID:15812476

78 FR 15358 - DOE's Preferred Alternative for Certain Tanks Evaluated in the Final Tank Closure and Waste...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-11

... SUPPLEMENTARY INFORMATION.) \\1\\ Transuranic (TRU) waste is waste that contains alpha particle-emitting... available on the DOE NEPA Web site at http://energy.gov/nepa . Additional information on the Final TC & WM... INFORMATION CONTACT: For further information on the Final TC & WM EIS, contact Ms. Burandt as listed in...

Pre-Clinical Assessment of Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease.

PubMed

Ray, Geoffrey L; Baidoo, Kwamena E; Keller, Lanea M M; Albert, Paul S; Brechbiel, Martin W; Milenic, Diane E

2011-12-22

Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand the repertoire of trastuzumab as a radioimmunoconjugate (RIC) vector, use of (177)Lu was investigated. The combination of a 6.7 d half-life, lower energy β(-)-emissions (500 keV max; 130 keV ave), and an imagable γ-emission make (177)Lu an attractive candidate for radioimmunotherapy (RIT) regimens for treatment of larger tumor burdens not possible with α-zparticle radiation. Radiolabeling trastuzumab-CHX-A"-DTPA with (177)Lu was efficient with a specific binding of 60.8 ± 6.8% with HER2 positive SKOV-3 cells. Direct quantitation of tumor targeting and normal tissue uptake was performed with athymic mice bearing subcutaneous and intraperitoneal LS-174T xenografts; a peak tumor %ID/g of 24.70 ± 10.29 (96 h) and 31.70 ± 16.20 (72 h), respectively, was obtained. Normal tissue uptake of the RIC was minimal. Tumor targeting was also demonstrated by γ-scintigraphy. A therapy study administering escalating doses of (177)Lu-trastuzumab to mice bearing three day LS-174T i.p. xenografts established the effective therapeutic dose of i.p. administered (177)Lu-trastuzumab at 375 μCi with a median survival of 124.5 d while a median survival of 10 d was noted for the control (untreated) group. In conclusion, trastuzumab radiolabeled with (177)Lu has potential for treatment of disseminated, HER2 positive, peritoneal disease.

Development of the MICROMEGAS detector for measuring the energy spectrum of alpha particles by using a 241Am source

NASA Astrophysics Data System (ADS)

Kim, Do Yoon; Ham, Cheolmin; Shin, Jae Won; Park, Tae-Sun; Hong, Seung-Woo; Andriamonje, Samuel; Kadi, Yacine; Tenreiro, Claudio

2016-05-01

We have developed MICROMEGAS (MICRO MEsh GASeous) detectors for detecting a particles emitted from an 241Am standard source. The voltage applied to the ionization region of the detector is optimized for stable operation at room temperature and atmospheric pressure. The energy of a particles from the 241Am source can be varied by changing the flight path of the a particle from the 241Am source. The channel numbers of the experimentally-measured pulse peak positions for different energies of the a particles are associated with the energies deposited by the alpha particles in the ionization region of the detector as calculated by using GEANT4 simulations; thus, the energy calibration of the MICROMEGAS detector for a particles is done. For the energy calibration, the thickness of the ionization region is adjusted so that a particles may completely stop in the ionization region and their kinetic energies are fully deposited in the region. The efficiency of our MICROMEGAS detector for a particles under the present conditions is found to be ~97.3%.

Meta-[{sup 211}At]astatobenzylguanidine (MABG): In vivo evaluation in an athymic mouse human neuroblastoma xenograft model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vaidyanathan, G.; Friedman, H.S.; Keir, S.T.

1996-05-01

Because of the short range and high linear energy transfer of {sup 211}At {alpha}-particles, the MIBG analogue MABG might be useful for the therapy of micrometastatic neuroblastoma and previous in vitro studies have demonstrated that under single-cell conditions, the cytotoxicity of MABG is > 1000 times higher than [{sup 131}I]MIBG. A paired label protocol was used to compare the tissue distribution of MABG and [{sup 131}I]MIBG in athymic mice bearing subcutaneous SK-N-SH human neuroblastoma xenografts from 1-24 hr after injection. In tumor, significantly higher (p < 0.05) uptake was observed for MABG (3.8 {plus_minus} 0.8%ID/g vs 3.1 {plus_minus} 0.7%ID/g atmore » 8 hr). Pretreatment with desipramine reduced tumor uptake of MABG by 43%, suggesting that accumulation was related to the uptake-1 mechanism. Significantly higher uptake of MABG also was observed in normal tissue targets. For example, at 8 hr, heart uptake of MABG was 6.0 {plus_minus} 0.9 % ID/g compared with 4.5 {plus_minus} 0.8%ID/g for [{sup 131}I]MIBG. Two strategies were investigated to increase the tumor-to-hear uptake ratio. Pretreatment of mice with unlabeled MIBG (4 mg/kg) increased MABG tumor uptake by 1.5-fold while reducing uptake in several normal tissues including heart. The vesicular uptake blocker tetrabenazine (TBZ; 20 mg/kg), reduced MABG hear uptake by 30% of control values with not significant decrease in tumor levels. We conclude that MABG deserves further evaluation as a potential agent for the treatment of neuroblastoma, particularly in combination with strategies to minimize radiation dose to normal target tissues.« less

21 CFR 211.125 - Labeling issuance.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Labeling issuance. 211.125 Section 211.125 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Packaging and Labeling Control...

21 CFR 211.125 - Labeling issuance.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Labeling issuance. 211.125 Section 211.125 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Packaging and Labeling Control...

21 CFR 211.125 - Labeling issuance.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Labeling issuance. 211.125 Section 211.125 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Packaging and Labeling Control...

21 CFR 211.125 - Labeling issuance.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Labeling issuance. 211.125 Section 211.125 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Packaging and Labeling Control...

{sup 12}C formation: A classical quest in new light

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tengblad, O.; Alcorta, M.; Borge, M. J. G.

2011-10-28

In this work we have studied the break-up of {sup 12}C following the reactions {sup 10}B({sup 3}He,p{alpha}{alpha}{alpha}) and {sup 11}B({sup 3}He,d{alpha}{alpha}{alpha}). The study was performed at the 5 MV tandem in Madrid. The break-up gives us information on excited states in {sup 12}C from the famous Hoyle state up to an energy of almost 18 MeV. Using a highly segmented experimental set-up the simultaneous detection of the three alpha particles in coincidence with a proton or deuteron respectively made possible a full kinematic reconstruction of the break-up. On the basis of the energies of the 3 {alpha} particles and theirmore » angular correlations it has been possible to determine the spin and parity of states for cases in which the assignment has been doubtful. Some of these levels will also de-excite via electromagnetic emission. The comparison between the energy of proton that populate a state of {sup 12}C and the sum of the energies of the 3{alpha} emitted from the same state makes possible to determine the presence of electromagnetic disintegration ({gamma}) to lower states within {sup 12}C followed by the 3{alpha} break-up.« less

Feasibility Study and System Architecture of Radioisotope Thermoelectric Generation Power Systems for USMC Forward Operating Bases

DTIC Science & Technology

2013-06-01

isotopes decay primarily through alpha particle emission, a small critical mass will cause sustained nuclear chain reaction, emitting gamma neutron...viii 1. Strontium-90 (Example) ....................................................................33 a. Pure Radioisotope Mass to Produce 300W...Power .................33 b. Compound Mass to Produce 300W Power .............................33 c. Estimated cost to Produce 300W power at BOL

Single nucleotide polymorphism detection in aldehyde dehydrogenase 2 (ALDH2) gene using bacterial magnetic particles based on dissociation curve analysis.

PubMed

Maruyama, Kohei; Takeyama, Haruko; Nemoto, Etsuo; Tanaka, Tsuyoshi; Yoda, Kiyoshi; Matsunaga, Tadashi

2004-09-20

Single nucleotide polymorphism (SNP) detection for aldehyde dehydrogenase 2 (ALDH2) gene based on DNA thermal dissociation curve analysis was successfully demonstrated using an automated system with bacterial magnetic particles (BMPs) by developing a new method for avoiding light scattering caused by nanometer-size particles when using commercially available fluorescent dyes such as FITC, Cy3, and Cy5 as labeling chromophores. Biotin-labeled PCR products in ALDH2, two allele-specific probes (Cy3-labeled detection probe for ALDH2*1 and Cy5-labeled detection probe for ALDH2*2), streptavidin-immobilized BMPs (SA-BMPs) were simultaneously mixed. The mixture was denatured at 70 degrees C for 3 min, cooled slowly to 25 degrees C, and incubated for 10 min, allowing the DNA duplex to form between Cy3- or Cy5-labeled detection probes and biotin-labeled PCR products on SA-BMPs. Then duplex DNA-BMP complex was heated to 58 degrees C, a temperature determined by dissociation curve analysis and a dissociated single-base mismatched detection probe was removed at the same temperature under precise control. Furthermore, fluorescence signal from the detection probe was liberated into the supernatant from completely matched duplex DNA-BMP complex by heating to 80 degrees C and measured. In the homozygote target DNA (ALDH2*1/*1 and ALDH2*2/*2), the fluorescence signals from single-base mismatched were decreased to background level, indicating that mismatched hybridization was efficiently removed by the washing process. In the heterozygote target DNA (ALDH2*1/*2), each fluorescence signals was at a similar level. Therefore, three genotypes of SNP in ALDH2 gene were detected using the automated detection system with BMPs. Copyright 2004 Wiley Periodicals, Inc.

Pulse shape discrimination of plastic scintillator EJ 299-33 with radioactive sources

NASA Astrophysics Data System (ADS)

Pagano, E. V.; Chatterjee, M. B.; De Filippo, E.; Russotto, P.; Auditore, L.; Cardella, G.; Geraci, E.; Gnoffo, B.; Guazzoni, C.; Lanzalone, G.; De Luca, S.; Maiolino, C.; Martorana, N. S.; Pagano, A.; Papa, M.; Parsani, T.; Pirrone, S.; Politi, G.; Porto, F.; Quattrocchi, L.; Rizzo, F.; Trifirò, A.; Trimarchi, M.

2018-05-01

The present study has been carried out in order to investigate about the possibility of using EJ 299-33 scintillator in a multi-detector array to detect neutrons along with light charged particles. In a reaction induced by stable and exotic heavy-ions beams, where copious production of neutrons and other light charged particles occurs, discrimination with low identification threshold of these particles are of great importance. In view of this, EJ 299-33 scintillator having dimension of 3 cm × 3 cm × 3 cm backed by a photomultiplier tube was tested and used under vacuum to detect neutrons, gamma-rays and alpha particles emitted by radioactive sources. Anode pulses from the photomultiplier tube were digitized through GET electronics, recorded and stored in a data acquisition system for the purpose of an off-line analysis. The measurements, under vacuum and low background conditions, show good pulse shape discrimination properties characterized by low identification threshold for neutrons, gamma-rays and alpha particles. The Figures of Merit for neutron-gamma and alpha particles-gamma discriminations have been evaluated together with the energy resolution for gamma-ray and alpha particles.

Measured 19F(α,n) with VANDLE for Nuclear Safeguards

NASA Astrophysics Data System (ADS)

Peters, William; Clement, R. C. C.; Smith, M. S.; Pain, S.; Febbraro, M.; Pittman, S.; Thomspon, S.; Grinder, M.; Cizewski, J. A.; Reingold, C.; Manning, B.; Burcher, S.; Bardayan, D. W.; Tan, W.-P.; Stech, E.; Smith, M. K.; Avetisyan, R.; Gyurjinyan, A.; Lowe, M.; Ilyushkin, S.; Grzywacz, R.; Madurga, M.; Paulauskas, S. V.; Taylor, S. Z.; Smith, K.

2015-10-01

One of the most promising non-destructive assay (NDA) methods to monitor UF6 canisters consists of measuring gross neutron rates induced by uranium-decay alpha particles reacting with the fluorine and emitting a neutron. This method currently lacks reliable nuclear data on the 19F(α,n) reaction cross section to determine an accurate neutron yield rate for a given sample of UF6. We have measured the cross section and coincident neutron spectrum for the alpha-decay energy range using the VANDLE system. This experiment had two parts: first at Notre Dame with a LaF3 target and and a pulsed alpha-particle beam, and second at ORNL with a windowless He-gas target and a 19F beam. The motivation for this measurement and cross section results will be presented. This work is funded in part by the DOE Office of Science, the National Nuclear Security Administration SSAA and the Office of Defense Nuclear Nonproliferation R&D, and the NSF.

Modifications of the optical properties for DAM-ADC nuclear track detector exposed to alpha particles

NASA Astrophysics Data System (ADS)

Rammah, Y. S.; Awad, E. M.

2018-05-01

Modifications of the optical properties of diallyl maleate-allyl diglycol carbonate (DAM-ADC) nuclear detector induced by alpha particles are described. DAM-ADC samples were irradiated perpendicularly by thin 241Am disk source that emits alpha particles with 5.48 MeV. The optical absorption has been measured using the ultraviolet-visible (UV-1100) spectroscopy. It was found that DAM-ADC polymer shows substantial modifications in its optical characteristics upon irradiated with alpha particles with different energies. The optical energy band gap (Egap) for the detector was calculated for the direct and the indirect allowed transitions in K-space using two approaches (Tauc's model and absorption spectrum fitting (ASF) method). Urbach's energy (Ea), number of carbon atoms per conjugated length (N), number of carbon atoms per cluster (M), and refractive index (n) for the present samples were determined. Results reveal that the values of energy gap in direct transition are greater than those of indirect, before and after irradiation. (Egap), (Ea), (N), (M), and (n) of the present samples are changed significantly with irradiation time and value of alpha energy. Results reflect the possibility of using DAM-ADC polymer track detectors to estimate alpha particle energies using the variation of the absorbance.

Apparatus for detecting alpha radiation in difficult access areas

DOEpatents

Steadman, Peter; MacArthur, Duncan W.

1997-09-02

An electrostatic alpha radiation detector for measuring alpha radiation emitted from inside an enclosure comprising an electrically conductive expandable electrode for insertion into the enclosure. After insertion, the electrically conductive expandable electrode is insulated from the enclosure and defines a decay cavity between the electrically conductive expandable electrode and the enclosure so that air ions generated in the decay cavity are electrostatically captured by the electrically conductive expandable electrode and the enclosure when an electric potential is applied between the electrically conductive expandable electrode and the enclosure. Indicator means are attached to the electrically conductive expandable electrode for indicating an electrical current produced by generation of the air ions generated in the decay cavity by collisions between air molecules and the alpha particles emitted from the enclosure. A voltage source is connected between the indicator means and the electrically conductive enclosure for creating an electric field between the electrically conductive expandable electrode and the enclosure.

40 CFR 211.208 - Export provisions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Export provisions. 211.208 Section 211... PRODUCT NOISE LABELING Hearing Protective Devices § 211.208 Export provisions. (a) The outside of each package or container containing a hearing protective device intended solely for export must be so labeled...

Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study.

PubMed

Murthy, Rashmi; Borges, Virginia F; Conlin, Alison; Chaves, Jorge; Chamberlain, Marc; Gray, Todd; Vo, Alex; Hamilton, Erika

2018-05-24

Tucatinib is a potent and selective oral HER2 tyrosine kinase inhibitor, with the potential to provide a well tolerated new treatment option for patients whose disease has progressed on currently available therapies. We aimed to determine the recommended phase 2 dose, safety, pharmacokinetics, and preliminary activity of tucatinib in combination with capecitabine or trastuzumab in patients with HER2-positive breast cancer with or without brain metastases. In this non-randomised, open-label, phase 1b trial done in five sites in the USA, we recruited patients aged 18 years or older with HER2-positive progressive breast cancer who had been previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. Eligible patients required HER2-positivity assessed locally, evaluable lesions as defined per Response Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Tucatinib was administered twice a day in conjunction with capecitabine 1000 mg/m 2 orally twice a day for 14 days of a 21-day cycle, trastuzumab 6 mg/kg intravenously once every 21 days, or both. A modified 3 + 3 dose-escalation design was used to determine the recommended phase 2 dose, starting with tucatinib in combination with capecitabine or trastuzumab, and subsequently evaluating the triplet combination. The primary endpoint was to establish the maximum tolerated dose and recommended phase 2 dose of tucatinib, evaluated by toxicity assessments. Efficacy was assessed in all patients by contrast CT of the body. Analyses included all patients who had received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, number NCT02025192. Between Jan 15, 2014, and Dec 15, 2015, 60 patients were enrolled and treated. The current report is from mature data as of June 30, 2017. The tucatinib recommended phase 2 dose was determined to be 300 mg orally twice a day, equivalent to single-agent maximum tolerated dose. Pharmacokinetic analysis showed that there was no drug-drug interaction with capecitabine. Adverse events seen at the recommended phase 2 dose regardless of causality, grade, and treatment group included diarrhoea (35 [67%] of 52 patients), nausea (31 [60%] patients), palmar-plantar erythrodysaesthesia syndrome (23 [44%] patients), fatigue (20 [38%] patients), and vomiting (20 [38%] patients). In all patients, treatment-related toxicities of grade 3 and worse included fatigue (five [8%] patients), diarrhoea (four [7%] patients), and palmar-plantar erythrodysaesthesia (four [7%] patients). No treatment-related deaths were reported. The proportion of patients with measurable disease achieving objective response was 83% (five of six patients) in the combination of tucatinib with capecitabine, 40% (six of 15 patients) in the combination of tucatinib with trastuzumab, and 61% (14 of 23 patients) in the combination of tucatinib with both capecitabine and trastuzumab. Tucatinib in combination with capecitabine and trastuzumab had acceptable toxicity and showed preliminary anti-tumour activity. Validation of the current study results will be determined in the double-blinded randomised study, HER2CLIMB (ONT-380-206; NCT02614794). Cascadian Therapeutics, a wholly owned subsidiary of Seattle Genetics. Copyright © 2018 Elsevier Ltd. All rights reserved.

Radiation detector

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taleyarkhan, Rusi P.

Alpha particle detecting devices are disclosed that have a chamber that can hold a fluid in a tensioned metastable state. The chamber is tuned with a suitable fluid and tension such that alpha emitting materials such as radon and one or more of its decay products can be detected. The devices can be portable and can be placed in areas, such as rooms in dwellings or laboratories and used to measure radon in these areas, in situ and in real time. The disclosed detectors can detect radon at and below 4 pCi/L in air; also, at and below 4,000 pCi/Lmore » or 300 pCi/L in water.« less

Cleaning products and air fresheners: emissions and resulting concentrations of glycol ethers and terpenoids.

PubMed

Singer, B C; Destaillats, H; Hodgson, A T; Nazaroff, W W

2006-06-01

Experiments were conducted to quantify emissions and concentrations of glycol ethers and terpenoids from cleaning product and air freshener use in a 50-m3 room ventilated at approximately 0.5/h. Five cleaning products were applied full-strength (FS); three were additionally used in dilute solution. FS application of pine-oil cleaner (POC) yielded 1-h concentrations of 10-1300 microg/m3 for individual terpenoids, including alpha-terpinene (90-120), d-limonene (1000-1100), terpinolene (900-1300), and alpha-terpineol (260-700). One-hour concentrations of 2-butoxyethanol and/or d-limonene were 300-6000 microg/m3 after FS use of other products. During FS application including rinsing with sponge and wiping with towels, fractional emissions (mass volatilized/dispensed) of 2-butoxyethanol and d-limonene were 50-100% with towels retained, and approximately 25-50% when towels were removed after cleaning. Lower fractions (2-11%) resulted from dilute use. Fractional emissions of terpenes from FS use of POC were approximately 35-70% with towels retained, and 20-50% with towels removed. During floor cleaning with dilute solution of POC, 7-12% of dispensed terpenes were emitted. Terpene alcohols were emitted at lower fractions: 7-30% (FS, towels retained), 2-9% (FS, towels removed), and 2-5% (dilute). During air-freshener use, d-limonene, dihydromyrcenol, linalool, linalyl acetate, and beta-citronellol) were emitted at 35-180 mg/day over 3 days while air concentrations averaged 30-160 microg/m3. While effective cleaning can improve the healthfulness of indoor environments, this work shows that use of some consumer cleaning agents can yield high levels of volatile organic compounds, including glycol ethers--which are regulated toxic air contaminants--and terpenes that can react with ozone to form a variety of secondary pollutants including formaldehyde and ultrafine particles. Persons involved in cleaning, especially those who clean occupationally or often, might encounter excessive exposures to these pollutants owing to cleaning product emissions. Mitigation options include screening of product ingredients and increased ventilation during and after cleaning. Certain practices, such as the use of some products in dilute solution vs. full-strength and the prompt removal of cleaning supplies from occupied spaces, can reduce emissions and exposures to 2-butoxyethanol and other volatile constituents. Also, it may be prudent to limit use of products containing ozone-reactive constituents when indoor ozone concentrations are elevated either because of high ambient ozone levels or because of the indoor use of ozone-generating equipment.

An Alpha Proton X-Ray Spectrometer for Mars-96 and Mars Pathfinder

NASA Astrophysics Data System (ADS)

Rieder, R.; Wanke, H.; Economou, T.

1996-09-01

Mars Pathfinder and the Russian Mars-96 will carry an Alpha Proton X-Ray Spectrometer (APXS) for the determination of the chemical composition of Martian rocks and soil. The instrument will measure the concentration of all major and many minor elements, including C,N and O, at levels above typically 1%. The method employed consist of bombarding a sample of 50 mm diameter with alpha particles from a radioactive source (50 mCi of Cm-244) and measuring: (i) backscattered alpha particles (alpha mode) (ii) protons from (a,p) reactions with some light elements (proton mode) (iii) characteristic X-rays emitted from the sample (X-ray mode). The APXS has a long standing space heritage, going back to Surveyor V,VI and VII (1967/68) and the Soviet Phobos (1988) missions. The present design is the result of an endeavour to reduce mass and power consumption to 600g/ 300mW. It consist of a sensor head containing the alpha sources, a telescope of a silicon detectors for the detection of the alpha particles and protons and a separate X-ray detector with its preamplifier, and an electronics box (80x70x60 mm) containing a microcontroller based multichannel spectrometer. The paper will describe the APXS flight hardware and present results obtained with the flight instrument that will show the instrument capabili- ties and the expected results to be obtained during surface operations on Mars.

Radiation from plutonium 238 used in space applications

NASA Technical Reports Server (NTRS)

Keenan, T. K.; Vallee, R. E.; Powers, J. A.

1972-01-01

The principal mode of the nuclear decay of plutonium 238 is by alpha particle emission at a rate of 17 curies per gram. Gamma radiation also present in nuclear fuels arises primarily from the nuclear de-excitation of daughter nuclei as a result of the alpha decay of plutonium 238 and reactor-produced impurities. Plutonium 238 has a spontaneous fission half life of 4.8 x 10 to the 10th power years. Neutrons associated with this spontaneous fission are emitted at a rate of 28,000 neutrons per second per gram. Since the space fuel form of plutonium 238 is the oxide pressed into a cermet with molybdenum, a contribution to the neutron emission rate arises from (alpha, n) reactions with 0-17 and 0-18 which occur in natural oxygen.

Effect of Alpha-Particle Irradiation on Brain Glycogen in the Rat

NASA Technical Reports Server (NTRS)

Wolfe, L. S.; Klatzo, Igor; Miquel, Jaime; Tobias, Cornelius; Haymaker, Webb

1962-01-01

The studies of Klatzo, Miquel, Tobias and Haymaker (1961) have shown that one of the earliest and most sensitive indications of the effects of alpha-particle irradiation on rat bran is the appearance of glycogen granules mainly in the neuroglia of the exposed area of the brain. Periodic acid-Schiff (PAS) positive, alpha-amylase soluble granules were demonstrated within 12 hr after irradiation, preceding by approximately 36 hr the first microscopically detectable vascular permeability disturbances, as shown by the fluorescein labeled serum protein technique. These studies suggested that the injurious effects of alpha-particle energy were on cellular elements primarily, according to the physical properties and distribution of the radiation in the tissue, and that the vascular permeability disturbances played a secondary role in pathogenesis. The purpose of this study was to correlate the histochemical observations on glycogen with a quantitative assessment of the glycogen in the irradiated brain tissue. It is felt that such a study may contribute to the understanding of radiation injury at the molecular level. A practical aspect of this problem is that the information on biological radiation effects due to accelerated particles from the cyclotron source, is employed in this study, is applicable to radiation from cosmic particles both in free space and entrapped in the Van Allen belts.

The microdistribution of α-active nuclides in the human lung

NASA Astrophysics Data System (ADS)

Henshaw, D. L.; Fews, A. P.

1984-06-01

Elsewhere (refs. [4,5]) the authors have discussed new and elaborate techniques for alpha-particle autoradiography using the nuclear track detector CR-39. These techniques are at present being applied in a major study of the microdistribution of alpha-active nuclides in the human lung. Whole lungs with trachea are obtained at autopsy. Case histories representing a wide spectrum of lung burden are sought but that from the general population serves as a baseline from which all abnormal levels may be compared. The lungs are dissected, loaded against CR-39 and stored deep frozen for 3-20 months. Subsequent analysis of the autoradiograph reveals: (i) The microdistribution of activity. This includes for example the pattern of deposition around the tracheal bifurcation and across the tracheal wall for both the total activity and separately that due to 222Rn + daughter nuclei and, the distribution of single and multiple decays from single points over the storage period of the autoradiograph. The information enables the frequency of single and multiple hits to sensitive cells in the lung to be calculated. This is an important step in estimating the frequency of radiation induced mutations. (ii) The absolute abundance of alpha-active nuclides present at each site. This quantity is determined at particular locations in lung such as bifurcations in the major airways, in corresponding positions on the posterior aspect of the trachea and bronchus and parenchymal lung for each of the five lobes and in the lymph nodes. The information is obtained in normal lung over a wide span of age. This overall information may be used to study the deposition, retention and clearance patterns of different alpha-emitting elements with associated differences in size and physical and chemical nature. These studies in normal lung may provide new information on the mechanism at work in lung for the clearance of particulate matter. They may also be used to predict the behaviour of inhaled alpha-particulate matter in lung and perform microdosimetric calculations. This information may be applied to cases of occupational exposure to alpha-emitting particles such as plutonium.

Comparative biokinetics of trivalent radionuclides with similar ionic dimensions: promethium-147, curium-242 and americium-241.

PubMed

Priest, N D

2007-09-01

Data on the distribution and redistribution patterns in the laboratory rat of three trivalent elements with a similar ionic radius have been compared. This showed that these distributions for the two ions with the same ionic radius (111 pm), i.e., those of promethium (a lanthanoid) and curium (an actinoid), were indistinguishable and that americium, with a slightly larger ion size (111.5 pm), behaved similarly. The results are consistent with the suggestion that ion size is the only important factor controlling the deposition and redistribution patterns of trivalent lanthanoids and actinoids in rats. The result is important because it suggests that the same radiological protection dosimetry models should be used for trivalent actinoids and lanthanoids, that human volunteer data generated for lanthanoid isotopes can be used to predict the behavior of actinoids with the same ion size, and that appropriate pairs of beta-particle-emitting lanthanoid and alpha-particle-emitting actinoids could be used to study the relative toxicity of alpha and beta particles in experimental animals.

21 CFR 211.130 - Packaging and labeling operations.

Code of Federal Regulations, 2010 CFR

2010-04-01

... (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Packaging and Labeling Control § 211.130 Packaging and labeling operations. There shall be written procedures designed to... manufacture and control of the batch. (d) Examination of packaging and labeling materials for suitability and...

Design, fabrication and calibration of alpha particle densitometers for measuring planetary atmospheric density

NASA Technical Reports Server (NTRS)

Sellers, B.; Hunerwadel, J. L.; Hanser, F. A.

1972-01-01

An alpha particle densitometer was developed for possible application to measurement of the atmospheric density-altitude profile on Martian entry. The device uses an Am-241 radioactive-foil source, which emits a distributed energy spectrum, located about 25 to 75 cm from a semiconductor detector. System response - defined as the number of alphas per second reaching the detector with energy above a fixed threshold - is given for Ar and CO2. The altitude profile of density measurement accuracy is given for a pure CO2 atmosphere with 5 mb surface pressure. The entire unit, including dc-dc converters, requires less than 350 milliwatts of power from +28 volts, weighs about 0.85 lb and occupies less than 15 cubic inches volume.

Influence of environmental factors and air composition on the emission of {alpha}-pinene from Quercus ilex leaves

DOE Office of Scientific and Technical Information (OSTI.GOV)

Loreto, F.; Tricoli, D.; Ciccioli, P.

1996-01-01

We studied the emission of {alpha}-pinene from Quercus ilex leaves. Only the abaxial side of the hypostomatous Q. ilex leaf emits {alpha}-pinene. Light induced photosynthesis and {alpha}-pinene emission. However, the response of photosynthesis to dark-to-light transitions was faster than that of {alpha}-pinene, suggesting that ATP controls the emission. The emission was higher at 30 than at 20{degrees}C, whereas photosynthesis did not change. Therefore, the relationship between photosynthesis and {alpha}-pinene emission does not always hold. When CO{sub 2} was removed from the air, transpiration was stimulated and transpiration was reduced, but {alpha}-pinene emission was unaffected. Therefore, the emission depends on themore » availability of photosynthetic carbon, is not saturated at ambient CO{sub 2}, and is not dependent on stomatal opening. The pattern of {alpha}-pinene emission from Q. ilex is different from that of plants having specialized structures for storage and emission of terpenes. We suggest that {alpha}-pinene emitted by Q. ilex leaves is synthesized in the chloroplasts and shares the same biochemical pathway with isoprene emitted by isoprene-emitting oak species. 28 refs., 8 figs., 1 tab.« less

Targets for production of the medical radioisotopes with alpha and proton or deuteron beams

NASA Astrophysics Data System (ADS)

Stolarz, Anna; Kowalska, J. A.; Jastrzebski, J.; Choiński, J.; Sitarz, M.; Szkliniarz, K.; Trzcińska, A.; Zipper, W.

2018-05-01

The research quantities of some medical radioisotopes were produced in reactions induced by 32 MeV internal alpha beam (211At, Sc isotopes), 16 MeV and 28 MeV proton beams (Sc isotopes) and 8 MeV deuteron beam (Sc isotopes). The frame-less targets used for irradiation with internal alpha beam were prepared from elemental (Bi for 211At) and compound (CaCO3 for Sc radioisotopes) materials. The CaCO3 powder targets were also used for production of Sc radioisotopes with proton or deuteron external beams. Methods developed for preparation of the targets suitable for the irradiating beam type are described in this work.

Application of proton boron fusion reaction to radiation therapy: A Monte Carlo simulation study

NASA Astrophysics Data System (ADS)

Yoon, Do-Kun; Jung, Joo-Young; Suh, Tae Suk

2014-12-01

Three alpha particles are emitted from the point of reaction between a proton and boron. The alpha particles are effective in inducing the death of a tumor cell. After boron is accumulated in the tumor region, the emitted from outside the body proton can react with the boron in the tumor region. An increase of the proton's maximum dose level is caused by the boron and only the tumor cell is damaged more critically. In addition, a prompt gamma ray is emitted from the proton boron reaction point. Here, we show that the effectiveness of the proton boron fusion therapy was verified using Monte Carlo simulations. We found that a dramatic increase by more than half of the proton's maximum dose level was induced by the boron in the tumor region. This increase occurred only when the proton's maximum dose point was located within the boron uptake region. In addition, the 719 keV prompt gamma ray peak produced by the proton boron fusion reaction was positively detected. This therapy method features the advantages such as the application of Bragg-peak to the therapy, the accurate targeting of tumor, improved therapy effects, and the monitoring of the therapy region during treatment.

N-Succinimidyl guanidinomethyl iodobenzoate protein radiohalogenation agents: Influence of isomeric substitution on radiolabeling and target cell residualization

PubMed Central

Choi, Jaeyeon; Vaidyanathan, Ganesan; Koumarianou, Eftychia; McDougald, Darryl; Pruszynski, Marek; Osada, Takuya; Lahoutte, Tony; Lyerly, H. Kim; Zalutsky, Michael R.

2014-01-01

Introduction N-succinimidyl 4-guanidinomethyl-3-[*I]iodobenzoate ([*I]SGMIB) has shown promise for the radioiodination of monoclonal antibodies (mAbs) and other proteins that undergo extensive internalization after receptor binding, enhancing tumor targeting compared to direct electrophilic radioiodination. However, radiochemical yields for [131I]SGMIB synthesis are low, which we hypothesize is due to steric hindrance from the Boc-protected guanidinomethyl group ortho to the tin moiety. To overcome this, we developed the isomeric compound, N-succinimidyl 3-guanidinomethyl-5-[131I]iodobenzoate (iso-[131I]SGMIB) wherein this bulky group was moved from ortho to meta position. Methods Boc2-iso-SGMIB standard and its tin precursor, N-succinimidyl 3-((1,2-bis(tert-butoxycarbonyl)guanidino)methyl)-5-(trimethylstannyl)benzoate (Boc2-iso-SGMTB), were synthesized using two disparate routes, and iso-[*I]SGMIB synthesized from the tin precursor. Two HER2-targeted vectors — trastuzumab (Tras) and a nanobody 5F7 (Nb) — were labeled using iso-[*I]SGMIB and [*I]SGMIB. Paired-label internalization assays in vitro with both proteins, and biodistribution in vivo with trastuzumab, labeled using the two isomeric prosthetic agents were performed. Results When the reactions were performed under identical conditions, radioiodination yields for the synthesis of Boc2-iso-[131I]SGMIB were significantly higher than those for Boc2-[131I]SGMIB (70.7 ± 2.0% vs 56.5 ± 5.5%). With both Nb and trastuzumab, conjugation efficiency also was higher with iso-[131I]SGMIB than with [131I]SGMIB (Nb, 33.1 ± 7.1% vs 28.9 ± 13.0%; Tras, 45.1 ± 4.5% vs 34.8 ± 10.3%); however, the differences were not statistically significant. Internalization assays performed on BT474 cells with 5F7 Nb indicated similar residualizing capacity over 6 h; however, at 24 h, radioactivity retained intracellularly for iso-[131I]SGMIB-Nb was lower than for [125I]SGMIB-Nb (46.4 ± 1.3% vs 56.5 ± 2.5%); similar results were obtained using Tras. Likewise, a paired-label biodistribution of Tras labeled using iso-[125I]SGMIB and [131I]SGMIB indicated an up to 22% tumor uptake advantage at later time points for [131I]SGMIB-Tras. Conclusion Given the higher labeling efficiency obtained with iso-SGMIB, this residualizing agent might be of value for use with shorter half-life radiohalogens. PMID:25156548

Interleukin-1beta-induced hyperresponsiveness to [Sar9,Met(O2)11]substance P in isolated human bronchi.

PubMed

Barchasz, E; Naline, E; Molimard, M; Moreau, J; Georges, O; Emonds-Alt, X; Advenier, C

1999-08-20

Interleukin-1beta has been reported to induce airway hyperresponsiveness in several animal models. In this study, we have investigated whether interleukin-1beta was able to potentiate the contractions of human isolated small bronchi (internal diameter < or = 1 mm) provoked by a specific tachykinin NK1 receptor agonist, [Sar9,Met(O2)11]substance P. Pre-incubation of human isolated small bronchi with interleukin-1beta (10 ng/ml, in Krebs-Henseleit solution, at 21 degrees C for 15 h) potentiated the contractile response to [Sar9,Met(O2)11]substance P. It also increased the [Sar9,Met(O2)11]substance P-induced release of thromboxane B2, the stable metabolite of thromboxane A2. Indomethacin (10(-6) M), a non-specific cyclooxygenase inhibitor, or GR 32191 ((1R-(1alpha(Z)),2beta,3beta,5alpha))-(+)-7-(5-(((1,1' -biphenyl)-4-yl)-methoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-hept enoic acid, hydrochloride) (10(-6) M), a prostanoid TP-receptor antagonist, blocked the contractions induced by [Sar9,Met(O2)11]substance P both in control experiments and after interleukin-1beta pre-treatment, indicating that prostanoids and thromboxane receptors are directly implicated in the [Sar9,Met(O2)11]substance P-induced contractile response. The thromboxane mimetic U-46619 (10(-8)-10(-6) M) (9,11-dideoxy-11alpha,9alpha-epoxymethano-prostaglandin F2alpha)-induced contractions of human isolated small bronchi were not enhanced by interleukin-1beta pre-treatment, suggesting that no up-regulation of thromboxane receptors occurred. Furthermore, the cyclooxygenase-2 inhibitor CGP 28238 (6-(2,4-difluorophenoxy)-5-methyl-sulfonylamino-1-indanon e) (10(-6) M) had no direct effect on [Sar9,Met(O2)11]substance P-provoked contractions, but inhibited the interleukin-1beta-induced potentiation of [Sar9,Met(O2)11]substance P response. In conclusion, our results show that interleukin-1beta pre-treatment is able to potentiate the contractions of isolated human small bronchi provoked by [Sar9,Met(O2)11]substance P both by increasing prostanoid synthesis and by inducing a cyclooxygenase-2 pathway.

Apparatus for detecting alpha radiation in difficult access areas

DOEpatents

Steadman, P.; MacArthur, D.W.

1997-09-02

An electrostatic alpha radiation detector for measuring alpha radiation emitted from inside an enclosure comprising an electrically conductive expandable electrode for insertion into the enclosure is disclosed. After insertion, the electrically conductive expandable electrode is insulated from the enclosure and defines a decay cavity between the electrically conductive expandable electrode and the enclosure so that air ions generated in the decay cavity are electrostatically captured by the electrically conductive expandable electrode and the enclosure when an electric potential is applied between the electrically conductive expandable electrode and the enclosure. Indicator means are attached to the electrically conductive expandable electrode for indicating an electrical current produced by generation of the air ions generated in the decay cavity by collisions between air molecules and the alpha particles emitted from the enclosure. A voltage source is connected between the indicator means and the electrically conductive enclosure for creating an electric field between the electrically conductive expandable electrode and the enclosure. 4 figs.

Patritumab plus trastuzumab and paclitaxel in human epidermal growth factor receptor 2-overexpressing metastatic breast cancer.

PubMed

Mukai, Hirofumi; Saeki, Toshiaki; Aogi, Kenjiro; Naito, Yoichi; Matsubara, Nobuaki; Shigekawa, Takashi; Ueda, Shigeto; Takashima, Seiki; Hara, Fumikata; Yamashita, Tomonari; Ohwada, Shoichi; Sasaki, Yasutsuna

2016-10-01

Human epidermal growth factor receptor 3 (HER3) expression in lung and breast cancers has a negative impact on survival. Patritumab, a human anti-HER3 mAb, has shown anticancer activity in preclinical models. This study examined the safety and pharmacokinetics of patritumab in combination with trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer. In this open-label, multicenter, dose-escalation, phase Ib study, patients received patritumab 9 or 18 mg/kg plus trastuzumab and paclitaxel at known tolerated doses. Safety and tolerability were assessed based on dose-limiting toxicities and other non-life threatening adverse events. The pharmacokinetic profile for patritumab was determined based on the target trough level. Clinical efficacy was evaluated based on the overall response rate and progression-free survival. Six patients received patritumab 9 mg/kg and 12 received 18 mg/kg. The most common adverse events were diarrhea, alopecia, leukopenia, neutropenia, and maculopapular rash. No dose-limiting toxicities were observed. The target trough serum concentration was achieved in all patients at a dose of 18 mg/kg. Overall response rate was 38.9% and median progression-free survival was 274 days. In conclusion, patritumab plus trastuzumab and paclitaxel was tolerable and efficacious at both doses. We recommend the dose level of 18 mg/kg for future phase II studies. (Clinical trial registration: JapicCTI-121772.). © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Anisotropic Cell Expansion Is Affected through the Bidirectional Mobility of Cellulose Synthase Complexes and Phosphorylation at Two Critical Residues on CESA31[OPEN

PubMed Central

Liu, Yanmei; Bauer, Stefan

2016-01-01

Here we report that phosphorylation status of S211 and T212 of the CESA3 component of Arabidopsis (Arabidopsis thaliana) cellulose synthase impacts the regulation of anisotropic cell expansion as well as cellulose synthesis and deposition and microtubule-dependent bidirectional mobility of CESA complexes. Mutation of S211 to Ala caused a significant decrease in the length of etiolated hypocotyls and primary roots, while root hairs were not significantly affected. By contrast, the S211E mutation stunted the growth of root hairs, but primary roots were not significantly affected. Similarly, T212E caused a decrease in the length of root hairs but not root length. However, T212E stunted the growth of etiolated hypocotyls. Live-cell imaging of fluorescently labeled CESA showed that the rate of movement of CESA particles was directionally asymmetric in etiolated hypocotyls of S211A and T212E mutants, while similar bidirectional velocities were observed with the wild-type control and S211E and T212A mutant lines. Analysis of cell wall composition and the innermost layer of cell wall suggests a role for phosphorylation of CESA3 S211 and T212 in cellulose aggregation into fibrillar bundles. These results suggest that microtubule-guided bidirectional mobility of CESA complexes is fine-tuned by phosphorylation of CESA3 S211 and T212, which may, in turn, modulate cellulose synthesis and organization, resulting in or contributing to the observed defects of anisotropic cell expansion. PMID:26969722

Alpha imaging confirmed efficient targeting of CD45-positive cells after astatine-211 (211At)-radioimmunotherapy for hematopoietic cell transplantation

PubMed Central

Frost, Sofia H.L.; Miller, Brian W.; Bäck, Tom A.; Santos, Erlinda B.; Hamlin, Donald K.; Knoblaugh, Sue E.; Frayo, Shani L.; Kenoyer, Aimee L.; Storb, Rainer; Press, Oliver W.; Wilbur, D. Scott; Pagel, John M.; Sandmaier, Brenda M.

2015-01-01

Alpha-radioimmunotherapy targeting CD45 may substitute for total body irradiation in hematopoietic cell transplantation (HCT) preparative regimens for lymphoma. Our goal was to optimize the anti-CD45 monoclonal antibody (MAb; CA12.10C12) protein dose for astatine-211 (211At)-radioimmunotherapy, extending the analysis to include intra-organ 211At activity distribution and α-imaging-based small-scale dosimetry, along with immunohistochemical staining. Methods Eight normal dogs were injected with either 0.75 (n=5) or 1.00 mg/kg (n=3) of 211At-B10-CA12.10C12 (11.5–27.6 MBq/kg). Two were euthanized and necropsied 19–22 hours post injection (p.i.), and six received autologous HCT three days after 211At-radioimmunotherapy, following lymph node and bone marrow biopsies at 2–4 and/or 19 hours p.i. Blood was sampled to study toxicity and clearance; CD45 targeting was evaluated by flow cytometry. 211At localization and small-scale dosimetry were assessed using two α-imaging systems: α-camera and iQID. Results Uptake of 211At was highest in spleen (0.31–0.61 %IA/g), lymph nodes (0.02–0.16 %IA/g), liver (0.11–0.12 %IA/g), and marrow (0.06–0.08 %IA/g). Lymphocytes in blood and marrow were efficiently targeted using either MAb dose. Lymph nodes remained unsaturated, but displayed targeted 211At localization in T lymphocyte-rich areas. Absorbed doses to blood, marrow, and lymph nodes were estimated at 3.1, 2.4, and 3.4 Gy/166 MBq, respectively. All transplanted dogs experienced transient hepatic toxicity. Liver enzyme levels were temporarily elevated in 5 of 6 dogs; 1 treated with 1.00 mg MAb/kg developed ascites and was euthanized 136 days after HCT. Conclusion 211At-anti-CD45 radioimmunotherapy with 0.75 mg MAb/kg efficiently targeted blood and marrow without severe toxicity. Dosimetry calculations and observed radiation-induced effects indicated that sufficient 211At-B10-CA12.10C12 localization was achieved for efficient conditioning for HCT. PMID:26338894

Anomaly in the quiet-time helium spectrum at 1 MeV per nucleon

NASA Technical Reports Server (NTRS)

Gloeckler, G.; Hovestadt, D.; Klecker, B.; Vollmer, O.; Fan, C. Y.

1975-01-01

An unusual spectral feature and anomalously large abundance of helium between 0.6 and approximately 2 MeV per nucleon observed during the most quiet time periods in 1974 and 1975 indicate the presence of low energy helium of an unknown origin. Alphas below 0.6 MeV per nucleon and protons below 1.5 MeV have an E to the minus 1.8 power spectrum and the proton to alpha ratio is about 30. These less than or equal 1 MeV particles are found to be emitted continuously by the sun even during its most inactive periods.

Far-Red Fluorescent Lipid-Polymer Probes for an Efficient Labeling of Enveloped Viruses.

PubMed

Lacour, William; Adjili, Salim; Blaising, Julie; Favier, Arnaud; Monier, Karine; Mezhoud, Sarra; Ladavière, Catherine; Place, Christophe; Pécheur, Eve-Isabelle; Charreyre, Marie-Thérèse

2016-08-01

Far-red emitting fluorescent lipid probes are desirable to label enveloped viruses, for their efficient tracking by optical microscopy inside autofluorescent cells. Most used probes are rapidly released from membranes, leading to fluorescence signal decay and loss of contrast. Here, water-soluble lipid-polymer probes are synthesized harboring hydrophilic or hydrophobic far-red emitting dyes, and exhibiting enhanced brightness. They efficiently label Hepatitis C Virus pseudotyped particles (HCVpp), more stably and reproducibly than commercial probes, and a strong fluorescence signal is observed with a high contrast. Labeling with such probes do not alter virion morphology, integrity, nor infectivity. Finally, it is shown by fluorescence microscopy that these probes enable efficient tracking of labeled HCVpp inside hepatocarcinoma cells used as model hepatocytes, in spite of their autofluorescence up to 700 nm. These novel fluorescent lipid-polymer probes should therefore enable a better characterization of early stages of infection of autofluorescent cells by enveloped viruses. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

POLONIUM-210: A VOLATILE RADIOELEMENT IN CIGARETTES.

PubMed

RADFORD, E P; HUNT, V R

1964-01-17

Polonium-210, which emits alpha particles, is a natural contaminant of tobacco. For an individual smoking two packages of cigarettes a day, the radiation dose to bronchial epithelium from Po(210) inhaled in cigarette smoke probably is at least seven times that from background sources, and in localized areas may be up to 1000 rem or more in 25 years. Radiation from this source may, therefore, be significant in the genesis of bronchial cancer in smokers.

21 CFR 211.130 - Packaging and labeling operations.

Code of Federal Regulations, 2014 CFR

2014-04-01

...) Identification of the drug product with a lot or control number that permits determination of the history of the... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Packaging and labeling operations. 211.130 Section 211.130 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

21 CFR 211.130 - Packaging and labeling operations.

Code of Federal Regulations, 2012 CFR

2012-04-01

...) Identification of the drug product with a lot or control number that permits determination of the history of the... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Packaging and labeling operations. 211.130 Section 211.130 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

21 CFR 211.130 - Packaging and labeling operations.

Code of Federal Regulations, 2011 CFR

2011-04-01

...) Identification of the drug product with a lot or control number that permits determination of the history of the... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Packaging and labeling operations. 211.130 Section 211.130 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

21 CFR 211.130 - Packaging and labeling operations.

Code of Federal Regulations, 2013 CFR

2013-04-01

...) Identification of the drug product with a lot or control number that permits determination of the history of the... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Packaging and labeling operations. 211.130 Section 211.130 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

Alpha and conversion electron spectroscopy of 238,239Pu and 241Am and alpha-conversion electron coincidence measurements

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dion, Michael P.; Miller, Brian W.; Warren, Glen A.

2016-09-01

A technique to determine the isotopics of a mixed actinide sample has been proposed by measuring the coincidence of the alpha particle during radioactive decay with the conversion electron (or Auger) emitted during the relaxation of the daughter isotope. This presents a unique signature to allow the deconvolution of isotopes that possess overlapping alpha particle energy. The work presented here are results of conversion electron spectroscopy of 241Am, 238Pu and 239Pu using a dual-stage peltier-cooled 25 mm2 silicon drift detector. A passivated ion implanted planar silicon detector provided measurements of alpha spectroscopy. The conversion electron spectra were evaluated from 20–55more » keV based on fits to the dominant conversion electron emissions, which allowed the relative conversion electron emission intensities to be determined. These measurements provide crucial singles spectral information to aid in the coincident measurement approach.« less

Local Control of Lung Derived Tumors by Diffusing Alpha-Emitting Atoms Released From Intratumoral Wires Loaded With Radium-224

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cooks, Tomer; Schmidt, Michael; Bittan, Hadas

2009-07-01

Purpose: Diffusing alpha-emitters radiation therapy (DART) is a new form of brachytherapy enabling the treatment of solid tumors with alpha radiation. The present study examines the antitumoral effects resulting from the release of alpha emitting radioisotopes into solid lung carcinoma (LL2, A427, and NCI-H520). Methods and Materials: An in vitro setup tested the dose-dependent killing of tumor cells exposed to alpha particles. In in vivo studies, radioactive wires (0.3 mm diameter, 5 mm long) with {sup 224}Ra activities in the range of 21-38 kBq were inserted into LL/2 tumors in C57BL/6 mice and into human-derived A427 or NCI-H520 tumors inmore » athymic mice. The efficacy of the short-lived daughters of {sup 224}Ra to produce tumor growth retardation and prolong life was assessed, and the spread of radioisotopes inside tumors was measured using autoradiography. Results: The insertion of a single DART wire into the center of 6- to 7-mm tumors had a pronounced retardation effect on tumor growth, leading to a significant inhibition of 49% (LL2) and 93% (A427) in tumor development and prolongations of 48% (LL2) in life expectancy. In the human model, more than 80% of the treated tumors disappeared or shrunk. Autoradiographic analysis of the treated sectioned tissue revealed the intratumoral distribution of the radioisotopes, and histological analysis showed corresponding areas of necrosis. In vitro experiments demonstrated a dose-dependent killing of tumors cells exposed to alpha particles. Conclusions: Short-lived diffusing alpha-emitters produced tumor growth retardation and increased survival in mice bearing lung tumor implants. These results justify further investigations with improved dose distributions.« less

Phase II Study of S-1 plus Trastuzumab for HER2-positive Metastatic Breast Cancer (GBCCSG-01).

PubMed

Fujii, Takaaki; Horiguchi, Jun; Yanagita, Yasuhiro; Koibuchi, Yukio; Ikeda, Fumihiro; Uchida, Nobuyuki; Kimura, Morihiko

2018-02-01

Treatment strategies for patients with human epidermal growth factor 2 (HER2)-positive metastatic breast cancer (MBC) have significantly progressed. The use of trastuzumab, a monoclonal antibody targeting the HER2 (human epidermal growth factor 2) protein, in combination with chemotherapy improves survival in patients with HER2-positive breast cancer. S-1, an oral combination of fluorouracil derivatives, is widely used in Japan and is more convenient than intravenous drugs. However, little is known about the combination of S-1 and trastuzumab in patients with HER2-positive MBC. We conducted a single-arm, open-label, multicenter prospective phase II study to evaluate the efficacy of an S-1 plus trastuzumab regimen for HER2-positive MBC. S-1 was administered orally [80-120 mg, based on body surface area (BSA)] twice a day for 14 consecutive days in a 3-week cycle. Patients with BSA of <1.25 m 2 received a total of 80 mg of S-1, those with BSA ≥1.5 m 2 received 120 mg, and the remaining received 100 mg daily in two divided doses. Trastuzumab was administered intravenously at 8 mg/kg on day 1 of the first cycle and at 6 mg/kg on day 1 of subsequent cycles, i.e., every 3 weeks. Between December 2008 and March 2013, 10 patients were enrolled and received a median of 17 (range=3-76) cycles of treatment. Overall response and clinical benefit rates were 60.0% and 90.0%, respectively. Progression-free survival was 15.8 (95% confidence interval=9.4-29.6) months and overall survival was 45.5 (95% confidence interval=37.1-62.2) months. Grade 3/4 adverse events included were neutropenia and hyperglycemia in one patient each (10.0%). There was no clinically significant cardiotoxicity. The combination of S-1 and trastuzumab was tolerable and had excellent efficacy with good response and disease control in this study. S-1 plus anti-HER2 therapy is a feasible treatment option for HER2-positive MBC. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Neratinib Plus Paclitaxel vs Trastuzumab Plus Paclitaxel in Previously Untreated Metastatic ERBB2-Positive Breast Cancer: The NEfERT-T Randomized Clinical Trial.

PubMed

Awada, Ahmad; Colomer, Ramon; Inoue, Kenichi; Bondarenko, Igor; Badwe, Rajendra A; Demetriou, Georgia; Lee, Soo-Chin; Mehta, Ajay O; Kim, Sung-Bae; Bachelot, Thomas; Goswami, Chanchal; Deo, Suryanarayan; Bose, Ron; Wong, Alvin; Xu, Feng; Yao, Bin; Bryce, Richard; Carey, Lisa A

2016-12-01

Efficacious ERBB2 (formerly HER2 or HER2/neu)-directed treatments, in addition to trastuzumab and lapatinib, are needed. To determine whether neratinib, an irreversible pan-ERBB tyrosine kinase inhibitor, plus paclitaxel improves progression-free survival compared with trastuzumab plus paclitaxel in the first-line treatment of recurrent and/or metastatic ERBB2-positive breast cancer. In the randomized, controlled, open-label NEfERT-T trial conducted from August 2009 to December 2014 at 188 centers in 34 countries in Europe, Asia, Africa, and North America, 479 women with previously untreated recurrent and/or metastatic ERBB2-positive breast cancer were randomized to 1 of 2 treatment arms (neratinib-paclitaxel [n = 242] or trastuzumab-paclitaxel [n = 237]). Women with asymptomatic central nervous system metastases were eligible, and randomization was stratified by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Women received neratinib (240 mg/d orally) or trastuzumab (4 mg/kg then 2 mg/kg weekly), each combined with paclitaxel (80 mg/m2 on days 1, 8, and 15 every 28 days). Primary prophylaxis for diarrhea was not mandatory. The primary outcome was progression-free survival. Secondary end points were response rate, clinical benefit rate, duration of response, frequency, and time to symptomatic and/or progressive central nervous system lesions, and safety. The intent-to-treat population comprised 479 women 18 years or older (neratinib-paclitaxel, n = 242; trastuzumab-paclitaxel, n = 237) randomized and stratified in their respective treatment arms by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Median progression-free survival was 12.9 months (95% CI, 11.1-14.9) with neratinib-paclitaxel and 12.9 months (95% CI, 11.1-14.8) with trastuzumab-paclitaxel (hazard ratio [HR], 1.02; 95% CI, 0.81-1.27; P =.89). With neratinib-paclitaxel, the incidence of central nervous system recurrences was lower (relative risk, 0.48; 95% CI, 0.29-0.79; P = .002) and time to central nervous system metastases delayed (HR, 0.45; 95% CI, 0.26-0.78; P = .004). Common grade 3 to 4 adverse events were diarrhea (73 of 240 patients [30.4%] with neratinib-paclitaxel and 9 of 234 patients [3.8%] with trastuzumab-paclitaxel), neutropenia (31 patients [12.9%] vs 34 patients [14.5%]) and leukopenia (19 patients [7.9%] vs 25 patients [10.7%]); no grade 4 diarrhea was observed. In first-line ERBB2-positive metastatic breast cancer, neratinib-paclitaxel was not superior to trastuzumab-paclitaxel in terms of progression-free survival. In spite of similar overall efficacy, neratinib-paclitaxel may delay the onset and reduce the frequency of central nervous system progression, a finding that requires a larger study to confirm. clinicaltrials.gov Identifier: NCT00915018.

40 CFR 600.211-08 - Sample calculation of fuel economy values for labeling.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 29 2010-07-01 2010-07-01 false Sample calculation of fuel economy values for labeling. 600.211-08 Section 600.211-08 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) ENERGY POLICY FUEL ECONOMY AND CARBON-RELATED EXHAUST EMISSIONS OF MOTOR VEHICLES Fuel Economy Regulations for 1977 and Later Model...

40 CFR 211.204-2 - Primary label size, print and color.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Primary label size, print and color... size, print and color. The primary label characteristics are the same as those specified in §§ 211.105... (d) The color of the label must be as specified in subpart A. [44 FR 56127, Sept. 28, 1979, as...

Comparison between proton boron fusion therapy (PBFT) and boron neutron capture therapy (BNCT): a monte carlo study.

PubMed

Jung, Joo-Young; Yoon, Do-Kun; Barraclough, Brendan; Lee, Heui Chang; Suh, Tae Suk; Lu, Bo

2017-06-13

The aim of this study is to compare between proton boron fusion therapy (PBFT) and boron neutron capture therapy (BNCT) and to analyze dose escalation using a Monte Carlo simulation. We simulated a proton beam passing through the water with a boron uptake region (BUR) in MCNPX. To estimate the interaction between neutrons/protons and borons by the alpha particle, the simulation yielded with a variation of the center of the BUR location and proton energies. The variation and influence about the alpha particle were observed from the percent depth dose (PDD) and cross-plane dose profile of both the neutron and proton beams. The peak value of the maximum dose level when the boron particle was accurately labeled at the region was 192.4% among the energies. In all, we confirmed that prompt gamma rays of 478 keV and 719 keV were generated by the nuclear reactions in PBFT and BNCT, respectively. We validated the dramatic effectiveness of the alpha particle, especially in PBFT. The utility of PBFT was verified using the simulation and it has a potential for application in radiotherapy.

Comparison between proton boron fusion therapy (PBFT) and boron neutron capture therapy (BNCT): a Monte Carlo study

PubMed Central

Barraclough, Brendan; Lee, Heui Chang; Suh, Tae Suk; Lu, Bo

2017-01-01

The aim of this study is to compare between proton boron fusion therapy (PBFT) and boron neutron capture therapy (BNCT) and to analyze dose escalation using a Monte Carlo simulation. We simulated a proton beam passing through the water with a boron uptake region (BUR) in MCNPX. To estimate the interaction between neutrons/protons and borons by the alpha particle, the simulation yielded with a variation of the center of the BUR location and proton energies. The variation and influence about the alpha particle were observed from the percent depth dose (PDD) and cross-plane dose profile of both the neutron and proton beams. The peak value of the maximum dose level when the boron particle was accurately labeled at the region was 192.4% among the energies. In all, we confirmed that prompt gamma rays of 478 keV and 719 keV were generated by the nuclear reactions in PBFT and BNCT, respectively. We validated the dramatic effectiveness of the alpha particle, especially in PBFT. The utility of PBFT was verified using the simulation and it has a potential for application in radiotherapy. PMID:28427153

POLONIUM-210: A VOLATILE RADIOELEMENT IN CIGARETTES

DOE Office of Scientific and Technical Information (OSTI.GOV)

Radford, E.P. Jr.; Hunt, V.R.

Polonium-210, which emits alpha particles, is a natural contaminant of tobacco. For an individual smoking bvo packages of cigarettes a day, the radiation dose to bronchial epithelium from Po/sup 210/ inhaled in cigarette smoke probably is at least seven times that from background sources, and in localized areas may be up to 1000 rem or more in 25 years. Radiation from this source may, therefore, be significant in the genesis of bronchial cancer in smokers. (auth)

Application of proton boron fusion reaction to radiation therapy: A Monte Carlo simulation study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yoon, Do-Kun; Jung, Joo-Young; Suh, Tae Suk, E-mail: suhsanta@catholic.ac.kr

2014-12-01

Three alpha particles are emitted from the point of reaction between a proton and boron. The alpha particles are effective in inducing the death of a tumor cell. After boron is accumulated in the tumor region, the emitted from outside the body proton can react with the boron in the tumor region. An increase of the proton's maximum dose level is caused by the boron and only the tumor cell is damaged more critically. In addition, a prompt gamma ray is emitted from the proton boron reaction point. Here, we show that the effectiveness of the proton boron fusion therapymore » was verified using Monte Carlo simulations. We found that a dramatic increase by more than half of the proton's maximum dose level was induced by the boron in the tumor region. This increase occurred only when the proton's maximum dose point was located within the boron uptake region. In addition, the 719 keV prompt gamma ray peak produced by the proton boron fusion reaction was positively detected. This therapy method features the advantages such as the application of Bragg-peak to the therapy, the accurate targeting of tumor, improved therapy effects, and the monitoring of the therapy region during treatment.« less

Bromine-80m-labeled estrogens: Auger-electron emitting, estrogen receptor-directed ligands with potential for therapy of estrogen receptor positive cancers

DOE Office of Scientific and Technical Information (OSTI.GOV)

DeSombre, E.R.; Mease, R.C.; Hughes, A.

1988-01-01

A triphenylbromoethylene, 1,1-bis(p-hydroxyphenyl)-2-bromo-2-phenylethylene, Br-BHPE, and a bromosteroidal estrogen, 17..cap alpha..- bromovinylestradiol, BrVE/sub 2/, were labeled with the Auger electron emitting nuclide bromine-80m, prepared by the (p,n) reaction with /sup 80/Se. To assess their potential as estrogen receptor (ER) directed therapeutic substrates the bromine-80m labeled estrogens were injected into immature female rats and the tissue distribution studied at 0.5 and 2 hours. Both radiobromoestrogens showed substantial diethylstilbesterol (DES)-inhibitable localization in the ER rich tissues, uterus, pituitary, ovary and vagina at both time points. While the percent dose per gram tissue was higher for the Br-BHPE, the BrVE/sub 2/ showed higher tissuemore » to blood ratios, especially at 2 hr, reflecting the lower blood concentrations of radiobromine following administration of the steroidal bromoestrogen. Comparing intraperitoneal, intravenous and subcutaneous routes of administration for the radiobromine labeled Br-BHPE, the intraperitoneal route was particularly advantageous to provide maximum, DES-inhibitable concentrations in the peritoneal, ER-rich target organs, the uterus, ovary and vagina. While uterine concentrations after BrBHPE were from 10--48% dose/g and after BrVE/sub 2/ were 15--25% dose/g, similar treatment with /sup 80m/Br as sodium bromide showed uniform low concentrations in all tissues at about the levels seen in blood. The effective specific activity of (/sup 80m/Br)BrBHPE, assayed by specific binding to ER in rat uterine cytosol, was 8700 Ci/mmole. 23 refs., 9 figs., 2 tabs.« less

Carbon-11 and Fluorine-18 Labeled Amino Acid Tracers for Positron Emission Tomography Imaging of Tumors

NASA Astrophysics Data System (ADS)

Sun, Aixia; Liu, Xiang; Tang, Ganghua

2017-12-01

Tumor cells have an increased nutritional demand for amino acids(AAs) to satisfy their rapid proliferation. Positron-emitting nuclide labeled AAs are interesting probes and are of great importance for imaging tumors using positron emission tomography (PET). Carbon-11 and fluorine-18 labeled AAs include the [1-11C] amino acids, labeling alpha-C- amino acids, the branched-chain of amino acids and N-substituted carbon-11 labeled amino acids. These tracers target protein synthesis or amino acid(AA) transport, and their uptake mechanism mainly involves AA transport. AA PET tracers have been widely used in clinical settings to image brain tumors, neuroendocrine tumors, prostate cancer, breast cancer, non–small cell lung cancer (NSCLC) and hepatocellular carcinoma. This review focuses on the fundamental concepts and the uptake mechanism of AAs, AA PET tracers and their clinical applications.

Apparatus having reduced background for measuring radiation activity in aerosol particles

DOEpatents

Rodgers, John C.; McFarland, Andrew R.; Oritz, Carlos A.; Marlow, William H.

1992-01-01

Apparatus having reduced background for measuring radiation activity in aerosol particles. A continuous air monitoring sampler is described for use in detecting the presence of alpha-emitting aerosol particles. An inlet fractionating screen has been demonstrated to remove about 95% of freshly formed radon progeny from the aerosol sample, and approximately 33% of partially aged progeny. Addition of an electrical condenser and a modified dichotomous virtual impactor are expected to produce considerable improvement in these numbers, the goal being to enrich the transuranic (TRU) fraction of the aerosols. This offers the possibility of improving the signal-to-noise ratio for the detected alpha-particle energy spectrum in the region of interest for detecting TRU materials associated with aerosols, thereby enhancing the performance of background-compensation algorithms for improving the quality of alarm signals intended to warn personnel of potentially harmful quantities of TRU materials in the ambient air.

Evaluation of 209At as a theranostic isotope for 209At-radiopharmaceutical development using high-energy SPECT

NASA Astrophysics Data System (ADS)

Crawford, J. R.; Robertson, A. K. H.; Yang, H.; Rodríguez-Rodríguez, C.; Esquinas, P. L.; Kunz, P.; Blinder, S.; Sossi, V.; Schaffer, P.; Ruth, T. J.

2018-02-01

The development of alpha-emitting radiopharmaceuticals using 211At requires quantitative determination of the time-dependent nature of the 211At biodistribution. However, imaging-based methods for acquiring this information with 211At have not found wide-spread use because of its low abundance of decay emissions suitable for external detection. In this publication we demonstrate the theranostic abilities of the 211At/209At isotope pair and present the first-ever 209At SPECT images. The VECTor microSPECT/PET/CT scanner was used to image 209At with a collimator suitable for the 511 keV annihilation photons of PET isotopes. Data from distinct photopeaks of the 209At energy spectrum (195 keV (22.6%), 239 keV (12.4 %), 545 keV (91.0 %), a combined 782/790 keV peak (147 %), and 209Po x-rays (139.0 %)) were independently evaluated for use in image reconstructions using Monte Carlo (GATE) simulations and phantom studies. 209At-imaging in vivo was demonstrated in a healthy mouse injected with 10 MBq of free [209At]astatide. Image-based measurements of 209At uptake in organs of interest—acquired in 5 min intervals—were compared to ex vivo gamma counter measurements of the same organs. Simulated and measured data indicated that—due to the large amount of scatter from high energy (>750 keV) gammas—reconstructed images using the x-ray peak outperformed those obtained from other peaks in terms of image uniformity and spatial resolution, determined to be  <0.85 mm. 209At imaging using the x-ray peak revealed a biodistribution that matched the known distribution of free astatide, and in vivo image-based measurements of 209At uptake in organs of interest matched ex vivo measurements within 10%. We have acquired the first 209At SPECT images and demonstrated the ability of quantitative SPECT imaging with 209At to accurately determine astatine biodistributions with high spatial and temporal resolution.

Synthesis and characterization of lanthanum phosphate nanoparticles as carriers for 223Ra and 225Ra for targeted alpha therapy

DOE PAGES

Rojas, J. V.; Woodward, J. D.; Chen, N.; ...

2015-03-19

Targeted alpha therapy (TAT) has the potential for killing specific tumor cells with minimum collateral damage to surrounding healthy tissue. Radionuclides such as 223Ra, 225Ra, and 225Ac are of special interest for radiotherapeutic applications as they emit multiple -particles during their decay. Utilizing appropriate carriers capable of retaining both the parent radioisotope as well as daughter products is important for the effective delivery of the radioisotope to the tumor site while mitigating global in vivo radiotoxicity. Methods. In this work, core and core+2 shells (NPs with 2 additional layers of cold LaPO 4 deposited on the core surfaces) LaPO4 nanoparticlesmore » (NPs) were synthesized containing either 223Ra or 225Ra/ 225Ac and the retention of the parents and daughters within the NPs in vitro was investigated. Results. The NPs crystallized in rhabdophane phase with mean diameters of 3.4 and 6.3 nm for core and core+2 shells, respectively. The core LaPO 4 NPs retained up to 88% of 223Ra over 35 days. However, in the core+2 shell NPs, the retention of 223Ra and its daughter, 211Pb, was improved to > 99.9% over 27 days. Additionally, the retention of 225Ra/ 225Ac parents was > 99.98% and ~80% for the 221Fr and 213Bi daughters over 35 days for the core+2 shell NPs. Conclusions. These results suggest that LaPO 4 NPs are potentially effective carriers of radium isotopes.« less

Synthesis and characterization of lanthanum phosphate nanoparticles as carriers for 223Ra and 225Ra for targeted alpha therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rojas, J. V.; Woodward, J. D.; Chen, N.

Targeted alpha therapy (TAT) has the potential for killing specific tumor cells with minimum collateral damage to surrounding healthy tissue. Radionuclides such as 223Ra, 225Ra, and 225Ac are of special interest for radiotherapeutic applications as they emit multiple -particles during their decay. Utilizing appropriate carriers capable of retaining both the parent radioisotope as well as daughter products is important for the effective delivery of the radioisotope to the tumor site while mitigating global in vivo radiotoxicity. Methods. In this work, core and core+2 shells (NPs with 2 additional layers of cold LaPO 4 deposited on the core surfaces) LaPO4 nanoparticlesmore » (NPs) were synthesized containing either 223Ra or 225Ra/ 225Ac and the retention of the parents and daughters within the NPs in vitro was investigated. Results. The NPs crystallized in rhabdophane phase with mean diameters of 3.4 and 6.3 nm for core and core+2 shells, respectively. The core LaPO 4 NPs retained up to 88% of 223Ra over 35 days. However, in the core+2 shell NPs, the retention of 223Ra and its daughter, 211Pb, was improved to > 99.9% over 27 days. Additionally, the retention of 225Ra/ 225Ac parents was > 99.98% and ~80% for the 221Fr and 213Bi daughters over 35 days for the core+2 shell NPs. Conclusions. These results suggest that LaPO 4 NPs are potentially effective carriers of radium isotopes.« less

40 CFR 211.210 - Requirements.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 25 2011-07-01 2011-07-01 false Requirements. 211.210 Section 211.210 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING Hearing Protective Devices § 211.210 Requirements. ...

40 CFR 211.210 - Requirements.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 26 2013-07-01 2013-07-01 false Requirements. 211.210 Section 211.210 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING Hearing Protective Devices § 211.210 Requirements. ...

40 CFR 211.210 - Requirements.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 26 2012-07-01 2011-07-01 true Requirements. 211.210 Section 211.210 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING Hearing Protective Devices § 211.210 Requirements. ...

Quantitative comparisons of cancer induction in humans by internally deposited radionuclides and external radiation.

PubMed

Harrison, J D; Muirhead, C R

2003-01-01

To compare quantitative estimates of lifetime cancer risk in humans for exposures to internally deposited radionuclides and external radiation. To assess the possibility that risks from radionuclide exposures may be underestimated. Risk estimates following internal exposures can be made for a small number of alpha-particle-emitting nuclides. (1) Lung cancer in underground miners exposed by inhalation to radon-222 gas and its short-lived progeny. Studies of residential (222)Rn exposure are generally consistent with predictions from the miner studies. (2) Liver cancer and leukaemia in patients given intravascular injections of Thorotrast, a thorium-232 oxide preparation that concentrates in liver, spleen and bone marrow. (3) Bone cancer in patients given injections of radium-224, and in workers exposed occupationally to (226)Ra and (228)Ra, mainly by ingestion. (4) Lung cancer in Mayak workers exposed to plutonium-239, mainly by inhalation. Liver and bone cancers were also seen, but the dosimetry is not yet sufficiently good enough to provide quantitative estimates of risks. Comparisons can be made between risk estimates for radiation-induced cancer derived for radionuclide exposure and those derived for the A-bomb survivors, exposed mainly to low-LET (linear energy transfer) external radiation. Data from animal studies, using dogs and rodents, allow comparisons of cancer induction by a range of alpha- and beta-/gamma-emitting radionuclides. They provide information on relative biological effectiveness (RBE), dose-response relationships, dose-rate effects and the location of target cells for different malignancies. For lung and liver cancer, the estimated values of risk per Sv for internal exposure, assuming an RBE for alpha-particles of 20, are reasonably consistent with estimates for external exposure to low-LET radiation. This also applies to bone cancer when risk is calculated on the basis of average bone dose, but consideration of dose to target cells on bone surfaces suggests a low RBE for alpha-particles. Similarly, for leukaemia, the comparison of risks from alpha-irradiation ((232)Th and progeny) and external radiation suggest a low alpha RBE; this conclusion is supported by animal data. Risk estimates for internal exposure are dependent on the assumptions made in calculating dose. Account is taken of the distribution of radionuclides within tissues and the distribution of target cells for cancer induction. For the lungs and liver, the available human and animal data provide support for current assumptions. However, for bone cancer and leukaemia, it may be that changes are required. Bone cancer risk may be best assessed by calculating dose to a 50 micro m layer of marrow adjacent to endosteal (inner) bone surfaces rather than to a single 10 micro m cell layer as currently assumed. Target cells for leukaemia may be concentrated towards the centre of marrow cavities so that the risk of leukaemia from bone-seeking radionuclides, particularly alpha emitters, may be overestimated by the current assumption of uniform distribution of target cells throughout red bone marrow. The lifetime risk estimates considered here for exposure to internally deposited radionuclides and to external radiation are subject to uncertainties, arising from the dosimetric assumptions made, from the quality of cancer incidence and mortality data and from aspects of risk modelling; including variations in baseline rates between populations for some cancer types. Bearing in mind such uncertainties, comparisons of risk estimates for internal emitters and external radiation show good agreement for lung and liver cancers. For leukaemia, the available data suggest that the assumption of an alpha-particle RBE of 20 can result in overestimates of risk. For bone cancer, it also appears that current assumptions will overestimate risks from alpha-particle-emitting nuclides, particularly at low doses.

Single Upconversion Nanoparticle-Bacterium Cotrapping for Single-Bacterium Labeling and Analysis.

PubMed

Xin, Hongbao; Li, Yuchao; Xu, Dekang; Zhang, Yueli; Chen, Chia-Hung; Li, Baojun

2017-04-01

Detecting and analyzing pathogenic bacteria in an effective and reliable manner is crucial for the diagnosis of acute bacterial infection and initial antibiotic therapy. However, the precise labeling and analysis of bacteria at the single-bacterium level are a technical challenge but very important to reveal important details about the heterogeneity of cells and responds to environment. This study demonstrates an optical strategy for single-bacterium labeling and analysis by the cotrapping of single upconversion nanoparticles (UCNPs) and bacteria together. A single UCNP with an average size of ≈120 nm is first optically trapped. Both ends of a single bacterium are then trapped and labeled with single UCNPs emitting green light. The labeled bacterium can be flexibly moved to designated locations for further analysis. Signals from bacteria of different sizes are detected in real time for single-bacterium analysis. This cotrapping method provides a new approach for single-pathogenic-bacterium labeling, detection, and real-time analysis at the single-particle and single-bacterium level. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Characteristics study of projectile's lightest fragment for 84Kr36-emulsion interaction at around 1 A GeV

NASA Astrophysics Data System (ADS)

Marimuthu, N.; Singh, V.; Inbanathan, S. S. R.

2017-04-01

In this article, we present the results of our investigations on the projectile's lightest fragment (proton) multiplicity and probability distributions with 84Kr36 emulsion collision at around 1 A GeV. The multiplicity and normalized multiplicity of projectile's lightest fragment (proton) are correlated with the compound particles, shower particles, black particles, grey particles; alpha (helium nucleus) fragments and heavily ionizing charged particles. It is found that projectile's lightest fragment (proton) is strongly correlated with compound particles and shower particles rather than other particles and the average multiplicity of projectile's lightest fragment (proton) increases with increasing compound, shower and heavily ionizing charge particles. Normalized projectile's lightest fragment (proton) is strongly correlated with compound particles, shower particles and heavily ionizing charge particles. The multiplicity distribution of the projectile's lightest fragment (proton) emitted in the 84Kr36 + emulsion interaction at around 1 A GeV with different target has been well explained by KNO scaling. The mean multiplicity of projectile's lightest fragments (proton) depends on the mass number of the projectile and does not significantly dependent of the projectile energy. The mean multiplicity of projectile's lightest fragment (proton) increases with increasing the target mass number.

Measurement of the Solar Absorptance and Thermal Emittance of Lunar Simulants

NASA Technical Reports Server (NTRS)

Gaier, James R.; Street, Kenneth W.; Gustafson, Robert J.

2010-01-01

The first comparative study of the reflectance spectra of lunar simulants is presented. All of the simulants except one had a wavelength-dependent reflectivity, rho(lambda), near 0.10 over the wavelength range of 8 to 25 microns, so they are highly emitting at room temperature and lower. The 300 K emittance, epsilon, of all the lunar simulants except one ranged from 0.884 to 0.906. The 300 K epsilon of JSC Mars-1 simulant was 0.927. There was considerably more variation in the lunar simulant reflectance in the solar spectral range (250 to 2500 nm) than in the thermal infrared. Larger particle size simulants reflected much less than those with smaller particle size. As expected, the lunar highlands simulants were more reflective in this wavelength range than the lunar mare simulants. The alpha of the simulants ranged from 0.413 to 0.817 for those with smaller particles and 0.669 to 0.906 for large particles. Although spectral differences were observed, the total integrated alpha for the simulants appears to be similar to that of lunar soils (0.65 to 0.88). These data are now available to be used in modeling the effects of dust on thermal control surfaces.

Fluorine-18 Labeling of the HER2-Targeting Single-Domain Antibody 2Rs15d Using a Residualizing Label and Preclinical Evaluation.

PubMed

Zhou, Zhengyuan; Vaidyanathan, Ganesan; McDougald, Darryl; Kang, Choong Mo; Balyasnikova, Irina; Devoogdt, Nick; Ta, Angeline N; McNaughton, Brian R; Zalutsky, Michael R

2017-12-01

Our previous studies with F-18-labeled anti-HER2 single-domain antibodies (sdAbs) utilized 5F7, which binds to the same epitope on HER2 as trastuzumab, complicating its use for positron emission tomography (PET) imaging of patients undergoing trastuzumab therapy. On the other hand, sdAb 2Rs15d binds to a different epitope on HER2 and thus might be a preferable vector for imaging in these patients. The aim of this study was to evaluate the tumor targeting of F-18 -labeled 2Rs15d in HER2-expressing breast carcinoma cells and xenografts. sdAb 2Rs15d was labeled with the residualizing labels N-succinimidyl 3-((4-(4-[ 18 F]fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate ([ 18 F]RL-I) and N-succinimidyl 4-guanidinomethyl-3-[ 125 I]iodobenzoate ([ 125 I]SGMIB), and the purity and HER2-specific binding affinity and immunoreactivity were assessed after labeling. The biodistribution of I-125- and F-18-labeled 2Rs15d was determined in SCID mice bearing subcutaneous BT474M1 xenografts. MicroPET/x-ray computed tomograph (CT) imaging of [ 18 F]RL-I-2Rs15d was performed in this model and compared to that of nonspecific sdAb [ 18 F]RL-I-R3B23. MicroPET/CT imaging was also done in an intracranial HER2-positive breast cancer brain metastasis model after administration of 2Rs15d-, 5F7-, and R3B23-[ 18 F]RL-I conjugates. [ 18 F]RL-I was conjugated to 2Rs15d in 40.8 ± 9.1 % yield and with a radiochemical purity of 97-100 %. Its immunoreactive fraction (IRF) and affinity for HER2-specific binding were 79.2 ± 5.4 % and 7.1 ± 0.4 nM, respectively. [ 125 I]SGMIB was conjugated to 2Rs15d in 58.4 ± 8.2 % yield and with a radiochemical purity of 95-99 %; its IRF and affinity for HER2-specific binding were 79.0 ± 12.9 % and 4.5 ± 0.8 nM, respectively. Internalized radioactivity in BT474M1 cells in vitro for [ 18 F]RL-I-2Rs15d was 43.7 ± 3.6, 36.5 ± 2.6, and 21.7 ± 1.2 % of initially bound radioactivity at 1, 2, and 4 h, respectively, and was similar to that seen for [ 125 I]SGMIB-2Rs15d. Uptake of [ 18 F]RL-I-2Rs15d in subcutaneous xenografts was 16-20 %ID/g over 1-3 h. Subcutaneous tumor could be clearly delineated by microPET/CT imaging with [ 18 F]RL-I-2Rs15d but not with [ 18 F]RL-I-R3B23. Intracranial breast cancer brain metastases could be visualized after intravenous administration of both [ 18 F]RL-I-2Rs15d and [ 18 F]RL-I-5F7. Although radiolabeled 2Rs15d conjugates exhibited lower tumor cell retention both in vitro and in vivo than that observed previously for 5F7, given that it binds to a different epitope on HER2 from those targeted by the clinically utilized HER2-targeted therapeutic antibodies trastuzumab and pertuzumab, F-18-labeled 2Rs15d has potential for assessing HER2 status by PET imaging after trastuzumab and/or pertuzumab therapy.

Lyophilized Kit for the Preparation of the PET Perfusion Agent [(68)Ga]-MAA.

PubMed

Amor-Coarasa, Alejandro; Milera, Andrew; Carvajal, Denny; Gulec, Seza; McGoron, Anthony J

2014-01-01

Rapid developments in the field of medical imaging have opened new avenues for the use of positron emitting labeled microparticles. The radioisotope used in our research was (68)Ga, which is easy to obtain from a generator and has good nuclear properties for PET imaging. Methods. Commercially available macroaggregated albumin (MAA) microparticles were suspended in sterile saline, centrifuged to remove the free albumin and stannous chloride, relyophilized, and stored for later labeling with (68)Ga. Labeling was performed at different temperatures and times. (68)Ga purification settings were also tested and optimized. Labeling yield and purity of relyophilized MAA microparticles were compared with those that were not relyophilized. Results. MAA particles kept their original size distribution after relyophilization. Labeling yield was 98% at 75°C when a (68)Ga purification system was used, compared to 80% with unpurified (68)Ga. Radiochemical purity was over 97% up to 4 hours after the labeling. The relyophilized MAA and labeling method eliminate the need for centrifugation purification of the final product and simplify the labeling process. Animal experiments demonstrated the high in vivo stability of the obtained PET agent with more than 95% of the activity remaining in the lungs after 4 hours.

Radioactive ion detector

DOEpatents

Bower, Kenneth E.; Weeks, Donald R.

1997-01-01

Apparatus for detecting the presence, in aqueous media, of substances which emit alpha and/or beta radiation and determining the oxidation state of these radioactive substances, that is, whether they are in cationic or anionic form. In one embodiment, a sensor assembly has two elements, one comprised of an ion-exchange material which binds cations and the other comprised of an ion-exchange material which binds anions. Each ion-exchange element is further comprised of a scintillation plastic and a photocurrent generator. When a radioactive substance to which the sensor is exposed binds to either element and emits alpha or beta particles, photons produced in the scintillation plastic illuminate the photocurrent generator of that element. Sensing apparatus senses generator output and thereby indicates whether cationic species or anionic species or both are present and also provides an indication of species quantity.

Radioactive ion detector

DOEpatents

Bower, K.E.; Weeks, D.R.

1997-08-12

Apparatus for detecting the presence, in aqueous media, of substances which emit alpha and/or beta radiation and determining the oxidation state of these radioactive substances, that is, whether they are in cationic or anionic form. In one embodiment, a sensor assembly has two elements, one comprised of an ion-exchange material which binds cations and the other comprised of an ion-exchange material which binds anions. Each ion-exchange element is further comprised of a scintillation plastic and a photocurrent generator. When a radioactive substance to which the sensor is exposed binds to either element and emits alpha or beta particles, photons produced in the scintillation plastic illuminate the photocurrent generator of that element. Sensing apparatus senses generator output and thereby indicates whether cationic species or anionic species or both are present and also provides an indication of species quantity. 2 figs.

Effect of americium-241 alpha-particles on the dose-response of chromosome aberrations in human lymphocytes analysed by fluorescence in situ hybridization.

PubMed

Barquinero, J F; Stephan, G; Schmid, E

2004-02-01

To evaluate by the fluorescent in-situ hybridization (FISH) technique the dose-response and intercellular distribution of alpha-particle-induced chromosome aberrations. In particular, the validity of using the yield of characteristic types of chromosome abnormalities in stable cells as quantitative indicators for retrospective dose reconstruction has been evaluated. Monolayers of human peripheral lymphocytes were exposed at doses from 0.02 to 1 Gy to alpha-particles emitted from a source of americium-241. The most probable energy of the alpha-particles entering the cells was 2.7 MeV. FISH painting was performed using DNA probes for chromosomes 2, 4 and 8 in combination with a pan-centromeric probe. In complete first-division cells, identified by harlequin staining, aberrations involving painted target chromosomal material were recorded as well as aberrations involving only unpainted chromosomal material. In total, the percentage of complex aberrations was about 35% and no dose dependence was observed. When complex-type exchanges were reduced to simple base types, the different cell distributions were clearly over-dispersed, and the linear coefficients of the dose-effect curves for translocations were significantly higher than for dicentrics. For past dose reconstruction, only a few complex aberrations were in stable cells. The linear coefficient obtained for transmissible aberrations in stable cells was more than seven times lower than that obtained in all analysed cells, i.e. including unstable cells. FISH-based analysis of complex rearrangements allows discrimination between partial-body exposures to low-linear energy transfer radiation and high-linear energy transfer exposures. In assessing past or chronic exposure to alpha-particles, the use of a dose-effect curve obtained by FISH-based translocation data, which had not excluded data determined in unstable cells, would underestimate the dose. Insertions are ineffective biomarkers because their frequency is too low.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Scott, B.R.; Muggenburg, B.A.; Welsh, C.A.

The alpha emitter plutonium-238 ({sup 238}Pu), which is produced in uranium-fueled, light-water reactors, is used as a thermoelectric power source for space applications. Inhalation of a mixed oxide form of Pu is the most likely mode of exposure of workers and the general public. Occupational exposures to {sup 238}PuO{sub 2} have occurred in association with the fabrication of radioisotope thermoelectric generators. Organs and tissue at risk for deterministic and stochastic effects of {sup 238}Pu-alpha irradiation include the lung, liver, skeleton, and lymphatic tissue. Little has been reported about the effects of inhaled {sup 238}PuO{sub 2} on peripheral blood cell countsmore » in humans. The purpose of this study was to investigate hematological responses after a single inhalation exposure of Beagle dogs to alpha-emitting {sup 238}PuO{sub 2} particles and to extrapolate results to humans.« less

Half-lives of 221Fr, 217At, 213Bi, 213Po and 209Pb from the 225Ac decay series.

PubMed

Suliman, G; Pommé, S; Marouli, M; Van Ammel, R; Stroh, H; Jobbágy, V; Paepen, J; Dirican, A; Bruchertseifer, F; Apostolidis, C; Morgenstern, A

2013-07-01

The half-lives of (221)Fr, (217)At, (213)Bi, (213)Po, and (209)Pb were measured by means of an ion-implanted planar Si detector for alpha and beta particles emitted from weak (225)Ac sources or from recoil sources, which were placed in a quasi-2π counting geometry. Recoil sources were prepared by collecting atoms from an open (225)Ac source onto a glass substrate. The (221)Fr and (213)Bi half-lives were determined by following the alpha particle emission rate of recoil sources as a function of time. Similarly, the (209)Pb half-life was determined from the beta particle count rate. The shorter half-lives of (217)At and (213)Po were deduced from delayed coincidence measurements on weak (225)Ac sources using digital data acquisition in list mode. The resulting values: T1/2((221)Fr)=4.806 (6) min, T1/2((217)At)=32.8 (3)ms, T1/2((213)Bi)=45.62 (6)min, T1/2((213)Po)=3.708 (8) μs, and T1/2((209)Pb)=3.232 (5)h were in agreement only with the best literature data. Copyright © 2013 Elsevier Ltd. All rights reserved.

Radon and lung cancer: assessing and mitigating the risk.

PubMed

Choi, Humberto; Mazzone, Peter

2014-09-01

Radon is a naturally occurring radioactive gas. Its progenies emit alpha particles capable of causing tissue damage. Radon exposure is estimated to be the second most common cause of lung cancer in the United States. Management of patients with a history of radon exposure should involve a lung cancer specialist. Copyright© 2014 The Cleveland Clinic Foundation.

Defect annealing of alpha-particle irradiated n-GaAs

NASA Astrophysics Data System (ADS)

Goodman, S. A.; Auret, F. D.; Myburg, G.

1994-09-01

The annealing behaviour of irradiation induced defects in n-type GaAs irradiated at 300 K with 5.4 MeV alpha-particles from an americium-241 (Am-241) radio nuclide have been investigated. The annealing kinetics are presented for the alpha-particle induced defects Eα1 Eα5 detected in Organo-Metallic Vapor Phase Epitaxially (OMVPE) grown n-GaAs doped with silicon to 1.2×1016 cm-3, these kinetics are compared to those obtained for similar defects (E1 E5) detected after electron irradiation. While defects Pα1 and Pα2 were detected after removal of the electron defects Eα4 and Eα5, respectively, a new defect labelled Pα0, located 0.152 eV below the conduction band, was introduced by annealing. The thermal behaviour and trap characteristics of these three defects (Pα0 Pα2) are presented. In an attempt to further characterise defects Pα0 and Pα1 a preiliminary study investigating the emission rate field dependence of these defects was conducted, it was observed that defect Pα0 exhibited a fairly strong field dependence while Pα1 exhibited a much weaker dependence.

Deep UV emitting scintillators for alpha and beta particle detection

NASA Astrophysics Data System (ADS)

Zhou, Y.; Jia, D. D.; Lewis, L. A.; Feofilov, S. P.; Meltzer, R. S.

2011-03-01

Several deep UV emitting scintillators, whose emission falls in the solar blind region of the spectrum (200-280 nm), are described and their scintillator properties are characterized. They include LaPO 4:Pr, YPO 4:Pr, YAlO 3:Pr, Pr(PO 3) 3, YPO 4:Bi and ScPO 4. These materials would facilitate the detection of ionizing radiation in open areas, even during the daylight hours, and could be used to support large area surveys that monitor for the presence of ionization radiation due, for example, to system leaks or transfer contamination. These materials can be used in the form of powders, thin films or paints for radiation detection. They are characterized for both beta radiation using electron beams (2-35 keV) and 137Cs and alpha radiations using 241Am sources. Their absolute light yields are estimated and are compared to that of Y 2SiO 5:Ce. Their light yields decrease as a function of electron energy but at 10 keV they approach 8000 ph/MeV.

Lyman Alpha Searches at Redshift Z>7

NASA Astrophysics Data System (ADS)

Willis, Jon

2007-05-01

The ZEN survey is a narrow J-band survey for Ly-alpha emitting galaxies at z > 7. I will briefly review the pros and cons of narrow band observations before summarising the ZEN1 and ZEN2 searches based upon deep ISAAC pointings. I will then present ZEN3, consisting of wide field, narrow band observations of two fields using the CFHT WIRCam facility. I will conclude by reviewing the current sample of candidates and what we have learned about the z > 7 Ly-alpha emitting population.

Cardiac dysfunction in the trastuzumab clinical trials experience.

PubMed

Seidman, Andrew; Hudis, Clifford; Pierri, Mary Kathryn; Shak, Steven; Paton, Virginia; Ashby, Mark; Murphy, Maureen; Stewart, Stanford J; Keefe, Deborah

2002-03-01

This study sought to estimate cardiac dysfunction (CD) risk for patients receiving trastuzumab; to characterize observed CD by severity, treatment, and clinical outcome; to assess effects of baseline clinical risk factors on CD; and to assess effects of cumulative doses of anthracyclines and trastuzumab on CD. A retrospective review of records for patients enrolled onto any of seven phase II and III trastuzumab clinical trials was performed. Predefined criteria were used for the diagnosis, and the New York Heart Association functional classification system was used to document CD severity. Product-limit estimates were used to summarize the cumulative anthracycline and trastuzumab doses at the time of CD onset. Patients treated with trastuzumab were found to be at an increased risk for CD. The incidence was greatest in patients receiving concomitant trastuzumab and anthracycline plus cyclophosphamide (27%). The risk was substantially lower in patients receiving paclitaxel and trastuzumab (13%) or trastuzumab alone (3% to 7%); however, most of these patients had received prior anthracycline therapy. CD was noted in 8% of patients receiving anthracycline plus cyclophosphamide and 1% receiving paclitaxel alone. Most trastuzumab-treated patients developing CD were symptomatic (75%), and most improved with standard treatment for congestive heart failure (79%). Trastuzumab is associated with an increased risk of CD, which is greatest in patients receiving concurrent anthracyclines. In most patients with metastatic breast cancer, the risk of CD can be justified given the improvement in overall survival previously reported with trastuzumab.

New Methods for Targeted Alpha Radiotherapy

NASA Astrophysics Data System (ADS)

Robertson, J. David

2014-03-01

Targeted radiotherapies based on alpha emitters are a promising alternative to beta emitting radionuclides. Because of their much shorter range, targeted α-radiotherapy (TAT) agents have great potential for application to small, disseminated tumors and micro metastases and treatment of hematological malignancies consisting of individual, circulating neoplastic cells. A promising approach to TAT is the use of the in vivo α-generator radionuclides 223 = 11.4 d) and 225Ac 1/2 = 10.0 d). In addition to their longer half-lives, these two isotopes have the potential of dramatically increasing the therapeutic efficacy of TAT as they each emit four α particles in their decay chain. This principle has recently been exploited in the development of Xofigo®, the first TAT agent approved for clinical use by the U.S. FDA. Xofigo, formulated as 223RaCl2, is used for treatment of metastatic bone cancer in men with castration-resistant prostate cancer. TAT with 223Ra works, however, only in the case of bone cancer because radium, as a chemical analogue of calcium, efficiently targets bone. In order to bring the benefits of TAT with 223Ra or 225Ac to other tumor types, a new delivery method must be devised. Retaining the in vivo α generator radionuclides at the target site through the decay process is one of the major challenges associated with the development of TAT. Because the recoil energy of the daughter radionuclides from the α-emission is ~ 100 keV - a value which is four orders of magnitude greater than the energy of a covalent bond - the daughters will not remain bound to the bioconjugate at the targeting site. Various approaches have been attempted to achieve retention of the α-generator daughter radionuclides at the target site, including incorporation of the in vivo generator into liposomes and fullerenes. Unfortunately, to date single wall liposomes and fullerenes are able to retain less than 10% of the daughter radionuclides. We have recently demonstrated that a multilayered nanoparticle-antibody conjugate can deliver multiple α radiations from the in vivo α-generator 225Ac at biologically relevant receptor sites. The nanoparticles retained over 90% of the 221Fr daughter over the course of three weeks in in vitro experiments. In in vivo experiments, approximately 90% of the 213Bi was retained in the target tissue 24 hours after injection of the antibody labeled nanoparticle. An overview of the development and application of this promising, new approach to targeted alpha therapy will be presented.

Anti-tumor effects of retinoids combined with trastuzumab or tamoxifen in breast cancer cells: induction of apoptosis by retinoid/trastuzumab combinations.

PubMed

Koay, Debbie C; Zerillo, Cynthia; Narayan, Murli; Harris, Lyndsay N; DiGiovanna, Michael P

2010-01-01

HER2 and estrogen receptor (ER) are important in breast cancer and are therapeutic targets of trastuzumab (Herceptin) and tamoxifen, respectively. Retinoids inhibit breast cancer growth, and modulate signaling by HER2 and ER. We hypothesized that treatment with retinoids and simultaneous targeting of HER2 and/or ER may have enhanced anti-tumor effects. The effects of retinoids combined with trastuzumab or tamoxifen were examined in two human breast cancer cell lines in culture, BT474 and SKBR3. Assays of proliferation, apoptosis, differentiation, cell cycle distribution, and receptor signaling were performed. In HER2-overexpressing/ER-positive BT474 cells, combining all-trans retinoic acid (atRA) with tamoxifen or trastuzumab synergistically inhibited cell growth, and altered cell differentiation and cell cycle. Only atRA/trastuzumab-containing combinations induced apoptosis. BT474 and HER2-overexpressing/ER-negative SKBR3 cells were treated with a panel of retinoids (atRA, 9-cis-retinoic acid, 13-cis-retinoic acid, or N-(4-hydroxyphenyl) retinamide (fenretinide) (4-HPR)) combined with trastuzumab. In BT474 cells, none of the single agents except 4-HPR induced apoptosis, but again combinations of each retinoid with trastuzumab did induce apoptosis. In contrast, the single retinoid agents did cause apoptosis in SKBR3 cells; this was only modestly enhanced by addition of trastuzumab. The retinoid drug combinations altered signaling by HER2 and ER. Retinoids were inactive in trastuzumab-resistant BT474 cells. Combining retinoids with trastuzumab maximally inhibits cell growth and induces apoptosis in trastuzumab-sensitive cells. Treatment with such combinations may have benefit for breast cancer patients.

Photon hormesis deactivates alpha-particle induced bystander effects between zebrafish embryos

NASA Astrophysics Data System (ADS)

Ng, C. Y. P.; Cheng, S. H.; Yu, K. N.

2017-04-01

In the present work, we studied the effects of low-dose X-ray photons on the alpha-particle induced bystander effects between embryos of the zebrafish, Danio rerio. The effects on the naive whole embryos were studied through quantification of apoptotic signals (amounts of cells undergoing apoptosis) at 24 h post fertilization (hpf) using vital dye acridine orange staining, followed by counting the stained cells under a fluorescent microscope. We report data showing that embryos at 5 hpf subjected to a 4.4 mGy alpha-particle irradiation could release a stress signal into the medium, which could induce bystander effect in partnered naive embryos sharing the same medium. We also report that the bystander effect was deactivated when the irradiated embryos were subjected to a concomitant irradiation of 10 or 14 mGy of X-rays, but no such deactivation was achieved if the concomitant X-ray dose dropped to 2.5 or 5 mGy. In the present study, the significant drop in the amount of apoptotic signals on the embryos having received 4.4 mGy alpha particles together X-rays irradiation from 2.5 or 5 mGy to 10 or 14 mGy, together with the deactivation of RIBE with concomitant irradiation of 10 or 14 mGy of X-rays supported the participation of photon hormesis with an onset dose between 5 and 10 mGy, which might lead to removal of aberrant cells through early apoptosis or induction of high-fidelity DNA repair. As we found that photons and alpha particles could have opposite biological effects when these were simultaneously irradiated onto living organisms, these ionizing radiations could be viewed as two different environmental stressors, and the resultant effects could be regarded as multiple stressor effects. The present work presented the first study on a multiple stressor effect which occurred on bystander organisms. In other words, this was a non-targeted multiple stressor effect. The photon hormesis could also explain some failed attempts to observe neutron-induced bystander effects in previous studies, as neutron sources invariably emit neutrons with concomitant gamma-ray photons, which is often referred to as gamma-ray contamination.

Occurrence of radium-224, radium-226, and radium-228 in water of the unconfined Kirkwood-Cohansey aquifer system, southern New Jersey

USGS Publications Warehouse

Szabo, Zoltan; dePaul, Vincent T.; Kraemer, Thomas F.; Parsa, Bahman

2005-01-01

Water in the unconfined Kirkwood-Cohansey aquifer system in the New Jersey Coastal Plain contains elevated concentrations (above 3 pCi/L (picocuries per liter)) of the alpha-particle-emitting radionuclide radium-224. Previously, water from the aquifer system had been found to contain radium-226 and radium-228. This observation is of concern because the previously undetected presence of radium-224 may pose an additional, quantifiable health risk that currently is not accounted for by the Maximum Contaminant Level (MCL) of 5 pCi/L for combined radium (the sum of radium-226 plus radium-228 is termed 'combined radium') in drinking water. Water samples were collected from a regional network of 88 wells for determination of concentrations of radium-224, radium-226, and radium-228; gross alpha-particle activity; and concentrations of major ions and selected trace elements. Both gamma and alpha spectroscopic techniques were used to determine concentrations of radium-224, which ranged from <0.5 to 16.8 pCi/L (median 2.1 pCi/L, interquartile range 1.2-3.7 pCi/L). Concentrations of radium-226 and radium-228 in the same samples ranged from <0.5 to 17.4 pCi/L (median 1.7 pCi/L, interquartile range 0.9-2.9 pCi/L) and <0.5 to 12.8 pCi/L (median 1.6 pCi/L, interquartile range, 0.9-2.6 pCi/L), respectively. Concentrations of radium-224 typically were greater than those of the other two radium radionuclides, as evidenced by the highest median, third quartile, and maximum concentrations, as well as the highest concentration among the three radium radioisotopes in 52 (59 percent) of the 88 samples. Concentrations of 5.0 to 5.5 pCi/L of radium-224 result in a gross alpha-particle activity of about 15 pCi/L (the MCL) 36 to 48 hours, respectively, after sample collection when ingrowth of radium-224 progeny radionuclides is considered, even with the unlikely assumption that no other alpha-particle-emitting radionuclide is present in the water. Concentrations of 3.4 to 3.7 pCi/L radium-224 result in a gross alpha-particle activity of 10 pCi/L 36 to 48 hours, respectively, after sample collection when ingrowth of Ra-224 progeny radionuclides is considered. In this latter case, it is possible that the summed alpha-particle activity from radium-226 present at a concentration less than or equal to 5 pCi/L (the MCL for combined radium) and from radium-224 present at a concentration about 3.4 pCi/L or greater may exceed the 15-pCi/L MCL for gross alpha-particle activity. In this study, gross alpha-particle activities were measured within 48 hours after sample collection and were found to exceed the MCL of 15 pCi/L in nearly half (43) of the 88 samples collected. The concentration of radium-224 exceeded that of radium-226 in 55 (62.5 percent) of the 88 samples. Concentrations of radium-224 correlate strongly with those of both radium-226 and radium-228 (Spearman correlation coefficients r=0.74 and 0.91, respectively). Concentrations of radium-224, radium-226, and radium-228 were greatest in the most acidic ground water. Concentrations of radium-224 and combined radium-226 and radium-228 in samples of ground water with pH less than 4.7 exceeded 5 pCi/L in 33 and 67 percent of the samples, respectively. Concentrations of radium-224, radium-226, and radium-228 (measured separately) were greatest in water from the southern part of the aquifer outcrop area. In water from the northern part of the aquifer system outcrop area, radium-224 concentrations were as high as 3.6 pCi/L, and concentrations of combined radium and gross alpha-particle activity in some samples exceeded their respective MCLs. The presence of gross alpha-particle activities greater than 15 pCi/L and combined radium-226 and radium-228 concentrations greater than 5 pCi/L in the southwestern part of the aquifer system outcrop area is common and had been documented before 1997. Results of this study confirm these earlier findings. In northeastern and southeastern parts of the aquifer

Method of treating inflammatory diseases using a radiolabeled ferric hydroxide calloid

DOEpatents

Atcher, Robert W.; Hines, John J.

1992-01-01

A ferric hydroxide colloid having an alpha-emitting radionuclide essentially on the outer surfaces and a method of forming same. The method includes oxidizing a ferrous hydroxide to ferric hydroxide in the presence of a preselected radionuclide to form a colloid having the radionuclide on the outer surface thereof, and thereafter washing the colloid, and suspending the washed colloid in a suitable solution. The labelled colloid is useful in cancer therapy and for the treatment of inflamed joints.

Alpha particle emission in the interaction of 12C with 59Co and 93Nb at incident energies of 300 and 400 MeV

NASA Astrophysics Data System (ADS)

Gadioli, E.; Cavinato, M.; Fabrici, E.; Gadioli Erba, E.; Birattari, C.; Mica, I.; Solia, S.; Steyn, G. F.; Förtsch, S. V.; Lawrie, J. J.; Nortier, F. M.; Stevens, T. G.; Connell, S. H.; Sellschop, J. P. F.; Cowley, A. A.

1999-08-01

The results of measured inclusive double differential cross section of α particles emitted in the interaction of 12C ions with 59Co and 93Nb at incident energies of 300 and 400 MeV are presented. The analysis of these data allows us to isolate the contributions of the different reaction mechanisms, thereby confirming previous conclusions of a comprehensive analysis of a large number of excitation function, forward recoil ranges and angular distributions of residues produced in the interaction of 12C with a target nucleus in the same mass range. In particular, the probabilities associated with α-particle reemission following incomplete fussion processes have been reaffirmed. Several refinements to the theoretical model proposed in earlier studies of the interaction of 12C with nuclei are presented.

40 CFR 211.206-2 - Alternative test data.

Code of Federal Regulations, 2010 CFR

2010-07-01

... PROGRAMS PRODUCT NOISE LABELING Hearing Protective Devices § 211.206-2 Alternative test data. (a) In lieu of testing according to § 211.206-1, manufacturers may use the latest available test data obtained...

Development of an Ultra-Pure, Carrier-Free 209Po Solution Standard

PubMed Central

Collé, R.; Fitzgerald, R. P.; Laureano-Perez, L.

2015-01-01

Ultra-pure, carrier-free 209Po solution standards have been prepared and standardized for their massic alpha-particle emission rate. The standards, which will be disseminated by the National Institute of Standards and Technology (NIST) as Standard Reference Material SRM 4326a, have a mean mass of (5.169 ± 0.003) g of a solution of polonium in nominal 2.0 mol▪L−1 HCl (having a solution density of (1.032 ± 0.002) g▪ mL−1 at 20 °C) that are contained in 5 mL, flame-sealed, borosilicate glass ampoules. They are certified to contain a 209Po massic alpha-particle emission rate of (39.01 ± 0.18) s−1▪g−1 as of a reference time of 1200 EST, 01 December 2013. This new standard series replaces SRM 4326 that was issued by NIST in 1994. The standardization was based on 4πα liquid scintillation (LS) spectrometry with two different LS counting systems and under wide variations in measurement and counting source conditions. The methodology for the standardization, with corrections for detection of the low-energy conversion electrons from the delayed 2 keV isomeric state in 205Pb and for the radiations accompanying the small 0.45 % electron-capture branch to 209Bi, involves a unique spectral analysis procedure that is specific for the case of 209Po decay. The entire measurement protocol is similar, but revised and improved from that used for SRM 4326. Spectroscopic impurity analyses revealed that no photon-emitting or alpha-emitting radionuclidic impurities were detected. The most common impurity associated with 209Po is 208Po and the activity ratio of 208Po/209Po was < 10−7. PMID:26958444

Concept design of a time-of-flight spectrometer for the measurement of the energy of alpha particles.

PubMed

García-Toraño, E

2018-04-01

The knowledge of the energies of the alpha particles emitted in the radioactive decay of a nuclide is a key factor in the construction of its decay scheme. Virtually all existing data are based on a few absolute measurements made by magnetic spectrometry (MS), to which most other MS measurements are traced. An alternative solution would be the use of time-of-flight detectors. This paper discusses the main aspects to be considered in the design of such detectors, and the performances that could be reasonably expected. Based on the concepts discussed here, it is estimated that an energy resolution about 2.5keV may be attainable with a good quality source. Copyright © 2017 Elsevier Ltd. All rights reserved.

Skeletal dosimetry models for alpha-particles for use in molecular radiotherapy

NASA Astrophysics Data System (ADS)

Watchman, Christopher J.

Molecular radiotherapy is a cancer treatment methodology whereby a radionuclide is combined with a biologically active molecule to preferentially target cancer cells. Alpha-particle emitting radionuclides show significant potential for use in molecular radiotherapy due to the short range of the alpha-particles in tissue and their high rates of energy deposition. Current radiation dosimetry models used to assess alpha emitter dose in the skeleton were developed originally for occupational applications. In medical dosimetry, individual variability in uptake, translocation and other biological factors can result in poor correlation of clinical outcome with marrow dose estimates determined using existing skeletal models. Methods presented in this work were developed in response to the need for dosimetry models which account for these biological and patient-specific factors. Dosimetry models are presented for trabecular bone alpha particle dosimetry as well as a model for cortical bone dosimetry. These radiation transport models are the 3D chord-based infinite spongiosa transport model (3D-CBIST) and the chord-based infinite cortical transport model (CBICT), respectively. Absorbed fraction data for several skeletal tissues for several subjects are presented. Each modeling strategy accounts for biological parameters, such as bone marrow cellularity, not previously incorporated into alpha-particle skeletal dosimetry models used in radiation protection. Using these data a study investigating the variability in alpha-particle absorbed fractions in the human skeleton is also presented. Data is also offered relating skeletal tissue masses in individual bone sites for a range of ages. These data are necessary for dose calculations and have previously only been available as whole body tissue masses. A revised 3D-CBIST model is also presented which allows for changes in endosteum thickness to account for revised target cell location of tissues involved in the radiological induction of bone cancer. In addition, new data are presented on the location of bone-marrow stem cells within the marrow cavities of trabecular bone of the pelvis. All results presented in this work may be applied to occupational exposures, but their greatest utility lies in dose assessments for alpha-emitters in molecular radiotherapy.

40 CFR Appendix A to Part 211 - Compliance Audit Testing Report

Code of Federal Regulations, 2011 CFR

2011-07-01

... Appendix A to Part 211 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING Pt. 211, App. A Appendix A to Part 211—Compliance Audit Testing... 250 500 1000 2000 3150 4000 6300 8000 Noise Reduction Rating: If replacement hearing protector was...

21 CFR 211.134 - Drug product inspection.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Drug product inspection. 211.134 Section 211.134 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS... § 211.134 Drug product inspection. (a) Packaged and labeled products shall be examined during finishing...

21 CFR 211.134 - Drug product inspection.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Drug product inspection. 211.134 Section 211.134 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS... § 211.134 Drug product inspection. (a) Packaged and labeled products shall be examined during finishing...

21 CFR 211.134 - Drug product inspection.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Drug product inspection. 211.134 Section 211.134 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS... § 211.134 Drug product inspection. (a) Packaged and labeled products shall be examined during finishing...

21 CFR 211.134 - Drug product inspection.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Drug product inspection. 211.134 Section 211.134 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS... § 211.134 Drug product inspection. (a) Packaged and labeled products shall be examined during finishing...

40 CFR 211.212-5 - Reporting of test results.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 26 2012-07-01 2011-07-01 true Reporting of test results. 211.212-5 Section 211.212-5 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING Hearing Protective Devices § 211.212-5 Reporting of test results. (a)(1...

40 CFR 211.212-5 - Reporting of test results.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Reporting of test results. 211.212-5 Section 211.212-5 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING Hearing Protective Devices § 211.212-5 Reporting of test results. (a)(1...

40 CFR 211.212-5 - Reporting of test results.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 25 2014-07-01 2014-07-01 false Reporting of test results. 211.212-5 Section 211.212-5 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING Hearing Protective Devices § 211.212-5 Reporting of test results. (a)(1...

40 CFR 211.212-5 - Reporting of test results.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 26 2013-07-01 2013-07-01 false Reporting of test results. 211.212-5 Section 211.212-5 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING Hearing Protective Devices § 211.212-5 Reporting of test results. (a)(1...

40 CFR 211.212-5 - Reporting of test results.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 25 2011-07-01 2011-07-01 false Reporting of test results. 211.212-5 Section 211.212-5 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING Hearing Protective Devices § 211.212-5 Reporting of test results. (a)(1...

40 CFR Appendix A to Part 211 - Compliance Audit Testing Report

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 25 2014-07-01 2014-07-01 false Compliance Audit Testing Report A Appendix A to Part 211 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING Pt. 211, App. A Appendix A to Part 211—Compliance Audit Testing...

40 CFR Appendix A to Part 211 - Compliance Audit Testing Report

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Compliance Audit Testing Report A Appendix A to Part 211 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING Pt. 211, App. A Appendix A to Part 211—Compliance Audit Testing...

Clustering of galaxies near damped Lyman-alpha systems with (z) = 2.6

NASA Technical Reports Server (NTRS)

Wolfe, A. M

1993-01-01

The galaxy two-point correlation function, xi, at (z) = 2.6 is determined by comparing the number of Ly-alpha-emitting galaxies in narrowband CCD fields selected for the presence of damped L-alpha absorption to their number in randomly selected control fields. Comparisons between the presented determination of (xi), a density-weighted volume average of xi, and model predictions for (xi) at large redshifts show that models in which the clustering pattern is fixed in proper coordinates are highly unlikely, while better agreement is obtained if the clustering pattern is fixed in comoving coordinates. Therefore, clustering of Ly-alpha-emitting galaxies around damped Ly-alpha systems at large redshifts is strong. It is concluded that the faint blue galaxies are drawn from a parent population different from normal galaxies, the presumed offspring of damped Ly-alpha systems.

An automated flow system incorporating in-line acid dissolution of bismuth metal from a cyclotron irradiated target assembly for use in the isolation of astatine-211

DOE Office of Scientific and Technical Information (OSTI.GOV)

O’Hara, Matthew J.; Krzysko, Anthony J.; Niver, Cynthia M.

Astatine-211 (211At) is a promising cyclotron-produced radionuclide being investigated for use in targeted alpha therapy of blood borne and metastatic cancers, as well as treatment of tumor remnants after surgical resections. The isolation of trace quantities of 211At, produced within several grams of a Bi metal cyclotron target, involves a complex, multi-step procedure: (1) Bi metal dissolution in strong HNO3, (2) distillation of the HNO3 to yield Bi salts containing 211At, (3) dissolution of the salts in strong HCl, (4) solvent extraction of 211At from bismuth salts with diisopropyl ether (DIPE), and (5) back-extraction of 211At from DIPE into NaOH,more » leading to a purified 211At product. Step (1) has been addressed first to begin the process of automating the onerous 211At isolation process. A computer-controlled Bi target dissolution system has been designed. The system performs in-line dissolution of Bi metal from the target assembly using an enclosed target dissolution block, routing the resulting solubilized 211At/Bi mixture to the subsequent process step. The primary parameters involved in Bi metal solubilization (HNO3 concentration and influent flow rate) were optimized prior to evaluation of the system performance on replicate cyclotron irradiated targets. The results indicate that the system performs reproducibly, having nearly quantitative release of 211At from irradiated targets, with cumulative 211At recoveries that follow a sigmoidal function. The predictable nature of the 211At release profile allows the user to tune the system to meet target processing requirements.« less

The Sound Field Around a Tuning Fork and the Role of a Resonance Box

NASA Astrophysics Data System (ADS)

Bogacz, Bogdan F.; Pedziwiatr, Antoni T.

2015-02-01

Atypical two-tine tuning fork is barely audible when held vibrating at an arm's length. It is enough, however, to touch its base to a table or, better, to a resonance box and the emitted sound becomes much louder. An inquiring student may pose questions: —Why is a bare tuning fork such a weak emitter of sound?—What is the role of the resonance box?—Where does energy connected with larger intensity of emitted acoustic waves come from?

Characterisation of an engineered trastuzumab IgE antibody and effector cell mechanisms targeting HER2/neu-positive tumour cells

PubMed Central

2010-01-01

Trastuzumab (Herceptin®), a humanized IgG1 antibody raised against the human epidermal growth factor receptor 2 (HER2/neu), is the main antibody in clinical use against breast cancer. Pre-clinical evidence and clinical studies indicate that trastuzumab employs several anti-tumour mechanisms that most likely contribute to enhanced survival of patients with HER2/neu-positive breast carcinomas. New strategies are aimed at improving antibody-based therapeutics like trastuzumab, e.g. by enhancing antibody-mediated effector function mechanisms. Based on our previous findings that a chimaeric ovarian tumour antigen-specific IgE antibody showed greater efficacy in tumour cell killing, compared to the corresponding IgG1 antibody, we have produced an IgE homologue of trastuzumab. Trastuzumab IgE was engineered with the same light- and heavy-chain variable-regions as trastuzumab, but with an epsilon in place of the gamma-1 heavy-chain constant region. We describe the physical characterisation and ligand binding properties of the trastuzumab IgE and elucidate its potential anti-tumour activities in functional assays. Both trastuzumab and trastuzumab IgE can activate monocytic cells to kill tumour cells, but they operate by different mechanisms: trastuzumab functions in antibody-dependent cell-mediated phagocytosis (ADCP), whereas trastuzumab IgE functions in antibody-dependent cell-mediated cytotoxicity (ADCC). Trastuzumab IgE, incubated with mast cells and HER2/neu-expressing tumour cells, triggers mast cell degranulation, recruiting against cancer cells a potent immune response, characteristic of allergic reactions. Finally, in viability assays both antibodies mediate comparable levels of tumour cell growth arrest. These functional characteristics of trastuzumab IgE, some distinct from those of trastuzumab, indicate its potential to complement or improve upon the existing clinical benefits of trastuzumab. PMID:18941743

Adjuvant Chemotherapy and Trastuzumab Is Safe and Effective in Older Women With Small, Node-Negative, HER2-Positive Early-Stage Breast Cancer.

PubMed

Cadoo, Karen A; Morris, Patrick G; Cowell, Elizabeth P; Patil, Sujata; Hudis, Clifford A; McArthur, Heather L

2016-12-01

The benefit of adjuvant trastuzumab with chemotherapy is well established for women with higher risk human epidermal growth factor receptor 2-positive (HER2 + ) breast cancer. However, its role in older patients with smaller, node-negative tumors is less clear. We conducted a retrospective, sequential cohort study of this population to describe the impact of trastuzumab on breast cancer outcomes and cardiac safety. Women ≥ 55 years with ≤ 2 cm, node-negative, HER2 + breast cancer were identified and electronic medical records reviewed. A no-trastuzumab cohort of 116 women diagnosed between January 1, 1999 and May 14, 2004 and a trastuzumab cohort of 128 women diagnosed between May 16, 2006 and December 31, 2010 were identified. Overall survival and distant relapse-free survival were estimated by Kaplan-Meier methods. The median ages of the trastuzumab and no-trastuzumab cohorts were 62 and 64 years, respectively. More patients in the trastuzumab cohort had grade III (P = .001), lymphovascular invasion (P = .001), or estrogen receptor-negative (P < .001) cancers. The majority of the trastuzumab cohort received chemotherapy versus one-half of the no-trastuzumab cohort (98% vs. 53%; P < .0001). The median follow-up was 4 versus 9 years in the trastuzumab versus no-trastuzumab cohorts; therefore, outcomes at 4 years are reported. Despite the higher-risk tumor features in the trastuzumab group, the 4-year overall survival was 99% in both cohorts; the distant relapse-free survival was 99% versus 97% in the trastuzumab versus no-trastuzumab cohorts. Four (3.1%; 95% confidence interval, 1.0%-7.8%) women in the trastuzumab cohort and 1 in the no-trastuzumab cohort developed symptomatic heart failure. There were no cardiac-related deaths in either arm. Following adjuvant trastuzumab with chemotherapy, selected older women with small, node-negative, HER2 + breast cancers have excellent disease control. The rate of cardiac events is low. Copyright © 2016 Elsevier Inc. All rights reserved.

Clean galena, contaminated lead, and soft errors in memory chips

NASA Astrophysics Data System (ADS)

Lykken, G. I.; Hustoft, J.; Ziegler, B.; Momcilovic, B.

2000-10-01

Lead (Pb) disks were exposed to a radon (Rn)-rich atmosphere and surface alpha particle emissions were detected over time. Cumulative 210Po alpha emission increased nearly linearly with time. Conversely, cumulative emission for each of 218Po and 214Po was constant after one and two hours, respectively. Processing of radiation-free Pb ore (galena) in inert atmospheres was compared with processing in ambient air. Galena processed within a flux heated in a graphite crucible while exposed to an inert atmosphere, resulted in lead contaminated with 210Po (Trial 1). A glove box was next used to prepare a baseline radiation-free flux sample in an alumina crucible that was heated in an oven with an inert atmosphere (Trials 2 and 3). Ambient air was thereafter introduced, in place of the inert atmosphere, to the radiation-free flux mixture during processing (Trial 4). Ambient air introduced Rn and its progeny (RAD) into the flux during processing so that the processed Pb contained Po isotopes. A typical coke used in lead smelting also emitted numerous alpha particles. We postulate that alpha particles from tin/lead solder bumps, a cause of computer chip memory soft errors, may originate from Rn and RAD in the ambient air and/or coke used as a reducing agent in the standard galena smelting procedure.

Direct Imaging of Radionuclide-Produced Electrons and Positrons with an Ultrathin Phosphor

PubMed Central

Chen, Liying; Gobar, Lisa S.; Knowles, Negar G.; Liu, Zhonglin; Gmitro, Arthur F.; Barrett, Harrison H.

2008-01-01

Current electron detectors are either unable to image in vivo or lack sufficient spatial resolution because of electron scattering in thick detector materials. This study was aimed at developing a sensitive high-resolution system capable of detecting electron-emitting isotopes in vivo. Methods The system uses a lens-coupled charge-coupled-device camera to capture the scintillation light excited by an electron-emitting object near an ultrathin phosphor. The spatial resolution and sensitivity of the system were measured with a 3.7-kBq 90Y/90Sr β-source and a 70-µm resin bead labeled with 99mTc. Finally, we imaged the 99mTc-pertechnetate concentration in the mandibular gland of a mouse in vivo. Results Useful images were obtained with only a few hundred emitted β particles from the 90Y/90Sr source or conversion electrons from the 99mTc bead source. The in vivo image showed a clear profile of the mandibular gland and many fine details with exposures of as low as 30 s. All measurements were consistent with a spatial resolution of about 50 µm, corresponding to 2.5 detector pixels with the current camera. Conclusion Our new electron-imaging system can image electron-emitting isotope distributions at high resolution and sensitivity. The system is useful for in vivo imaging of small animals and small, exposed regions on humans. The ability to image β particles, positrons, and conversion electrons makes the system applicable to most isotopes. PMID:18552136

New bifunctional chelator for 64Cu-immuno-positron emission tomography.

PubMed

Pandya, Darpan N; Bhatt, Nikunj; Dale, Ajit V; Kim, Jung Young; Lee, Hochun; Ha, Yeong Su; Lee, Ji-Eun; An, Gwang Il; Yoo, Jeongsoo

2013-08-21

A new tetraazamacrocyclic bifunctional chelator, TE2A-Bn-NCS, was synthesized in high overall yield from cyclam. An extra functional group (NCS) was introduced to the N-atom of TE2A for specific conjugation with antibody. The Cu complex of TE2A-Bn-NCS showed high kinetic stability in acidic decomplexation and cyclic voltammetry studies. X-ray structure determination of the Cu-TE2A-Bn-NH2 complex confirmed octahedral geometry, in which copper atom is strongly coordinated by four macrocyclic nitrogens in equatorial positions and two carboxylate oxygen atoms occupy the elongated axial positions. Trastuzumab was conjugated with TE2A-Bn-NCS and then radiolabeled with 64Cu quantitatively at room temperature within 10 min. Biodistribution studies showed that the 64Cu-labeled TE2A-Bn-NCS-trastuzumab conjugates maintain high stability in physiological conditions, and NIH3T6.7 tumors were clearly visualized up to 3 days by 64Cu-immuno-positron emission tomography imaging in animal models.

Lyophilized Kit for the Preparation of the PET Perfusion Agent [68Ga]-MAA

PubMed Central

Amor-Coarasa, Alejandro; Milera, Andrew; Gulec, Seza; McGoron, Anthony J.

2014-01-01

Rapid developments in the field of medical imaging have opened new avenues for the use of positron emitting labeled microparticles. The radioisotope used in our research was 68Ga, which is easy to obtain from a generator and has good nuclear properties for PET imaging. Methods. Commercially available macroaggregated albumin (MAA) microparticles were suspended in sterile saline, centrifuged to remove the free albumin and stannous chloride, relyophilized, and stored for later labeling with 68Ga. Labeling was performed at different temperatures and times. 68Ga purification settings were also tested and optimized. Labeling yield and purity of relyophilized MAA microparticles were compared with those that were not relyophilized. Results. MAA particles kept their original size distribution after relyophilization. Labeling yield was 98% at 75°C when a 68Ga purification system was used, compared to 80% with unpurified 68Ga. Radiochemical purity was over 97% up to 4 hours after the labeling. The relyophilized MAA and labeling method eliminate the need for centrifugation purification of the final product and simplify the labeling process. Animal experiments demonstrated the high in vivo stability of the obtained PET agent with more than 95% of the activity remaining in the lungs after 4 hours. PMID:24800071

Computational modeling of radiobiological effects in bone metastases for different radionuclides.

PubMed

Liberal, Francisco D C Guerra; Tavares, Adriana Alexandre S; Tavares, João Manuel R S

2017-06-01

Computational simulation is a simple and practical way to study and to compare a variety of radioisotopes for different medical applications, including the palliative treatment of bone metastases. This study aimed to evaluate and compare cellular effects modelled for different radioisotopes currently in use or under research for treatment of bone metastases using computational methods. Computational models were used to estimate the radiation-induced cellular effects (Virtual Cell Radiobiology algorithm) post-irradiation with selected particles emitted by Strontium-89 ( 89 Sr), Samarium-153 ( 153 Sm), Lutetium-177 ( 177 Lu), and Radium-223 ( 223 Ra). Cellular kinetics post-irradiation using 89 Sr β - particles, 153 Sm β -  particles, 177 Lu β -  particles and 223 Ra α particles showed that the cell response was dose- and radionuclide-dependent. 177 Lu beta minus particles and, in particular, 223 Ra alpha particles, yielded the lowest survival fraction of all investigated particles. 223 Ra alpha particles induced the highest cell death of all investigated particles on metastatic prostate cells in comparison to irradiation with β -  radionuclides, two of the most frequently used radionuclides in the palliative treatment of bone metastases in clinical routine practice. Moreover, the data obtained suggest that the used computational methods might provide some perception about cellular effects following irradiation with different radionuclides.

40 CFR 211.206-1 - Real ear method.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 25 2011-07-01 2011-07-01 false Real ear method. 211.206-1 Section 211... PRODUCT NOISE LABELING Hearing Protective Devices § 211.206-1 Real ear method. (a) The value of sound... “Method for the Measurement of Real-Ear Protection of Hearing Protectors and Physical Attenuation of...

40 CFR 211.103 - Number and gender.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Number and gender. 211.103 Section 211... PRODUCT NOISE LABELING General Provisions § 211.103 Number and gender. In this part, words in the singular will be understood to include the plural, and words in the masculine gender will be understood to...

40 CFR 211.103 - Number and gender.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 25 2014-07-01 2014-07-01 false Number and gender. 211.103 Section 211... PRODUCT NOISE LABELING General Provisions § 211.103 Number and gender. In this part, words in the singular will be understood to include the plural, and words in the masculine gender will be understood to...

40 CFR 211.103 - Number and gender.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 26 2012-07-01 2011-07-01 true Number and gender. 211.103 Section 211... PRODUCT NOISE LABELING General Provisions § 211.103 Number and gender. In this part, words in the singular will be understood to include the plural, and words in the masculine gender will be understood to...

40 CFR 211.103 - Number and gender.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 26 2013-07-01 2013-07-01 false Number and gender. 211.103 Section 211... PRODUCT NOISE LABELING General Provisions § 211.103 Number and gender. In this part, words in the singular will be understood to include the plural, and words in the masculine gender will be understood to...

40 CFR 211.103 - Number and gender.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 25 2011-07-01 2011-07-01 false Number and gender. 211.103 Section 211... PRODUCT NOISE LABELING General Provisions § 211.103 Number and gender. In this part, words in the singular will be understood to include the plural, and words in the masculine gender will be understood to...

40 CFR 211.206-1 - Real ear method.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Real ear method. 211.206-1 Section 211... PRODUCT NOISE LABELING Hearing Protective Devices § 211.206-1 Real ear method. (a) The value of sound... “Method for the Measurement of Real-Ear Protection of Hearing Protectors and Physical Attenuation of...

40 CFR 211.206-1 - Real ear method.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 26 2013-07-01 2013-07-01 false Real ear method. 211.206-1 Section 211... PRODUCT NOISE LABELING Hearing Protective Devices § 211.206-1 Real ear method. (a) The value of sound... “Method for the Measurement of Real-Ear Protection of Hearing Protectors and Physical Attenuation of...

40 CFR 211.206-1 - Real ear method.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 25 2014-07-01 2014-07-01 false Real ear method. 211.206-1 Section 211... PRODUCT NOISE LABELING Hearing Protective Devices § 211.206-1 Real ear method. (a) The value of sound... “Method for the Measurement of Real-Ear Protection of Hearing Protectors and Physical Attenuation of...

40 CFR 211.206-1 - Real ear method.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 26 2012-07-01 2011-07-01 true Real ear method. 211.206-1 Section 211... PRODUCT NOISE LABELING Hearing Protective Devices § 211.206-1 Real ear method. (a) The value of sound... “Method for the Measurement of Real-Ear Protection of Hearing Protectors and Physical Attenuation of...

40 CFR 211.212-1 - Test request.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 25 2011-07-01 2011-07-01 false Test request. 211.212-1 Section 211... PRODUCT NOISE LABELING Hearing Protective Devices § 211.212-1 Test request. (a) The Administrator will request all testing under this section by means of a test request addressed to the -manufacturer. (b) The...

Treatment of solid tumors by interstitial release of recoiling short-lived alpha emitters

NASA Astrophysics Data System (ADS)

Arazi, L.; Cooks, T.; Schmidt, M.; Keisari, Y.; Kelson, I.

2007-08-01

A new method utilizing alpha particles to treat solid tumors is presented. Tumors are treated with interstitial radioactive sources which continually release short-lived alpha emitting atoms from their surface. The atoms disperse inside the tumor, delivering a high dose through their alpha decays. We implement this scheme using thin wire sources impregnated with 224Ra, which release by recoil 220Rn, 216Po and 212Pb atoms. This work aims to demonstrate the feasibility of our method by measuring the activity patterns of the released radionuclides in experimental tumors. Sources carrying 224Ra activities in the range 10-130 kBq were used in experiments on murine squamous cell carcinoma tumors. These included gamma spectroscopy of the dissected tumors and major organs, Fuji-plate autoradiography of histological tumor sections and tissue damage detection by Hematoxylin-Eosin staining. The measurements focused on 212Pb and 212Bi. The 220Rn/216Po distribution was treated theoretically using a simple diffusion model. A simplified scheme was used to convert measured 212Pb activities to absorbed dose estimates. Both physical and histological measurements confirmed the formation of a 5-7 mm diameter necrotic region receiving a therapeutic alpha-particle dose around the source. The necrotic regions shape closely corresponded to the measured activity patterns. 212Pb was found to leave the tumor through the blood at a rate which decreased with tumor mass. Our results suggest that the proposed method, termed DART (diffusing alpha-emitters radiation therapy), may potentially be useful for the treatment of human patients.

Quality assurance of alpha-particle dosimetry using peeled-off Gafchromic EBT3® film

NASA Astrophysics Data System (ADS)

Ng, C. Y. P.; Chun, S. L.; Yu, K. N.

2016-08-01

A novel alpha-particle dosimetry technique using Gafchromic EBT3 film has recently been proposed for calibrating the activity of alpha-emitting radiopharmaceuticals. In the present paper, we outlined four measures which could further help assure the quality of the method. First, we suggested an alternative method in fabricating the peeled-off EBT3 film. Films with a chosen size were cut from the original films and all the edges were sealed with silicone. These were immersed into deionized water for 19 d and the polyester covers of the EBT3 films could then be easily peeled off. The active layers in these peeled-off EBT3 films remained intact, and these films could be prepared reproducibly with ease. Second, we proposed a check on the integrity of the peeled-off film by comparing the responses of the pristine and peeled-off EBT3 films to the same X-ray irradiation. Third, we highlighted the importance of scanning directions of the films. The ;landscape; and ;portrait; scanning directions were defined as the scanning directions perpendicular and parallel to the long edge of the original EBT3 films, respectively. Our results showed that the responses were different for different scanning directions. As such, the same scanning direction should be used every time. Finally, we cautioned the need to confirm the uniformity of the alpha-particle source used for calibration. Radiochromic films are well known for their capability of providing two-dimensional dosimetric information. As such, EBT3 films could also be conveniently used to check the uniformity of the alpha-particle source.

64Cu-DOTA-trastuzumab PET imaging in patients with HER2-positive breast cancer.

PubMed

Tamura, Kenji; Kurihara, Hiroaki; Yonemori, Kan; Tsuda, Hitoshi; Suzuki, Junko; Kono, Yuzuru; Honda, Natsuki; Kodaira, Makoto; Yamamoto, Harukaze; Yunokawa, Mayu; Shimizu, Chikako; Hasegawa, Koki; Kanayama, Yousuke; Nozaki, Satoshi; Kinoshita, Takayuki; Wada, Yasuhiro; Tazawa, Shusaku; Takahashi, Kazuhiro; Watanabe, Yasuyoshi; Fujiwara, Yasuhiro

2013-11-01

The purpose of this study was to determine the safety, distribution, internal dosimetry, and initial human epidermal growth factor receptor 2 (HER2)-positive tumor images of (64)Cu-DOTA-trastuzumab in humans. PET was performed on 6 patients with primary or metastatic HER2-positive breast cancer at 1, 24, and 48 h after injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity data were collected from the blood, urine, and normal-tissue samples of these 6 patients, and the multiorgan biodistribution and internal dosimetry of the probe were evaluated. Safety data were collected for all the patients after the administration of (64)Cu-DOTA-trastuzumab and during the 1-wk follow-up period. According to our results, the best timing for the assessment of (64)Cu-DOTA-trastuzumab uptake by the tumor was 48 h after injection. Radiation exposure during (64)Cu-DOTA-trastuzumab PET was equivalent to that during conventional (18)F-FDG PET. The radioactivity in the blood was high, but uptake of (64)Cu-DOTA-trastuzumab in normal tissues was low. In 2 patients, (64)Cu-DOTA-trastuzumab PET showed brain metastases, indicative of blood-brain barrier disruptions. In 3 patients, (64)Cu-DOTA-trastuzumab PET imaging also revealed primary breast tumors at the lesion sites initially identified by CT. The findings of this study indicated that (64)Cu-DOTA-trastuzumab PET is feasible for the identification of HER2-positive lesions in patients with primary and metastatic breast cancer. The dosimetry and pharmacologic safety results were acceptable at the dose required for adequate PET imaging.

The delivery of chlorofluorocarbon-propelled versus hydrofluoroalkane-propelled beclomethasone dipropionate aerosol to the mechanically ventilated patient: a laboratory study.

PubMed

Mitchell, Jolyon P; Nagel, Mark W; Wiersema, Kimberly J; Doyle, Cathy C; Migounov, Vladimir A

2003-11-01

We describe a laboratory investigation comparing the delivery of chlorofluorocarbon (CFC)- and hydrofluoroalkane (HFA)-formulated beclomethasone dipropionate (BDP) by metered-dose inhaler and holding chamber (AeroChamber HC MV) in a simulation of a mechanically ventilated adult patient. We equipped each HC MV (n = 5) with an 8.0 mm diameter endotracheal tube (ETT), locating the HC MV in the inspiratory limb of a breathing circuit linked to a mechanical ventilator set to simulate tidal breathing at tidal volume = 830 mL, respiratory rate = 15 breaths/min, inspiratory-expiratory ratio of 1:2.1, peak inspiratory pressure = 20 cm H(2)O. Temperature and humidity settings were 35+/-1 degrees C and 100% relative humidity (close to body conditions). We compared delivery of 5-actuations of CFC- and HFA-BDP (both 50 microg/actuation), measuring total emitted mass captured by a filter at the distal end of the ETT. In a separate study, we inserted the distal end of the ETT within the entry cone of a cascade impactor so that the aerosol particle size distribution could be determined with the circuit at similar environmental conditions as described previously. We made benchmark measurements with circuit temperature and humidity at room ambient conditions (21+/-1 degrees C and 54+/-5% RH respectively). Total emitted mass (5 measurements/device) was significantly greater for HFA-BDP (14.1+/-1.1 microg/actuation) compared with CFC-BDP (2.4+/-0.8 microg/actuation) (paired t test, p < 0.001). More HFA-BDP (2.7 +/- 0.2 microg/actuation) was lost from the delivery system during exhalation (0.9 +/- 0.4 microg/actuation for CFC-BDP) (p < 0.001). The mass median aerodynamic diameter (MMAD) increased from 1.2 microm (room ambient) to 2.8 microm (higher temperature and humidity conditions) for HFA-BDP. In contrast, MMAD for CFC-BDP remained close to 4.6 microm under either condition, but particles finer than about 4.0 microm increased in size when the circuit was saturated. Total emitted mass for HFA-BDP was increased by a factor of 5.8 compared with CFC-BDP, due largely to the finer particle size distribution of the HFA-based solution formulation. Additional water vapor required to operate the breathing circuit at close to body conditions resulted in fine particle growth with both formulations.

40 CFR 211.110-1 - Testing exemption.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 211.110-1 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING General Provisions § 211.110-1 Testing exemption. (a) A new product intended to be used solely for research, investigations, studies, demonstrations or training, and so...

Magnetic vesicles as MRI-trackable biogenic nanovectors

NASA Astrophysics Data System (ADS)

Andriola Silva, Amanda K.; Luciani, Nathalie; Gazeau, Florence; Wilhelm, Claire

2012-03-01

Magnetic labeling renders cells MRI-detectable which provides attractive solutions for tracking the fate of a transplanted cell population. Understanding the interplay of magnetic nanoparticles and cells is then an important point that should not be neglected. Here we show that in the condition of food starvation, macrophage cells emit vesicles containing nanoparticles. First, we inferred the intracellular iron oxide load from the magnetophoretic velocity of cells at a calibrated magnetic field gradient. After magnetic labeling and culture in stress conditions, the intracellular iron oxide load was once more determined and a detectable difference was observed before and after stress. Moreover, we identified in the stress conditioned medium membrane vesicle structures carrying magnetic particles. Besides pointing out the role of cell-derived vesicles in the sequestration of the intracellular magnetic label, experiments also demonstrated that vesicles were able to chaperone the magnetic cargo into naïve cells.

Radiotoxicity of Gadolinium-148 and Radium-223 in Mouse Testes: Relative Biological Effectiveness of Alpha-Particle Emitters In Vivo

PubMed Central

Howell, Roger W.; Goddu, S. Murty; Narra, Venkat R.; Fisher, Darrell R.; Schenter, Robert E.; Rao, Dandamudi V.

2012-01-01

The biological effects of radionuclides that emit α particles are of considerable interest in view of their potential for therapy and their presence in the environment. The present work is a continuation of our ongoing effort to study the radiotoxicity of α-particle emitters in vivo using the survival of murine testicular sperm heads as the biological end point. Specifically, the relative biological effectiveness (RBE) of very low-energy α particles (3.2 MeV) emitted by 148Gd is investigated and determined to be 7.4 ± 2.4 when compared to the effects of acute external 120 kVp X rays. This datum, in conjunction with our earlier results for 210Po and 212Pb in equilibrium with its daughters, is used to revise and extend the range of validity of our previous RBE–energy relationship for α particles emitted by tissue-incorporated radionuclides. The new empirical relationship is given by RBEα = 9.14 − 0.510 Eα, where 3 < Eα < 9 MeV. The validity of this empirical relationship is tested by determining the RBE of the prolific α-particle emitter 223Ra (in equilibrium with its daughters) experimentally in the same biological model and comparing the value obtained experimentally with the predicted value. The resulting RBE values are 5.4 ± 0.9 and 5.6, respectively. This close agreement strongly supports the adequacy of the empirical RBE-Eα relationship to predict the biological effects of α-particle emitters in Vivo. PMID:9052681

Tumor Immunotargeting Using Innovative Radionuclides

PubMed Central

Kraeber-Bodéré, Françoise; Rousseau, Caroline; Bodet-Milin, Caroline; Mathieu, Cédric; Guérard, François; Frampas, Eric; Carlier, Thomas; Chouin, Nicolas; Haddad, Ferid; Chatal, Jean-François; Faivre-Chauvet, Alain; Chérel, Michel; Barbet, Jacques

2015-01-01

This paper reviews some aspects and recent developments in the use of antibodies to target radionuclides for tumor imaging and therapy. While radiolabeled antibodies have been considered for many years in this context, only a few have reached the level of routine clinical use. However, alternative radionuclides, with more appropriate physical properties, such as lutetium-177 or copper-67, as well as alpha-emitting radionuclides, including astatine-211, bismuth-213, actinium-225, and others are currently reviving hopes in cancer treatments, both in hematological diseases and solid tumors. At the same time, PET imaging, with short-lived radionuclides, such as gallium-68, fluorine-18 or copper-64, or long half-life ones, particularly iodine-124 and zirconium-89 now offers new perspectives in immuno-specific phenotype tumor imaging. New antibody analogues and pretargeting strategies have also considerably improved the performances of tumor immunotargeting and completely renewed the interest in these approaches for imaging and therapy by providing theranostics, companion diagnostics and news tools to make personalized medicine a reality. PMID:25679452

Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study.

PubMed

Jones, Stephen E; Collea, Rufus; Paul, Devchand; Sedlacek, Scot; Favret, Anne M; Gore, Ira; Lindquist, Deborah L; Holmes, Frankie Ann; Allison, Mary Ann K; Brooks, Barry D; Portillo, Raul M; Vukelja, Svetislava J; Steinberg, Michael S; Stokoe, Christopher; Crockett, Maria W; Wang, Yunfei; Asmar, Lina; Robert, Nicholas J; O'Shaughnessy, Joyce

2013-10-01

Previous results suggest that docetaxel plus cyclophosphamide improves disease-free survival (DFS) and overall survival compared with doxorubicin plus cyclophosphamide in early stage breast cancer. We assessed the addition of 1 year of trastuzumab to a non-anthracycline regimen, docetaxel plus cyclophosphamide, in patients with HER2-amplified early stage breast cancer and examined whether this regimen was equally effective in patients with TOP2A-amplified and TOP2A-non-amplified disease. This was an open-label, single-group, phase 2 study. Eligible patients were aged 18-75 years; had Eastern Cooperative Oncology Group performance status of 1 or less; HER2-amplified early stage breast cancer; operable, histologically confirmed, invasive carcinoma of the breast; adequate tumour specimen available for FISH analysis of TOP2A status; and adequate haematological, renal, hepatic, and cardiac function. Patients received four 21-day cycles of intravenous docetaxel 75 mg/m(2), plus intravenous cyclophosphamide 600 mg/m(2), plus intravenous trastuzumab 4 mg/kg (loading dose) on day 1 and 2 mg/kg on days 1, 8, and 15 during chemotherapy, followed by trastuzumab 6 mg/kg every three weeks for the remainder of 1 year. The primary endpoint was 2-year DFS in TOP2A-amplified and TOP2A-non-amplified patients; the primary analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00493649. 493 patients were enrolled between June 15, 2007, and Aug 5, 2009. After a median follow-up of 36·1 months (IQR 35·5-36·7), 2-year DFS was 97·8% (95% CI 94·2-99·2) and 2-year overall survival was 99·5% (95% CI 96·2-99·9) for the 190 patients with TOP2A-amplified disease; 2-year DFS was 97·9% (95% CI 94·9-99·1) and 2-year overall survival was 98·8% (95% CI 96·2-99·6) for the 248 patients with TOP2A-non-amplified disease; 55 patients were not assessable for TOP2A status. In the 486 patients who received at least one dose of study drug, the most common adverse events of any grade were fatigue (284 patients, 58·4%), neutropenia (250, 51·4%), and nausea (217, 44·7%). The most common grade 3-4 toxic effects were neutropenia (229, 47·1%), febrile neutropenia (30, 6·2%), fatigue (21, 4·3%), and diarrhoea (16, 3·3%). Cardiac dysfunction occurred in 29 (6·0%) patients (12 [2·5%] grade 1, 15 [3·1%] grade 2, and two [0·4%] grade 3). 23 patients had at least one study-related serious adverse event. 16 patients stopped trastuzumab because of cardiac dysfunction. A short, four-cycle regimen of docetaxel and cyclophosphamide combined with trastuzumab could be an option for adjuvant treatment of women with lower risk HER2-amplified early breast cancer, irrespective of TOP2A status. Sanofi. Copyright © 2013 Elsevier Ltd. All rights reserved.

Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer

PubMed Central

Mullooly, Maeve; Bennett, Ruth; Bouguern, Noujoude; Pedersen, Kasper; O'Brien, Neil A; Roxanis, Ioannis; Li, Ji-Liang; Bridge, Esther; Finn, Richard; Slamon, Dennis; McGowan, Patricia; Duffy, Michael J.

2013-01-01

Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. We confirmed that neratinib was significantly more active in HER2-amplified than HER2 non-amplified cell lines. Neratinib decreased the activation of the 4 HER receptors and inhibited downstream pathways. However, HER3 and Akt were reactivated at 24 hours, which was prevented by the combination of trastuzumab and neratinib. Neratinib also decreased pHER2 and pHER3 in acquired trastuzumab resistant cells. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Innately trastuzumab resistant cell lines showed sensitivity to neratinib, but the combination did not enhance response compared to neratinib alone. Levels of HER2 and phospho-HER2 showed a direct correlation with sensitivity to neratinib. Our data indicate that neratinib is an effective anti-HER2 therapy and counteracted both innate and acquired trastuzumab resistance in HER2 positive breast cancer. Our results suggest that combined treatment with trastuzumab and neratinib is likely to be more effective than either treatment alone for both trastuzumab-sensitive breast cancer as well as HER2-positive tumors with acquired resistance to trastuzumab. PMID:24009064

Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer.

PubMed

Canonici, Alexandra; Gijsen, Merel; Mullooly, Maeve; Bennett, Ruth; Bouguern, Noujoude; Pedersen, Kasper; O'Brien, Neil A; Roxanis, Ioannis; Li, Ji-Liang; Bridge, Esther; Finn, Richard; Siamon, Dennis; McGowan, Patricia; Duffy, Michael J; O'Donovan, Norma; Crown, John; Kong, Anthony

2013-10-01

Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. We confirmed that neratinib was significantly more active in HER2-amplified than HER2 non-amplified cell lines. Neratinib decreased the activation of the 4 HER receptors and inhibited downstream pathways. However, HER3 and Akt were reactivated at 24 hours, which was prevented by the combination of trastuzumab and neratinib. Neratinib also decreased pHER2 and pHER3 in acquired trastuzumab resistant cells. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Innately trastuzumab resistant cell lines showed sensitivity to neratinib, but the combination did not enhance response compared to neratinib alone. Levels of HER2 and phospho-HER2 showed a direct correlation with sensitivity to neratinib. Our data indicate that neratinib is an effective anti-HER2 therapy and counteracted both innate and acquired trastuzumab resistance in HER2 positive breast cancer. Our results suggest that combined treatment with trastuzumab and neratinib is likely to be more effective than either treatment alone for both trastuzumab-sensitive breast cancer as well as HER2-positive tumors with acquired resistance to trastuzumab.

Cigarette smoke radioactivity and lung cancer risk.

PubMed

Karagueuzian, Hrayr S; White, Celia; Sayre, James; Norman, Amos

2012-01-01

To determine the tobacco industry's policy and action with respect to radioactive polonium 210 ((210)Po) in cigarette smoke and to assess the long-term risk of lung cancer caused by alpha particle deposits in the lungs of regular smokers. Analysis of major tobacco industries' internal secret documents on cigarette radioactivity made available online by the Master Settlement Agreement in 1998. The documents show that the industry was well aware of the presence of a radioactive substance in tobacco as early as 1959. Furthermore, the industry was not only cognizant of the potential "cancerous growth" in the lungs of regular smokers but also did quantitative radiobiological calculations to estimate the long-term (25 years) lung radiation absorption dose (rad) of ionizing alpha particles emitted from the cigarette smoke. Our own calculations of lung rad of alpha particles match closely the rad estimated by the industry. According to the Environmental Protection Agency, the industry's and our estimate of long-term lung rad of alpha particles causes 120-138 lung cancer deaths per year per 1,000 regular smokers. Acid wash was discovered in 1980 to be highly effectively in removing (210)Po from the tobacco leaves; however, the industry avoided its use for concerns that acid media would ionize nicotine converting it into a poorly absorbable form into the brain of smokers thus depriving them of the much sought after instant "nicotine kick" sensation. The evidence of lung cancer risk caused by cigarette smoke radioactivity is compelling enough to warrant its removal.

WE-FG-BRA-10: Radiodosimetry of a Novel Alpha Particle Therapy Targeted to Uveal Melanoma: Absorbed Dose to Organs in Mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tichacek, Christopher J.; Tafreshi, Narges K.; Budzevich, Mikalai M.

Purpose: The melanocortin-1 receptor (MC1R) is expressed in 94% of uveal melanomas and is described as an ideal target for this untreatable disease. MC1RL is a high affinity MC1R specific peptidomimetic ligand that can serve as a scaffold for therapeutic conjugates such as alpha particle emitting isotopes. The purpose of this study was to assess normal tissue distribution and risk as a result of using the DOTA chelator conjugated to MC1RL to deliver {sup 225}Ac: MC1RL-DOTA-{sup 225}Ac. Methods: 17 non-tumor bearing BALB/c mice were intravenously injected with the novel MC1RL-DOTA-{sup 225}Ac radiopharmaceutical with an average initial administered activity of 2.5more » µCi. After the injection, three groups of animals (6, 6, and 5 per group) were euthanized at 24, 48, and 96 hour time points. A total of 11 organs of interest were harvested at each time point including kidneys and liver. Since the emitted alpha particles from {sup 225}Ac and its daughter products are not easy to detect directly, the isomeric gamma spectra were measured instead in the tissue samples using a modified Atomlab™ Gamma Counter (Biodex Medical Systems, Inc) and converted using factors for gamma ray abundance per alpha decay. Dosimetry was performed using measured radioactivity distribution in organs and the generalized internal dosimetry schema of MIRD pamphlet #21. Results: Our calculations have shown that the maximum absorbed dose was delivered to the liver with a total of 47 cGy per 96 hour period. The average dose per kidney was calculated to be 21 cGy. Heart, brain, lung, spleen, skin doses ranged from 0.01 to 1 cGy over the same time period. All animals gained weight over the 110 day decay period and no organ damage was observed by pathology. Conclusion: Based on our results, the risk of using the MC1RL-DOTA-{sup 225}Ac compound is relatively small in terms of deterministic radiation effects. Funding Support: NIH/NCI P50CA168536-03 Skin SPORE; NIH/NCI Phase I SBIR Contract #HHSN261201500067C; Imaging and Technology Center of Excellence at Moffitt. Disclosures and Conflict of Interest: Collaboration with Modulation Therapeutics, Inc.(MTI) and has been partially funded by sub-contracts from MTI via collaboration on a NIH/NCI phase I SBIR contract.« less

Progress in obtaining an absolute calibration of a total deuterium-tritium neutron yield diagnostic based on copper activationa)

NASA Astrophysics Data System (ADS)

Ruiz, C. L.; Chandler, G. A.; Cooper, G. W.; Fehl, D. L.; Hahn, K. D.; Leeper, R. J.; McWatters, B. R.; Nelson, A. J.; Smelser, R. M.; Snow, C. S.; Torres, J. A.

2012-10-01

The 350-keV Cockroft-Walton accelerator at Sandia National laboratory's Ion Beam facility is being used to calibrate absolutely a total DT neutron yield diagnostic based on the 63Cu(n,2n)62Cu(β+) reaction. These investigations have led to first-order uncertainties approaching 5% or better. The experiments employ the associated-particle technique. Deuterons at 175 keV impinge a 2.6 μm thick erbium tritide target producing 14.1 MeV neutrons from the T(d,n)4He reaction. The alpha particles emitted are measured at two angles relative to the beam direction and used to infer the neutron flux on a copper sample. The induced 62Cu activity is then measured and related to the neutron flux. This method is known as the F-factor technique. Description of the associated-particle method, copper sample geometries employed, and the present estimates of the uncertainties to the F-factor obtained are given.

Progress in obtaining an absolute calibration of a total deuterium-tritium neutron yield diagnostic based on copper activation.

PubMed

Ruiz, C L; Chandler, G A; Cooper, G W; Fehl, D L; Hahn, K D; Leeper, R J; McWatters, B R; Nelson, A J; Smelser, R M; Snow, C S; Torres, J A

2012-10-01

The 350-keV Cockroft-Walton accelerator at Sandia National laboratory's Ion Beam facility is being used to calibrate absolutely a total DT neutron yield diagnostic based on the (63)Cu(n,2n)(62)Cu(β+) reaction. These investigations have led to first-order uncertainties approaching 5% or better. The experiments employ the associated-particle technique. Deuterons at 175 keV impinge a 2.6 μm thick erbium tritide target producing 14.1 MeV neutrons from the T(d,n)(4)He reaction. The alpha particles emitted are measured at two angles relative to the beam direction and used to infer the neutron flux on a copper sample. The induced (62)Cu activity is then measured and related to the neutron flux. This method is known as the F-factor technique. Description of the associated-particle method, copper sample geometries employed, and the present estimates of the uncertainties to the F-factor obtained are given.

Integrating molecular mechanisms and clinical evidence in the management of trastuzumab resistant or refractory HER-2⁺ metastatic breast cancer.

PubMed

Wong, Hilda; Leung, Roland; Kwong, Ava; Chiu, Joanne; Liang, Raymond; Swanton, Charles; Yau, Thomas

2011-01-01

Human epidermal growth factor receptor (HER)-2(+) breast cancer is a distinct molecular and clinical entity, the prognosis of which is improved by trastuzumab. However, primary resistance to trastuzumab is observed in >50% of patients with HER-2(+) advanced breast cancer, and the majority of patients who initially respond to treatment eventually develop disease progression. To facilitate crosstrial comparisons and the understanding of resistance mechanisms, we propose a unifying definition of trastuzumab resistance as progression at first radiological reassessment at 8-12 weeks or within 3 months after first-line trastuzumab in the metastatic setting or new recurrences diagnosed during or within 12 months after adjuvant trastuzumab. In contrast, we define trastuzumab-refractory breast cancer as disease progression after two or more lines of trastuzumab-containing regimens that initially achieved disease response or stabilization at first radiological assessment. We review mechanisms of trastuzumab resistance mediated by p95HER-2 overexpression, phosphoinositide 3-kinase pathway activation, and signaling pathway activation driven by HER-3, epidermal growth factor receptor, and insulin-like growth factor 1 receptor. We distinguish in vitro from in vivo evidence, highlighting that most data describing trastuzumab resistance are derived from preclinical studies or small retrospective patient cohorts, and discuss targeted therapeutic approaches to overcome resistance. Prospective analysis through clinical trials with robust tissue collection procedures, prior to and following acquisition of resistance, integrated with next-generation tumor genome sequencing technologies, is identified as a priority area for development. The identification of predictive biomarkers is of paramount importance to optimize health economic costs and enhance stratification of anti-HER-2 targeted therapies.

HannaH phase III randomised study: Association of total pathological complete response with event-free survival in HER2-positive early breast cancer treated with neoadjuvant-adjuvant trastuzumab after 2 years of treatment-free follow-up.

PubMed

Jackisch, Christian; Hegg, Roberto; Stroyakovskiy, Daniil; Ahn, Jin-Seok; Melichar, Bohuslav; Chen, Shin-Cheh; Kim, Sung-Bae; Lichinitser, Mikhail; Starosławska, Elżbieta; Kunz, Georg; Falcon, Silvia; Chen, Shou-Tung; Crepelle-Fléchais, Aulde; Heinzmann, Dominik; Shing, Mona; Pivot, Xavier

2016-07-01

In the phase III, open-label, randomised HannaH study, fixed-dose neoadjuvant-adjuvant subcutaneous trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive early breast cancer was non-inferior to standard weight-based intravenous infusion in terms of serum trough concentration and pathological complete response (pCR). Evidence suggests that pCR, particularly total pCR (tpCR), is likely to predict clinical benefit. We report associations between tpCR and event-free survival (EFS) from HannaH (the largest population from a single study of patients presenting with newly diagnosed HER2-positive breast cancer treated with neoadjuvant-adjuvant trastuzumab to date) plus long-term efficacy and safety. Eligible patients received four cycles of neoadjuvant docetaxel followed by four cycles of fluorouracil/epirubicin/cyclophosphamide administered concurrently with 3-weekly subcutaneous (600 mg fixed dose) or intravenous trastuzumab (8 mg/kg loading, 6 mg/kg maintenance doses). Post-surgery, patients received adjuvant trastuzumab as randomised to complete 1 year of standard treatment. In exploratory analyses, we used Cox regression to assess associations between tpCR and EFS. EFS rates per subgroup were estimated using the Kaplan-Meier method. Three-year EFS rates were 76% for subcutaneous and 73% for intravenous trastuzumab (unstratified hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.69-1.30; intention-to-treat population). Three-year overall survival rates were 92% for subcutaneous and 90% for intravenous trastuzumab (unstratified HR 0.76, 95% CI 0.44-1.32). tpCR was associated with a reduced risk of an EFS event: subcutaneous arm HR 0.38 (95% CI 0.22-0.65); intravenous arm HR 0.32 (95% CI 0.18-0.60). Results were similar for subgroups, including oestrogen receptor status. The few additional adverse events occurring during treatment-free follow-up were balanced between arms. Long-term efficacy supports the established non-inferiority of subcutaneous trastuzumab, and its safety profile remains consistent with the known intravenous profile. In each of HannaH's treatment arms, tpCR was associated with improved EFS, adding to evidence that tpCR is associated with clinical benefit in HER2-positive early breast cancer. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

21 CFR 211.122 - Materials examination and usage criteria.

Code of Federal Regulations, 2011 CFR

2011-04-01

... differentiated by size, shape, or color. (g) If cut labeling is used, packaging and labeling operations shall.... (e) Obsolete and outdated labels, labeling, and other packaging materials shall be destroyed. (f) Use...

21 CFR 211.137 - Expiration dating.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Expiration dating. 211.137 Section 211.137 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Packaging and Labeling Control...

21 CFR 211.137 - Expiration dating.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Expiration dating. 211.137 Section 211.137 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Packaging and Labeling Control...

21 CFR 211.137 - Expiration dating.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Expiration dating. 211.137 Section 211.137 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Packaging and Labeling Control...

21 CFR 211.137 - Expiration dating.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Expiration dating. 211.137 Section 211.137 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Packaging and Labeling Control...

40 CFR 211.204-4 - Supporting information.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 25 2011-07-01 2011-07-01 false Supporting information. 211.204-4... PROGRAMS PRODUCT NOISE LABELING Hearing Protective Devices § 211.204-4 Supporting information. The following minimum supporting information must accompany the device in a manner that insures its availability...

Memory impairment, oxidative damage and apoptosis induced by space radiation: ameliorative potential of alpha-lipoic acid.

PubMed

Manda, Kailash; Ueno, Megumi; Anzai, Kazunori

2008-03-05

Exposure to high-energy particle radiation (HZE) may cause oxidative stress and cognitive impairment in the same manner that seen in aged mice. This phenomenon has raised the concerns about the safety of an extended manned mission into deep space where a significant portion of the radiation burden would come from HZE particle radiation. The present study aimed at investigating the role of alpha-lipoic acid against space radiation-induced oxidative stress and antioxidant status in cerebellum and its correlation with cognitive dysfunction. We observed spontaneous motor activities and spatial memory task of mice using pyroelectric infrared sensor and programmed video tracking system, respectively. Whole body irradiation of mice with high-LET (56)Fe beams (500 MeV/nucleon, 1.5 Gy) substantially impaired the reference memory at 30 day post-irradiation; however, no significant effect was observed on motor activities of mice. Acute intraperitoneal treatment of mice with alpha-lipoic acid prior to irradiation significantly attenuated such memory dysfunction. Radiation-induced apoptotic damage in cerebellum was examined using a neuronal-specific terminal deoxynucleotidyl transferase-mediated nick end-labeling method (NeuroTACS). Radiation-induced apoptotic and necrotic cell death of granule cells and Purkinje cells were inhibited significantly by alpha-lipoic acid pretreatment. Alpha-lipoic acid pretreatment exerted a very high magnitude of protection against radiation-induced augmentation of DNA damage (comet tail movement and serum 8-OHdG), lipid proxidation products (MDA+HAE) and protein carbonyls in mice cerebellum. Further, radiation-induced decline of non-protein sulfhydryl (NP-SH) contents of cerebellum and plasma ferric reducing power (FRAP) was also inhibited by alpha-lipoic acid pre-treatment. Results clearly indicate that alpha-lipoic acid is a potent neuroprotective antioxidant. Moreover, present finding also support the idea suggesting the cerebellar involvement in cognition.

A Ly{alpha} GALAXY AT REDSHIFT z = 6.944 IN THE COSMOS FIELD

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rhoads, James E.; Hibon, Pascale; Malhotra, Sangeeta

2012-06-20

Ly{alpha} emitting galaxies can be used to study cosmological reionization, because a neutral intergalactic medium (IGM) scatters Ly{alpha} photons into diffuse halos whose surface brightness falls below typical survey detection limits. Here, we present the Ly{alpha} emitting galaxy LAE J095950.99+021219.1, identified at redshift z = 6.944 in the COSMOS field using narrowband imaging and follow-up spectroscopy with the IMACS instrument on the Magellan I Baade telescope. With a single object spectroscopically confirmed so far, our survey remains consistent with a wide range of IGM neutral fraction at z Almost-Equal-To 7, but further observations are planned and will help clarify themore » situation. Meantime, the object we present here is only the third Ly{alpha}-selected galaxy to be spectroscopically confirmed at z {approx}> 7, and is {approx}2-3 times fainter than the previously confirmed z Almost-Equal-To 7 Ly{alpha} galaxies.« less

Mucolytic Agents Can Enhance HER2 Receptor Accessibility for [(89)Zr]Trastuzumab, Improving HER2 Imaging in a Mucin-Overexpressing Breast Cancer Xenograft Mouse Model.

PubMed

Wimana, Zéna; Gebhart, G; Guiot, T; Vanderlinden, B; Morandini, R; Doumont, G; Sherer, F; Van Simaeys, G; Goldman, S; Ghanem, G; Flamen, P

2015-10-01

Binding of trastuzumab to HER2 receptors can be impaired by steric hindrance caused by mucin MUC4. As mucolytic drugs can breakdown disulfide bonds of mucoproteins, we checked if this approach could positively affect zirconium-89-labeled trastuzumab ([(89)Zr]T) binding/uptake. The effect of N-acetylcysteine (NAC) and MUC4 knockdown/stimulation on [(89)Zr]T binding/uptake were evaluated in MCF7(HER2-), BT474 and SKBr3(HER2+/MUC4-), and JIMT1(HER2+/MUC4+) cell lines. The results were then validated in SKBR3 and JIMT1 tumor-bearing nude mice with a microPET-CT and ex vivo analysis. Significant increases in [(89)Zr]T binding/uptake were observed in JIMT1 cells following MUC4 knockdown (62.4 ± 6.5%) and exposure to NAC (62.8 ± 19.4%). Compared to controls, mice treated with NAC showed a significant increase in [(89)Zr]T uptake in MUC4 tumors on microPET-CT (SUVmean (18.3 ± 4.7%), SUVmax (41.7 ± 8.4%)) and individual organ counting (37.3 ± 18.3%). In contrast, no significant differences were observed in SKBr3. NAC can enhance [(89)Zr]T accumulation and improve the HER2 imaging of MUC4-overexpressing tumors. The potential positive impact on trastuzumab-based treatment deserves further investigation.

Neutral particle beam sensing and steering

DOEpatents

Maier, II, William B.; Cobb, Donald D.; Robiscoe, Richard T.

1991-01-01

The direction of a neutral particle beam (NPB) is determined by detecting Ly.alpha. radiation emitted during motional quenching of excited H(2S) atoms in the beam during movement of the atoms through a magnetic field. At least one detector is placed adjacent the beam exit to define an optical axis that intercepts the beam at a viewing angle to include a volume generating a selected number of photons for detection. The detection system includes a lens having an area that is small relative to the NPB area and a pixel array located in the focal plane of the lens. The lens viewing angle and area pixel array are selected to optimize the beam tilt sensitivity. In one embodiment, two detectors are placed coplanar with the beam axis to generate a difference signal that is insensitive to beam variations other than beam tilt.

Alpha voltaic batteries and methods thereof

NASA Technical Reports Server (NTRS)

Jenkins, Phillip (Inventor); Scheiman, David (Inventor); Castro, Stephanie (Inventor); Raffaelle, Ryne P. (Inventor); Wilt, David (Inventor); Chubb, Donald (Inventor)

2011-01-01

An alpha voltaic battery includes at least one layer of a semiconductor material comprising at least one p/n junction, at least one absorption and conversion layer on the at least one layer of semiconductor layer, and at least one alpha particle emitter. The absorption and conversion layer prevents at least a portion of alpha particles from the alpha particle emitter from damaging the p/n junction in the layer of semiconductor material. The absorption and conversion layer also converts at least a portion of energy from the alpha particles into electron-hole pairs for collection by the one p/n junction in the layer of semiconductor material.

2016 Research Outreach Program report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Hye Young; Kim, Yangkyu

2016-10-13

This paper is the research activity report for 4 weeks in LANL. Under the guidance of Dr. Lee, who performs nuclear physics research at LANSCE, LANL, I studied the Low Energy NZ (LENZ) setup and how to use the LENZ. First, I studied the LENZ chamber and Si detectors, and worked on detector calibrations, using the computer software, ROOT (CERN developed data analysis tool) and EXCEL (Microsoft office software). I also performed the calibration experiments that measure alpha particles emitted from a Th-229 source by using a S1-type detector (Si detector). And with Dr. Lee, we checked the result.

21 CFR 211.134 - Drug product inspection.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Drug product inspection. 211.134 Section 211.134 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Packaging and Labeling Control...

Pertuzumab for the Neoadjuvant Treatment of Early-Stage HER2-Positive Breast Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

PubMed

Squires, Hazel; Pandor, Abdullah; Thokala, Praveen; Stevens, John W; Kaltenthaler, Eva; Clowes, Mark; Coleman, Robert; Wyld, Lynda

2018-01-01

As part of its single technology appraisal process, the National Institute for Health and Care Excellence invited the manufacturer of pertuzumab (Perjeta ® ; Roche Products Limited) to submit evidence of its clinical and cost- effectiveness for the neoadjuvant treatment of women with high-risk, early-stage, HER2-positive breast cancer when used in combination with trastuzumab and chemotherapy. High-risk women included those with locally advanced (including inflammatory) breast cancer and women with high-risk early-stage breast cancer (classified as T2/3 or N1). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group. This article presents the critical review of the company's submission by the Evidence Review Group and the outcome of the National Institute for Health and Care Excellence guidance. The clinical data were mainly taken from a phase II, randomised, open-label, active controlled study (NeoSphere), which reported a significant advantage in terms of pathological complete response rates of pertuzumab in combination with trastuzumab and chemotherapy, compared with trastuzumab alone with chemotherapy (45.8 vs. 29.0%, p = 0.0141). The company did not make any indirect comparisons. A meta-analysis of 12 neoadjuvant studies investigating the relationship between pathological complete response and event-free survival was used to extrapolate the outcomes reported in the NeoSphere study. A cardiac safety study (TRYPHAENA) demonstrated the safety of pertuzumab. The company undertook a model-based economic evaluation of neoadjuvant pertuzumab plus trastuzumab and docetaxel compared with neoadjuvant trastuzumab and docetaxel over a lifetime horizon from the National Health Service and Personal Social Services perspective. The probabilistic incremental cost-effectiveness ratio was estimated to be £20,104 per quality-adjusted life-year gained for pertuzumab alongside trastuzumab and docetaxel compared with trastuzumab and docetaxel, which was revised to £21,869 per quality-adjusted life-year gained following the clarification process. The Evidence Review Group corrected an error in the digitisation of the survivor functions and modified the clinically inappropriate assumption that recurrence is zero after 7 years. The Evidence Review Group's probabilistic base case was £23,962 per quality-adjusted life-year gained. During the appraisal, to mitigate the uncertainties associated with the evidence, the company offered a patient access scheme, which led to the National Institute for Health and Care Excellence Appraisal Committee recommending pertuzumab in this patient group, subject to the company providing the agreed discount in the patient access scheme.

Augmenting Trastuzumab Therapy Against Breast Cancer Through Selective Activation of NK Cells

DTIC Science & Technology

2013-10-01

selection and assessed for purity (>90% purity as defined by CD3-CD56+ flow cytometry ) and activation (>50% expression of CD137). Breast cancer cell lines...at a ratio of 1:1. After 24 hours, NK cells were isolated by negative selection and assessed for purity (>90% purity as defined by CD3-CD56+ flow ... cytometry ) and activation (>50% expression of CD137). Chromium-labeled breast cancer cell lines including MCF7 (A), BT474M1 (B), HER18 (C), and SKBR3

The Discovery of Artificial Radioactivity

NASA Astrophysics Data System (ADS)

Guerra, Francesco; Leone, Matteo; Robotti, Nadia

2012-03-01

We reconstruct Frédéric Joliot and Irène Curie's discovery of artificial radioactivity in January 1934 based in part on documents preserved in the Joliot-Curie Archives in Paris, France. We argue that their discovery followed from the convergence of two parallel lines of research, on the neutron and on the positron, that were focused on a well-defined experimental problem, the nuclear transmutation of aluminum and other light elements. We suggest that a key role was played by a suggestion that Francis Perrin made at the seventh Solvay Conference at the end of October 1933, that the alpha-particle bombardment of aluminum produces an intermediate unstable isotope of phosphorus, which then decays by positron emission. We also suggest that a further idea that Perrin published in December 1933, and the pioneering theory of beta decay that Enrico Fermi also first published in December 1933, established a new theoretical framework that stimulated Joliot to resume the researches that he and Curie had interrupted after the Solvay Conference, now for the first time using a Geiger-Müller counter to detect the positrons emitted when he bombarded aluminum with polonium alpha particles.

First-line trastuzumab plus taxane-based chemotherapy for metastatic breast cancer: cost-minimization analysis.

PubMed

Nerich, Virginie; Chelly, Jennifer; Montcuquet, Philippe; Chaigneau, Loïc; Villanueva, Cristian; Fiteni, Frédéric; Meneveau, Nathalie; Perrin, Sophie; Voidey, Aline; Monnot, Tess; Pivot, Xavier; Limat, Samuel

2014-10-01

To carry out a cost-minimization analysis including a comparison of the costs arising from first-line treatment by trastuzumab plus docetaxel versus trastuzumab plus paclitaxel in patients with metastatic breast cancer. All consecutive patients with human epidermal growth receptor 2-postive metastatic breast cancer who were treated at Besançon University Hospital and Saint Vincent private hospital between 2001 and 2010 by first-line therapy containing trastuzumab plus taxane were retrospectively studied. Economic analysis took into account costs related to drugs, hospitalization, and healthcare travel. Progression-free survival difference between the two treatments was not significant (p = 0.65). First-line treatment by trastuzumab plus taxane was estimated at approximately €68,000 (p = 0.74). The drug costs represented around 70-75% of the total cost, mainly related to the use of trastuzumab. Our economic analysis shows that although the costs of the two trastuzumab plus taxane regimens are similar, they may contribute to the on-going debate about the availability and use of innovative chemotherapy drugs, in particular in human epidermal growth factor receptor 2-positive metastatic breast cancer with new therapies such as trastuzumab-DM1 and pertuzumab. © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

40 CFR 211.110-3 - Export exemptions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Export exemptions. 211.110-3 Section... PROGRAMS PRODUCT NOISE LABELING General Provisions § 211.110-3 Export exemptions. (a) A new product intended solely for export, and which has satisfied the requirements of other applicable regulations of...

ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer

PubMed Central

Feldinger, Katharina; Generali, Daniele; Kramer-Marek, Gabriela; Gijsen, Merel; Ng, Tzi Bun; Wong, Jack Ho; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele; Li, Ji-Liang; Bridges, Esther; Turley, Helen; Leek, Russell; Roxanis, Ioannis; Capala, Jacek; Murphy, Gillian; Harris, Adrian L.; Kong, Anthony

2014-01-01

Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p≤0.001 in BT474; p≤0.01 in SKBR3) and in vivo (p≤0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naïve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p≤0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p≤0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p≤0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients. PMID:24952873

In situ X-ray diffraction study of reduction processes of Fe{sub 3}O{sub 4}- and Fe{sub 1-x}O-based ammonia-synthesis catalysts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng Yifan, E-mail: zhengyifan@zjut.edu.c; Catalysis Institute, Zhejiang University of Technology, Hangzhou 310014; Liu Huazhang

2009-09-15

The temperature-programmed reduction process of two types of industrial ammonia-synthesis catalysts, A110 and ZA-5, which are, respectively, based on Fe{sub 3}O{sub 4} and Fe{sub 1-x}O precursors, were studied by in situ X-ray power diffraction (XRD). It has been found that the ZA-5 has lower reduction temperature and faster reduction rate, and its active phase alpha-Fe possesses a higher value of lattice microstrain than A110. The simulation based on Rietveld refinement has also shown that the shape of alpha-Fe grain of ZA-5 has a mixed shape of cube and sphere with more exposing (111) and (211) planes, while that of A110more » looks like a concave cube with more exposing (110) planes. Based on the results obtained, a growth model of alpha-Fe during the reduction of Fe{sub 3}O{sub 4}- and Fe{sub 1-x}O-based ammonia-synthesis catalysts is proposed, and the origins for the activity difference has been also discussed. - Graphical Abstract: A proposed growth model of active phase alpha-Fe during reduction. Due to H{sub 2} diffusing easily into the pores, reduction starts on outside and inside surface simultaneously to form 'microcrystalline film', and the particles shrink during reduction which results in breaking of the aggregated oxide particle.« less

Hot spot temperature measurements in DT layered implosions

NASA Astrophysics Data System (ADS)

Patel, Pravesh; Ma, T.; Macphee, A.; Callahan, D.; Chen, H.; Cerjan, C.; Clark, D.; Edgell, D.; Hurricane, O.; Izumi, N.; Khan, S.; Jarrott, L.; Kritcher, A.; Springer, P.

2015-11-01

The temperature of the burning DT hot spot in an ICF implosion is a crucial parameter in understanding the thermodynamic conditions of the fuel at stagnation and and the performance of the implosion in terms of alpha-particle self-heating and energy balance. The continuum radiation spectrum emitted from the hot spot provides an accurate measure of the emissivity-weighted electron temperature. Absolute measurements of the emitted radiation are made with several independent instruments including spatially-resolved broadband imagers, and space- and time-integrated monochromatic detectors. We present estimates of the electron temperature in DT layered implosions derived from the radiation spectrum most consistent with the available measurements. The emissivity-weighted electron temperatures are compared to the neutron-averaged apparent ion temperatures inferred from neutron time-of-flight detectors. This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.

An integrated multiple-analyte pharmacokinetic model to characterize trastuzumab emtansine (T-DM1) clearance pathways and to evaluate reduced pharmacokinetic sampling in patients with HER2-positive metastatic breast cancer.

PubMed

Lu, Dan; Joshi, Amita; Wang, Bei; Olsen, Steve; Yi, Joo-Hee; Krop, Ian E; Burris, Howard A; Girish, Sandhya

2013-08-01

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate recently approved by the US Food and Drug Administration for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer previously treated with trastuzumab and taxane chemotherapy. It comprises the microtubule inhibitory cytotoxic agent DM1 conjugated to the HER2-targeted humanized monoclonal antibody trastuzumab via a stable linker. To characterize the pharmacokinetics of T-DM1 in patients with metastatic breast cancer, concentrations of multiple analytes were quantified, including serum concentrations of T-DM1 conjugate and total trastuzumab (the sum of conjugated and unconjugated trastuzumab), as well as plasma concentrations of DM1. The clearance of T-DM1 conjugate is approximately 2 to 3 times faster than its parent antibody, trastuzumab. However, the clearance pathways accounting for this faster clearance rate are unclear. An integrated population pharmacokinetic model that simultaneously fits the pharmacokinetics of T-DM1 conjugate and total trastuzumab can help to elucidate the clearance pathways of T-DM1. The model can also be used to predict total trastuzumab pharmacokinetic profiles based on T-DM1 conjugate pharmacokinetic data and sparse total trastuzumab pharmacokinetic data, thereby reducing the frequency of pharmacokinetic sampling. T-DM1 conjugate and total trastuzumab serum concentration data, including baseline trastuzumab concentrations prior to T-DM1 treatment, from phase I and II studies were used to develop this integrated population pharmacokinetic model. Based on a hypothetical T-DM1 catabolism scheme, two-compartment models for T-DM1 conjugate and trastuzumab were integrated by assuming a one-step deconjugation clearance from T-DM1 conjugate to trastuzumab. The ability of the model to predict the total trastuzumab pharmacokinetic profile based on T-DM1 conjugate pharmacokinetics and various sampling schemes of total trastuzumab pharmacokinetics was assessed to evaluate total trastuzumab sampling schemes. The final model reflects a simplified catabolism scheme of T-DM1, suggesting that T-DM1 clearance pathways include both deconjugation and proteolytic degradation. The model fits T-DM1 conjugate and total trastuzumab pharmacokinetic data simultaneously. The deconjugation clearance of T-DM1 was estimated to be ~0.4 L/day. Proteolytic degradation clearances for T-DM1 and trastuzumab were similar (~0.3 L/day). This model accurately predicts total trastuzumab pharmacokinetic profiles based on T-DM1 conjugate pharmacokinetic data and sparse total trastuzumab pharmacokinetic data sampled at preinfusion and end of infusion in cycle 1, and in one additional steady state cycle. This semi-mechanistic integrated model links T-DM1 conjugate and total trastuzumab pharmacokinetic data, and supports the inclusion of both proteolytic degradation and deconjugation as clearance pathways in the hypothetical T-DM1 catabolism scheme. The model attributes a faster T-DM1 conjugate clearance versus that of trastuzumab to the presence of a deconjugation process and suggests a similar proteolytic clearance of T-DM1 and trastuzumab. Based on the model and T-DM1 conjugate pharmacokinetic data, a sparse pharmacokinetic sampling scheme for total trastuzumab provides an entire pharmacokinetic profile with similar predictive accuracy to that of a dense pharmacokinetic sampling scheme.

Method for the preparation of radon-211. [Patent application

DOEpatents

Meyer, G.J.; Lambrecht, R.M.

1980-10-10

A method is claimed for the production of /sup 211/Rn which can be easily isolated from the target and obtained in high yields. It is claimed that the radioisotope /sup 211/Rn can be prepared by the bombardment of /sup 209/Bi with /sup 7/Li particles using the nuclear reaction /sup 209/Bi(/sup 7/Li,5n)/sup 211/Rn. The /sup 211/Rn can be isolated from the target quite easily by degassing at elevated temperatures and the radiochemical purity of the product is better than 98%. It can thus be used as a generator system for /sup 211/At which is of potential interest in biomedical applications. The excitation function for this reaction is about from 40 to 60 MeV and the cross section for /sup 211/Rn production reaches 650 mb at 53 MeV producing a saturation yield of 5.5 ..mu..Ci/nA.

Pregnancy occurring during or following adjuvant trastuzumab in patients enrolled in the HERA trial (BIG 01-01).

PubMed

Azim, Hatem A; Metzger-Filho, Otto; de Azambuja, Evandro; Loibl, Sibylle; Focant, Florine; Gresko, Ekaterina; Arfi, Mounir; Piccart-Gebhart, Martine

2012-05-01

Only few case reports describe the pregnancy course and outcome of breast cancer patients, who were under treatment with trastuzumab at the time of conception or who have completed trastuzumab therapy before becoming pregnant. The HERA trial is a large phase III randomized clinical trial in which patients with early HER2-positive breast cancer were randomized to receive 1 or 2 years of trastuzumab or observation following completion of primary chemotherapy. To examine the effect of trastuzumab on pregnancy outcome, we report all pregnancy events that occurred until March 2010 in patients enrolled in the study. For the sake of this analysis, patients were assigned to three groups: (1) pregnancy occurring during and up to 3 months after trastuzumab exposure (group 1); (2) pregnancy occurring >3 months of last trastuzumab dose (group 2); and (3) pregnancy occurring in patients without prior exposure to trastuzumab (group 3). Sixteen, 45 and 9 pregnancies took place in groups 1, 2, and 3, respectively. 25 and 16% of patients in groups 1 and 2 experienced spontaneous abortion, the former being higher than figures reported in the general population. However, short-term fetal outcome appeared normal across the three groups. Only 2 congenital anomalies were reported, one in group 2 and one in group 3. No congenital anomalies were reported in those exposed to trastuzumab in utero. This is the first report from a large randomized trial assessing the effect of trastuzumab on pregnancy course and outcome. Based on our results, trastuzumab does not appear to affect fetal outcome in patients who manage to complete their pregnancy. We are currently initiating a collaboration to collect similar data from the other large adjuvant trastuzumab trials to confirm these findings.

Prostaglandin E and F2 alpha receptors in human myometrium during the menstrual cycle and in pregnancy and labor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giannopoulos, G.; Jackson, K.; Kredentser, J.

The binding of prostaglandins E1 and F2 alpha has been studied in the human myometrium and cervix during the menstrual cycle and in the myometrium of pregnant patients at term before and during labor. Tritium-labeled prostaglandin E1 and F2 alpha binding was saturable and reversible. Scatchard analysis of tritium-labeled prostaglandin E1 binding was linear, which suggests a single class of high-affinity binding sites with an estimated apparent equilibrium dissociation constant of 2.5 to 5.4 nmol/L and inhibitor affinities of 0.9, 273, 273, and 217 nmol/L for prostaglandins E2, A1, B1, and F2 alpha, respectively. Scatchard analysis of tritium-labeled prostaglandin F2more » alpha, binding was also linear, but the affinity of these binding sites was much lower, with an average dissociation constant of 50 nmol/L and inhibitor affinities of 1.6, 2.2, and 11.2 nmol/L for prostaglandins E1, E2, and A1, respectively. In nonpregnant patients, the concentrations and affinities of tritium-labeled prostaglandin E1 binding sites were similar in the myometrium during the proliferative and secretory phases of the menstrual cycle, but the concentration of these sites was much lower in the cervix. The concentration of the tritium-labeled prostaglandin E1 binding sites was significantly lower in the myometrium of pregnant patients at term than in the myometrium of nonpregnant patients. The concentrations and affinities of tritium-labeled prostaglandin E1 binding sites were not significantly different in the upper and lower myometrium of pregnant patients at term or in the myometrium of such patients before and during labor. The concentrations of the tritium-labeled prostaglandin F2 alpha binding sites during the menstrual cycle and in pregnancy at term were similar to those of tritium-labeled prostaglandin E1 binding sites.« less

Breakup fusion theory of nuclear reactions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mastroleo, R.C.

1987-01-01

Continuum spectra of particles emitted in incomplete fusion reactions are one of the major interests in current nuclear reaction studies. Based on an idea of the so-called breakup fusion (BF) reaction, several authors derived closed formulas for the singles cross section of the particles that are emitted. There have been presented, however, two conflicting cross section formulas for the same BF reaction. For convenience, we shall call one of them the IAV (Ichimura, Austern and Vincent) and the other UT (Udagawa and Tamura) cross section formulas. In this work, the formulation of the UT cross section formula (prior-form) is presented,more » and the post-form version of the IAV cross section formula is evaluted for a few {alpha}- and d-induced reactions based on the exact finite range method. It is shown that the values thus calculated are larger by an order of magnitude as compared with the experimental cross sections for the {alpha}-induced reactions, while they are comparable with the experimental cross sections for the d-induced reactions. A possible origin of why such a large cross section is resulted in the case of {alpha}-induced reactions is also discussed. Polarization of the residual compound nucleus produced in breakup fusion reactions are calculated and compared with experiments. It is shown that the polarization is rather sensitive to the deflection angles of the strongly absortive partial waves and to obtain a good fit with the experimental data a l-dependent potential in the incident channel is needed in order to stress the lower partial waves.« less

Adjuvant trastuzumab in HER2-positive breast cancer.

PubMed

Slamon, Dennis; Eiermann, Wolfgang; Robert, Nicholas; Pienkowski, Tadeusz; Martin, Miguel; Press, Michael; Mackey, John; Glaspy, John; Chan, Arlene; Pawlicki, Marek; Pinter, Tamas; Valero, Vicente; Liu, Mei-Ching; Sauter, Guido; von Minckwitz, Gunter; Visco, Frances; Bee, Valerie; Buyse, Marc; Bendahmane, Belguendouz; Tabah-Fisch, Isabelle; Lindsay, Mary-Ann; Riva, Alessandro; Crown, John

2011-10-06

Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab. We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety. At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study. The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk-benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 ClinicalTrials.gov number, NCT00021255.).

Adjuvant Trastuzumab in HER2-Positive Breast Cancer

PubMed Central

Slamon, Dennis; Eiermann, Wolfgang; Robert, Nicholas; Pienkowski, Tadeusz; Martin, Miguel; Press, Michael; Mackey, John; Glaspy, John; Chan, Arlene; Pawlicki, Marek; Pinter, Tamas; Valero, Vicente; Liu, Mei-Ching; Sauter, Guido; von Minckwitz, Gunter; Visco, Frances; Bee, Valerie; Buyse, Marc; Bendahmane, Belguendouz; Tabah-Fisch, Isabelle; Lindsay, Mary-Ann; Riva, Alessandro; Crown, John

2011-01-01

BACKGROUND Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab. METHODS We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety. RESULTS At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study. CONCLUSIONS The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk–benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 ClinicalTrials.gov number, NCT00021255.) PMID:21991949

21 CFR 211.188 - Batch production and control records.

Code of Federal Regulations, 2010 CFR

2010-04-01

... (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Records and... percentage of theoretical yield at appropriate phases of processing; (8) Complete labeling control records...

21 CFR 211.188 - Batch production and control records.

Code of Federal Regulations, 2011 CFR

2011-04-01

... (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Records and... percentage of theoretical yield at appropriate phases of processing; (8) Complete labeling control records...

[Color-tunable nano-material alpha-NaYF4 : Yb, Er, Tm prepared by microemulsion-hydrothermal method].

PubMed

Long, Dan-Dan; Zhang, Qing-Xia; Wang, Yu; Zhang, Fan; Wang, Yan-Fei; Zhou, Xin; Qi, Xiao-Hua; Zhang, Heng; Yan, Jing-Hui; Zou, Ming-Qiang

2013-08-01

NaYF4 : Yb3+, Er3+, Tm3+ nanoparticles were prepared by microemulsion-hydrothermal method. Crystal phase, morphology and structure of the samples were characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM). The luminescence properties were studied by up-conversional fluorescence spectroscopy. The XRD patterns of as-prepared samples were in agreement with the PDF # 77-2042 of cubic NaYF4. SEM images of the particles showed that the samples were cotton-like spherical in shape and which were assembled by smaller nano-particles. The average size was 120 nm, while the shape was regular and the particle size was homogeneous. Under the excitation of 980 nm, the as-prepared particles could emit blue (438 and 486 nm), green (523 and 539 nm) and red (650 nm) light simultaneously. It can be seen from the color coordinates figure (CIE) that when doping concentration ratio of Tm3+ and E3+ increased from 0 to 2, the whole emitting light color of samples movedto green region. While the ratio was 1 : 1, pseudo white light was obtained. As the ratio changed from 2 to 7, the luminous color was moved to red region.

The binding site on cochlear stereocilia for antisera raised against renal Na+ channels is blocked by amiloride and dihydrostreptomycin.

PubMed

Furness, D N; Hackney, C M; Benos, D J

1996-04-01

The mechanoelectrical transduction channels on hair cells have been suggested to be operated by tip links that are stretched when the hair bundle is deflected in the direction of the tallest row of stereocilia. Localising these channels is therefore an important test of this hypothesis. The transduction channels are known to be amiloride-sensitive and immunogold labelling with antibodies raised against the amiloride-sensitive epithelial Na+ channel from kidney (alpha NaCh), has suggested that sites with similar characteristics are located in the region where the tips of the shorter stereocilia appear to come into contact with the sides of the adjacent taller stereocilia rather than being associated directly with the tip links. Now, further immunocytochemical experiments have been performed to determine if amiloride and dihydrostreptomycin, both of which can block transduction, can affect this labelling. Immunofluorescent labelling of the stereocilia is obtained when surface preparations of the organ of Corti are fixed and incubated with alpha NaCh followed by an appropriate secondary antibody. This labelling is abolished by trypsinization prior to fixation but retained if the tissue is pretreated with amiloride and then trypsinized in its presence. Because amiloride is known to protect amiloride-binding sites from degradation by trypsin, these results suggest that alpha NaCh is revealing amiloride-binding sites on the stereocilia. Similarly, immunofluorescent labelling of the stereocilia is abolished if cochlear tissue is pretreated with dihydrostreptomycin (DHS) and fixed in its presence prior to incubation with alpha NaCh. Quantitative analysis of colloidal gold labelling using transmission electron microscopy shows that DHS treatment produces a significant reduction in the number of gold particles on stereocilia, especially in the region of contact between them. These results suggest that anti-Na+ recognises a site with characteristics similar to the mechanoelectrical transduction channels.

Thermal Optical Properties of Lunar Dust Simulants and Their Constituents

NASA Technical Reports Server (NTRS)

Gaier, James R.; Ellis, Shaneise; Hanks, Nichole

2011-01-01

The total reflectance spectra of lunar simulant dusts (less than 20 micrometer particles) were measured in order to determine their integrated solar absorptance (alpha) and their thermal emittance (e) for the purpose of analyzing the effect of dust on the performance of thermal control surfaces. All of the simulants except one had a wavelength-dependant reflectivity (p(lambda)) near 0.10 over the wavelength range of 8 to 25 micrometers, and so are highly emitting at room temperature and lower. The 300 K emittance (epsilon) of all the lunar simulants except one ranged from 0.78 to 0.92. The exception was Minnesota Lunar Simulant 1 (MLS-1), which has little or no glassy component. In all cases the epsilon was lower for the less 20 micrometer particles than for larger particles reported earlier. There was considerably more variation in the lunar simulant reflectance in the solar spectral range (250 to 2500 nanometers) than in the thermal infrared. As expected, the lunar highlands simulants were more reflective in this wavelength range than the lunar mare simulants. The integrated solar absorptance (alpha) of the simulants ranged from 0.39 to 0.75. This is lower than values reported earlier for larger particles of the same simulants (0.41 to 0.82), and for representative mare and highlands lunar soils (0.74 to 0.91). Since the alpha of some mare simulants more closely matched that of highlands lunar soils, it is recommended that and values be the criteria for choosing a simulant for assessing the effects of dust on thermal control surfaces, rather than whether a simulant has been formulated as a highlands or a mare simulant.

Supercritical fluid extraction of 11C-labeled metabolites in tissue using supercritical ammonia.

PubMed

Jacobson, G B; Moulder, R; Lu, L; Bergström, M; Markides, K E; Långström, B

1997-02-01

Supercritical fluid extraction (SFE) of 11C-labeled tracer compounds and their metabolites from biological tissue was performed using supercritical ammonia in an attempt to develop a rapid extraction procedure that allowed subsequent analysis of the labeled metabolites. Metabolites were extracted from kidneys and brain in rats given in vivo injections of the radiotracers O-[2-11C]acetyl-L-carnitine and N-[11C]methylpiperidyl benzilate, respectively. Only a minimal sample pretreatment of the tissue was necessary, i.e., cutting into 10-20 pieces and mixing with the drying agent Hydromatrix, before it was loaded into the extraction vessel. Extraction efficiency was measured for SFE at temperatures over the range of 70-150 degrees C and a pressure of 400 bar. For O-[2-11C]acetyl-L-carnitine, 66% of the radioactivity was trapped in the collected fractions and 12% remained in the extraction vessel. For the more lipophilic N-[11C]methylpiperidyl benzilate, 93% of the activity was collected and less than 1% remained in the extraction vessel. Labeled metabolites were analyzed by LC and also, in the case, of O-[2-11C]acetyl-L-carnitine by LC/MS. The complete extraction procedure, from removal of the biological tissue until an extract was ready for analysis, was 25 min, corresponding to about one half-life of the radionuclide 11C.

Tensile properties to 650 C and deformation structures in a precipitation strengthened titanium-aluminum alloy

NASA Technical Reports Server (NTRS)

Mendiratta, M. G.

1973-01-01

Appreciable strength levels were retained to 650 C in a Ti-10Al-1Si alloy aged in the (alpha + alpha sub 2) phase field to yield optimum room temperature strength and ductility. The aging treatment precipitated a uniform distribution of alpha sub 2-particles such that, at room temperature, dislocations bypassed instead of shearing the particles at low strains. Specimens fractured at room temperature exhibited fine uniform dimples even for those aging conditions that imparted no macroscopic ductility. The main crack appeared to propagate through the planar slip bands that had cut through the alpha sub 2-particles. A two-step aging process produced a higher volume fraction of bimodally distributed alpha sub 2-particles that led to higher strength levels at elevated temperatures. Both for the single size and the bimodal alpha sub 2-particle distributions, elevated-temperature deformation structures consisted mainly of planar slip bands that sheared through the alpha sub 2-particles.

Overview of the trastuzumab (Herceptin) anti-HER2 monoclonal antibody clinical program in HER2-overexpressing metastatic breast cancer. Herceptin Multinational Investigator Study Group.

PubMed

Shak, S

1999-08-01

The recombinant humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin; Genentech, San Francisco, CA) was evaluated in human clinical trials for treatment of women with metastatic breast cancer who have tumors that overexpress HER2. The trastuzumab clinical program consisted of a series of phase I, phase II, and phase III clinical trials. Clinical experience with this novel biologic has been obtained in more than 1,000 women with HER2-overexpressing metastatic breast cancer. Two pivotal trials were performed to evaluate trastuzumab efficacy and safety: (1) trastuzumab in combination with chemotherapy as first-line therapy and (2) trastuzumab as a single agent in second- and third-line chemotherapy. Preliminary results of the pivotal clinical trials that have been presented at national meetings are summarized below. The data suggest that trastuzumab will be an important new treatment option for women with HER2-overexpressing metastatic breast cancer.

A comparative evaluation of the chelators H4octapa and CHX-A″-DTPA with the therapeutic radiometal (90)Y.

PubMed

Price, Eric W; Edwards, Kimberly J; Carnazza, Kathryn E; Carlin, Sean D; Zeglis, Brian M; Adam, Michael J; Orvig, Chris; Lewis, Jason S

2016-09-01

To compare the radiolabeling performance, stability, and practical efficacy of the chelators CHX-A″-DTPA and H4octapa with the therapeutic radiometal (90)Y. The bifunctional chelators p-SCN-Bn-H4octapa and p-SCN-Bn-CHX-A″-DTPA were conjugated to the HER2-targeting antibody trastuzumab. The resulting immunoconjugates were radiolabeled with (90)Y to compare radiolabeling efficiency, in vitro and in vivo stability, and in vivo performance in a murine model of ovarian cancer. High radiochemical yields (>95%) were obtained with (90)Y-CHX-A″-DTPA-trastuzumab and (90)Y-octapa-trastuzumab after 15min at room temperature. Both (90)Y-CHX-A″-DTPA-trastuzumab and (90)Y-octapa-trastuzumab exhibited excellent in vitro and in vivo stability. Furthermore, the radioimmunoconjugates displayed high tumoral uptake values (42.3±4.0%ID/g for (90)Y-CHX-A″-DTPA-trastuzumab and 30.1±7.4%ID/g for (90)Y-octapa-trastuzumab at 72h post-injection) in mice bearing HER2-expressing SKOV3 ovarian cancer xenografts. Finally, (90)Y radioimmunotherapy studies performed in tumor-bearing mice demonstrated that (90)Y-CHX-A″-DTPA-trastuzumab and (90)Y-octapa-trastuzumab are equally effective therapeutic agents, as treatment with both radioimmunoconjugates yielded substantially decreased tumor growth compared to controls. Ultimately, this work demonstrates that the acyclic chelators CHX-A″-DTPA and H4octapa have comparable radiolabeling, stability, and in vivo performance, making them both suitable choices for applications requiring (90)Y. Copyright © 2016 Elsevier Inc. All rights reserved.

Trastuzumab for metastatic breast cancer: Real world outcomes from an Australian whole-of-population cohort (2001-2016).

PubMed

Daniels, Benjamin; Kiely, Belinda E; Lord, Sarah J; Houssami, Nehmat; Lu, Christine Y; Ward, Robyn L; Pearson, Sallie-Anne

2018-04-01

Outcomes for patients treated in clinical trials may not reflect the experience in routine clinical care. We aim to describe the real-world treatment patterns and overall survival (OS) for women receiving trastuzumab for metastatic breast cancer (MBC). Retrospective, whole-of-population cohort study using demographic, dispensing, and medical services data for women in the Herceptin Program for HER2+MBC. We estimated time on trastuzumab and OS from first dispensing of trastuzumab for MBC and rates of cardiac monitoring prior to and during treatment. We stratified outcomes by two groups based on year of initiation: 2001-2008 and 2009-2015. We benchmarked outcomes to two key trastuzumab clinical trials: H0648g (median OS 25 months) and CLEOPATRA (control group median OS 41 months). Median age of the 5899 women at first trastuzumab dispensing was 57 years (interquartile range [IQR]: 48-66). Median time on trastuzumab increased from 15 months (7-33) in Group One to 18 months (8-42) in Group Two. Median OS increased from 27 months (12-57) in Group One to 38 months (16-83) in Group Two. Rates of cardiac monitoring increased at baseline (52%-76%), and on-treatment (47%-67%), in Group One and Two, respectively. OS, duration of trastuzumab, and frequency of cardiac monitoring increased over the study period. Outcomes for trastuzumab in this heterogeneous real world population were reassuringly comparable to those from clinical trials, with the median OS > 3 years in Group Two and 25% of patients living 7 years or longer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Apparatus and method for quantitative assay of generic transuranic wastes from nuclear reactors

DOEpatents

Caldwell, J.T.; Kunz, W.E.; Atencio, J.D.

1982-03-31

A combination of passive and active neutron measurements which yields quantitative information about the isotopic composition of transuranic wastes from nuclear power or weapons material manufacture reactors is described. From the measurement of prompt and delayed neutron emission and the incidence of two coincidentally emitted neutrons from induced fission of fissile material in the sample, one can quantify /sup 233/U, /sup 235/U and /sup 239/Pu isotopes in waste samples. Passive coincidence counting, including neutron multiplicity measurement and determination of the overall passive neutron flux additionally enables the separate quantitative evaluation of spontaneous fission isotopes such as /sup 240/Pu, /sup 244/Cm and /sup 252/Cf, and the spontaneous alpha particle emitter /sup 241/Am. These seven isotopes are the most important constituents of wastes from nuclear power reactors and once the mass of each isotope present is determined by the apparatus and method of the instant invention, the overall alpha particle activity can be determined to better than 1 nCi/g from known radioactivity data. Therefore, in addition to the quantitative analysis of the waste sample useful for later reclamation purposes, the alpha particle activity can be determined to decide whether permanent low-level burial is appropriate for the waste sample.

Apparatus and method for quantitative assay of generic transuranic wastes from nuclear reactors

DOEpatents

Caldwell, John T.; Kunz, Walter E.; Atencio, James D.

1984-01-01

A combination of passive and active neutron measurements which yields quantitative information about the isotopic composition of transuranic wastes from nuclear power or weapons material manufacture reactors is described. From the measurement of prompt and delayed neutron emission and the incidence of two coincidentally emitted neutrons from induced fission of fissile material in the sample, one can quantify .sup.233 U, .sup.235 U and .sup.239 Pu isotopes in waste samples. Passive coincidence counting, including neutron multiplicity measurement and determination of the overall passive neutron flux additionally enables the separate quantitative evaluation of spontaneous fission isotopes such as .sup.240 Pu, .sup.244 Cm and .sup.252 Cf, and the spontaneous alpha particle emitter .sup.241 Am. These seven isotopes are the most important constituents of wastes from nuclear power reactors and once the mass of each isotope present is determined by the apparatus and method of the instant invention, the overall alpha particle activity can be determined to better than 1 nCi/g from known radioactivity data. Therefore, in addition to the quantitative analysis of the waste sample useful for later reclamation purposes, the alpha particle activity can be determined to decide whether "permanent" low-level burial is appropriate for the waste sample.

Observation of lunar radon emanation with the Apollo 15 alpha particle spectrometer.

NASA Technical Reports Server (NTRS)

Gorenstein, P.; Bjorkholm, P.

1972-01-01

The alpha particle spectrometer, a component of the orbital Sim Bay group of 'geochemistry' experiments on Apollo 15, was designed to detect alpha particles emitted during the decay of isotopes of radon gas and her daughter products. The purpose was to measure the gross activity of radon on the lunar surface and to find possible regions of increased local activity. Results are presented from a partial analysis of Apollo 15 data. For the moon as a whole, Rn220 was not observed and the upper limit on its decay rate above the lunar surface is 0.00038 disintegrations/sq cm-sec. Rn222 was marginally observed. Possible variations of radon activity on the lunar surface are being investigated. Po210 (a daughter product of Rn222) has been detected in a broad region from west of Mare Crisium to the Van de Graaff-Orlov region. The observed count rate is (4.6 plus or minus 1.4) x 0.001 disintegrations/sq cm-sec. The observed level of Po210 activity is in excess of the amount that would be in equilibrium with Rn222 by about an order of magnitude. This implies that larger levels of radon emanation have occurred on the moon within a time scale of 10 to 100 years.

Detection of Charged Particles in Superfluid Helium

NASA Astrophysics Data System (ADS)

Bandler, Simon Richard

1995-01-01

At the present time the measurement of the flux of neutrinos from the sun remains a challenging experimental problem. The ideal detector would be able to detect neutrinos at high rate, in real time, with good energy resolution and would have a threshold which is low enough for investigation of the entire solar neutrino spectrum. A new detection scheme using superfluid helium as a target has been proposed which has the potential to meet most of the criteria of the ideal detector. In this scheme a neutrino would be detected when it elastically scatters off an atomic electron in superfluid helium. The electron loses energy via a number of processes eventually leading to the generation of phonons and rotons in the liquid. At low temperatures these excitations propagate ballistically through the superfluid helium. When the excitations reach the free surface some of them are able to evaporate helium atoms. These atoms can be detected by an array of calorimeters suspended above the liquid surface. In this thesis, results are presented for a small -scale prototype of this type of detector. Experiments have been performed using various radioactive sources to generate energy depositions in the liquid. The results reveal details about the processes of generation of rotons and phonons, the propagation of these excitations through the superfluid, the evaporation of helium atoms and the adsorption of helium atoms onto the wafer. Results are also presented on the detection of fluorescent photons generated in the liquid. One source of energy depositions was 241{rm Am} which produces monoenergetic 5.5 MeV alpha particles. It was found that the ratio of the energy deposited in a calorimeter to the energy deposited in liquid helium was 0.084 when alpha's are emitted parallel to the liquid surface, and 0.020 for alpha's emitted perpendicular. The difference is due to the anisotropic distribution of helium excitations generated. A 113{rm Sn} source of 360 keV electrons stopped in superfluid helium have also produced signals in a calorimeter and this ratio was similar. Finally, the implications of these results to the design of a full-scale detector of solar neutrinos are discussed.

Effects of ionizing radiation on the light sensing elements of the retina. [Structural and physiological effects of carbon, helium, and neon ions on rods and cones of salamanders and mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Malachowski, M.J.

1978-07-01

This investigation was undertaken to quantitate possible morphological and physiological effects of particles of high linear energy transfer on the retina, in comparison with x-ray effects. The particles used were accelerated atomic nuclei of helium, carbon, and neon at kinetic energies of several hundred MeV/nucleon. For morphological studies, scanning and transmission electron microscopy and light microscopy were used. Physiological studies consisted of autoradiographic data of the rate of incorporation of labeled protein in the structures (opsin) of the outer segment of visual cells. Structural changes were found in the nuclei, as well as the inner and outer segments of visualmore » cells, rods and cones. At a low dose of 10 rad, x rays and helium had no statistically significant morphological effects, but carbon and neon beams did cause significant degeneration of individual cells, pointing to the existence of a linear dose--effect relationship. At high doses of several hundred rads, a Pathologic Index determined the relative biological effectiveness of neon against alpha particles to have a value of greater than 6. The severity of effects per particle increased with atomic number. Labeling studies demonstrated a decreased rate of incorporation of labeled proteins in the structural organization of the outer segments of visual rods. The rate of self-renewal of visual rod discs was punctuated by irradiation and the structures themselves were depleted of amino acids. A model of rod discs (metabolic and catabolic) was postulated for correlated early and late effects to high and low doses.« less

40 CFR 211.204-4 - Supporting information.

Code of Federal Regulations, 2010 CFR

2010-07-01

... level as measured at the ear is 92 dBA. 2. The NRR is (value on label) decibels (dB). 3. The level of... must be affixed to the bulk container or dispenser in the same manner as the label, and in a readily... entering a person's ear, when hearing protector is worn as directed, is closely approximated by the...

Catecholamine-Induced β2-adrenergic receptor activation mediates desensitization of gastric cancer cells to trastuzumab by upregulating MUC4 expression.

PubMed

Shi, Ming; Yang, Zhengyan; Hu, Meiru; Liu, Dan; Hu, Yabin; Qian, Lu; Zhang, Wei; Chen, Hongyu; Guo, Liang; Yu, Ming; Song, Lun; Ma, Yuanfang; Guo, Ning

2013-06-01

Trastuzumab is currently used for patients with Her2(+) advanced gastric cancer. However, the response rate to trastuzumab among the patients is low. The molecular mechanisms underlying trastuzumab resistance in gastric cancer are unknown. Our in vitro data show that activation of β2-adrenergic receptor (β2-AR) triggered by catecholamine caused "targeting failure" of trastuzumab in gastric cancer cells. The antitumor activities of trastuzumab were significantly impeded by chronic catecholamine stimulation in gastric cancer cells and in the mice bearing human gastric cancer xenografts. Mechanistically, catecholamine induced upregulation of the MUC4 expression at both transcription and protein levels via activating STAT3 and ERK. The effects of catecholamine could be effectively blocked by β2-AR antagonist ICI-118,551, indicating that β2-AR-mediated signaling pathway plays a key role in upregulation of MUC4, which was previously demonstrated to interfere with the recognition and physical binding of trastuzumab to Her2 molecules. Moreover, a significant elevation of the MUC4 level was observed in the xenograft tissues in nude mice chronically treated with isoproterenol. Knockdown of MUC4 restored the binding activities of trastuzumab to Her2-overexpressing gastric cancer cells. In addition, coexpression of β2-AR and MUC4 were observed in gastric cancer tissues. Our data indicated a novel trastuzumab resistance mechanism, by which catecholamine-induced β2-AR activation mediates desensitization of gastric cancer cells to trastuzumab through upregulating the MUC4 expression.

Sample collection system for gel electrophoresis

DOEpatents

Olivares, Jose A.; Stark, Peter C.; Dunbar, John M.; Hill, Karen K.; Kuske, Cheryl R.; Roybal, Gustavo

2004-09-21

An automatic sample collection system for use with an electrophoretic slab gel system is presented. The collection system can be used with a slab gel have one or more lanes. A detector is used to detect particle bands on the slab gel within a detection zone. Such detectors may use a laser to excite fluorescently labeled particles. The fluorescent light emitted from the excited particles is transmitted to low-level light detection electronics. Upon the detection of a particle of interest within the detection zone, a syringe pump is activated, sending a stream of buffer solution across the lane of the slab gel. The buffer solution collects the sample of interest and carries it through a collection port into a sample collection vial.

Synthesis of carbon-11-labeled bivalent β-carbolines as new PET agents for imaging of cholinesterase in Alzheimer's disease.

PubMed

Wang, Min; Zheng, David X; Gao, Mingzhang; Hutchins, Gary D; Zheng, Qi-Huang

2011-04-01

Carbon-11-labeled bivalent β-carbolines, 9,9'-(pentane-1,5-diyl)bis(2-[(11)C]methyl-9H-pyrido[3,4-b]indol-2-ium)iodide ([(11)C]2a), 9,9'-(nonane-1,9-diyl)bis(2-[(11)C]methyl-9H-pyrido[3,4-b]indol-2-ium)iodide ([(11)C]2b), 9,9'-(dodecane-1,12-diyl)bis(2-[(11)C]methyl-9H-pyrido[3,4-b]indol-2-ium)iodide ([(11)C]2c) and 1,9-bis(2-[(11)C]methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)nonane ([(11)C]3), were prepared by N-[(11)C]methylation of their corresponding amine precursors using [(11)C]CH(3)I and isolated by either a simplified solid-phase extraction (SPE) method or HPLC in 40-60% radiochemical yields based on [(11)C]CO(2) and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 20-30min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 185-370 GBq/μmol. Copyright © 2011 Elsevier Ltd. All rights reserved.

40 CFR 211.210-1 - General requirements.

Code of Federal Regulations, 2010 CFR

2010-07-01

... this regulation: (1) Must be labeled at the point of ultimate purchase or distribution to the...) Manufacturers who distribute protectors in commerce to another manufacturer for packaging for ultimate purchase...

A sensitive label-free electrochemical immunosensor for detection of cytokeratin 19 fragment antigen 21-1 based on 3D graphene with gold nanopaticle modified electrode.

PubMed

Zeng, Yan; Bao, Jing; Zhao, Yanan; Huo, Danqun; Chen, Mei; Yang, Mei; Fa, Huanbao; Hou, Changjun

2018-02-01

Previous studies have confirmed that cytokeratin 19 fragment antigen 21-1 (CYFRA 21-1) serves as a powerful biomarker in non-small cell lung cancer (NSCLC). Herein, we report for the first time a label-free electrochemical immunosensor for sensitive and selective detection of tumor marker CYFRA21-1. In this work, three-dimensional graphene @ gold nanoparticles (3D-G@Au) nanocomposite was modified on the glassy carbon electrode (GCE) surface to enhance the conductivity of immunosensor. The anti-CYFRA21-1 captured and fixed on the modified GCE through the cross-linking of chitosan (CS), glutaraldehyde (GA) and anti-CYFRA21-1. The differential pulse voltammetry (DPV) peak current change due to the specific interaction between anti-CYFRA21-1 and CYFRA21-1 on the modified electrode surface was utilized to detect CYFRA21-1. Under optimized conditions, the proposed electrochemical immunosensor was employed to detect CYFRA21-1 and exhibited a wide linear range of 0.25-800ngmL -1 and low detection limit of 100pgmL -1 (S/N = 3). Moreover, the recovery rates of serum samples were in the range from 95.2% to 108.7% and the developed immunosensor also shows a good correlation (less than 6.6%) with enzyme-linked immunosorbent assay (ELISA) in the detection of clinical serum samples. Therefore, it is expected that the proposed immunosensor based on a 3D-G@Au has great potential in clinical medical diagnosis of CYFRA21-1. Copyright © 2017 Elsevier B.V. All rights reserved.

Budget Impact Analysis of Biosimilar Trastuzumab for the Treatment of Breast Cancer in Croatia.

PubMed

Cesarec, August; Likić, Robert

2017-04-01

Breast cancer is the most common cancer in women and has considerable impact on healthcare budgets and patients' quality of life. Trastuzumab (Herceptin ® ) is a monoclonal antibody directed against the human epidermal growth factor receptor (HER2) for the treatment of breast cancer. Several trastuzumab biosimilars are currently in development. In 2015, trastuzumab was the drug with the highest financial consumption among all drugs in Croatia. This model estimates the 1-year budget impact of the introduction of biosimilar trastuzumab in Croatia. A budget impact model, based on approvals for trastuzumab treatment in 2015, was developed for the introduction of biosimilars. Two biosimilar scenarios were developed: biosimilar scenario 1, based on all approvals in 2015, and biosimilar scenario 2, based on approvals after February 2015 and the reimbursement of the subcutaneous formulation of trastuzumab in Croatia. Only trastuzumab-naïve patients and drug-acquisition costs were used in the model. Uptake of biosimilar was assumed at 50 %. Scenarios were calculated with price discounts of 15, 25 and 35 %. The robustness of the model was tested by extensive sensitivity analyses. The projected drug cost savings from the introduction of biosimilar trastuzumab range from €0.26 million (scenario 2, 15 % price discount) to €0.69 million (scenario 1, 35 % price discount). If budget savings were reinvested to treat additional patients with trastuzumab, 14 (scenario 2, 15 % price discount) to 47 (scenario 1, 35 % price discount) additional patients could be treated. Sensitivity analyses showed that the incidence of breast cancer had the highest impact on the model, with a 10 % decrease in incidence leading to an 11.3 % decrease in projected savings. The introduction of biosimilar trastuzumab could lead to significant drug cost savings in Croatia.

An atlas of H-alpha-emitting regions in M33: A systematic search for SS433 star candidates

NASA Technical Reports Server (NTRS)

Calzetti, Daniela; Kinney, Anne L.; Ford, Holland; Doggett, Jesse; Long, Knox S.

1995-01-01

We report finding charts and accurate positions for 432 compact H-alpha emitting regions in the Local Group galaxy M 33 (NGC 598), in an effort to isolate candidates for an SS433-like stellar system. The objects were extracted from narrow band images, centered in the rest-frame H-alpha (lambda 6563 A) and in the red continuum at 6100 A. The atlas is complete down to V approximately equal to 20 and includes 279 compact HII regions and 153 line emitting point-like sources. The point-like sources undoubtedly include a variety of objects: very small HII regions, early type stars with intense stellar winds, and Wolf-Rayet stars, but should also contain objects with the characteristics of SS433. This extensive survey of compact H-alpha regions in M 33 is a first step towards the identification of peculiar stellar systems like SS433 in external galaxies.

Cherenkov light identification in TeO2 crystals with Si low-temperature detectors

NASA Astrophysics Data System (ADS)

Gironi, L.; Biassoni, M.; Brofferio, C.; Capelli, S.; Carniti, P.; Cassina, L.; Clemenza, M.; Cremonesi, O.; Faverzani, M.; Ferri, E.; Giachero, A.; Gotti, C.; Maino, M.; Margesin, B.; Nucciotti, A.; Pavan, M.; Pessina, G.; Pozzi, S.; Previtali, E.; Puiu, A.; Sisti, M.; Terranova, F.

2017-09-01

Low temperature thermal detectors with particle identification capabilities are among the best detectors for next generation experiments for the search of neutrinoless double beta decay. Thermal detectors allow to reach excellent energy resolution and to optimize the detection efficiency, while the possibility to identify the interacting particle allows to greatly reduce the background. Tellurium dioxide is one of the favourite compounds since it has long demonstrated the first two features and could reach the third through Cherenkov emission tagging [1]. A new generation of cryogenic light detectors are however required to detect the few Cherenkov photons emitted by electrons of few MeV energy. Preliminary measurements with new Si light detectors demonstrated a clear event-by-event discrimination between alpha and beta/gamma interactions at the 130Te neutrinoless double beta decay Q-value (2528 keV).

ARRONAX, a high-energy and high-intensity cyclotron for nuclear medicine.

PubMed

Haddad, Ferid; Ferrer, Ludovic; Guertin, Arnaud; Carlier, Thomas; Michel, Nathalie; Barbet, Jacques; Chatal, Jean-François

2008-07-01

This study was aimed at establishing a list of radionuclides of interest for nuclear medicine that can be produced in a high-intensity and high-energy cyclotron. We have considered both therapeutic and positron emission tomography radionuclides that can be produced using a high-energy and a high-intensity cyclotron such as ARRONAX, which will be operating in Nantes (France) by the end of 2008. Novel radionuclides or radionuclides of current limited availability have been selected according to the following criteria: emission of positrons, low-energy beta or alpha particles, stable or short half-life daughters, half-life between 3 h and 10 days or generator-produced, favourable dosimetry, production from stable isotopes with reasonable cross sections. Three radionuclides appear well suited to targeted radionuclide therapy using beta ((67)Cu, (47)Sc) or alpha ((211)At) particles. Positron emitters allowing dosimetry studies prior to radionuclide therapy ((64)Cu, (124)I, (44)Sc), or that can be generator-produced ((82)Rb, (68)Ga) or providing the opportunity of a new imaging modality ((44)Sc) are considered to have a great interest at short term whereas (86)Y, (52)Fe, (55)Co, (76)Br or (89)Zr are considered to have a potential interest at middle term. Several radionuclides not currently used in routine nuclear medicine or not available in sufficient amount for clinical research have been selected for future production. High-energy, high-intensity cyclotrons are necessary to produce some of the selected radionuclides and make possible future clinical developments in nuclear medicine. Associated with appropriate carriers, these radionuclides will respond to a maximum of unmet clinical needs.

Trastuzumab, paclitaxel, cisplatin, and radiation for adenocarcinoma of the esophagus: a phase I study.

PubMed

Safran, Howard; DiPetrillo, Thomas; Nadeem, Ahmed; Steinhoff, Margaret; Tantravahi, Umadevi; Rathore, Ritesh; Wanebo, Harold; Hughes, Marilyn; Maia, Chris; Tsai, James Y; Pasquariello, Terry; Pepperell, John R; Cioffi, William; Kennedy, Teresa; Reeder, Laurie; Ng, Thomas; Adrian, Alyn; Goldstein, Lisa; Chak, Bapsi; Choy, Hak

2004-01-01

To conduct a phase I study incorporating trastuzumab with paclitaxel, cisplatin, and radiation for adenocarcinoma of the esophagus. Patients with adenocarcinoma of the esophagus without distant organ metastases were eligible. All patients received cisplatin 25 mg/m2 and paclitaxel 50 mg/m2 weekly for 6 weeks with radiation 50.4 Gy. HER-2/neu-positive patients (2+/3+ by immunohistochemistry) received weekly trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg, respectively. HER-2/neu-negative patients received the same chemoradiation without trastuzumab as a control for toxicity. Dose-limiting toxicities were defined as grade 3 esophageal, cardiac, or pulmonary toxicity. Twelve of 36 screened patients (33%) overexpressed HER-2/neu by immunohistochemistry (seven 3+ and five 2+). Eight of 12 patients with HER-2/neu overexpression by IHC had an increase in the number of HER-2/neu genes, six from amplification of the HER-2/ neu gene and two were hypderdiploid for chromosome 17. Thirty patients were enrolled (12 HER-2/neu-positive and 18 HER-2/neu-negative controls). No increase in toxicity was seen with the addition of trastuzumab. One of 12 patients in the trastuzumab arm and 8 of 17 in the control arm had grade 3 esophagitis (p < or = .026). Mean left ventricular ejection fraction for the trastuzumab group was 57% before treatment and 56% after treatment. HER-2/neu is overexpressed in approximately one-third of esophageal adenocarcinomas. Trastuzumab can be added at full dose to cisplatin, paclitaxel, and radiation. Future studies of trastuzumab in esophageal adenocarcinoma are indicated.

TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer.

PubMed

Mercogliano, María F; De Martino, Mara; Venturutti, Leandro; Rivas, Martín A; Proietti, Cecilia J; Inurrigarro, Gloria; Frahm, Isabel; Allemand, Daniel H; Deza, Ernesto Gil; Ares, Sandra; Gercovich, Felipe G; Guzmán, Pablo; Roa, Juan C; Elizalde, Patricia V; Schillaci, Roxana

2017-02-01

Although trastuzumab administration improved the outcome of HER2-positive breast cancer patients, resistance events hamper its clinical benefits. We demonstrated that TNFα stimulation in vitro induces trastuzumab resistance in HER2-positive breast cancer cell lines. Here, we explored the mechanism of TNFα-induced trastuzumab resistance and the therapeutic strategies to overcome it. Trastuzumab-sensitive breast cancer cells, genetically engineered to stably overexpress TNFα, and de novo trastuzumab-resistant tumors, were used to evaluate trastuzumab response and TNFα-blocking antibodies effectiveness respectively. Immunohistochemistry and antibody-dependent cell cytotoxicity (ADCC), together with siRNA strategy, were used to explore TNFα influence on the expression and function of its downstream target, mucin 4 (MUC4). The clinical relevance of MUC4 expression was studied in a cohort of 78 HER2-positive breast cancer patients treated with adjuvant trastuzumab. TNFα overexpression turned trastuzumab-sensitive cells and tumors into resistant ones. Histopathologic findings revealed mucin foci in TNFα-producing tumors. TNFα induced upregulation of MUC4 that reduced trastuzumab binding to its epitope and impaired ADCC. Silencing MUC4 enhanced trastuzumab binding, increased ADCC, and overcame trastuzumab and trastuzumab-emtansine antiproliferative effects in TNFα-overexpressing cells. Accordingly, administration of TNFα-blocking antibodies downregulated MUC4 and sensitized de novo trastuzumab-resistant breast cancer cells and tumors to trastuzumab. In HER2-positive breast cancer samples, MUC4 expression was found to be an independent predictor of poor disease-free survival (P = 0.008). We identified TNFα-induced MUC4 expression as a novel trastuzumab resistance mechanism. We propose MUC4 expression as a predictive biomarker of trastuzumab efficacy and a guide to combination therapy of TNFα-blocking antibodies with trastuzumab. Clin Cancer Res; 23(3); 636-48. ©2016 AACR. ©2016 American Association for Cancer Research.

Medical resource utilization for administration of trastuzumab in a New Zealand oncology outpatient setting: a time and motion study

PubMed Central

North, Richard T; Harvey, Vernon J; Cox, Levonne C; Ryan, Stuart N

2015-01-01

Background In New Zealand, trastuzumab is standard therapy for human epidermal growth factor receptor-2 (HER2)-positive early and metastatic breast cancer. Given the requirement for ongoing adjuvant or maintenance treatment and intravenous (IV) delivery, such a regimen consumes considerable health care resources. The development of a subcutaneous (SC) trastuzumab formulation with a short administration time offers the potential to reduce hospital expenditure. The aim of this study was to determine medical resource utilization associated with administration of trastuzumab SC injection via handheld syringe vs trastuzumab IV infusion in patients with HER2-positive breast cancer in New Zealand. Methods This noninterventional, descriptive study was conducted at the outpatient oncology centers at Auckland City and Tauranga Hospitals. Trained observers recorded times associated with health care professional (HCP) tasks and consumables use associated with preparation and administration of trastuzumab IV or SC in women with early or metastatic breast cancer. The cost for each formulation was calculated as the mean cost of HCP time (based on Pharmaceutical Management Agency hourly rates) plus the mean cost of consumables used. Results Use of trastuzumab SC vs IV reduced mean chair time by 36.95 minutes and total nurse time by 6.12 minutes; there was a 20.45-minute reduction in pharmacist time when the SC formulation was used. After adding consumable costs, the overall estimated saving with trastuzumab SC vs IV was $76.94 (New Zealand dollars) per patient per cycle. Conclusions Compared with trastuzumab IV infusion, administration of trastuzumab via SC injection reduced time spent in the clinic and decreased HCP resources and consumables needed to administer treatment. These reductions could contribute to a decrease in health care costs and an improvement in the efficiency of HER2-positive breast cancer treatment delivery. PMID:26251623

Self absorption of alpha and beta particles in a fiberglass filter.

PubMed

Luetzelschwab, J W; Storey, C; Zraly, K; Dussinger, D

2000-10-01

Environmental air sampling uses fiberglass filters to collect particulate matter from the air and then a gas flow detector to measure the alpha and beta activity on the filter. When counted, the filter is located close to the detector so the alpha and beta particles emerging from the filter travel toward the detector at angles ranging from zero to nearly 90 degrees to the normal to the filter surface. The particles at small angles can readily pass through the filter, but particles at large angles pass through a significant amount of filter material and can be totally absorbed. As a result, counting losses can be great. For 4 MeV alpha particles, the filter used in this experiment absorbs 43% of the alpha particles; for 7.5 MeV alphas, the absorption is 13%. The measured beta activities also can have significant counting losses. Beta particles with maximum energies of 0.2 and 2.0 MeV have absorptions of 44 and 2%, respectively.

Use of adjuvant trastuzumab in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer by race/ethnicity and education within the National Comprehensive Cancer Network.

PubMed

Freedman, Rachel A; Hughes, Melissa E; Ottesen, Rebecca A; Weeks, Jane C; He, Yulei; Wong, Yu-Ning; Theriault, Richard; Keating, Nancy L

2013-02-15

Trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive breast cancer is highly efficacious yet costly and time-intensive, and few data are available about its use. The authors of this report examined receipt and completion of adjuvant trastuzumab by race/ethnicity and education for women with HER2-positive disease. The National Comprehensive Cancer Network Breast Cancer Outcomes Database was used to identify 1109 women who were diagnosed with stage I through III, HER2-positive breast cancer during September 2005 through December 2008 and were followed for ≥1 year. The authors used multivariable logistic regression to assess the association of race/ethnicity and education with the receipt of trastuzumab and, among those women who initiated trastuzumab, with the completion of > 270 days of therapy. The cohort was 75% white, 8% black, and 9% Hispanic; and 20% of women had attained a high school degree or less. Most women (83%) received trastuzumab, and no significant differences were observed according to race/ethnicity or socioeconomic status. Among the women who initiated trastuzumab, 73% of black women versus 87% of white women (P = .007) and 70% of women with less than a high school education versus 90% of women with a college degree completed > 270 days of therapy (P = .006). In adjusted analyses, black women (vs white women) and women without a high school degree (vs those with a college degree) had lower odds of completing therapy (black women: odds ratio, 0.45; 95% confidence interval, 0.27-074; white women: odds ratio, 0.27, 95% confidence interval, 0.14-0.51). Differences in completing trastuzumab therapy were observed according to race and educational attainment among women who received treatment at National Comprehensive Cancer Network centers. Efforts to assure the appropriate use of trastuzumab and to understand treatment barriers are needed and may lead to improved outcomes. The authors report differences in the rate at which patients complete treatment with trastuzumab according to race and education among women who receive treatment at National Comprehensive Cancer Network centers. Efforts to assure the appropriate use of trastuzumab and to understand treatment barriers are needed and may lead to improved outcomes. Copyright © 2012 American Cancer Society.

Cardiac Outcomes of Patients Receiving Adjuvant Weekly Paclitaxel and Trastuzumab for Node-Negative, ERBB2-Positive Breast Cancer.

PubMed

Dang, Chau; Guo, Hao; Najita, Julie; Yardley, Denise; Marcom, Kelly; Albain, Kathy; Rugo, Hope; Miller, Kathy; Ellis, Matthew; Shapira, Iuliana; Wolff, Antonio C; Carey, Lisa A; Moy, Beverly; Groarke, John; Moslehi, Javid; Krop, Ian; Burstein, Harold J; Hudis, Clifford; Winer, Eric P; Tolaney, Sara M

2016-01-01

Trastuzumab is a life-saving therapy but is associated with symptomatic and asymptomatic left ventricular ejection fraction (LVEF) decline. We report the cardiac toxic effects of a nonanthracycline and trastuzumab-based treatment for patients with early-stage human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu)-positive breast cancer. To determine the cardiac safety of paclitaxel with trastuzumab and the utility of LVEF monitoring in patients with node-negative, ERBB2-positive breast cancer. In this secondary analysis of an uncontrolled, single group study across 14 medical centers, enrollment of 406 patients with node-negative, ERBB2-positive breast cancer 3 cm, or smaller, and baseline LVEF of greater than or equal to 50% occurred from October 9, 2007, to September 3, 2010. Patients with a micrometastasis in a lymph node were later allowed with a study amendment. Median patient age was 55 years, 118 (29%) had hypertension, and 30 (7%) had diabetes. Patients received adjuvant paclitaxel for 12 weeks with trastuzumab, and trastuzumab was continued for 1 year. Median follow-up was 4 years. Treatment consisted of weekly 80-mg/m2 doses of paclitaxel administered concurrently with trastuzumab intravenously for 12 weeks, followed by trastuzumab monotherapy for 39 weeks. During the monotherapy phase, trastuzumab could be administered weekly 2-mg/kg or every 3 weeks as 6-mg/kg. Radiation and hormone therapy were administered per standard guidelines after completion of the 12 weeks of chemotherapy. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year. Cardiac safety data, including grade 3 to 4 left ventricular systolic dysfunction (LVSD) and significant asymptomatic LVEF decline, as defined by our study, were reported. Overall, 2 patients (0.5%) (95% CI, 0.1%-1.8%) developed grade 3 LVSD and came off study, and 13 (3.2%) (95% CI, 1.9%-5.4%) had significant asymptomatic LVEF decline, 11 of whom completed study treatment. Median LVEF at baseline was 65%; 12 weeks, 64%; 6 months, 64%; and 1 year, 64%. Cardiac toxic effects from paclitaxel with trastuzumab, manifesting as grade 3 or 4 LVSD or asymptomatic LVEF decline, were low. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year, and our findings suggest that LVEF monitoring during trastuzumab therapy without anthracyclines could be simplified for many individuals.

Inactivation of chloroplast H(+)-ATPase by modification of Lys beta 359, Lys alpha 176 and Lys alpha 266.

PubMed

Horbach, M; Meyer, H E; Bickel-Sandkötter, S

1991-09-01

Treatment of isolated, latent chloroplast ATPase with pyridoxal-5-phosphate (pyridoxal-P) in presence of Mg2+ causes inhibition of dithiothreitol-activated plus heat-activated ATP hydrolysis. The amount of [3H]pyridoxal-P bound to chloroplast coupling factor 1 (CF1) was estimated to run up to 6 +/- 1 pyridoxal-P/enzyme, almost equally distributed between the alpha- and beta-subunits. Inactivation, however, is complete after binding of 1.5-2 pyridoxal-P/CF1, suggesting that two covalently modified lysines prevent the activation of the enzyme. ADP as well as ATP in presence of Mg2+ protects the enzyme against inactivation and concomittantly prevents incorporation of a part of the 3H-labeled pyridoxal-P into beta- and alpha-subunits. Phosphate prevents labeling of the alpha-subunit, but has only a minor effect on protection against inactivation. The data indicate a binding site at the interface between the alpha- and beta-subunits. Cleavage of the pyridoxal-P-labeled subunits with cyanogen bromide followed by sequence analysis of the labeled peptides led to the detection of Lys beta 359, Lys alpha 176 and Lys alpha 266, which are closely related to proposed nucleotide-binding regions of the alpha- and beta-subunits.

Intrathecal trastuzumab in the management of HER2+ breast leptomeningeal disease: a single institution experience.

PubMed

Figura, Nicholas B; Long, Wendy; Yu, Michael; Robinson, Timothy J; Mokhtari, Sepideh; Etame, Arnold B; Tran, Nam D; Diaz, Roberto; Soliman, Hatem; Han, Heather S; Sahebjam, Solmaz; Forsyth, Peter A; Ahmed, Kamran A

2018-06-01

Leptomeningeal disease is a rare and devastating presentation of advanced stage metastatic breast cancer with historically poor overall survival. We assessed the safety and feasibility of intrathecal (IT) trastuzumab in HER2+ leptomeningeal disease. A total of 13 patients were treated at our institution with IT trastuzumab beginning November 2012 and followed until November 2017. Outcomes including craniospinal progression as well as overall survival (OS) following initiation of IT trastuzumab were assessed from review of the clinical chart and radiologic examinations. The median age of patients was 48 (range 29-75). Median time from breast cancer diagnosis to development of brain metastases was 87.7 months with a median of 4.6 months from brain metastases diagnosis to the development of leptomeningeal disease. Previous whole brain radiotherapy was received by the majority of patients (92%) and prior surgery for brain metastases was performed in 23%. Median duration of IT trastuzumab treatment was 6.4 months. Median time from IT trastuzumab start to craniospinal progression was 5.7 months with 6- and 12-month Kaplan-Meier rates of 41 and 21%, respectively. Sustained responses > 6 months were achieved in 4 patients. Median survival from the start of IT trastuzumab was 10.6 months with 6- and 12-month OS rates of 68 and 47%, respectively. IT trastuzumab was well tolerated with one patient developing ventriculitis, which resolved with IV antibiotics. IT trastuzumab was well tolerated with prolongation of OS over historical controls. IT trastuzumab should be considered for management of HER2+ leptomeningeal disease patients.

[Case Report on Treatment of Metastatic Breast Cancer with Trastuzumab during Pregnancy].

PubMed

Rasenack, R; Gaupp, N; Rautenberg, B; Stickeler, E; Prömpeler, H

2016-04-01

The increasing number of pregnant breast cancer patients calls for a therapy that is as efficient as possible. After 10 years of collecting data on pregnant breast cancer patients in the German Breast Group (GBG), proposals for diagnostic measures and therapy regarding this special situation have been developed on the basis of 500 observed cases. Chemotherapy is regarded as safe from the 14(th) week of gestation on, but it is strongly advised not to use trastuzumab. Adverse outcomes for the newborn were predominantly observed in cases of early preterms. In our department, a 29-year-old second gravida with metastatic breast cancer first diagnosed 7 years ago continued to receive trastuzumab treatment at her express request after detailed information and advice. Trastuzumab treatment had been started 1.5 years before the pregnancy after surgical removal of a lymph node metastasis. After 7 intravenous administrations at intervals of 3 weeks, an oligohydramnios occurred in the 24(th) week of pregnancy. For this reason, trastuzumab treatment was interrupted for 7 weeks, during which time the quantity of amniotic fluid returned to a normal level. As the 8(th) administration of trastuzumab led to a renewed oligohydramnios, the trastuzumab treatment was suspended until birth. The quantity of amniotic fluid having recovered to normal, labour was induced after 36 weeks of pregnancy, followed by a Caesarian section because of prolonged labour. The newborn boy showed no sign of respiratory or renal dysfunction and has developed normally, having at present reached the age of 3 years. From the few reported cases of pregnancies with trastuzumab therapy, it seems that an occurring oligohydramnios is the typical complication with the problem of life-threatening RDS after birth. Probably the reduction of amniotic fluid can be reversed by interrupting the trastuzumab therapy, as we observed in our case. © Georg Thieme Verlag KG Stuttgart · New York.

40 CFR 211.101 - Applicability.

Code of Federal Regulations, 2010 CFR

2010-07-01

... regulation, unless they are made inapplicable by product-specific regulations. ... Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING General Provisions § 211.101 Applicability. The provisions of subpart A apply to all products for...

A peristaltic pump driven 89Zr separation module

NASA Astrophysics Data System (ADS)

Siikanen, J.; Peterson, M.; Tran, T. A.; Roos, P.; Ohlsson, T.; Sandell, A.

2012-12-01

To facilitate the separation of 89Zr produced in yttrium foils, an automated separation module was designed and assembled. The module separates more than 85% of produced 89Zr - activity in 3 g foils in less than 90 min. About 10 % remains in the dissolving vial. The quality of the separated 89Zr activity was investigated for labeling of the HER2-binding monoclonal antibody fragment, trastuzumab-Fab.

Counting Particles Emitted by Stratospheric Aircraft and Measuring Size of Particles Emitted by Stratospheric Aircraft

NASA Technical Reports Server (NTRS)

Wilson, James Charles

1994-01-01

There were two principal objectives of the cooperative agreement between NASA and the University of Denver. The first goal was to modify the design of the ER-2 condensation nuclei counter (CNC) so that the effective lower detection limit would be improved at high altitudes. This improvement was sought because, in the instrument used prior to 1993, diffusion losses prevented the smallest detectable particles from reaching the detection volume of the instrument during operation at low pressure. Therefore, in spite of the sensor's ability to detect particles as small as 0.008 microns in diameter, many of these particles were lost in transport to the sensing region and were not counted. Most of the particles emitted by aircraft are smaller than 0.1 micron in diameter. At the start date of this work, May 1990, continuous sizing techniques available on the ER-2 were only capable of detecting particles larger than 0.17 micron. Thus, the second objective of this work was to evaluate candidate sizing techniques in an effort to gain additional information concerning the size of particles emitted by aircraft.

Autoradiographic localization of voltage-dependent sodium channels on the mouse neuromuscular junction using /sup 125/I-alpha scorpion toxin. I. Preferential labeling of glial cells on the presynaptic side

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boudier, J.L.; Jover, E.; Cau, P.

1988-05-01

Alpha-scorpion toxins bind specifically to the voltage-sensitive sodium channel in excitable membranes, and binding is potential-dependent. The radioiodinated toxin II from the scorpion Androctonus australis Hector (alpha ScTx) was used to localize voltage-sensitive sodium channels on the presynaptic side of mouse neuromuscular junctions (NMJ) by autoradiography using both light and electron microscopy. Silver grain localization was analyzed by the cross-fire method. At the light-microscopic level, grain density over NMJ appeared 6-8x higher than over nonjunctional muscle membrane. The specificity of labeling was verified by competition/displacement with an excess of native alpha ScTx. Labeling was also inhibited by incubation in depolarizingmore » conditions, showing its potential-dependence. At the electron-microscopic level, analysis showed that voltage-sensitive sodium channels labeled with alpha ScTx were almost exclusively localized on membranes, as expected. Due to washout after incubation, appreciable numbers of binding sites were not found on the postsynaptic membranes. However, on the presynaptic side, alpha ScTx-labeled voltage-sensitive sodium channels were localized on the membrane of non-myelin-forming Schwann cells covering NMJ. The axonal presynaptic membrane was not labeled. These results show that voltage-sensitive sodium channels are present on glial cells in vivo, as already demonstrated in vitro. It is proposed that these glial channels could be indirectly involved in the ionic homeostasis of the axonal environment.« less

(64)Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients.

PubMed

Kurihara, Hiroaki; Hamada, Akinobu; Yoshida, Masayuki; Shimma, Schuichi; Hashimoto, Jun; Yonemori, Kan; Tani, Hitomi; Miyakita, Yasuji; Kanayama, Yousuke; Wada, Yasuhiro; Kodaira, Makoto; Yunokawa, Mayu; Yamamoto, Harukaze; Shimizu, Chikako; Takahashi, Kazuhiro; Watanabe, Yasuyoshi; Fujiwara, Yasuhiro; Tamura, Kenji

2015-01-01

The purpose of this study was to determine whether brain metastases from HER2-positive breast cancer could be detected noninvasively using positron emission tomography (PET) with (64)Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-trastuzumab. PET was performed on five patients with brain metastases from HER2-positive breast cancer, at 24 or 48 h after the injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity in metastatic brain tumors was evaluated based on PET images in five patients. Autoradiography, immunohistochemistry (IHC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis were performed in one surgical case to confirm HER2 specificity of (64)Cu-DOTA-trastuzumab. Metastatic brain lesions could be visualized by (64)Cu-DOTA-trastuzumab PET in all of five cases, which might indicated that trastuzumab passes through the blood-brain barrier (BBB). The HER2 specificity of (64)Cu-DOTA-trastuzumab was demonstrated in one patient by autoradiography, immunohistochemistry, and LC-MS/MS. Cu-DOTA-trastuzumab PET could be a potential noninvasive procedure for serial identification of metastatic brain lesions in patients with HER2-positive breast cancer. UMIN000004170.

Charged-particle emission tomography

PubMed Central

Ding, Yijun; Caucci, Luca; Barrett, Harrison H.

2018-01-01

Purpose Conventional charged-particle imaging techniques —such as autoradiography —provide only two-dimensional (2D) black ex vivo images of thin tissue slices. In order to get volumetric information, images of multiple thin slices are stacked. This process is time consuming and prone to distortions, as registration of 2D images is required. We propose a direct three-dimensional (3D) autoradiography technique, which we call charged-particle emission tomography (CPET). This 3D imaging technique enables imaging of thick tissue sections, thus increasing laboratory throughput and eliminating distortions due to registration. CPET also has the potential to enable in vivo charged-particle imaging with a window chamber or an endoscope. Methods Our approach to charged-particle emission tomography uses particle-processing detectors (PPDs) to estimate attributes of each detected particle. The attributes we estimate include location, direction of propagation, and/or the energy deposited in the detector. Estimated attributes are then fed into a reconstruction algorithm to reconstruct the 3D distribution of charged-particle-emitting radionuclides. Several setups to realize PPDs are designed. Reconstruction algorithms for CPET are developed. Results Reconstruction results from simulated data showed that a PPD enables CPET if the PPD measures more attributes than just the position from each detected particle. Experiments showed that a two-foil charged-particle detector is able to measure the position and direction of incident alpha particles. Conclusions We proposed a new volumetric imaging technique for charged-particle-emitting radionuclides, which we have called charged-particle emission tomography (CPET). We also proposed a new class of charged-particle detectors, which we have called particle-processing detectors (PPDs). When a PPD is used to measure the direction and/or energy attributes along with the position attributes, CPET is feasible. PMID:28370094

Charged-particle emission tomography.

PubMed

Ding, Yijun; Caucci, Luca; Barrett, Harrison H

2017-06-01

Conventional charged-particle imaging techniques - such as autoradiography - provide only two-dimensional (2D) black ex vivo images of thin tissue slices. In order to get volumetric information, images of multiple thin slices are stacked. This process is time consuming and prone to distortions, as registration of 2D images is required. We propose a direct three-dimensional (3D) autoradiography technique, which we call charged-particle emission tomography (CPET). This 3D imaging technique enables imaging of thick tissue sections, thus increasing laboratory throughput and eliminating distortions due to registration. CPET also has the potential to enable in vivo charged-particle imaging with a window chamber or an endoscope. Our approach to charged-particle emission tomography uses particle-processing detectors (PPDs) to estimate attributes of each detected particle. The attributes we estimate include location, direction of propagation, and/or the energy deposited in the detector. Estimated attributes are then fed into a reconstruction algorithm to reconstruct the 3D distribution of charged-particle-emitting radionuclides. Several setups to realize PPDs are designed. Reconstruction algorithms for CPET are developed. Reconstruction results from simulated data showed that a PPD enables CPET if the PPD measures more attributes than just the position from each detected particle. Experiments showed that a two-foil charged-particle detector is able to measure the position and direction of incident alpha particles. We proposed a new volumetric imaging technique for charged-particle-emitting radionuclides, which we have called charged-particle emission tomography (CPET). We also proposed a new class of charged-particle detectors, which we have called particle-processing detectors (PPDs). When a PPD is used to measure the direction and/or energy attributes along with the position attributes, CPET is feasible. © 2017 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Absorbed dose in target cell nuclei and dose conversion coefficient of radon progeny in the human lung.

PubMed

Nikezic, D; Lau, B M F; Stevanovic, N; Yu, K N

2006-01-01

To calculate the absorbed dose in the human lung due to inhaled radon progeny, ICRP focussed on the layers containing the target cells, i.e., the basal and secretory cells. Such an approach did not consider details of the sensitive cells in the layers. The present work uses the microdosimetric approach and determines the absorbed alpha-particle energy in non-spherical nuclei of target cells (basal and secretory cells). The absorbed energy for alpha particles emitted by radon progeny in the human respiratory tract was calculated in basal- and secretory-cell nuclei, assuming conical and ellipsoidal forms for these cells. Distributions of specific energy for different combinations of alpha-particle sources, energies and targets are calculated and shown. The dose conversion coefficient for radon progeny is reduced for about 2mSv/WLM when conical and ellipsoidal cell nuclei are considered instead of the layers. While changes in the geometry of secretory-cell nuclei do not have significant effects on their absorbed dose, changes from spherical to conical basal-cell nuclei have significantly reduced their absorbed dose from approximately 4 to approximately 3mGy/WLM. This is expected because basal cells are situated close to the end of the range of 6MeV alpha particles. This also underlines the significance of better and more precise information on targets in the T-B tree. A further change in the dose conversion coefficient can be achieved if a different weighting scheme is adopted for the doses for the cells. The results demonstrate the necessity for better information on the target cells for more accurate dosimetry for radon progeny.

Alpha4 containing nicotinic receptors are positioned to mediate postsynaptic effects on serotonin neurons in the rat dorsal raphe nucleus

PubMed Central

Commons, Kathryn G.

2008-01-01

Nicotinic acetylcholine receptors containing the alpha4 and beta2 subunits constitute the most abundant high-affinity binding site of nicotine in the brain and are critical for the addictive qualities of nicotine. Serotonin neurotransmission is thought to be an important contributor to nicotine addiction. Therefore in this study it was examined how alpha4-containing receptors are positioned to modulate the function of serotonin neurons using ultrastructural analysis of immunolabeling for the alpha4 receptor subunit in the dorsal raphe nucleus (DR), a primary source of forebrain serotonin in the rat. Of 150 profiles labeled for the alpha4 subunit, 140 or 93% consisted of either soma or dendrites, these were often small-caliber (distal) dendrites <1.5 um in diameter (63/150 or 42%). The majority (107/150 or 71%) of profiles containing labeling for alpha4 were dually labeled for the synthetic enzyme for serotonin, tryptophan hydroxylase (TPH). Within dendrites immunogold labeling for alpha4 was present on the plasma membrane or near postsynaptic densities. However, labeling for alpha4 was commonly localized to the cytoplasmic compartment often associated with smooth endoplasmic reticulum, plausibly representing receptors in transit to or from the plasma membrane. Previous studies have suggested that nicotine presynaptically regulates activity onto serotonin neurons, however alpha4 immunolabeling was detected in only 10 axons in the DR or 7% of profiles sampled. This finding suggest that alpha4 containing receptors are minor contributors to presynaptic regulation of synaptic activity onto serotonin neurons, but rather alpha4 containing receptors are positioned to influence serotonin neurons directly at postsynaptic sites. PMID:18403129

A Search for z>6.5 Lyman-alpha Emitting Galaxies with WISP

NASA Astrophysics Data System (ADS)

Bagley, Micaela B.; Scarlata, Claudia; Dai, Yu Sophia; Rafelski, Marc; Baronchelli, Ivano; Colbert, James W.; Dominguez, Alberto; Hathi, Nimish P.; Henry, Alaina L.; Malkan, Matthew Arnold; Martin, Crystal L.; Mehta, Vihang; Pahl, Anthony; Ross, Nathaniel; Rutkowski, Michael J.; Teplitz, Harry I.; WISP Team

2016-01-01

The observed number density of Lyman-alpha emitting galaxies at z>6 provides an important probe of the reionization history of the universe. Because Lyman-alpha photons are very sensitive to the presence of neutral hydrogen, the evolution of the galaxy number density above redshift 6 can be used as a measurement on the progress of reionization. However, the Lyman-alpha luminosity function is currently poorly constrained at high-z. We present the results of a systematic search for Lyman-alpha emitters (LAEs) at redshifts of ~6.5 to 7.5 using the HST WFC3 Infrared Spectroscopic Parallels (WISP) survey. WISP's uncorrelated fields are well-suited to the study of bright LAEs, minimizing the effects of clustering introduced by a patchy reionization. From the 30 deepest WISP fields, we compile a sample of single-line emitters, confirm redshifts with broadband colors, and identify LAE candidates that have "dropped out" (are undetected at the 1 sigma level) of the WFC3 UVIS filters. By combining our results with other z~7 studies, we determine whether the number density of LAEs evolves past z~6.5.

Unraveling the Molecular Mechanism(s) Underlying ER+/PR- Breast Tumorigenesis Using a Novel Genetically Engineered Mouse Model

DTIC Science & Technology

2010-09-01

Gria4 Glutamate receptor ionotropic , AMPA 4 NM_019691 transport ion transport 3.00 Slc2a1 solute carrier family 2,member 1 NM_011400...unlimited 13. SUPPLEMENTARY NOTES 14. A BSTRACT Estrogen-rece ptor alpha (E Rα)-positive Progesterone receptor ne gative (ER+ /PR-) breast ductal...fo r t reating ER+/PR- breast cancers that are resistant to tamoxifen or trastuzumab. 15. SUBJECT TERMS Estrogen receptor , Progesterone receptor

A phoswich detector for simultaneous alpha-gamma spectroscopy

NASA Astrophysics Data System (ADS)

Moghadam, S. Rajabi; Feghhi, S. A. H.; Safari, M. J.

2015-11-01

Phoswich detectors are of value for radiation spectroscopy, especially in cases where a low-cost solution for a mixed radiation field is desired. Meanwhile, simultaneous spectroscopy of alpha particles and gamma-rays has many applications in quantification and distinguishing the alpha-emitting radionuclides which usually occur in the analysis of environmental solid samples. Here, we have developed a system for detection of radioactive actinides (e.g., 241Am) based on the alpha-gamma coincidence technique. The underlying concept, is to assemble two appropriately selected scintillators (i.e., a fast and a slow one) together with a discriminating unit for analysis of their data. Detailed Monte Carlo simulation procedure has been developed using the GEANT4 toolkit to design and find enough knowledge about the response of the system in the studied radiation field. Various comparisons were made between experimental and simulation data which showed appropriate agreement between them. The calibration was performed and the MDA was estimated as 60 mBq for the phoswich system.

Preparation and preclinical evaluation of 131 I-trastuzumab for breast cancer.

PubMed

Kameswaran, Mythili; Gota, Vikram; Ambade, Rajwardhan; Gupta, Sudeep; Dash, Ashutosh

2017-01-01

Trastuzumab that targets the human epidermal growth factor receptor type 2 (HER2) is known to benefit patients with HER2+ metastatic breast cancer. The objective was to explore the potential of 131 I-trastuzumab for treatment of breast cancers. Radioiodination of trastuzumab was carried out by chloramine-T method, purified by using PD-10 column, and characterized by size exclusion high-performance liquid chromatography on a gel column. In vitro studies were carried out in HER2+ cells to determine the specificity of the radioimmunoconjugate. Uptake and retention of 131 I-trastuzumab were determined by biodistribution studies in tumor-bearing non-obese diabetic/severe combined immunodeficiency and normal severe combined immunodeficiency mice. The radiochemical purity (RCP) of 131 I-trastuzumab was 98 ± 0.4% with retention time of 17 minutes by high-performance liquid chromatography. In vitro stability studies exhibited RCP of more than 90% in serum at 37°C after 120 hours of radioiodination. In vitro cell binding with 131 I-trastuzumab in HER2+ cells showed binding of 28% to 35% which was inhibited significantly, with unlabeled trastuzumab confirming its specificity. K d value of 131 I-trastuzumab was 0.5 nM, while its immunoreactivity was more than 80%. Uptake of more than 12% and retention were observed in the tumors up to 120 hours p.i. 131 I-trastuzumab prepared in-house-exhibited RCP of more than 98%, excellent immunoreactivity, affinity to HER2+ cell lines and good tumor uptake thereby indicating its potential for further evaluation in HER2+ breast cancers. Copyright © 2016 John Wiley & Sons, Ltd.

Use of trastuzumab as an adjuvant/neoadjuvant therapy in patients with HER2-positive breast cancer in China: The Nvwa study.

PubMed

Li, Junjie; Shao, Zhimin; Xu, Binghe; Jiang, Zefei; Cui, Shude; Zhang, Jin; Liao, Ning; Jiang, Jun; Wang, Yongsheng; Ouyang, Quchang; Ying, Ziwei

2018-05-01

The aim of this study was to understand current trends in trastuzumab use in China as a neoadjuvant/adjuvant therapy for human epidermal growth factor receptor-2 positive (HER2+) breast cancer and identify factors influencing trastuzumab use.This was a retrospective, multicenter, cross-sectional study of patients diagnosed with HER2+ breast cancer (stage I-III), between July 2013 and June 2014, at 155 hospitals in 29 provinces/cities in China. Demographic and clinical data, including tumor characteristics and details of adjuvant/neoadjuvant therapies used, were collected. Data analysis included univariate analysis, multivariate logistic regression, and subgroup analyses.Of 4994 HER2+ patients (mean age 51.1 ± 9.9 years) included, only 29.8% received trastuzumab, with 30.5% in adjuvant therapy and 18.3% in neoadjuvant therapy. The highest rates of adjuvant trastuzumab were in Beijing (59.3%), Jiangsu (57.1%), and Ningxia (50.0%), while those of neoadjuvant trastuzumab were in Guangdong (24.8%), Beijing (14.1%), and Zhejiang (10.7%). Multivariate regression results revealed that factors associated with trastuzumab use were medical insurance cover for trastuzumab, residing locally to the hospital, more lymph node involvement, and more advanced tumor stage. Subgroup analysis revealed that patients receiving neoadjuvant therapy were likely to be younger, premenopausal and non-local, and had lymph node metastases, more advanced tumor, and progesterone receptor positive tumor.Trastuzumab use in patients with HER2+ breast cancer is relatively low in China, especially for neoadjuvant therapy. Insurance coverage seems to be the most correlated factor that influences the use of trastuzumab in Chinese patients with HER2+ breast cancer.

Nuclear Threshold States: Yesterday, Today, Tomorrow

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ogloblin, A. A.; Danilov, A. N.; Demyanova, A. S.

2010-04-30

50 years ago exotic nuclear states with abnormally large radii located close to the thresholds of emission of nucleons or clusters were predicted. Recently a hypothesis of possible existence of alpha-particle Bose condensation was proposed. The 0{sup +}{sub 2}(7.65 MeV) state of {sup 12}C(so-called Hoyle state) is considered to be the prototype of such condensed state and have a dilute structure. We propose two methods for searching the alpha-condensate signatures in the Hoyle state and some other ones near the alpha-thresholds by using inelastic diffractive and rainbow scattering. Inelastic scattering of {sup 2}H, {sup 3}He, {sup 4}He, {sup 6}Li, andmore » {sup 12}C on {sup 12}C was studied and the enhancement of the {sup 12}C radius in the Hoyle state relatively the ground state radius by a factor of 1.2 was demonstrated. Another signature of the condensate structure, 70% probability of all three alpha-particles to be in the s-state, was observed for the Hoyle state by studying the {sup 8}Be transfer reaction. The analogs of the Hoyle state with enhanced radii were identified in {sup 11}B and {sup 13}C. The proposed methods of measuring the nuclear radii allowed observation of neutron halos in the excited states of {sup 9}Be and {sup 13}C. The conception of abnormal dimensions of the threshold states finds its confirmation in many nuclear phenomena both well-known and new ones. One of the perspective domains of its manifestation are the nuclei heavier than {sup 100}Sn with N = Z, which are able to emit several alpha particles.« less

Alpha-SNAP functions in insulin exocytosis from mature, but not immature secretory granules in pancreatic beta cells.

PubMed

Nakamichi, Y; Nagamatsu, S

1999-06-24

To explore alpha-SNAP function in insulin exocytosis from either immature or mature secretory granules in pancreatic beta cells, we studied the effects of overexpression of adenovirus-mediated wild-type alpha-SNAP and C-terminally deleted alpha-SNAP mutant (1-285) on newly synthesized proinsulin and insulin release by rat islets and MIN6 cells. Rat islets overexpressing alpha-SNAP and mutant alpha-SNAP were pulse-chased. Exocytosis from immature and mature insulin secretory granules was measured as fractional (%) labeled-proinsulin release immediately after the pulse-labeling and percentage labeled-insulin release after a 3-h chase period, respectively. There was no difference in percentage labeled-proinsulin release between the control and alpha-SNAP or mutant alpha-SNAP-overexpressed islets. Although percentage labeled-insulin release after a 3-h chase period was significantly increased in alpha-SNAP-overexpressed islets, it was decreased in mutant alpha-SNAP-overexpressed islets. Thus, the results demonstrated that alpha-SNAP overexpression in rat islets primarily increased exocytosis from mature, but not immature insulin secretory granules. On the other hand, in MIN6 cells, alpha-SNAP overexpression scarcely affected glucose-stimulated insulin release; therefore, we examined the effect of mutant alpha-SNAP overexpression as the dominant-negative inhibitor on the newly synthesized proinsulin/insulin release using the same protocol as in the rat islet experiments. alpha-SNAP mutant (1-285) overexpression in MIN6 cells decreased the percentage labeled insulin release from mature secretory granules, but not percentage labeled proinsulin release from immature secretory granules. Thus, our data demonstrate that alpha-SNAP functions mainly in the mature insulin secretory granules in pancreatic beta cells. Copyright 1999 Academic Press.

21 CFR 211.42 - Design and construction features.

Code of Federal Regulations, 2014 CFR

2014-04-01

... product containers, closures, labeling, in-process materials, or drug products, and to prevent contamination. The flow of components, drug product containers, closures, labeling, in-process materials, and... withholding from use of components, drug product containers, closures, and labeling, pending the appropriate...

21 CFR 211.42 - Design and construction features.

Code of Federal Regulations, 2012 CFR

2012-04-01

... product containers, closures, labeling, in-process materials, or drug products, and to prevent contamination. The flow of components, drug product containers, closures, labeling, in-process materials, and... withholding from use of components, drug product containers, closures, and labeling, pending the appropriate...

21 CFR 211.42 - Design and construction features.

Code of Federal Regulations, 2013 CFR

2013-04-01

... product containers, closures, labeling, in-process materials, or drug products, and to prevent contamination. The flow of components, drug product containers, closures, labeling, in-process materials, and... withholding from use of components, drug product containers, closures, and labeling, pending the appropriate...

21 CFR 211.42 - Design and construction features.

Code of Federal Regulations, 2011 CFR

2011-04-01

... product containers, closures, labeling, in-process materials, or drug products, and to prevent contamination. The flow of components, drug product containers, closures, labeling, in-process materials, and... withholding from use of components, drug product containers, closures, and labeling, pending the appropriate...

LncRNA PRNCR1 regulates osteogenic differentiation in osteolysis after hip replacement by targeting miR-211-5p.

PubMed

Gong, Zong-Ming; Tang, Zhen-Yu; Sun, Xiao-Liang

2018-05-11

Background Osteogenic differentiation and osteolysis after hip replacement are both associated with bone metabolism. Interaction between the long non-coding RNA (lncRNA) prostate cancer non-coding RNA 1 (PRNCR1) and miR-211-5p was analyzed to illuminate their roles in osteogenic differentiation and osteolysis. Methods The expression of PRNCR1, miR-211-5p and C-X-C chemokine receptor-4 (CXCR4) protein in tissues and mesenchymal stem cells (MSCs) were determined by qRT-PCR and western blot, separately. The osteogenic differentiation was assessed with Alkaline phosphatase (ALP) activity detection and ARS staining. The endogenous expressions of genes were modulated by recombinant plasmid and cell transfection. Combination condition and interaction between RNA and protein were determined with RIP and RNA pull-down assay, respectively. Interaction between miR-211-5p and CXCR4 was examined with Dual luciferase reporter assay. Results PRNCR1 and CXCR4 were up-regulated in wear particles around prosthesis and in MSCs incubated with Polymethylmethacrylate (PMMA), while miR-211-5p was down-regulated. Repression of PRNCR1 weakened the inhibitory effect of wear particles on osteogenic differentiation. PRNCR1 positively regulated CXCR4 through inhibiting miR-211-5p. Wear particles regulated CXCR4 level through miR-211-5p to affect osteogenic differentiation of MSCs. Wear particles regulated the miR-211-5p level through PRNCR1 to affect osteogenic differentiation of MSCs. Conclusion LncRNA PRNCR1 up-regulates CXCR4 through inhibiting miR-211-5p, which inhibits osteogenic differentiation and thereby leading to osteolysis after hip replacement. ©2018 The Author(s).

In-flight flow visualization characteristics of the NASA F-18 high alpha research vehicle at high angles of attack

NASA Technical Reports Server (NTRS)

Fisher, David F.; Delfrate, John H.; Richwine, David M.

1991-01-01

Surface and off-surface flow visualization techniques were used to visualize the 3-D separated flows on the NASA F-18 high alpha research vehicle at high angles of attack. Results near the alpha = 25 to 26 deg and alpha = 45 to 49 deg are presented. Both the forebody and leading edge extension (LEX) vortex cores and breakdown locations were visualized using smoke. Forebody and LEX vortex separation lines on the surface were defined using an emitted fluid technique. A laminar separation bubble was also detected on the nose cone using the emitted fluid technique and was similar to that observed in the wind tunnel test, but not as extensive. Regions of attached, separated, and vortical flow were noted on the wing and the leading edge flap using tufts and flow cones, and compared well with limited wind tunnel results.

A randomized, single-blind, single-dose study evaluating the pharmacokinetic equivalence of proposed biosimilar ABP 980 and trastuzumab in healthy male subjects.

PubMed

Hanes, Vladimir; Chow, Vincent; Zhang, Nan; Markus, Richard

2017-05-01

This study compared the pharmacokinetic (PK) profiles of the proposed biosimilar ABP 980 and trastuzumab in healthy males. In this single-blind study, 157 healthy males were randomized 1:1:1 to a single 6 mg/kg intravenous infusion of ABP 980, FDA-licensed trastuzumab [trastuzumab (US)], or EU-authorized trastuzumab [trastuzumab (EU)]. Primary endpoints were area under the serum concentration-time curve from time 0 to infinity (AUC inf ) and maximum observed serum concentration (C max ). To establish equivalence, the geometric mean ratio (GMR) and 90% confidence interval (CI) for C max and AUC inf had to be within the equivalence criteria of 0.80-1.25. The GMRs and 90% CIs for C max and AUC inf , respectively, were: 1.04 (0.99-1.08) and 1.06 (1.00-1.12) for ABP 980 versus trastuzumab (US); 0.99 (0.95-1.03) and 1.00 (0.95-1.06) for ABP 980 versus trastuzumab (EU); and 0.96 (0.92-1.00) and 0.95 (0.90-1.01) for trastuzumab (US) versus trastuzumab (EU). All comparisons were within the equivalence criteria of 0.80-1.25. Treatment-emergent adverse events (TEAEs) were reported in 84.0, 75.0, and 78.2 of subjects in the ABP 980, trastuzumab (US), and trastuzumab (EU) groups, respectively. There were no deaths or TEAEs leading to study discontinuation and no binding or neutralizing anti-drug anti-bodies were detected. This study demonstrated the PK similarity of ABP 980 to both trastuzumab (US) and trastuzumab (EU), and of trastuzumab (US) to trastuzumab (EU). No differences in safety and tolerability between treatments were noted; no subject tested positive for binding anti-bodies.

CACA-TOCSY with alternate 13C-12C labeling: a 13Calpha direct detection experiment for mainchain resonance assignment, dihedral angle information, and amino acid type identification.

PubMed

Takeuchi, Koh; Frueh, Dominique P; Sun, Zhen-Yu J; Hiller, Sebastian; Wagner, Gerhard

2010-05-01

We present a (13)C direct detection CACA-TOCSY experiment for samples with alternate (13)C-(12)C labeling. It provides inter-residue correlations between (13)C(alpha) resonances of residue i and adjacent C(alpha)s at positions i - 1 and i + 1. Furthermore, longer mixing times yield correlations to C(alpha) nuclei separated by more than one residue. The experiment also provides C(alpha)-to-sidechain correlations, some amino acid type identifications and estimates for psi dihedral angles. The power of the experiment derives from the alternate (13)C-(12)C labeling with [1,3-(13)C] glycerol or [2-(13)C] glycerol, which allows utilizing the small scalar (3)J(CC) couplings that are masked by strong (1)J(CC) couplings in uniformly (13)C labeled samples.

Neutron radiation characteristics of plutonium dioxide fuel

NASA Technical Reports Server (NTRS)

Taherzadeh, M.

1972-01-01

The major sources of neutrons from plutonium dioxide nuclear fuel are considered in detail. These sources include spontaneous fission of several of the Pu isotopes, (alpha, n) reactions with low Z impurities in the fuel, and (alpha, n) reactions with O-18. For spontaneous fission neutrons a value of (1.95 + or - 0.07) X 1,000 n/s/g PuO2 is obtained. The neutron yield from (alpha, n) reactions with oxygen is calculated by integrating the reaction rate equation over all alpha-particle energies and all center-of-mass angles. The results indicate a neutron emission rate of (1.14 + or - 0.26) X 10,000 n/s/g PuO2. The neutron yield from (alpha, n) reactions with low Z impurities in the fuel is presented in tabular form for one part part per million of each impurity. The total neutron yield due to the combined effects of all the impurities depends upon the fractional weight concentration of each impurity. The total neutron flux emitted from a particular fuel geometry is estimated by adding the neutron yield due to the induced fission to the other neutron sources.

Induction of single- and double-strand breaks in plasmid DNA by monoenergetic alpha-particles with energies below the Bragg-maximum.

PubMed

Scholz, V; Weidner, J; Köhnlein, W; Frekers, D; Wörtche, H J

1997-01-01

The yield of single-strand breaks (ssb) and double-strand breaks (dsb) produced by alpha-particles at the end of their track in DNA-films was determined experimentally. Helium nuclei were accelerated to 600 keV in the 400 kV ion accelerator and scattered at a carbon target. The elastically scattered alpha-particles with energies of 344 keV and 485 keV were used to irradiate supercircular plasmid DNA in vacuo. For the dosimetry of the alpha-particles a surface barrier detector was used and the energy distribution of the alpha-particles determined. The energy loss of the particles in the DNA-layer was calculated. DNA samples were separated into the three conformational isomers using agarose gel electrophoresis. After fluorochromation the number of ssb and dsb per plasmid DNA molecule was established from the band intensities assuming the validity of Poisson statistics. Linear dose effect correlations were found for ssb and dsb per plasmid molecule. In the case of 344 keV-alpha-particles the yield of dsb was (8.6 +/- 0.9) x 10(-11) breaks/Gy x dalton. The ratio of ssb/dsb was 0.5 +/- 0.2. This is at least a factor of six larger than the ratio found in experiments with higher energy alpha-particles and from model calculations. Similar experiments with protons yielded a relative biological effectiveness (rbe) value of 2.8 for the induction of double-strand breaks by track end alpha-particles.

Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab.

PubMed

Oliveira, Mafalda; Braga, Sofia; Passos-Coelho, José Luís; Fonseca, Ricardo; Oliveira, João

2011-06-01

Trastuzumab, a monoclonal antibody against the HER2 receptor, is a major breakthrough in the treatment of HER2+ breast cancer. However, its high molecular weight precludes it from crossing the intact blood-brain barrier, making the central nervous system a sanctuary to HER2+ breast cancer metastases. We prospectively assessed functional outcome and toxicity of administering trastuzumab directly into the cerebrospinal fluid of a patient with leptomeningeal carcinomatosis (LC) and brain metastases from HER2+ breast cancer that had already been treated with other intrathecal chemotherapy, with no benefit. Upon signed informed consent, weekly lumbar puncture with administration of trastuzumab 25 mg was begun to a 44 year-old women with metastatic breast cancer (lymph node, bone, lung, and liver involvement) previously treated with tamoxifen, letrozole, anthracyclines, taxanes, capecitabine, intravenous trastuzumab, and lapatinib. She received 67 weekly administrations of intrathecal trastuzumab with marked clinical improvement and no adverse events. She survived 27 months after LC diagnosis. A complete leptomeningeal response, with no evidence of leptomeningeal metastasis at necropsy, was achieved. We believe that intrathecal trastuzumab administration should be prospectively evaluated to confirm clinical activity and optimize dose, schedule, and duration of treatment.

Self-powered microthermionic converter

DOEpatents

Marshall, Albert C.; King, Donald B.; Zavadil, Kevin R.; Kravitz, Stanley H.; Tigges, Chris P.; Vawter, Gregory A.

2004-08-10

A self-powered microthermionic converter having an internal thermal power source integrated into the microthermionic converter. These converters can have high energy-conversion efficiencies over a range of operating temperatures. Microengineering techniques are used to manufacture the converter. The utilization of an internal thermal power source increases potential for mobility and incorporation into small devices. High energy efficiency is obtained by utilization of micron-scale interelectrode gap spacing. Alpha-particle emitting radioisotopes can be used for the internal thermal power source, such as curium and polonium isotopes.

APXS on board Chandrayaan-2 Rover

NASA Astrophysics Data System (ADS)

Shanmugam, M.; Sripada, V. S. Murty; Acharya, Y. B.; Goyal, S. K.

2012-07-01

Alpha Particle X-ray Spectrometer (APXS) is a well proven instrument for quantitative in situ elemental analysis of the planetary surfaces and has been successfully employed for Mars surface exploration. Chandrayaan-2, ISRO's second lunar mission having an Orbiter, Lander and Rover has provided an opportunity to explore the lunar surface with superior detectors such as Silicon Drift Detector (SDD) with energy resolution of about 150eV @ 5.9keV. The objective of the APXS instrument is to analyse several soil/rock samples along the rover traverse for the major elements with characteristic X-rays in 1 to 25keV range. The working principle of APXS involves measuring the intensity of characteristic X-rays emitted from the sample due to Alpha Particle Induced X-ray Emission (PIXE) and X-ray florescence (XRF) processes using suitable radioactive sources, allowing the determination of elements from Na to Br, spanning the energy range of 0.9 to 16keV. For this experiment ^{244}Cm radioactive source has been chosen which emits both Alpha particles (5.8MeV) and X-rays (14.1keV, 18keV). APXS uses six Alpha sources, each about 5mCi activity. Unlike Mars, lunar environment poses additional challenges due to the regolith and extreme surface temperature changes, to operate the APXS. Our APXS instrument consists of two packages namely APXS sensor head and APXS signal electronics. The sensor head assembly contains SDD, six alpha sources and front end electronic circuits such as preamplifier and shaper circuits and will be mounted on a robotic arm which on command brings the sensor head close to the lunar surface at a height of 35±10mm. SDD module to be used in the experiment has 30mm ^{2} active detector area with in-built peltier cooler and heat sink to maintain the detector at about -35°C. The detector is covered with 8 micron thick Be window which results in the low energy threshold of about 1keV. The size of the APXS sensor head is 70x70x70mm ^{3} (approx). APXS signal electronics consists of a PCB having digital, power and rover interface electronics circuits, which are housed inside the Warm Electronics Box (WEB) mounted under the rover chassis where the temperature is maintained between -50°C to +70°C. Presently, we have completed the design verification model of the APXS payload and engineering model of the payload is in progress. The developed system has been tested using laboratory X-ray sources and observed an energy resolution of about 150eV at 5.9keV when the detector is cooled to -35°C. We also carried out the detection of X-ray fluorescence for some of the USGS standards for a fixed geometry of detector, source and sample, using ^{55}Fe and ^{241}Am X-ray sources. It is shown that the count rate of a given peak varies linearly with the concentration of the corresponding element. The detailed developments and results will be discussed at the conference.

Occurrence and hydrogeochemistry of radiochemical constituents in groundwater of Jefferson County and surrounding areas, southwestern Montana, 2007 through 2010

USGS Publications Warehouse

Caldwell, Rodney R.; Nimick, David A.; DeVaney, Rainie M.

2014-01-01

The U.S. Geological Survey, in cooperation with Jefferson County and the Jefferson Valley Conservation District, sampled groundwater in southwestern Montana to evaluate the occurrence and concentration of naturally-occurring radioactive constituents and to identify geologic settings and environmental conditions in which elevated concentrations occur. A total of 168 samples were collected from 128 wells within Broadwater, Deer Lodge, Jefferson, Lewis and Clark, Madison, Powell, and Silver Bow Counties from 2007 through 2010. Most wells were used for domestic purposes and were primary sources of drinking water for individual households. Water-quality samples were collected from wells completed within six generalized geologic units, and analyzed for constituents including uranium, radon, gross alpha-particle activity, and gross beta-particle activity. Thirty-eight wells with elevated concentrations or activities were sampled a second time to examine variability in water quality throughout time. These water-quality samples were analyzed for an expanded list of radioactive constituents including the following: three isotopes of uranium (uranium-234, uranium-235, and uranium-238), three isotopes of radium (radium-224, radium-226, and radium-228), and polonium-210. Existing U.S. Geological Survey and Montana Bureau of Mines and Geology uranium and radon water-quality data collected as part of other investigations through 2011 from wells within the study area were compiled as part of this investigation. Water-quality data from this study were compared to data collected nationwide by the U.S. Geological Survey through 2011. Radionuclide samples for this study typically were analyzed within a few days after collection, and therefore data for this study may closely represent the concentrations and activities of water being consumed locally from domestic wells. Radioactive constituents were detected in water from every well sampled during this study regardless of location or geologic unit. Nearly 41 percent of sampled wells had at least one radioactive constituent concentration that exceeded U.S. Environmental Protection Agency drinking-water standards or screening levels. Uranium concentrations were higher than the U.S. Environmental Protection Agency maximum contaminant level (MCL) of 30 micrograms per liter in samples from 14 percent of the wells. Radon concentrations exceeded a proposed MCL of 4,000 picocuries per liter in 27 percent of the wells. Combined radium (radium-226 and radium-228) exceeded the MCL of 5 picocuries per liter in samples from 10 of 47 wells. About 40 percent (42 of 104 wells) of the wells had gross alpha-particle activities (72-hour count) at or greater than a screening level of 15 pCi/L. Gross beta-particle activity exceeded the U.S. Environmental Protection Agency 50 picocuries per liter screening level in samples from 5 of 104 wells. Maximum radium-224 and polonium-210 activities in study wells were 16.1 and 3.08 picocuries per liter, respectively; these isotopes are constituents of human-health concern, but the U.S. Environmental Protection Agency has not established MCLs for them. Radioactive constituent concentrations or activities exceeded at least one established drinking-water standard, proposed drinking-water standard, or screening level in groundwater samples from five of six generalized geologic units assessed during this study. Radioactive constituent concentrations or activities were variable not only within each geologic unit, but also among wells that were completed in the same geologic unit and in close proximity to one another. Established or proposed drinking-water standards were exceeded most frequently in water from wells completed in the generalized geologic unit that includes rocks of the Boulder batholith and other Tertiary through Cretaceous igneous intrusive rocks (commonly described as granite). Specifically, of the wells completed in the Boulder batholith and related rocks sampled as part of this study, 24 percent exceeded the MCL of 30 micrograms per liter for uranium, 50 percent exceeded the proposed alternative MCL of 4,000 picocuries per liter for radon, and 27 percent exceeded the MCL of 5 micrograms per liter for combined radium-226 and radium-228. Elevated radioactive constituent values were detected in samples representing a large range of field properties and water types. Correlations between radioactive constituents and pH, dissolved oxygen, and most major ions were not statistically significant (p-value > 0.05) or were weakly correlated with Spearman correlation coefficients (rho) ranging from -0.5 to 0.5. Moderate correlations did exist between gross beta-particle activity and potassium (rho = 0.72 to 0.82), likely because one potassium isotope (potassium-40) is a beta-particle emitter. Total dissolved solids and specific conductance also were moderately correlated (rho = 0.62 to 0.71) with gross alpha-particle and gross beta-particle activity, indicating that higher radioactivity values can be associated with higher total dissolved solids. Correlations were evaluated among radioactive constituents. Moderate to strong correlations occurred between gross alpha-particle and beta-particle activities (rho = 0.77 to 0.96) and radium isotopes (rho = 0.78 to 0.92). Correlations between gross alpha-particle activity (72-hour count) and all analyzed radioactive constituents were statistically significant (p-value Radiochemical results varied temporally in samples from several of the thirty-eight wells sampled at least twice during the study. The time between successive sampling events ranged from about 1 to 10 months for 29 wells to about 3 years for the other 9 wells. Radiochemical constituents that varied by greater than 30 percent between sampling events included uranium (29 percent of the resampled wells), and radon (11 percent of the resampled wells), gross alpha-particle activity (38 percent of the resampled wells), and gross beta-particle activity (15 percent of the resampled wells). Variability in uranium concentrations from two wells was sufficiently large that concentrations were less than the MCL in the first set of samples and greater than the MCL in the second. Sample holding times affect analytical results in this study. Gross alpha-particle and gross beta-particle activities were measured twice, 72 hours and 30 days after sample collection. Gross alpha-particle activity decreased an average of 37 percent between measurements, indicating the presence of short-lived alpha-emitting radionuclides in these samples. Gross beta-particle activity increased an average of 31 percent between measurements, indicating ingrowth of longer-lived beta-emitting radionuclides.

Basal/HER2 breast carcinomas

PubMed Central

Martin-Castillo, Begoña; Oliveras-Ferraros, Cristina; Vazquez-Martin, Alejandro; Cufí, Silvia; Moreno, José Manuel; Corominas-Faja, Bruna; Urruticoechea, Ander; Martín, Ángel G.; López-Bonet, Eugeni; Menendez, Javier A.

2013-01-01

High rates of inherent primary resistance to the humanized monoclonal antibody trastuzumab (Herceptin) are frequent among HER2 gene-amplified breast carcinomas in both metastatic and adjuvant settings. The clinical efficacy of trastuzumab is highly correlated with its ability to specifically and efficiently target HER2-driven populations of breast cancer stem cells (CSCs). Intriguingly, many of the possible mechanisms by which cancer cells escape trastuzumab involve many of the same biomarkers that have been implicated in the biology of CS-like tumor-initiating cells. In the traditional, one-way hierarchy of CSCs in which all cancer cells descend from special self-renewing CSCs, HER2-positive CSCs can occur solely by self-renewal. Therefore, by targeting CSC self-renewal and resistance, trastuzumab is expected to induce tumor shrinkage and further reduce breast cancer recurrence rates when used alongside traditional therapies. In a new, alternate model, more differentiated non-stem cancer cells can revert to trastuzumab-refractory, CS-like cells via the activation of intrinsic or microenvironmental paths-to-stemness, such as the epithelial-to-mesenchymal transition (EMT). Alternatively, stochastic transitions of trastuzumab-responsive CSCs might also give rise to non-CSC cellular states that lack major attributes of CSCs and, therefore, can remain “hidden” from trastuzumab activity. Here, we hypothesize that a better understanding of the CSC/non-CSC social structure within HER2-overexpressing breast carcinomas is critical for trastuzumab-based treatment decisions in the clinic. First, we decipher the biological significance of CSC features and the EMT on the molecular effects and efficacy of trastuzumab in HER2-positive breast cancer cells. Second, we reinterpret the genetic heterogeneity that differentiates trastuzumab-responders from non-responders in terms of CSC cellular states. Finally, we propose that novel predictive approaches aimed at better forecasting early tumor responses to trastuzumab should identify biological determinants that causally underlie the intrinsic flexibility of HER2-positive CSCs to “enter” into or “exit” from trastuzumab-sensitive states. An accurate integration of CSC cellular states and EMT-related biomarkers with the currently available breast cancer molecular taxonomy may significantly improve our ability to make a priori decisions about whether patients belonging to HER2 subtypes differentially enriched with a “mesenchymal transition signature” (e.g., luminal/HER2 vs. basal/HER2) would distinctly benefit from trastuzumab-based therapy ab initio. PMID:23255137

Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression

PubMed Central

Li, Wei; Fan, Kexing; Qian, Weizhu; Hou, Sheng; Wang, Hao; Dai, Jianxin; Wei, Huafeng; Guo, Yajun

2014-01-01

Although HER2-targeting antibody trastuzumab confers a substantial benefit for patients with HER2-overexpressing breast and gastric cancer, overcoming trastuzumab resistance remains a large unmet need. In this study, we revealed a STAT3-centered positive feedback loop that mediates the resistance of trastuzumab. Mechanistically, chronic exposure of trastuzumab causes the upregulation of fibronection (FN), EGF and IL-6 in parental trastuzumab-sensitive breast and gastric cells and convergently leads to STAT3 hyperactivation. Activated STAT3 enhances the expression of FN, EGF and IL-6, thus constituting a positive feedback loop which amplifies and maintains the STAT3 signal; furthermore, hyperactivated STAT3 signal promotes the expression of MUC1 and MUC4, consequently mediating trastuzumab resistance via maintenance of persistent HER2 activation and masking of trastuzumab binding to HER2 respectively. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-dependent positive feedback loop and recovered the trastuzumab sensitivity partially due to increased apoptosis induction. Combined trastuzumab with STAT3 inhibition synergistically suppressed the growth of the trastuzumab-resistant tumor xenografts in vivo. Taken together, our results suggest that feedback activation of STAT3 constitutes a key node mediating trastuzumab resistance. Combinatorial targeting on both HER2 and STAT3 may enhance the efficacy of trastuzumab or other HER2-targeting agents in HER2-positive breast and gastric cancer. PMID:25327561

Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression.

PubMed

Li, Guangchao; Zhao, Likun; Li, Wei; Fan, Kexing; Qian, Weizhu; Hou, Sheng; Wang, Hao; Dai, Jianxin; Wei, Huafeng; Guo, Yajun

2014-09-30

Although HER2-targeting antibody trastuzumab confers a substantial benefit for patients with HER2-overexpressing breast and gastric cancer, overcoming trastuzumab resistance remains a large unmet need. In this study, we revealed a STAT3-centered positive feedback loop that mediates the resistance of trastuzumab. Mechanistically, chronic exposure of trastuzumab causes the upregulation of fibronection (FN), EGF and IL-6 in parental trastuzumab-sensitive breast and gastric cells and convergently leads to STAT3 hyperactivation. Activated STAT3 enhances the expression of FN, EGF and IL-6, thus constituting a positive feedback loop which amplifies and maintains the STAT3 signal; furthermore, hyperactivated STAT3 signal promotes the expression of MUC1 and MUC4, consequently mediating trastuzumab resistance via maintenance of persistent HER2 activation and masking of trastuzumab binding to HER2 respectively. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-dependent positive feedback loop and recovered the trastuzumab sensitivity partially due to increased apoptosis induction. Combined trastuzumab with STAT3 inhibition synergistically suppressed the growth of the trastuzumab-resistant tumor xenografts in vivo. Taken together, our results suggest that feedback activation of STAT3 constitutes a key node mediating trastuzumab resistance. Combinatorial targeting on both HER2 and STAT3 may enhance the efficacy of trastuzumab or other HER2-targeting agents in HER2-positive breast and gastric cancer.

Ablation of breast cancer cells using trastuzumab-functionalized multi-walled carbon nanotubes and trastuzumab-diphtheria toxin conjugate.

PubMed

Oraki Kohshour, Mojtaba; Mirzaie, Sako; Zeinali, Majid; Amin, Mansour; Said Hakhamaneshi, Mohammad; Jalili, Ali; Mosaveri, Nader; Jamalan, Mostafa

2014-03-01

Trastuzumab (Herceptin(®) ) is a monoclonal antibody (mAb) for specific ablation of HER2-overexpressing malignant breast cancer cells. Intensification of antiproliferative activity of trastuzumab through construction of immunotoxins and nano-immunoconjugates is a promising approach for treatment of cancer. In this study, trastuzumab was directly conjugated to diphtheria toxin (DT). Also, conjugates of trastuzumab and multiwalled carbon nanotubes (MWCNT) were constructed by covalent immobilization of trastuzumab onto MWCNTs. Then, antiproliferative activity of the fusion constructs against HER2-overexpressing SK-BR-3 and also HER2-negative MCF-7 cancer cell lines were examined. Cells treated with trastuzumab-MWCNT conjugates were irradiated with near-infrared (NIR) light. Efficient absorption of NIR radiation and its conversion to heat by MWCNTs can be resulted to thermal ablation of cancerous cells. Our results strongly showed that both trastuzumab-MWCNT and trastuzumab-DT conjugates were significantly efficient in the specific killing of SK-BR-3 cells. Targeting of MWCNTs to cancerous cells using trastuzumab followed by exposure of cells to NIR radiation was more efficient in repression of cell proliferation than treatment for cancer cells with trastuzumab-DT. Our results also showed that conjugation linkers can significantly affect the cytotoxicity of MWCNT-immunoconjugates. In conclusion, our data demonstrated that trastuzumab-MWCNT is a promising nano-immunoconjugate for killing of HER2-overexpressing cancerous cells. © 2013 John Wiley & Sons A/S.

The growth of deactivated layers on CsI(Na) scintillating crystals

NASA Technical Reports Server (NTRS)

Goodman, N. B.

1975-01-01

An effective and sensitive measurement of the depth of a deactivated or dead layer can be obtained from the relative attenuation of the 22.162 KeV and 87.9 KeV X-rays emitted by Cd 109. The alpha-particles emitted by Am 241 are also useful in measuring dead layers less than 25 microns. The properties and temporal development of dead layers are discussed in detail. The rate of growth of a deal layer is closely related to the ambient humidity, and the damage to the crystal is irreversible by any known process. The dead layer can be minimized by polishing all crystal surfaces and by keeping the crystal in a vacuum or a dry atmosphere. Since a dead layer seriously inhibits the response of a crystal to X-rays of energies below approximately 20 keV, CsI(Na) detectors should not be used at these energies unless precautions are taken to ensure that no dead layer forms.

N-Acetylcysteine breaks resistance to trastuzumab caused by MUC4 overexpression in human HER2 positive BC-bearing nude mice monitored by 89Zr-Trastuzumab and 18F-FDG PET imaging

PubMed Central

Wimana, Zéna; Gebhart, Geraldine; Guiot, Thomas; Vanderlinden, Bruno; Larsimont, Denis; Doumont, Gilles; Van Simaeys, Gaetan; Goldman, Serge; Flamen, Patrick; Ghanem, Ghanem

2017-01-01

Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab (89Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy. Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity (89Zr-Trastuzumab HER2-immunoPET) and glucose metabolism (18F-FDG-PET/CT), as well as tumor volume and the expression of key proteins. In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumab-sensitivity of the MUC4-negative SKBr3-tumors. These findings suggest that improving HER2-accessibility by reducing MUC4-masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4. PMID:28915583

N-Acetylcysteine breaks resistance to trastuzumab caused by MUC4 overexpression in human HER2 positive BC-bearing nude mice monitored by 89Zr-Trastuzumab and 18F-FDG PET imaging.

PubMed

Wimana, Zéna; Gebhart, Geraldine; Guiot, Thomas; Vanderlinden, Bruno; Larsimont, Denis; Doumont, Gilles; Van Simaeys, Gaetan; Goldman, Serge; Flamen, Patrick; Ghanem, Ghanem

2017-08-22

Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab ( 89 Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy. Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity ( 89 Zr-Trastuzumab HER2-immunoPET) and glucose metabolism ( 18 F-FDG-PET/CT), as well as tumor volume and the expression of key proteins. In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumab-sensitivity of the MUC4-negative SKBr3-tumors. These findings suggest that improving HER2-accessibility by reducing MUC4-masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4.

Infused Therapy and Survival in Older Patients Diagnosed with Metastatic Breast Cancer who Received Trastuzumab

PubMed Central

Griffiths, Robert I; Lalla, Deepa; Herbert, Robert J; Doan, Justin F; Brammer, Melissa G; Danese, Mark D

2011-01-01

We used Surveillance, Epidemiology, and End Results-Medicare data (2000-2006) to describe treatment and survival in women diagnosed with metastatic breast cancer (MBC) who received trastuzumab. There were 610 patients with a mean age of 74 years. Overall, 32% received trastuzumab alone and 47% received trastuzumab plus a taxane. In multivariate analysis, trastuzumab plus chemotherapy was associated with a lower adjusted cancer mortality rate (Hazard Ratio [HR] 0.54; 95% Confidence Interval [CI] 0.39-0.74; p < .001) than trastuzumab alone among patients who received trastuzumab as part of first-line therapy. Adding chemotherapy to first-line trastuzumab for metastatic breast cancer is associated with improved cancer survival. PMID:21929325

Development of ultrahigh resolution alpha particle imaging detector using 1 mm channel size Si-PM array

NASA Astrophysics Data System (ADS)

Yamamoto, Seiichi; Kawaguchi, Wataru

2018-06-01

For precise distribution measurements of alpha particles, a high-resolution alpha particle imaging detector is required. Although combining a thin scintillator with a silicon photomultiplier (Si-PM) array is a promising method for achieving high resolution, the spatial resolution is limited. Reducing the size of the Si-PM array is a possible approach to improving the spatial resolution of the alpha particle imaging detector. Consequently, we employed a 1 mm channel size Si-PM array combined with a thin ZnS(Ag) sheet to form an alpha particle imaging detector and evaluated the performance. For the developed alpha particle imaging detector, an Si-PM array with 1 mm x 1 mm channel size arranged 8 x 8 was optically coupled to a ZnS(Ag) sheet with a 1-mm-thick light guide between them. The size of the alpha particle imaging detector was 9.5 mm x 9.5 mm. The spatial resolution of the developed alpha particle imaging detector was 0.14 mm FWHM, and the energy resolution was 74% FWHM for 5.5 MeV alpha particles. The uniformity of the imaging detector at the central part of the field of view (FOV) was ±4.7%. The background count rate was 0.06 counts/min. We obtained various high-resolution phantom images for alpha particles with the developed system. We conclude that the developed imaging detector is promising for high-resolution distribution measurements of alpha particles.

40 CFR 211.110-1 - Testing exemption.

Code of Federal Regulations, 2011 CFR

2011-07-01

... respect to each new product, originally intended for research, investigations, studies, demonstrations, or... PROGRAMS PRODUCT NOISE LABELING General Provisions § 211.110-1 Testing exemption. (a) A new product intended to be used solely for research, investigations, studies, demonstrations or training, and so...

Trastuzumab and survival of patients with metastatic breast cancer.

PubMed

Kast, Karin; Schoffer, Olaf; Link, Theresa; Forberger, Almuth; Petzold, Andrea; Niedostatek, Antje; Werner, Carmen; Klug, Stefanie J; Werner, Andreas; Gatzweiler, Axel; Richter, Barbara; Baretton, Gustavo; Wimberger, Pauline

2017-08-01

Prognosis of Her2-positive breast cancer has changed since the introduction of trastuzumab for treatment in metastatic and early breast cancer. It was described to be even better compared to prognosis of Her2-negative metastatic breast cancer. The purpose of this study was to evaluate the effect of trastuzumab in our cohort. Besides the effect of adjuvant pretreatment with trastuzumab on survival of patients with metastatic Her2-positive breast cancer was analyzed. All patients with primary breast cancer of the Regional Breast Cancer Center Dresden diagnosed during the years 2001-2013 were analyzed for treatment with or without trastuzumab in the adjuvant and in the metastatic treatment setting using Kaplan-Meier survival estimation and Cox regression. Age and tumor stage at time of first diagnosis of breast cancer as well as hormone receptor status, grading, time, and site of metastasis at first diagnosis of distant metastatic disease were analyzed. Of 4.481 female patients with primary breast cancer, 643 presented with metastatic disease. Her2-positive status was documented in 465 patients, including 116 patients with primary or secondary metastases. Median survival of patients with Her2-positive primary metastatic disease was 3.0 years (95% CI 2.3-4.0). After adjustment for other factors, survival was better in patients with Her2-positive breast cancer with trastuzumab therapy compared to Her2-negative metastatic disease (HR 2.10; 95% CI 1.58-2.79). Analysis of influence of adjuvant therapy with and without trastuzumab by Kaplan-Meier showed a trend for better survival in not pretreated patients. Median survival was highest in hormone receptor-positive Her2-positive (triple-positive) primary metastatic breast cancer patients with 3.3 years (95% CI 2.3-4.6). Prognosis of patients with Her2-positive metastatic breast cancer after trastuzumab treatment is more favorable than for Her2-negative breast cancer. The role of adjuvant chemotherapy with or without trastuzumab warrants further research. Survival is best in triple-positive metastatic breast cancer. This will effect counseling at the time of first diagnosis of metastatic breast cancer.

Specific lysine labeling by 18OH- during alkaline cleavage of the alpha-1-antitrypsin-trypsin complex.

PubMed Central

Cohen, A B; Gruenke, L D; Craig, J C; Geczy, D

1977-01-01

alpha-1-Antitrypsin is a serum protein that inhibits many proteolytic enzymes. Recently, it was suggested that the alpha-1-antitrypsin-trypsin complex is an acyl ester analogous to the acyl intermediate that forms between trypsin and its substrates. In previous work we showed that the alpha-1-antitrypsin-trypsin complex can be split at high pH, releasing a component of alpha-1-antitrypsin. This component had a new carboxyl-terminal lysine, and it had lost a peptide of about 4000 daltons. In order to determine whether the alpha-1-antitrypsin is bound to trypsin through the new carboxy-terminal lysine, as would be expected if the above hypothesis is correct, we split the complex in the presence of 18OH-. When the new carboxy-terminal lysine was cleaved with carboxypeptidase B, singly labeled, doubly labeled, and unlabeled lysine were recovered. These data support the hypothesis that the alpha-1-antitrypsin-trypsin complex is an acyl ester or a tetrahedral precursor that is transformed into the acyl ester form at high pH. If other enzymes are bound by a similar mechanism, the methods used may be useful in determining which amino acids on alpha-1-antitrypsin bind covalently to each enzyme. PMID:303770

40 CFR 211.106 - Graphical requirements.

Code of Federal Regulations, 2010 CFR

2010-07-01

... contrast sufficiently with each other and with any information or material surrounding the label so that... label must be Helvetica Medium. (d) Character Size. All letters and numerals that appear on the...

40 CFR 211.106 - Graphical requirements.

Code of Federal Regulations, 2011 CFR

2011-07-01

... contrast sufficiently with each other and with any information or material surrounding the label so that... label must be Helvetica Medium. (d) Character Size. All letters and numerals that appear on the...

Measurement of Bremsstrahlung radiation for in vivo monitoring of 14C tracer distribution between fruit and roots of kiwifruit (Actinidia arguta) cuttings.

PubMed

Black, Marykate Z; Minchin, Peter E H; Gould, Nick; Patterson, Kevin J; Clearwater, Michael J

2012-10-01

In vivo measurements of (14)C tracer distribution have usually involved monitoring the β(-) particles produced as (14)C decays. These particles are only detectable over short distances, limiting the use of this technique to thin plant material. In the present experiments, X-ray detectors were used to monitor the Bremsstrahlung radiation emitted since β(-) particles were absorbed in plant tissues. Bremsstrahlung radiation is detectable through larger tissue depths. The aim of these experiments was to demonstrate the Bremsstrahlung method by monitoring in vivo tracer-labelled photosynthate partitioning in small kiwifruit (Actinidia arguta (Siebold & Zucc.) Planch. ex Miq.) plants in response to root pruning. A source shoot, consisting of four leaves, was pulse labelled with (14)CO(2). Detectors monitored import into a fruit and the root system, and export from a source leaf. Repeat pulse labelling enabled the comparison of pre- and post-treatment observations within an individual plant. Diurnal trends were observed in the distribution of tracer, with leaf export reduced at night. Tracer accumulated in the roots declined after approximately 48 h, which may have resulted from export of (14)C from the roots in carbon skeletons. Cutting off half the roots did not affect tracer distribution to the remaining half. Tracer distribution to the fruit was increased after root pruning, demonstrating the higher competitive strength of the fruit than the roots for carbohydrate supply. Increased partitioning to the fruit following root pruning has also been demonstrated in kiwifruit field trials.

Luminous phenomena and electromagnetic VHF wave emission originated from earthquake-related radon exhalation

NASA Astrophysics Data System (ADS)

Seki, A.; Tobo, I.; Omori, Y.; Muto, J.; Nagahama, H.

2013-12-01

Anomalous luminous phenomena and electromagnetic wave emission before or during earthquakes have been reported (e.g., the 1965 Matsushiro earthquake swarm). However, their mechanism is still unsolved, in spite of many models for these phenomena. Here, we propose a new model about luminous phenomena and electromagnetic wave emission during earthquake by focusing on atmospheric radon (Rn-222) and its daughter nuclides (Po-218 and Po-214). Rn-222, Po-218 and Po-214 are alpha emitters, and these alpha particles ionize atmospheric molecules. A light emission phenomenon, called 'the air luminescence', is caused by de-excitation of the ionized molecules of atmospheric nitrogen due to electron impact ionization from alpha particles. The de-excitation is from the second positive system of neutral nitrogen molecules and the first negative system of nitrogen molecule ion. Wavelengths of lights by these transitions include the visible light wavelength. So based on this mechanism, we proposed a new luminous phenomenon model before or during earthquake: 1. The concentration of atmospheric radon and its daughter nuclides increase anomalously before or during earthquakes, 2. Nitrogen molecules and their ions are excited by alpha particles emitted from Rn-222, Po-218 and Po-214, and air luminescence is generated by their de-excitation. Similarly, electromagnetic VHF wave emission can be explained by ionizing effect of radon and its daughter nuclides. Boyarchuk et al. (2005) proposed a model that electromagnetic VHF wave emission is originated when excited state of neutral clusters changes. Radon gas ionizes atmosphere and forms positively and negatively charged heavy particles. The process of ion hydration in ordinary air can be determined by the formation of complex chemically active structures of the various types of ion radicals. As a result of the association of such hydration radical ions, a neutral cluster, which is dipole quasi-molecules, is formed. A neutral cluster's rotation-rotation transition causes electromagnetic VHF wave emission. We also discuss a possibility of electromagnetic VHF wave emission from excitation of polyatomic molecules by alpha particles from Rn-222 and its daughter nuclides, similar to air luminescence by excitation of nitrogen molecule in the viewpoint of electromagnetic radiation in quantum theory.

Environmental radon daughters reveal pathognomonic changes in the brain proteins and lipids in patients with Alzheimer's disease and Parkinson's disease, and cigarette smokers.

PubMed

Momcilović, B; Alkhatib, H A; Duerre, J A; Cooley, M A; Long, W M; Harris, R T; Lykken, G I

1999-12-01

This paper presents an investigation of the retention of environmental radon daughters, 210Po (alpha particle emitting radio-nuclide) and 210Bi (beta particle emitting radio-nuclide), in lipid and protein fractions of the cortical grey and subcortical white matter from the frontal and temporal brain lobes of patients who had suffered from Alzheimer's disease or Parkinson's disease, of cigarette smokers, and of control subjects. 210Po and 210Bi radioactivity increased tenfold in the cortical grey and subcortical white protein fraction in patients with Alzheimer's disease and smokers, and tenfold in the cortical grey and subcortical white lipid fraction in patients with Parkinson's disease. Free radicals generated by radon daughters may add to the severity of the radio-chemical injury to the brain astrocytes. The pathognomonic distribution of radon daughters to lipids in patients with Parkinson's disease and to proteins in patients with Alzheimer's disease was attributed to high chlorine affinity of radon daughters. The changes in the membrane protein pores, channels, and gates in patients with Alzheimer's disease and in the lipid bilayer in patients with Parkinson's disease are at the core of what the authors think are two systemic brain diseases.

Nanodosimetry of Auger electrons: A case study from the decay of 125I and 0-18-eV electron stopping cross sections of cytosine

NASA Astrophysics Data System (ADS)

Michaud, M.; Bazin, M.; Sanche, L.

2013-03-01

Radiopharmaceuticals emitting Auger electrons are often injected into patients undergoing cancer treatment with targeted radionuclide therapy (TRT). In this type of radiotherapy, the radiation source is radial and most of the emitted primary particles are low-energy electrons (LEEs) having kinetic energies distributed mostly from zero to a few hundred electron volts with very short ranges in biological media. These LEEs generate a high density of energy deposits and clustered damage, thus offering a relative biological effectiveness comparable to that of alpha particles. In this paper, we present a simple model and corresponding measurements to assess the energy deposited near the site of the radiopharmaceuticals in TRT. As an example, a calculation is performed for the decay of a single 125I radionuclide surrounded by a 1-nm-radius spherical shell of cytosine molecules using the energy spectrum of LEEs emitted by 125I along with their stopping cross sections between 0 and 18 eV. The dose absorbed by the cytosine shell, which occupies a volume of 4 nm3, is extremely high. It amounts to 79 kGy per decay of which 3%, 39%, and 58% is attributed to vibrational excitations, electronic excitations, and ionization processes, respectively.

Measurements of geomagnetically trapped alpha particles, 1968-1970. I - Quiet time distributions

NASA Technical Reports Server (NTRS)

Krimigis, S. M.; Verzariu, P.

1973-01-01

Results of observations of geomagnetically trapped alpha particles over the energy range from 1.18 to 8 MeV performed with the aid of the Injun 5 polar-orbiting satellite during the period from September 1968 to May 1970. Following a presentation of a time history covering this entire period, a detailed analysis is made of the magnetically quiet period from Feb. 11 to 28, 1970. During this period the alpha particle fluxes and the intensity ratio of alpha particles to protons attained their lowest values in approximately 20 months; the alpha particle intensity versus L profile was most similar to the proton profile at the same energy per nucleon interval; the intensity ratio was nearly constant as a function of L in the same energy per nucleon representation, but rose sharply with L when computed in the same total energy interval; the variation of alpha particle intensity with B suggested a steep angular distribution at small equatorial pitch angles, while the intensity ratio showed little dependence on B; and the alpha particle spectral parameter showed a markedly different dependence on L from the equivalent one for protons.

21 CFR 211.125 - Labeling issuance.

Code of Federal Regulations, 2010 CFR

2010-04-01

... shall be used to reconcile the quantities of labeling issued, used, and returned, and shall require... issued when such discrepancies are outside narrow preset limits based on historical operating data. Such....122(g)(2). (d) All excess labeling bearing lot or control numbers shall be destroyed. (e) Returned...

Off-label use of TNF-alpha inhibitors in a dermatological university department: retrospective evaluation of 118 patients.

PubMed

Sand, Freja Lærke; Thomsen, Simon Francis

2015-01-01

Tumor necrosis factor-alpha (TNF)-alpha inhibitors are licensed for patients with severe refractory psoriasis and psoriatic arthritis. However, TNF-alpha inhibitors have also been used off-label for various recalcitrant mucocutaneous diseases. This study aimed to evaluate the efficacy and safety of TNF-alpha inhibitors used for off-label dermatological indications. We retrospectively evaluated patient records of 118 patients treated off-label with TNF-alpha inhibitors in a dermatological university department. Patients presented with severe aphthous stomatitis/genital aphthous lesions (26), chronic urticaria (25), hidradenitis suppurativa (29), acne conglobata (11), dissecting cellulitis of the scalp (two), orofacial granulomatosis (four), sarcoidosis (four), granuloma annulare (two), granulomatous rosacea (one), granuloma faciale (one), subcorneal pustulosis (one), pyoderma gangrenosum (four), Sweet's syndrome (four), Well's syndrome (one), benign familial pemphigus (one), lichen planus (one), and folliculitis decalvans (one). A significant number of these patients went into remission during therapy with TNF-alpha inhibitors. A total of 11 patients (9%) experienced severe adverse effects during therapy. Off-label therapy with TNF-alpha inhibitors may be considered for selected patients with severe recalcitrant mucocutaneous diseases. The risk of severe adverse effects signals that a thorough benefit-risk assessment should be performed before initiating off-label treatment with TNF-alpha inhibitors for these conditions. © 2015 Wiley Periodicals, Inc.

Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study.

PubMed

Doi, Toshihiko; Shitara, Kohei; Naito, Yoichi; Shimomura, Akihiko; Fujiwara, Yasuhiro; Yonemori, Kan; Shimizu, Chikako; Shimoi, Tatsunori; Kuboki, Yasutoshi; Matsubara, Nobuaki; Kitano, Atsuko; Jikoh, Takahiro; Lee, Caleb; Fujisaki, Yoshihiko; Ogitani, Yusuke; Yver, Antoine; Tamura, Kenji

2017-11-01

Antibody-drug conjugates have emerged as a powerful strategy in cancer therapy and combine the ability of monoclonal antibodies to specifically target tumour cells with the highly potent killing activity of drugs with payloads too toxic for systemic administration. Trastuzumab deruxtecan (also known as DS-8201) is an antibody-drug conjugate comprised of a humanised antibody against HER2, a novel enzyme-cleavable linker, and a topoisomerase I inhibitor payload. We assessed its safety and tolerability in patients with advanced breast and gastric or gastro-oesophageal tumours. This was an open-label, dose-escalation phase 1 trial done at two study sites in Japan. Eligible patients were at least 20 years old with breast or gastric or gastro-oesophageal carcinomas refractory to standard therapy regardless of HER2 status. Participants received initial intravenous doses of trastuzumab deruxtecan from 0·8 to 8·0 mg/kg and dose-limiting toxicities were assessed over a 21-day cycle; thereafter, dose reductions were implemented as needed and patients were treated once every 3 weeks until they had unacceptable toxic effects or their disease progressed. Primary endpoints included identification of safety and the maximum tolerated dose or recommended phase 2 dosing and were analysed in all participants who received at least one dose of study drug. The dose-escalation study is the first part of a two-part study with the second dose-expansion part ongoing and enrolling patients as of July 8, 2017, in Japan and the USA. This trial is registered at ClinicalTrials.gov, number NCT02564900. Between Aug 28, 2015, and Aug 26, 2016, 24 patients were enrolled and received trastuzumab deruxtecan (n=3 for each of 0·8, 1·6, 3·2, and 8·0 mg/kg doses; n=6 for each of 5·4 and 6·4 mg/kg). Up to the study cutoff date of Feb 1, 2017, no dose-limiting toxic effects, substantial cardiovascular toxic effects, or deaths occurred. One patient was removed from the activity analysis because they had insufficient target lesions for analysis. The most common grade 3 adverse events were decreased lymphocyte (n=3) and decreased neutrophil count (n=2); and grade 4 anaemia was reported by one patient. Three serious adverse events-febrile neutropenia, intestinal perforation, and cholangitis-were reported by one patient each. Overall, in 23 evaluable patients, including six patients with low HER2-expressing tumours, ten patients achieved an objective response (43%, 95% CI 23·2-65·5). Disease control was achieved in 21 (91%; 95% CI 72·0-98·9) of 23 patients. Median follow-up time was 6·7 months (IQR 4·4-10·2), with nine (90%) of ten responses seen at doses of 5·4 mg/kg or greater. The maximum tolerated dose of trastuzumab deruxtecan was not reached. In this small, heavily pretreated study population, trastuzumab deruxtecan showed antitumour activity, even in low HER2-expressing tumours. Based on safety and activity, the most likely recommended phase 2 dosing is 5·4 or 6·4 mg/kg. Daiichi Sankyo Co, Ltd. Copyright © 2017 Elsevier Ltd. All rights reserved.

"Trapping" of the Radiation of an Excited Particle by Its Stark Interaction with the Nonresonant Levels of Surrounding Particles

NASA Astrophysics Data System (ADS)

Basharov, A. M.

2018-04-01

It has been shown analytically that an excited particle surrounded by immobile unlike atoms does not emit at a certain number of surrounding atoms. The necessary condition is the smallness of the region occupied by the particle and its environment compared to the wavelength of a photon emitted by an isolated particle in electromagnetic vacuum.

Enhanced homologous recombination is induced by alpha-particle radiation in somatic cells of Arabidopsis thaliana

NASA Astrophysics Data System (ADS)

Bian, Po; Liu, Ping; Wu, Yuejin

Almost 9 percent of cosmic rays which strike the earth's atmosphere are alpha particles. As one of the ionizing radiations (IR), its biological effects have been widely studied. However, the plant genomic instability induced by alpha-particle radiation was not largely known. In this research, the Arabidopsis thaliana transgenic for GUS recombination substrate was used to evaluate the genomic instability induced by alpha-particle radiation (3.3MeV). The pronounced effects of systemic exposure to alpha-particle radiation on the somatic homologous recombination frequency (HRF) were found at different doses. The 10Gy dose of radiation induced the maximal HRF which was 1.9-fold higher than the control. The local radiation of alpha-particle (10Gy) on root also resulted in a 2.5-fold increase of somatic HRF in non-radiated aerial plant, indicating that the signal(s) of genomic instability was transferred to non-radiated parts and initiated their genomic instability. Concurrent treatment of seedlings of Arabidopsis thaliana with alpha-particle and DMSO(ROS scavenger) both in systemic and local radiation signifi- cantly suppressed the somatic HR, indicating that the free radicals produced by alpha-particle radiation took part in the production of signal of genomic instability rather than the signal transfer. Key words: alpha-particle radiation, somatic homologous recombination, genomic instability

Seven-Year Follow-Up Assessment of Cardiac Function in NSABP B-31, a Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Paclitaxel (ACP) With ACP Plus Trastuzumab As Adjuvant Therapy for Patients With Node-Positive, Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

PubMed Central

Romond, Edward H.; Jeong, Jong-Hyeon; Rastogi, Priya; Swain, Sandra M.; Geyer, Charles E.; Ewer, Michael S.; Rathi, Vikas; Fehrenbacher, Louis; Brufsky, Adam; Azar, Catherine A.; Flynn, Patrick J.; Zapas, John L.; Polikoff, Jonathan; Gross, Howard M.; Biggs, David D.; Atkins, James N.; Tan-Chiu, Elizabeth; Zheng, Ping; Yothers, Greg; Mamounas, Eleftherios P.; Wolmark, Norman

2012-01-01

Purpose Cardiac dysfunction (CD) is a recognized risk associated with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2–positive breast cancer, especially when the treatment regimen includes anthracyclines. Given the demonstrated efficacy of trastuzumab, ongoing assessment of cardiac safety and identification of risk factors for CD are important for optimal patient care. Patients and Methods In National Surgical Adjuvant Breast and Bowel Project B-31, a phase III adjuvant trial, 1,830 patients who met eligibility criteria for initiation of trastuzumab were evaluated for CD. Recovery from CD was also assessed. A statistical model was developed to estimate the risk of severe congestive heart failure (CHF). Baseline patient characteristics associated with anthracycline-related decline in cardiac function were also identified. Results At 7-year follow-up, 37 (4.0%) of 944 patients who received trastuzumab experienced a cardiac event (CE) versus 10 (1.3%) of 743 patients in the control arm. One cardiac-related death has occurred in each arm of the protocol. A Cardiac Risk Score, calculated using patient age and baseline left ventricular ejection fraction (LVEF) by multiple-gated acquisition scan, statistically correlates with the risk of a CE. After stopping trastuzumab, the majority of patients who experienced CD recovered LVEF in the normal range, although some decline from baseline often persists. Only two CEs occurred more than 2 years after initiation of trastuzumab. Conclusion The late development of CHF after the addition of trastuzumab to paclitaxel after doxorubicin/ cyclophosphamide chemotherapy is uncommon. The risk versus benefit of trastuzumab as given in this regimen remains strongly in favor of trastuzumab. PMID:22987084

Density-induced suppression of the {alpha}-particle condensate in nuclear matter and the structure of {alpha}-cluster states in nuclei

DOE Office of Scientific and Technical Information (OSTI.GOV)

Funaki, Y.; Horiuchi, H.; International Institute for Advanced Studies, Kizugawa 619-0225

2008-06-15

At low densities, with decreasing temperatures, in symmetric nuclear matter {alpha} particles are formed, which eventually give raise to a quantum condensate with four-nucleon {alpha}-like correlations (quartetting). Starting with a model of {alpha} matter, where undistorted {alpha} particles interact via an effective interaction such as the Ali-Bodmer potential, the suppression of the condensate fraction at zero temperature with increasing density is considered. Using a Jastrow-Feenberg approach, it is found that the condensate fraction vanishes near saturation density. Additionally, the modification of the internal state of the {alpha} particle due to medium effects will further reduce the condensate. In finite systems,more » an enhancement of the S-state wave function of the center-of-mass orbital of {alpha}-particle motion is considered as the correspondence to the condensate. Wave functions have been constructed for self-conjugate 4n nuclei that describe the condensate state but are fully antisymmetrized on the nucleonic level. These condensate-like cluster wave functions have been successfully applied to describe properties of low-density states near the n{alpha} threshold. Comparison with orthogonality condition model calculations in {sup 12}C and {sup 16}O shows strong enhancement of the occupation of the S-state center-of-mass orbital of the {alpha} particles. This enhancement is decreasing if the baryon density increases, similar to the density-induced suppression of the condensate fraction in {alpha} matter. The ground states of {sup 12}C and {sup 16}O show no enhancement at all, thus a quartetting condensate cannot be formed at saturation densities.« less

INSTABILITIES DRIVEN BY THE DRIFT AND TEMPERATURE ANISOTROPY OF ALPHA PARTICLES IN THE SOLAR WIND

DOE Office of Scientific and Technical Information (OSTI.GOV)

Verscharen, Daniel; Bourouaine, Sofiane; Chandran, Benjamin D. G., E-mail: daniel.verscharen@unh.edu, E-mail: s.bourouaine@unh.edu, E-mail: benjamin.chandran@unh.edu

2013-08-20

We investigate the conditions under which parallel-propagating Alfven/ion-cyclotron (A/IC) waves and fast-magnetosonic/whistler (FM/W) waves are driven unstable by the differential flow and temperature anisotropy of alpha particles in the solar wind. We focus on the limit in which w{sub Parallel-To {alpha}} {approx}> 0.25v{sub A}, where w{sub Parallel-To {alpha}} is the parallel alpha-particle thermal speed and v{sub A} is the Alfven speed. We derive analytic expressions for the instability thresholds of these waves, which show, e.g., how the minimum unstable alpha-particle beam speed depends upon w{sub Parallel-To {alpha}}/v{sub A}, the degree of alpha-particle temperature anisotropy, and the alpha-to-proton temperature ratio. Wemore » validate our analytical results using numerical solutions to the full hot-plasma dispersion relation. Consistent with previous work, we find that temperature anisotropy allows A/IC waves and FM/W waves to become unstable at significantly lower values of the alpha-particle beam speed U{sub {alpha}} than in the isotropic-temperature case. Likewise, differential flow lowers the minimum temperature anisotropy needed to excite A/IC or FM/W waves relative to the case in which U{sub {alpha}} = 0. We discuss the relevance of our results to alpha particles in the solar wind near 1 AU.« less

The absorption of vitamin E is influenced by the amount of fat in a meal and the food matrix.

PubMed

Jeanes, Yvonne M; Hall, Wendy L; Ellard, Susan; Lee, Elizabeth; Lodge, John K

2004-10-01

Vitamin E absorption requires the presence of fat; however, limited information exists on the influence of fat quantity on optimal absorption. In the present study we compared the absorption of stable-isotope-labelled vitamin E following meals of varying fat content and source. In a randomised four-way cross-over study, eight healthy individuals consumed a capsule containing 150 mg (2)H-labelled RRR-alpha-tocopheryl acetate with a test meal of toast with butter (17.5 g fat), cereal with full-fat milk (17.5 g fat), cereal with semi-skimmed milk (2.7 g fat) and water (0 g fat). Blood was taken at 0, 0.5, 1, 1.5, 2, 3, 6 and 9 h following ingestion, chylomicrons were isolated, and (2)H-labelled alpha-tocopherol was analysed in the chylomicron and plasma samples. There was a significant time (P<0.001) and treatment effect (P<0.001) in (2)H-labelled alpha-tocopherol concentration in both chylomicrons and plasma between the test meals. (2)H-labelled alpha-tocopherol concentration was significantly greater with the higher-fat toast and butter meal compared with the low-fat cereal meal or water (P<0.001), and a trend towards greater concentration compared with the high-fat cereal meal (P=0.065). There was significantly greater (2)H-labelled alpha-tocopherol concentration with the high-fat cereal meal compared with the low-fat cereal meal (P<0.05). The (2)H-labelled alpha-tocopherol concentration following either the low-fat cereal meal or water was low. These results demonstrate that both the amount of fat and the food matrix influence vitamin E absorption. These factors should be considered by consumers and for future vitamin E intervention studies.

40 CFR 211.110-2 - National security exemptions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... ABATEMENT PROGRAMS PRODUCT NOISE LABELING General Provisions § 211.110-2 National security exemptions. (a) A new product which is produced to conform with specifications developed by national security agency... security exemption shall be void ab initio with respect to each new product, originally intended for a...

Guinea pig hepatocyte alpha 1A-adrenoceptors: characterization, signal transduction and regulation.

PubMed

García-Sáinz, J A; Romero-Avila, T; Olivares-Reyes, J A; Macías-Silva, M

1992-11-02

Activation of guinea pig hepatocyte alpha 1-adrenoceptors increases phosphatidylinositol (PI) labeling, [3H]inositol phosphate production and phosphorylase activity. These adrenergic actions were not altered by pretreatment with chlorethylclonidine but were blocked by 5-methyl urapidil and prazosin (the former being 3- to 10-fold more potent than the latter), indicating that alpha 1A-adrenoceptors were involved. When the cells were incubated in buffer without calcium and containing EGTA, the alpha 1A-adrenergic stimulation of PI labeling was diminished but not abolished and that of phosphorylase was not affected. The alpha 1A-adrenergic effects were insensitive to pertussis toxin treatment. Phorbol myristate acetate inhibited the alpha 1A-adrenergic actions, although at relatively large concentrations, and also those of other agents such as angiotensin II and NaF. Our data clearly indicate that guinea pig hepatocytes express alpha 1A-adrenoceptors whose activation stimulates phosphoinositide turnover, via a pertussis toxin-insensitive process; the alpha 1A-adrenergic effects were at least partially independent of extracellular calcium.

Augmenting Trastuzumab Therapy against Breast Cancer through Selective Activation of NK Cells

DTIC Science & Technology

2014-12-01

purity as defined by CD3-CD56+ flow cytometry ) and activation (>50% expression of CD137). Breast cancer cell lines including MCF7 (A and E...purity as defined by CD3-CD56+ flow cytometry ) and activation (>50% expression of CD137). Chromium-labeled breast cancer cell lines including MCF7 (A...and Whiteside, T.L. 2007. A novel multiparametric flow cytometry -based cytotoxicity assay simultaneously immunophenotypes effector cells: comparisons

Mapping of the acetylcholine binding site of the nicotinic acetylcholine receptor: ( sup 3 H)nicotine as an agonist photoaffinity label

DOE Office of Scientific and Technical Information (OSTI.GOV)

Middleton, R.E.; Cohen, J.B.

1991-07-16

The agonist ({sup 3}H)nicotine was used as a photoaffinity label for the acetylcholine binding sties on the Torpedo nicotinic acetylcholine receptor (AChR). ({sup 3}H)Nicotine binds at equilibrium with K{sub eq} = 0.6 {mu}M to the agonist binding sites. Irradiation with 254-nm light of AChR-rich membranes equilibrated with ({sup 3}H)nicotine resulted in covalent incorporation into the {alpha}- and {gamma}-subunits, which was inhibited by agonists and competitive antagonists but not by noncompetitive antagonists. Inhibition of labeling by d-tubocurarine demonstrated that the {alpha}-subunit was labeled via both agonist sites but the {gamma}-subunit was labeled only via the site that binds d-tubocurarine with highmore » affinity. Chymotryptic digestion of the {alpha}-subunit confirmed that Try-198 was the principal amino acid labeled by ({sup 3}H)nicotine. This confirmation required a novel radiosequencing strategy employing o-phthalaldehyde ({sup 3}H)Nicotine, which is the first photoaffinity agonist used, labels primarily Tyr-198 in contrast to competitive antagonist affinity labels, which label primarily Tyr-190 and Cys-192/Cys-193.« less

Therapeutic effects of autologous lymphocytes activated with trastuzumab for xenograft mouse models of human breast cancer.

PubMed

Nakagawa, Shinichiro; Matsuoka, Yusuke; Ichihara, Hideaki; Yoshida, Hitoji; Yoshida, Kenshi; Ueoka, Ryuichi

2013-01-01

Trastuzumab (TTZ) is molecular targeted drug used for metastatic breast cancer patients overexpressing human epidermal growth factor receptor 2 (HER2). Therapeutic effects of lymphocytes activated with TTZ (TTZ-LAK) using xenograft mouse models of human breast cancer (MDA-MB-453) cells were examined in vivo. Remarkable reduction of tumor volume in a xenograft mouse models intravenously treated with TTZ-LAK cells after the subcutaneously inoculated of MDA-MB-453 cells was verified in vivo. The migration of TTZ-LAK cells in tumor of mouse models subcutaneously inoculated MDA-MB-453 cells was observed on the basis of histological analysis using immunostaining with CD-3. Induction of apoptosis in tumor of xenograft mice treated with TTZ-LAK cells was observed in micrographs using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) method. It was noteworthy that the therapeutic effects of TTZ-LAK cells along with apoptosis were obtained for xenograft mouse models of human breast tumor in vivo.

Alpha particle spectrometry using superconducting microcalorimeters

NASA Astrophysics Data System (ADS)

Horansky, Robert; Ullom, Joel; Beall, James; Hilton, Gene; Stiehl, Gregory; Irwin, Kent; Plionis, Alexander; Lamont, Stephen; Rudy, Clifford; Rabin, Michael

2009-03-01

Alpha spectrometry is the preferred technique for analyzing trace samples of radioactive material because the alpha particle flux can be significantly higher than the gamma-ray flux from nuclear materials of interest. Traditionally, alpha spectrometry is performed with Si detectors whose resolution is at best 8 keV FWHM. Here, we describe the design and operation of a microcalorimeter alpha detector with an energy resolution of 1.06 keV FWHM at 5 MeV. We demonstrate the ability of the microcalorimeter to clearly resolve the alpha particles from Pu-239 and Pu-240, whose ratio differentiates reactor-grade Pu from weapons-grade. We also show the first direct observation of the decay of Po-209 to the ground state of Pb-205 which has traditionally been obscured by a much stronger alpha line 2 keV away. Finally, the 1.06 keV resolution observed for alpha particles is far worse than the 0.12 keV resolution predicted from thermal fluctuations and measurement of gamma-rays. The cause of the resolution degradation may be ion damage in the tin. Hence, alpha particle microcalorimeters may provide a novel tool for studying ion damage and lattice displacement energies in bulk materials.

Method for the preparation of radon-211

DOEpatents

Meyer, Geerd-J.; Lambrecht, Richard M.

1982-01-01

A method for the production of .sup.211 Rn comprising bombarding .sup.209 Bi with .sup.7 Li particles utilizing the nuclear reaction .sup.209 Bi(.sup.7 Li,5n).sup.211 Rn. The method provides a simple spectrum from which .sup.211 Rn can be easily isolated in a highly pure condition.

Morphologies and elemental compositions of local biomass burning particles at urban and glacier sites in southeastern Tibetan Plateau: Results from an expedition in 2010.

PubMed

Hu, Tafeng; Cao, Junji; Zhu, Chongshu; Zhao, Zhuzi; Liu, Suixin; Zhang, Daizhou

2018-07-01

Many studies indicate that the atmospheric environment over the southern part of the Tibetan Plateau is influenced by aged biomass burning particles that are transported over long distances from South Asia. However, our knowledge of the particles emitted locally (within the plateau region) is poor. We collected aerosol particles at four urban sites and one remote glacier site during a scientific expedition to the southeastern Tibetan Plateau in spring 2010. Weather and backward trajectory analyses indicated that the particles we collected were more likely dominated by particles emitted within the plateau. The particles were examined using an electron microscope and identified according to their sizes, shapes and elemental compositions. At three urban sites where the anthropogenic particles were produced mainly by the burning of firewood, soot aggregates were in the majority and made up >40% of the particles by number. At Lhasa, the largest city on the Tibetan Plateau, tar balls and mineral particles were also frequently observed because of the use of coal and natural gas, in addition to biofuel. In contrast, at the glacier site, large numbers of chain-like soot aggregates (~25% by number) were noted. The morphologies of these aggregates were similar to those of freshly emitted ones at the urban sites; moreover, physically or chemically processed ageing was rarely confirmed. These limited observations suggest that the biomass burning particles age slowly in the cold, dry plateau air. Anthropogenic particles emitted locally within the elevated plateau region may thus affect the environment within glaciated areas in Tibet differently than anthropogenic particles transported from South Asia. Copyright © 2018 Elsevier B.V. All rights reserved.

Identification of the protein responsible for pyruvate transport into rat liver and heart mitochondria by specific labelling with [3H]N-phenylmaleimide.

PubMed

Thomas, A P; Halestrap, A P

1981-05-15

1. N-Phenylmaleimide irreversibly inhibits pyruvate transport into rat heart and liver mitochondria to a much greater extent than does N-ethylmaleimide, iodoacetate or bromopyruvate. alpha-Cyanocinnamate protects the pyruvate transporter from attack by this thiol-blocking reagent. 2. In both heart and liver mitochondria alpha-cyanocinnamate diminishes labelling by [3H]N-phenylmaleimide of a membrane protein of subunit mol.wt. 15000 on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. 3. Exposure of mitochondrial to unlabelled N-phenylmaleimide in the presence of alpha-cyanocinnamate, followed by removal of alpha-cyanocinnamate and exposure to [3H]N-phenylmaleimide, produced specific labelling of the same protein. 4. Both labelling and kinetic experiments with inhibitors gave values for the approximate amount of carrier present in liver and heart mitochondria of 100 and 450 pmol/mg of mitochondrial protein respectively. 5. The turnover numbers for net pyruvate transport and pyruvate exchange at 0 degrees C were 6 and 200 min-1 respectively.

Tyrosine kinase inhibitors as modulators of trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity in breast cancer cell lines.

PubMed

Collins, Denis M; Gately, Kathy; Hughes, Clare; Edwards, Connla; Davies, Anthony; Madden, Stephen F; O'Byrne, Kenneth J; O'Donovan, Norma; Crown, John

2017-09-01

Trastuzumab is an anti-HER2 monoclonal antibody (mAb) therapy capable of antibody-dependent cell-mediated cytotoxicity (ADCC) and used in the treatment of HER2+ breast cancer. Through interactions with FcƴR+ immune cell subsets, trastuzumab functions as a passive immunotherapy. The EGFR/HER2-targeting tyrosine kinase inhibitor (TKI) lapatinib and the next generation TKIs afatinib and neratinib, can alter HER2 levels, potentially modulating the ADCC response to trastuzumab. Using LDH-release assays, we investigated the impact of antigen modulation, assay duration and peripheral blood mononuclear cell (PBMC) activity on trastuzumab-mediated ADCC in breast cancer models of maximal (SKBR3) and minimal (MCF-7) target antigen expression to determine if modulating the ADCC response to trastuzumab using TKIs may be a viable approach for enhancing tumor immune reactivity. HER2 levels were determined in lapatinib, afatinib and neratinib-treated SKBR3 and MCF-7 using high content analysis (HCA). Trastuzumab-mediated ADCC was assessed following treatment with TKIs utilising a colorimetric LDH release-based protocol at 4 and 12h timepoints. PBMC activity was assessed against non-MHC-restricted K562 cells. A flow cytometry-based method (CFSE/7-AAD) was also used to measure trastuzumab-mediated ADCC in medium-treated SKBR3 and MCF-7. HER2 antigen levels were significantly altered by the three TKIs in both cell line models. The TKIs significantly reduced LDH levels directly in SKBR3 cells but not MCF-7. Lapatinib and neratinib augment trastuzumab-related ADCC in SKBR3 but the effect was not consistent with antigen expression levels and was dependent on volunteer PBMC activity (vs. K562). A 12h assay timepoint produced more consistent results. Trastuzumab-mediated ADCC (PBMC:target cell ratio of 10:1) was measured at 7.6±4.7% (T12) by LDH assay and 19±3.2 % (T12) using the flow cytometry-based method in the antigen-low model MCF-7. In the presence of effector cells with high cytotoxic capacity, TKIs have the ability to augment the passive immunotherapeutic potential of trastuzumab in SKBR3, a model of HER2+ breast cancer. ADCC levels detected by LDH release assays are extremely low in MCF-7; the flow cytometry-based CFSE/7-AAD method is more sensitive and consistent for the determination of ADCC in HER2-low models. Copyright © 2017 Elsevier Inc. All rights reserved.

21 CFR 211.122 - Materials examination and usage criteria.

Code of Federal Regulations, 2010 CFR

2010-04-01

..., or associated with, manufacturing lines used to imprint labeling upon the drug product unit label or case shall be monitored to assure that all imprinting conforms to the print specified in the batch...

Comparison of the octadentate bifunctional chelator DFO*-pPhe-NCS and the clinically used hexadentate bifunctional chelator DFO-pPhe-NCS for 89Zr-immuno-PET.

PubMed

Vugts, Danielle J; Klaver, Chris; Sewing, Claudia; Poot, Alex J; Adamzek, Kevin; Huegli, Seraina; Mari, Cristina; Visser, Gerard W M; Valverde, Ibai E; Gasser, Gilles; Mindt, Thomas L; van Dongen, Guus A M S

2017-02-01

All clinical 89 Zr-immuno-PET studies are currently performed with the chelator desferrioxamine (DFO). This chelator provides hexadentate coordination to zirconium, leaving two coordination sites available for coordination with, e.g., water molecules, which are relatively labile ligands. The unsaturated coordination of DFO to zirconium has been suggested to result in impaired stability of the complex in vivo and consequently in unwanted bone uptake of 89 Zr. Aiming at clinical improvements, we report here on a bifunctional isothiocyanate variant of the octadentate chelator DFO* and the in vitro and in vivo comparison of its 89 Zr-DFO*-mAb complex with 89 Zr-DFO-mAb. The bifunctional chelator DFO*-pPhe-NCS was prepared from previously reported DFO* and p-phenylenediisothiocyanate. Subsequently, trastuzumab was conjugated with either DFO*-pPhe-NCS or commercial DFO-pPhe-NCS and radiolabeled with Zr-89 according to published procedures. In vitro stability experiments were carried out in saline, a histidine/sucrose buffer, and blood serum. The in vivo performance of the chelators was compared in N87 tumor-bearing mice by biodistribution studies and PET imaging. In 0.9 % NaCl 89 Zr-DFO*-trastuzumab was more stable than 89 Zr-DFO-trastuzumab; after 72 h incubation at 2-8 °C 95 % and 58 % intact tracer were left, respectively, while in a histidine-sucrose buffer no difference was observed, both products were ≥ 92 % intact. In vivo uptake at 144 h post injection (p.i.) in tumors, blood, and most normal organs was similar for both conjugates, except for skin, liver, spleen, ileum, and bone. Tumor uptake was 32.59 ± 11.95 and 29.06 ± 8.66 % ID/g for 89 Zr-DFO*-trastuzumab and 89 Zr-DFO-trastuzumab, respectively. The bone uptake was significantly lower for 89 Zr-DFO*-trastuzumab compared to 89 Zr-DFO-trastuzumab. At 144 h p.i. for 89 Zr-DFO*-trastuzumab and 89 Zr-DFO-trastuzumab, the uptake in sternum was 0.92 ± 0.16 and 3.33 ± 0.32 % ID/g, in femur 0.78 ± 0.11 and 3.85, ± 0.80 and in knee 1.38 ± 0.23 and 8.20 ± 2.94 % ID/g, respectively. The uptake in bone decreased from 24 h to 144 h p.i. about two fold for the DFO* conjugate, while it increased about two fold for the DFO conjugate. Zr-DFO*-trastuzumab showed superior in vitro stability and in vivo performance when compared to 89 Zr-DFO-trastuzumab. This makes the new octadentate DFO* chelator a candidate successor of DFO for future clinical 89 Zr-immuno-PET.

21 CFR 201.313 - Estradiol labeling.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Pharmacopeia under the designation “Alpha Estradiol.” The substance should no longer be referred to in drug labeling as “Alpha Estradiol.” The Food and Drug Administration would not object to label references to the... referred to the presence of “Estradiol (formerly known as Alpha Estradiol).” ...

21 CFR 201.313 - Estradiol labeling.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Pharmacopeia under the designation “Alpha Estradiol.” The substance should no longer be referred to in drug labeling as “Alpha Estradiol.” The Food and Drug Administration would not object to label references to the... referred to the presence of “Estradiol (formerly known as Alpha Estradiol).” ...

21 CFR 201.313 - Estradiol labeling.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Pharmacopeia under the designation “Alpha Estradiol.” The substance should no longer be referred to in drug labeling as “Alpha Estradiol.” The Food and Drug Administration would not object to label references to the... referred to the presence of “Estradiol (formerly known as Alpha Estradiol).” ...

21 CFR 201.313 - Estradiol labeling.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Pharmacopeia under the designation “Alpha Estradiol.” The substance should no longer be referred to in drug labeling as “Alpha Estradiol.” The Food and Drug Administration would not object to label references to the... referred to the presence of “Estradiol (formerly known as Alpha Estradiol).” ...

21 CFR 201.313 - Estradiol labeling.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Pharmacopeia under the designation “Alpha Estradiol.” The substance should no longer be referred to in drug labeling as “Alpha Estradiol.” The Food and Drug Administration would not object to label references to the... referred to the presence of “Estradiol (formerly known as Alpha Estradiol).” ...

Comparative analysis of 11 different radioisotopes for palliative treatment of bone metastases by computational methods

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guerra Liberal, Francisco D. C., E-mail: meb12020@fe.up.pt, E-mail: adriana-tavares@msn.com; Tavares, Adriana Alexandre S., E-mail: meb12020@fe.up.pt, E-mail: adriana-tavares@msn.com; Tavares, João Manuel R. S., E-mail: tavares@fe.up.pt

Purpose: Throughout the years, the palliative treatment of bone metastases using bone seeking radiotracers has been part of the therapeutic resources used in oncology, but the choice of which bone seeking agent to use is not consensual across sites and limited data are available comparing the characteristics of each radioisotope. Computational simulation is a simple and practical method to study and to compare a variety of radioisotopes for different medical applications, including the palliative treatment of bone metastases. This study aims to evaluate and compare 11 different radioisotopes currently in use or under research for the palliative treatment of bonemore » metastases using computational methods. Methods: Computational models were used to estimate the percentage of deoxyribonucleic acid (DNA) damage (fast Monte Carlo damage algorithm), the probability of correct DNA repair (Monte Carlo excision repair algorithm), and the radiation-induced cellular effects (virtual cell radiobiology algorithm) post-irradiation with selected particles emitted by phosphorus-32 ({sup 32}P), strontium-89 ({sup 89}Sr), yttrium-90 ({sup 90}Y ), tin-117 ({sup 117m}Sn), samarium-153 ({sup 153}Sm), holmium-166 ({sup 166}Ho), thulium-170 ({sup 170}Tm), lutetium-177 ({sup 177}Lu), rhenium-186 ({sup 186}Re), rhenium-188 ({sup 188}Re), and radium-223 ({sup 223}Ra). Results: {sup 223}Ra alpha particles, {sup 177}Lu beta minus particles, and {sup 170}Tm beta minus particles induced the highest cell death of all investigated particles and radioisotopes. The cell survival fraction measured post-irradiation with beta minus particles emitted by {sup 89}Sr and {sup 153}Sm, two of the most frequently used radionuclides in the palliative treatment of bone metastases in clinical routine practice, was higher than {sup 177}Lu beta minus particles and {sup 223}Ra alpha particles. Conclusions: {sup 223}Ra and {sup 177}Lu hold the highest potential for palliative treatment of bone metastases of all radioisotopes compared in this study. Data reported here may prompt future in vitro and in vivo experiments comparing different radionuclides for palliative treatment of bone metastases, raise the need for the careful rethinking of the current widespread clinical use of {sup 89}Sr and {sup 153}Sm, and perhaps strengthen the use of {sup 223}Ra and {sup 177}Lu in the palliative treatment of bone metastases.« less

The origins of cosmic rays and quantum effects on gravity

NASA Technical Reports Server (NTRS)

Tomozawa, Y.

1985-01-01

The energy spectrum of primary cosmic rays is explained by particles emitted during a thermal expansion of explosive objects inside and near the galaxy, remnants of which may be supernova and/or active talaxies, or even stars or galaxies that disappeared from our sight after the explosion. A power law energy spectrum for cosmic rays, E to the (-alpha -1, is obtained from an expansion rate T is proportional to R to the alpha. Using the solution of the Einstein equation, we obtain a spectrum which agrees very well with experimental data. The implication of an inflationary early universe on the cosmic ray spectrum is also discussed. It is also suggested that the conflict between this model and the singularity theorem in classical general relativity may be eliminated by quantum effects.

40 CFR 211.207 - Computation of the noise -reduction rating (NRR).

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 25 2011-07-01 2011-07-01 false Computation of the noise -reduction... (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING Hearing Protective Devices § 211.207 Computation of the noise -reduction rating (NRR). Calculate the NRR for hearing protective devices by...

Ferrocenemonocarboxylic-HRP@Pt nanoparticles labeled RCA for multiple amplification of electro-immunosensing.

PubMed

Su, Huilan; Yuan, Ruo; Chai, Yaqin; Mao, Li; Zhuo, Ying

2011-07-15

A multiple amplification immunoassay was proposed to detect alpha-fetoprotein (AFP), which was based on ferrocenemonocarboxylic-HRP conjugated on Pt nanoparticles as labels for rolling circle amplification (RCA). Firstly, the capture antibody (anti-AFP) was immobilized on glass carbon electrode (GCE) deposited nano-sized gold particles. After a typical immuno-sandwich protocol, primary DNA was immobilized by labeling secondary antibody, which acted as a precursor to initiate RCA. The products of RCA provide large amount of sites to link detection DNAs, which were labeled by signal probes (ferrocenemonocarboxylic) and horseradish peroxidase (HRP). Moreover, the enzymatic amplification signals could be produced by the catalysis of HRP and Pt nanoparticles with the addition of H₂O₂. These lead to multiple amplification signals monitoring by electrochemical instrument and further resulted in high sensitivity of the immunoassay with the detection limit of 1.7 pg/mL. Copyright © 2011 Elsevier B.V. All rights reserved.

Single particle mass spectral signatures from vehicle exhaust particles and the source apportionment of on-line PM2.5 by single particle aerosol mass spectrometry.

PubMed

Yang, Jian; Ma, Shexia; Gao, Bo; Li, Xiaoying; Zhang, Yanjun; Cai, Jing; Li, Mei; Yao, Ling'ai; Huang, Bo; Zheng, Mei

2017-09-01

In order to accurately apportion the many distinct types of individual particles observed, it is necessary to characterize fingerprints of individual particles emitted directly from known sources. In this study, single particle mass spectral signatures from vehicle exhaust particles in a tunnel were performed. These data were used to evaluate particle signatures in a real-world PM 2.5 apportionment study. The dominant chemical type originating from average positive and negative mass spectra for vehicle exhaust particles are EC species. Four distinct particle types describe the majority of particles emitted by vehicle exhaust particles in this tunnel. Each particle class is labeled according to the most significant chemical features in both average positive and negative mass spectral signatures, including ECOC, NaK, Metal and PAHs species. A single particle aerosol mass spectrometry (SPAMS) was also employed during the winter of 2013 in Guangzhou to determine both the size and chemical composition of individual atmospheric particles, with vacuum aerodynamic diameter (d va ) in the size range of 0.2-2μm. A total of 487,570 particles were chemically analyzed with positive and negative ion mass spectra and a large set of single particle mass spectra was collected and analyzed in order to identify the speciation. According to the typical tracer ions from different source types and classification by the ART-2a algorithm which uses source fingerprints for apportioning ambient particles, the major sources of single particles were simulated. Coal combustion, vehicle exhaust, and secondary ion were the most abundant particle sources, contributing 28.5%, 17.8%, and 18.2%, respectively. The fraction with vehicle exhaust species particles decreased slightly with particle size in the condensation mode particles. Copyright © 2017 Elsevier B.V. All rights reserved.

Adjuvant trastuzumab with chemotherapy is effective in women with small, node-negative, HER2-positive breast cancer.

PubMed

McArthur, Heather L; Mahoney, Kathleen M; Morris, Patrick G; Patil, Sujata; Jacks, Lindsay M; Howard, Jane; Norton, Larry; Hudis, Clifford A

2011-12-15

Several large, randomized trials established the benefits of adjuvant trastuzumab with chemotherapy. However, the benefit for women with small, node-negative HER2-positive (HER2+) disease is unknown, as these patients were largely excluded from these trials. Therefore, a retrospective, single-institution, sequential cohort study of women with small, node-negative, HER2+ breast cancer who did or did not receive adjuvant trastuzumab was conducted. Women with ≤ 2 cm, node-negative, HER2+ (immunohistochemistry 3+ or fluorescence in situ hybridization ≥ 2) breast cancer were identified through an institutional database. A "no-trastuzumab" cohort of 106 trastuzumab-untreated women diagnosed between January 1, 2002 and May 14, 2004 and a "trastuzumab" cohort of 155 trastuzumab-treated women diagnosed between May 16, 2005 and December 31, 2008 were described. Survival and recurrence outcomes were estimated by Kaplan-Meier methods. The cohorts were similar in age, median tumor size, histology, hormone receptor status, hormone therapy, and locoregional therapy. Chemotherapy was administered in 66% and 100% of the "no trastuzumab" and "trastuzumab" cohorts, respectively. The median recurrence-free and survival follow-up was: 6.5 years (0.7-8.5) and 6.8 years (0.7-8.5), respectively, for the "no trastuzumab" cohort and 3.0 years (0.5-5.2) and 3.0 years (0.6-5.2), respectively, for the "trastuzumab" cohort. The 3-year locoregional invasive recurrence-free, distant recurrence-free, invasive disease-free, and overall survival were 92% versus 98% (P = .0137), 95% versus 100% (P = .0072), 82% versus 97% (P < .0001), and 97% versus 99% (P = .18) for the "no trastuzumab" and "trastuzumab" cohorts, respectively. Women with small, node-negative, HER2+ primary breast cancers likely derive significant benefit from adjuvant trastuzumab with chemotherapy. Copyright © 2011 American Cancer Society.

Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer

PubMed Central

Nafi, Siti Norasikin Mohd; Generali, Daniele; Kramer-Marek, Gabriela; Gijsen, Merel; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele; Haider, Syed; Li, Ji-Liang; Bridges, Esther; Capala, Jacek; Ioannis, Roxanis; Harris, Adrian L; Kong, Anthony

2014-01-01

The role of HER4 in breast cancer is controversial and its role in relation to trastuzumab resistance remains unclear. We showed that trastuzumab treatment and its acquired resistance induced HER4 upregulation, cleavage and nuclear translocation. However, knockdown of HER4 by specific siRNAs increased trastuzumab sensitivity and reversed its resistance in HER2 positive breast cancer cells. Preventing HER4 cleavage by a γ-secretase inhibitor and inhibiting HER4 tyrosine kinase activity by neratinib decreased trastuzumab-induced HER4 nuclear translocation and enhanced trastuzumab response. There was also increased nuclear HER4 staining in the tumours from BT474 xenograft mice and human patients treated with trastuzumab. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was shown to be an independent poor prognostic factor in HER2 positive breast cancer. Our data suggest that HER4 plays a key role in relation to trastuzumab resistance in HER2 positive breast cancer. Therefore, our study provides novel findings that HER4 activation, cleavage and nuclear translocation influence trastuzumab sensitivity and resistance in HER2 positive breast cancer. Nuclear HER4 could be a potential prognostic and predictive biomarker and understanding the role of HER4 may provide strategies to overcome trastuzumab resistance in HER2 positive breast cancer. PMID:25153719

Correlation between positron emission tomography and Cerenkov luminescence imaging in vivo and ex vivo using 64Cu-labeled antibodies in a neuroblastoma mouse model.

PubMed

Maier, Florian C; Schmitt, Julia; Maurer, Andreas; Ehrlichmann, Walter; Reischl, Gerald; Nikolaou, Konstantin; Handgretinger, Rupert; Pichler, Bernd J; Thaiss, Wolfgang M

2016-10-11

Antibody-based therapies gain momentum in clinical therapy, thus the need for accurate imaging modalities with respect to target identification and therapy monitoring are of increasing relevance. Cerenkov luminescence imaging (CLI) are a novel method detecting charged particles emitted during radioactive decay with optical imaging. Here, we compare Position Emission Tomography (PET) with CLI in a multimodal imaging study aiming at the fast and efficient screening of monoclonal antibodies (mAb) designated for targeting of the neuroblastoma-characteristic epitope disialoganglioside GD2. Neuroblastoma-bearing SHO mice were injected with a 64Cu-labeled GD2-specific mAb. The tumor uptake was imaged 3 h, 24 h and 48 h after tracer injection with both, PET and CLI, and was compared to the accumulation in GD2-negative control tumors (human embryonic kidney, HEK-293). In addition to an in vivo PET/CLI-correlation over time, we also demonstrate linear correlations of CLI- and γ-counter-based biodistribution analysis. CLI with its comparably short acquisition time can thus be used as an attractive one-stop-shop modality for the longitudinal monitoring of antibody-based tumor targeting and ex vivo biodistribution.These findings suggest CLI as a reliable alternative for PET and biodistribution studies with respect to fast and high-throughput screenings in subcutaneous tumors traced with radiolabeled antibodies. However, in contrast to PET, CLI is not limited to positron-emitting isotopes and can therefore also be used for the visualization of mAb labeled with therapeutic isotopes like electron emitters.

Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial.

PubMed

von Minckwitz, Gunter; Colleoni, Marco; Kolberg, Hans-Christian; Morales, Serafin; Santi, Patricia; Tomasevic, Zorica; Zhang, Nan; Hanes, Vladimir

2018-06-04

ABP 980 (Amgen Inc, Thousand Oaks, CA, USA) is a biosimilar of trastuzumab, with analytical, functional, and pharmacokinetic similarities. We compared the clinical safety and efficacy of ABP 980 with that of trastuzumab in women with HER2-positive early breast cancer. We did a randomised, multicentre, double-blind, active-controlled equivalence trial at 97 study centres in 20 countries, mainly in Europe and South America. Eligible women were aged 18 years or older, had histologically confirmed HER2-positive invasive early breast cancer, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and were planning to have surgical resection of the breast tumour with sentinel or axillary lymph node dissection and neoadjuvant chemotherapy. After four cycles of run-in anthracycline-based chemotherapy, patients were assigned 1:1 to receive ABP 980 or trastuzumab with a permuted block design (blocks of four) computer-generated randomisation schedule. Patients received neoadjuvant therapy with a loading dose (8 mg/kg) of ABP 980 or trastuzumab plus paclitaxel 175 mg/m 2 in a 90 min intravenous infusion, followed by three cycles of 6 mg/kg intravenous ABP 980 or trastuzumab plus paclitaxel 175 mg/m 2 every 3 weeks in 30 min intravenous infusions (or 80 mg/m 2 paclitaxel once per week for 12 cycles if that was the local standard of care). Randomisation was stratified by T stage, node status, hormone receptor status, planned paclitaxel dosing schedule, and geographical region. Surgery was completed 3-7 weeks after the last dose of neoadjuvant treatment, after which adjuvant treatment with ABP 980 or trastuzumab was given every 3 weeks for up to 1 year after the first dose in the study. Patients had been randomly assigned at baseline to continue APB 980, continue trastuzumab, or switch from trastuzumab to APB 980 as their adjuvant treatment. The co-primary efficacy endpoints were risk difference and risk ratio (RR) of pathological complete response in breast tissue and axillary lymph nodes assessed at a local laboratory in all patients who were randomly assigned and received any amount of neoadjuvant investigational product and underwent surgery. We assessed safety in all patients who were randomly assigned and received any amount of investigational product. This trial is registered with ClinicalTrials.gov, number NCT01901146 and Eudra, number CT 2012-004319-29. Of 827 patients enrolled, 725 were randomly assigned to receive ABP 980 (n=364) or trastuzumab (n=361). The primary endpoint was assessable in 696 patients (358 who received ABP 980 and 338 who received trastuzumab). Pathological complete response was recorded in 172 (48%, 95% CI 43-53) of 358 patients in the ABP 980 group and 137 (41%, 35-46) of 338 in the trastuzumab group (risk difference 7·3%, 90% CI 1·2-13·4; RR 1·188, 90% CI 1·033-1·366), with the upper bounds of the CIs exceeding the predefined equivalence margins of 13% and 1·318, respectively. Pathological complete response in the central laboratory assessment was seen in 162 (48%) of 339 patients assigned to ABP 980 at baseline and 138 (42%) of 330 assigned to trastuzumab at baseline (risk difference 5·8%, 90% CI -0·5 to 12·0, and RR 1·142, 90% CI 0·993 to 1·312). Grade 3 or worse adverse events during the neoadjuvant phase occurred in 54 (15%) of 364 patients in the ABP 980 group and 51 (14%) of 361 patients in the trastuzumab group, of which the most frequent grade 3 or worse event of interest was neutropenia, occurring in 21 (6%) patients in both groups. In the adjuvant phase, grade 3 or worse adverse events occurred in 30 (9%) of 349 patients continuing ABP 980, 11 (6%) of 171 continuing trastuzumab, and 13 (8%) of 171 who switched from trastuzumab to ABP 980, the most frequent grade 3 or worse events of interest were infections and infestations (four [1%], two [1%], and two [1%]), neutropenia (three [1%], two [1%], and one [1%]), and infusion reactions (two [1%], two [1%], and three [2%]). Two patients died from adverse events judged to be unrelated to the investigational products: one died from pneumonia while receiving neoadjuvant ABP 980 and one died from septic shock while receiving adjuvant ABP 980 after trastuzumab. Although the lower bounds of the 90% CIs for RR and risk difference showed non-inferiority, the upper bounds exceeded the predefined equivalence margins when based on local laboratory review of tumour samples, meaning that non-superiority was non-conclusive. In our sensitivity analyses based on central laboratory evaluation of tumour samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study. Amgen. Copyright © 2018 Elsevier Ltd. All rights reserved.

Tracking Antibody Distribution with Near-Infrared Fluorescent Dyes: Impact of Dye Structure and Degree of Labeling on Plasma Clearance.

PubMed

Cilliers, Cornelius; Nessler, Ian; Christodolu, Nikolas; Thurber, Greg M

2017-05-01

Monoclonal antibodies labeled with near-infrared (NIR) fluorophores have potential use in disease detection, intraoperative imaging, and pharmacokinetic characterization of therapeutic antibodies in both the preclinical and clinical setting. Recent work has shown conjugation of NIR fluorophores to antibodies can potentially alter antibody disposition at a sufficiently high degree of labeling (DoL); however, other reports show minimal impact after labeling with NIR fluorophores. In this work, we label two clinically approved antibodies, Herceptin (trastuzumab) and Avastin (bevacizumab), with NIR dyes IRDye 800CW (800CW) or Alexa Fluor 680 (AF680), at 1.2 and 0.3 dyes/antibody and examine the impact of fluorophore conjugation on antibody plasma clearance and tissue distribution. At 0.3 DoL, AF680 conjugates exhibited similar clearance to unlabeled antibody over 17 days while 800CW conjugates diverged after 4 days, suggesting AF680 is a more suitable choice for long-term pharmacokinetic studies. At the 1.2 DoL, 800CW conjugates cleared faster than unlabeled antibodies after several hours, in agreement with other published reports. The tissue biodistribution for bevacizumab-800CW and -AF680 conjugates agreed well with literature reported biodistributions using radiolabels. However, the greater tissue autofluorescence at 680 nm resulted in limited detection above background at low (∼2 mg/kg) doses and 0.3 DoL for AF680, indicating that 800CW is more appropriate for short-term biodistribution measurements and intraoperative imaging. Overall, our work shows a DoL of 0.3 or less for non-site-specifically labeled antibodies (with a Poisson distribution) is ideal for limiting the impact of NIR fluorophores on antibody pharmacokinetics.

Combined effects of alpha particles and depleted uranium on Zebrafish (Danio rerio) embryos

PubMed Central

Ng, Candy Y.P.; Pereira, Sandrine; Cheng, Shuk Han; Adam-Guillermin, Christelle; Garnier-Laplace, Jacqueline; Yu, Kwan Ngok

2016-01-01

The combined effects of low-dose or high-dose alpha particles and depleted uranium (DU) in Zebrafish (Danio rerio) embryos were studied. Three schemes were examined—(i) [ILUL]: 0.44 mGy alpha-particle dose + 10 µg/l DU exposure, (ii) [IHUH]: 4.4 mGy alpha-particle dose + 100 µg/l DU exposure and (iii) [IHUL]: 4.4 mGy alpha-particle dose + 10 µg/l DU exposure—in which Zebrafish embryos were irradiated with alpha particles at 5 h post fertilization (hpf) and/or exposed to uranium at 5–6 hpf. The results were also compared with our previous work, which studied the effects of [ILUH]: 0.44 mGy alpha-particle dose + 100 µg/l DU exposure. When the Zebrafish embryos developed to 24 hpf, the apoptotic signals in the entire embryos, used as the biological endpoint for this study, were quantified. Our results showed that [ILUL] and [IHUL] led to antagonistic effects, whereas [IHUH] led to an additive effect. The effect found for the previously studied case of [ILUH] was difficult to define because it was synergistic with reference to the 100 µg/l DU exposure, but it was antagonistic with reference to the 0.44 mGy alpha-particle dose. All the findings regarding the four different schemes showed that the combined effects critically depended on the dose response to each individual stressor. We also qualitatively explained these findings in terms of promotion of early death of cells predisposed to spontaneous transformation by alpha particles, interacting with the delay in cell death resulting from various concentrations of DU exposure. PMID:26937024

Trastuzumab Benefits Women with Locally Advanced or Inflammatory

Cancer.gov

Women treated with trastuzumab (Herceptin) and chemotherapy before surgery and trastuzumab again after surgery had a reduced risk of the disease recurring or progressing compared with women who received pre-surgical chemotherapy but no trastuzumab, accord

Tunicamycin enhances the antitumor activity of trastuzumab on breast cancer in vitro and in vivo

PubMed Central

Huang, Shengshi; Zhang, Shu; Wang, Fengshan; Shi, Yikang

2015-01-01

Trastuzumab, a humanized monoclonal antibody targeting HER2, has demonstrated clinical benefits for women with HER2-positive breast cancer; however, trastuzumab resistance remains the biggest clinical challenge. In this study, results showed that tunicamycin, an inhibitor of N-glycosylation, synergistically enhanced the antitumor activity of trastuzumab against HER2-overexpressing breast cancer cells through induction of cell cycle arrest and apoptosis. Combined treatment of tunicamycin with trastuzumab dramatically decreased the expression of EGFR family and its down signaling pathway in SKBR3 and MCF-7/HER2 cells. Tunicamycin dose-dependently inhibited tumor growth in both of SKBR3 xenografts and MCF-7/HER2 xenografts. Optimal tunicamycin without inducing ER stress in liver tissue significantly increased the antitumor effect of trastuzumab in MCF-7/HER2 xenografts. Combinations of trastuzumab with N-glycosylation inhibitors tunicamycin may be a promising approach for improving clinical efficacy of trastuzumab. PMID:26498681

Risk of Lung Cancer Mortality in Nuclear Workers from Internal Exposure to Alpha Particle-emitting Radionuclides

PubMed Central

Atkinson, Will; Bérard, Philippe; Bingham, Derek; Birchall, Alan; Blanchardon, Eric; Bull, Richard; Guseva Canu, Irina; Challeton-de Vathaire, Cécile; Cockerill, Rupert; Do, Minh T.; Engels, Hilde; Figuerola, Jordi; Foster, Adrian; Holmstock, Luc; Hurtgen, Christian; Laurier, Dominique; Puncher, Matthew; Riddell, Anthony E.; Samson, Eric; Thierry-Chef, Isabelle; Tirmarche, Margot; Vrijheid, Martine; Cardis, Elisabeth

2017-01-01

Background: Carcinogenic risks of internal exposures to alpha-emitters (except radon) are poorly understood. Since exposure to alpha particles—particularly through inhalation—occurs in a range of settings, understanding consequent risks is a public health priority. We aimed to quantify dose–response relationships between lung dose from alpha-emitters and lung cancer in nuclear workers. Methods: We conducted a case–control study, nested within Belgian, French, and UK cohorts of uranium and plutonium workers. Cases were workers who died from lung cancer; one to three controls were matched to each. Lung doses from alpha-emitters were assessed using bioassay data. We estimated excess odds ratio (OR) of lung cancer per gray (Gy) of lung dose. Results: The study comprised 553 cases and 1,333 controls. Median positive total alpha lung dose was 2.42 mGy (mean: 8.13 mGy; maximum: 316 mGy); for plutonium the median was 1.27 mGy and for uranium 2.17 mGy. Excess OR/Gy (90% confidence interval)—adjusted for external radiation, socioeconomic status, and smoking—was 11 (2.6, 24) for total alpha dose, 50 (17, 106) for plutonium, and 5.3 (−1.9, 18) for uranium. Conclusions: We found strong evidence for associations between low doses from alpha-emitters and lung cancer risk. The excess OR/Gy was greater for plutonium than uranium, though confidence intervals overlap. Risk estimates were similar to those estimated previously in plutonium workers, and in uranium miners exposed to radon and its progeny. Expressed as risk/equivalent dose in sieverts (Sv), our estimates are somewhat larger than but consistent with those for atomic bomb survivors. See video abstract at, http://links.lww.com/EDE/B232. PMID:28520643

The Crimean Solar Maximum Year Workshop, selected reports

NASA Technical Reports Server (NTRS)

Emslie, A. G.; Gaizauskas, V.; Wu, S. T.

1980-01-01

Problems associated with the transport of energy and acceleration of charged particles in solar flares are considered. Existing theories are compared with observation with a view to either discriminating between rival theories (such as whether hard X-rays are emitted by thermal or nonthermal bremsstrahlung), constraining existing theories (such as deduction of the number of nonthermal electrons present from spectroscopic diagnostics in the soft X-ray part of the spectrum), or suggesting theories (such as attempting to explain the observed spatial structure of microwave emission relative to alpha).

Indirect calculation of monoclonal antibodies in nanoparticles using the radiolabeling process with technetium 99 metastable as primary factor: Alternative methodology for the entrapment efficiency.

PubMed

Helal-Neto, Edward; Cabezas, Santiago Sánchez; Sancenón, Félix; Martínez-Máñez, Ramón; Santos-Oliveira, Ralph

2018-05-10

The use of monoclonal antibodies (Mab) in the current medicine is increasing. Antibody-drug conjugates (ADCs) represents an increasingly and important modality for treating several types of cancer. In this area, the use of Mab associated with nanoparticles is a valuable strategy. However, the methodology used to calculate the Mab entrapment, efficiency and content is extremely expensive. In this study we developed and tested a novel very simple one-step methodology to calculate monoclonal antibody entrapment in mesoporous silica (with magnetic core) nanoparticles using the radiolabeling process as primary methodology. The magnetic core mesoporous silica were successfully developed and characterised. The PXRD analysis at high angles confirmed the presence of magnetic cores in the structures and transmission electron microscopy allowed to determine structures size (58.9 ± 8.1 nm). From the isotherm curve, a specific surface area of 872 m 2 /g was estimated along with a pore volume of 0.85 cm 3 /g and an average pore diameter of 3.15 nm. The radiolabeling process to proceed the indirect determination were well-done. Trastuzumab were successfully labeled (>97%) with Tc-99m generating a clear suspension. Besides, almost all the Tc-99m used (labeling the trastuzumab) remained trapped in the surface of the mesoporous silica for a period as long as 8 h. The indirect methodology demonstrated a high entrapment in magnetic core mesoporous silica surface of Tc-99m-traztuzumab. The results confirmed the potential use from the indirect entrapment efficiency methodology using the radiolabeling process, as a one-step, easy and cheap methodology. Copyright © 2018 Elsevier B.V. All rights reserved.

The anti-malarial chloroquine overcomes Primary resistance and restores sensitivity to Trastuzumab in HER2-positive breast cancer

PubMed Central

Cufí, Sílvia; Vazquez-Martin, Alejandro; Oliveras-Ferraros, Cristina; Corominas-Faja, Bruna; Cuyàs, Elisabet; López-Bonet, Eugeni; Martin-Castillo, Begoña; Joven, Jorge; Menendez, Javier A.

2013-01-01

Autophagy may control the de novo refractoriness of HER2 gene-amplified breast carcinomas to the monoclonal antibody trastuzumab (Herceptin). Tumor cells originally obtained from a patient who rapidly progressed on trastuzumab ab initio display increased cellular levels of the LC3-II protein—a finding that correlates with increased numbers of autophagosomes—and decreased levels of the autophagy receptor p62/SQSTM1, a protein selectively degraded by autophagy. Trastuzumab-refractory cells are in a state of “autophagy addiction” because genetic ablation of autophagy-specific genes (ATG8, ATG5, ATG12) notably reduces intrinsic refractoriness to trastuzumab. When the anti-malarial lysosomotropic drug chloroquine impedes autophagic resolution of the accumulation of autophagolysosomes formed in the presence of trastuzumab, cells commit to die by apoptosis. Accordingly, combination treatment with trastuzumab and chloroquine radically suppresses tumor growth by > 90% in a tumor xenograft completely refractory to trastuzumab. Adding chloroquine to trastuzumab-based regimens may therefore improve outcomes among women with autophagy-addicted HER2-positive breast cancer. PMID:23965851

The anti-malarial chloroquine overcomes primary resistance and restores sensitivity to trastuzumab in HER2-positive breast cancer.

PubMed

Cufí, Sílvia; Vazquez-Martin, Alejandro; Oliveras-Ferraros, Cristina; Corominas-Faja, Bruna; Cuyàs, Elisabet; López-Bonet, Eugeni; Martin-Castillo, Begoña; Joven, Jorge; Menendez, Javier A

2013-01-01

Autophagy may control the de novo refractoriness of HER2 gene-amplified breast carcinomas to the monoclonal antibody trastuzumab (Herceptin). Tumor cells originally obtained from a patient who rapidly progressed on trastuzumab ab initio display increased cellular levels of the LC3-II protein--a finding that correlates with increased numbers of autophagosomes--and decreased levels of the autophagy receptor p62/SQSTM1, a protein selectively degraded by autophagy. Trastuzumab-refractory cells are in a state of "autophagy addiction" because genetic ablation of autophagy-specific genes (ATG8, ATG5, ATG12) notably reduces intrinsic refractoriness to trastuzumab. When the anti-malarial lysosomotropic drug chloroquine impedes autophagic resolution of the accumulation of autophagolysosomes formed in the presence of trastuzumab, cells commit to die by apoptosis. Accordingly, combination treatment with trastuzumab and chloroquine radically suppresses tumor growth by > 90% in a tumor xenograft completely refractory to trastuzumab. Adding chloroquine to trastuzumab-based regimens may therefore improve outcomes among women with autophagy-addicted HER2-positive breast cancer.

ADP-ribosylation of transducin by pertussis toxin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watkins, P.A.; Burns, D.L.; Kanaho, Y.

1985-11-05

Transducin, the guanyl nucleotide-binding regulatory protein of retinal rod outer segments that couples the photon receptor, rhodopsin, with the light-activated cGMP phosphodiesterase, can be resolved into two functional components, T alpha and T beta gamma. T alpha (39 kDa), which is (TSP)ADP-ribosylated by pertussis toxin and (TSP)NAD in rod outer segments and in purified transducin, was also labeled by the toxin after separation from T beta gamma (36 kDa and approximately 10 kDa); neither component of T beta gamma was a pertussis toxin substrate. Labeling of T alpha was enhanced by T beta gamma and was maximal at approximately 1:1more » molar ratio of T alpha : T beta gamma. Limited proteolysis by trypsin of T alpha in the presence of guanyl-5'-yl imidodiphosphate (Gpp(NH)p) resulted in the sequential appearance of proteins of 38 and TS kDa. The amino terminus of both 38- and TS-kDa proteins was leucine, whereas that of T alpha could not be identified and was assumed to be blocked. The TS-kDa peptide was not a pertussis toxin substrate. Labeling of the 38-kDa protein was poor and was not enhanced by T beta gamma. Trypsin treatment of (TSP)ADP-ribosyl-T alpha produced a labeled 37-38-kDa doublet followed by appearance of radioactivity at the dye front. It appears, therefore, that, although the 38-kDa protein was poor toxin substrate, it contained the ADP-ribosylation site. Without rhodopsin, labeling of T alpha (in the presence of T beta gamma) was unaffected by Gpp(NH)p, guanosine 5'-O-(thiotriphosphate) (GTP gamma S), GTP, GDP, and guanosine 5'-O-(thiodiphosphate) (GDP beta S) but was increased by ATP. When photolyzed rhodopsin and T beta gamma were present, Gpp(NH)p and GTP gamma S decreased (TSP)ADP-ribosylation by pertussis toxin. Thus, pertussis toxin-catalyzed (TSP)ADP-ribosylation of T alpha was affected by nucleotides, rhodopsin and light in addition to T beta gamma.« less

Flow cytometry: a promising technique for the study of silicone oil-induced particulate formation in protein formulations.

PubMed

Ludwig, D Brett; Trotter, Joseph T; Gabrielson, John P; Carpenter, John F; Randolph, Theodore W

2011-03-15

Subvisible particles in formulations intended for parenteral administration are of concern in the biopharmaceutical industry. However, monitoring and control of subvisible particulates can be complicated by formulation components, such as the silicone oil used for the lubrication of prefilled syringes, and it is difficult to differentiate microdroplets of silicone oil from particles formed by aggregated protein. In this study, we demonstrate the ability of flow cytometry to resolve mixtures comprising subvisible bovine serum albumin (BSA) aggregate particles and silicone oil emulsion droplets with adsorbed BSA. Flow cytometry was also used to investigate the effects of silicone oil emulsions on the stability of BSA, lysozyme, abatacept, and trastuzumab formulations containing surfactant, sodium chloride, or sucrose. To aid in particle characterization, the fluorescence detection capabilities of flow cytometry were exploited by staining silicone oil with BODIPY 493/503 and model proteins with Alexa Fluor 647. Flow cytometric analyses revealed that silicone oil emulsions induced the loss of soluble protein via protein adsorption onto the silicone oil droplet surface. The addition of surfactant prevented protein from adsorbing onto the surface of silicone oil droplets. There was minimal formation of homogeneous protein aggregates due to exposure to silicone oil droplets, although oil droplets with surface-adsorbed trastuzumab exhibited flocculation. The results of this study demonstrate the utility of flow cytometry as an analytical tool for monitoring the effects of subvisible silicone oil droplets on the stability of protein formulations. Copyright © 2010 Elsevier Inc. All rights reserved.

Photoaffinity labeling of the Torpedo californica nicotinic acetylcholine receptor with an aryl azide derivative of phosphatidylserine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blanton, M.P.; Wang, H.H.

1990-02-06

A photoactivatable analogue of phosphatidylserine, {sup 125}I-labeled 4-azidosalicylic acid-phosphatidylserine ({sup 125}I ASA-PS), was used to label both native acetylcholine receptor (AchR)-rich membranes from Torpedo californica and AchR membranes affinity purified from Torpedo reconstituted into asolectin vesicles. The radioiodinated arylazido group attaches directly to the phospholipid head group and thus probes for regions of the AchR structure in contact with the negatively charged head group of phosphatidylserine. All four subunits of the AchR incorporated the label, with the {alpha} subunit incorporating approximately twice as much as each of the other subunits on a per mole basis. The regions of the AchRmore » {alpha} subunit that incorporated {sup 125}I ASA-PS were mapped by Staphylococcus aureus V8 protease digestion. The majority of label incorporated into fragments representing a more complete digestion of the {alpha} subunit was localized to 11.7- and 10.1-kDa V8 cleavage fragments, both beginning at Asn-339 and of sufficient length to contain the hydrophobic region M4. An 18.7-kDa fragment beginning at Ser-173 and of sufficient length to contain the hydrophobic regions M1, M2, and M3 was also significantly labeled. In contrast, V8 cleavage fragments representing roughly a third of the amino-terminal portion of the {alpha} subunit incorporated little or no detectable amount of probe.« less

Alpha-particle emission probabilities of ²³⁶U obtained by alpha spectrometry.

PubMed

Marouli, M; Pommé, S; Jobbágy, V; Van Ammel, R; Paepen, J; Stroh, H; Benedik, L

2014-05-01

High-resolution alpha-particle spectrometry was performed with an ion-implanted silicon detector in vacuum on a homogeneously electrodeposited (236)U source. The source was measured at different solid angles subtended by the detector, varying between 0.8% and 2.4% of 4π sr, to assess the influence of coincidental detection of alpha-particles and conversion electrons on the measured alpha-particle emission probabilities. Additional measurements were performed using a bending magnet to eliminate conversion electrons, the results of which coincide with normal measurements extrapolated to an infinitely small solid angle. The measured alpha emission probabilities for the three main peaks - 74.20 (5)%, 25.68 (5)% and 0.123 (5)%, respectively - are consistent with literature data, but their precision has been improved by at least one order of magnitude in this work. © 2013 Published by Elsevier Ltd.

The efficacy of adjuvant trastuzumab in HER-2 positive breast cancer with axillary lymph node metastases according to the treatment duration.

PubMed

Sendur, Mehmet A N; Aksoy, Sercan; Ozdemir, Nuriye Y; Yazici, Ozan; Zengin, Nurullah; Altundag, Kadri

2014-12-01

Trastuzumab is the first anti-HER-2 humanized monoclonal antibody. The benefit of adjuvant trastuzumab has been shown in randomized phase III trials. Despite trastuzumab being recommended for 52 weeks in the adjuvant treatment of HER-2 positive breast cancer according to the current breast cancer guidelines, there is still no consensus on the optimal duration of adjuvant trastuzumab. The aim of our study is to investigate the efficacy and safety of adjuvant trastuzumab for 9 weeks and 52 weeks in axillary lymph node positive HER-2 positive breast cancer patients. A total of 271 HER-2 and axillary node positive breast cancer patients who received trastuzumab in adjuvant treatment between the years 2005 and 2013 were retrospectively analyzed. Patients with axillary node positive HER-2 positive breast cancer who were non-metastatic were enrolled to the study. Patients were allocated to the 9 week trastuzumab group (n = 155) or the 52 week trastuzumab group (n = 116). Kaplan-Meier survival analysis was carried out for disease free survival (DFS) and overall survival (OS). Two-sided p values of <0.05 were considered statistically significant. The most important limitation of our manuscript is the retrospective design. The median follow-up time for this analysis was 34 (4-95) months. Patients' clinical and pathological characteristics were well balanced between the two treatment arms. In the 9 week trastuzumab treatment group, the DFS rate was 96.7%, 84.8% and 74.9% in the first, third and fifth years respectively, whereas in the 52 week trastuzumab treatment group it was 94.3%, 80.0% and 80.0% (P = 0.76). In the 9 week trastuzumab treatment group, the OS rate was 99.3%, 92.2% and 88.3% in the first, third and fifth years respectively, whereas in the 52 week trastuzumab treatment group it was 99.0%, 94.7% and 78.6% (P = 0.99). In both groups, symptomatic heart failure was not reported but asymptomatic left ventricular ejection fraction (LVEF) decline was observed 3 (1.9%) and 18 (15.5%) patients in the 9 week and 52 week trastuzumab treatment groups, respectively (P < 0.001). In our study, the efficacy of trastuzumab for 52 weeks and 9 weeks was similar in node-positive HER-2 positive breast cancer. Cardiotoxicity was significantly increased in the 52 week trastuzumab arm compared to the 9 week trastuzumab arm.

CNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: a retrospective substudy of the HERA trial (BIG 1-01).

PubMed

Pestalozzi, Bernhard C; Holmes, Eileen; de Azambuja, Evandro; Metzger-Filho, Otto; Hogge, Laurence; Scullion, Matt; Láng, István; Wardley, Andrew; Lichinitser, Mikhail; Sanchez, Roberto I Lopez; Müller, Volkmar; Dodwell, David; Gelber, Richard D; Piccart-Gebhart, Martine J; Cameron, David

2013-03-01

Several randomised trials have confirmed the benefit of adjuvant trastuzumab for patients with HER2-positive early breast cancer. However, concern has been expressed that adjuvant trastuzumab might be associated with an increased frequency of CNS relapses. We assessed the frequency and course of CNS relapses, either as first event or at any time, using data from the HERA trial. We estimated the cumulative incidence of first disease-free survival (DFS) events in the CNS versus other sites by competing risks analysis in patients with HER2-positive early breast cancer who had been randomly assigned to receive 1 year of trastuzumab or to observation in the HERA trial after a median follow-up of 4 years (IQR 3·5-4·8). To obtain further information about CNS relapse at any time before death, we circulated a data collection form to investigators to obtain standardised information about CNS events that occurred in all patients who had died before July, 2009. We estimated the cumulative incidence of CNS relapse at any time with a competing risks analysis. Of 3401 patients who had been assigned to receive 1 year of trastuzumab or to observation, 69 (2%) had a CNS relapse as first DFS event and 747 (22%) had a first DFS event not in the CNS. The frequency of CNS relapses as first DFS event did not differ between the group given 1 year of trastuzumab (37 [2%] of 1703 patients) and the observation group (32 [2%] of 1698; p=0·55 [Gray's test]). 481 data collection forms were distributed, of which 413 (86%) were returned. The proportion of patients who had died and experienced a CNS relapse was numerically higher in the observation group (129 [57%] of 227) than in the group given trastuzumab for 1 year (88 [47%] of 186; p=0·06 [Gray's test]). Most CNS relapses were symptomatic (189 [87%] of 217). Adjuvant trastuzumab does not increase the risk of CNS relapse in patients with HER2-positive early breast cancer. None. Copyright © 2013 Elsevier Ltd. All rights reserved.

Simulation of Alpha Particles in Rotating Plasma Interacting with a Stationary Ripple

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abraham J. Fetterman and Nathaniel J. Fisch

Superthermal ExB rotation can provide magnetohydrodynamic (MHD) stability and enhanced confinement to axisymmetric mirrors. However, the rotation speed has been limited by phenomena at end electrodes. A new prediction is that rotation might instead be produced using a magnetic ripple and alpha particle kinetic energy, in an extension of the alpha channeling concept. The interaction of alpha particles with the ripple results in visually interesting and practically useful orbits.

Evaluation of Left Ventricular Ejection Fractions in Breast Cancer Patients Undergoing Long-Term Trastuzumab Treatment.

PubMed

Sun, Yong; Li, Tao; Zhang, Yuanpeng; Zhang, Qiwen

2016-12-21

BACKGROUND The aim of this study was to assess the long-term clinical tolerance and cardiac safety during trastuzumab treatment for patients diagnosed as having breast cancer with human epidermal growth factor receptor 2 (HER2) overexpression. MATERIAL AND METHODS A total 105 female cases diagnosed as having breast cancer with high expression of Her2, were treated with trastuzumab (T). All of them underwent electrocardiography monitoring in the process of T treatment. Left ventricular ejection fractions (LVEFs) were estimated using echocardiography before the T treatment and every 3 months. General clinical data and above parameters were collected and reviewed as analysis. RESULTS The mean value of LVEFs with baseline was higher than those at other time points. All LVEFs were more than 50% during the course of trastuzumab treatment. The decline scope ≥15% of LVEFs ranged from 2 months to 16 months, and the ratios were counted for 3.1% at 2 months, 4.3% at 6 months, 3.8% at 10 months, and 5.4% at 16 months. Furthermore, a larger decrease of LVEF during the course occurred mainly in the patients with cumulative dose of A >300 mg/m², without CPD and 16-month duration of T treatment. There was a strong correlation between cumulative dose of A, cyto/cardio-protection drugs (CPD), duration of T, and the change of LVEF (P=0.82, P=0.744, and P=0.717, respectively), which indicated that 3 factors may be associated with the change in LVEF (P<0.05). CONCLUSIONS The LVEF in patients with trastuzumab treatment was significantly decreased, which may be seen as a favorable benefit-risk ratio for patients undergoing long-term trastuzumab treatment.

Fluorescent molecularly imprinted polymers as plastic antibodies for selective labeling and imaging of hyaluronan and sialic acid on fixed and living cells.

PubMed

Panagiotopoulou, Maria; Kunath, Stephanie; Medina-Rangel, Paulina Ximena; Haupt, Karsten; Tse Sum Bui, Bernadette

2017-02-15

Altered glycosylation levels or distribution of sialic acids (SA) or hyaluronan in animal cells are indicators of pathological conditions like infection or malignancy. We applied fluorescently-labeled molecularly imprinted polymer (MIP) particles for bioimaging of fixed and living human keratinocytes, to localize hyaluronan and sialylation sites. MIPs were prepared with the templates D-glucuronic acid (GlcA), a substructure of hyaluronan, and N-acetylneuraminic acid (NANA), the most common member of SA. Both MIPs were found to be highly selective towards their target monosaccharides, as no cross-reactivity was observed with other sugars like N-acetyl-D-glucosamine, N-acetyl-D-galactosamine, D-glucose and D-galactose, present on the cell surface. The dye rhodamine and two InP/ZnS quantum dots (QDs) emitting in the green and in the red regions were used as fluorescent probes. Rhodamine-MIPGlcA and rhodamine-MIPNANA were synthesized as monodispersed 400nm sized particles and were found to bind selectively their targets located in the extracellular region, as imaged by epifluorescence and confocal microscopy. In contrast, when MIP-GlcA and MIP-NANA particles with a smaller size (125nm) were used, the MIPs being synthesized as thin shells around green and red emitting QDs respectively, it was possible to stain the intracellular and pericellular regions as well. In addition, simultaneous dual-color imaging with the two different colored QDs-MIPs was demonstrated. Importantly, the MIPs were not cytotoxic and did not affect cell viability; neither was the cells morphology affected as demonstrated by live cell imaging. These synthetic receptors could offer a new and promising imaging tool to monitor disease progression. Copyright © 2016 Elsevier B.V. All rights reserved.

Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2-Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study.

PubMed

Perez, Edith A; Barrios, Carlos; Eiermann, Wolfgang; Toi, Masakazu; Im, Young-Hyuck; Conte, Pierfranco; Martin, Miguel; Pienkowski, Tadeusz; Pivot, Xavier; Burris, Howard; Petersen, Jennifer A; Stanzel, Sven; Strasak, Alexander; Patre, Monika; Ellis, Paul

2017-01-10

Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) -targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study. Methods In the MARIANNE study, 1,095 patients with centrally assessed, HER2-positive, advanced breast cancer and no prior therapy for advanced disease were randomly assigned 1:1:1 to control (trastuzumab plus taxane), T-DM1 plus placebo, hereafter T-DM1, or T-DM1 plus pertuzumab at standard doses. Primary end point was progression-free survival (PFS), as assessed by independent review. Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane (median PFS: 13.7 months with trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab). Neither experimental arm showed PFS superiority to trastuzumab plus taxane. Response rate was 67.9% in patients who were treated with trastuzumab plus taxane, 59.7% with T-DM1, and 64.2% with T-DM1 plus pertuzumab; median response duration was 12.5 months, 20.7 months, and 21.2 months, respectively. The incidence of grade ≥ 3 adverse events was numerically higher in the control arm (54.1%) versus the T-DM1 arm (45.4%) and T-DM1 plus pertuzumab arm (46.2%). Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms, and health-related quality of life was maintained for longer in the T-DM1 arms. Conclusion T-DM1 showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast cancer.

Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2–Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study

PubMed Central

Perez, Edith A.; Barrios, Carlos; Eiermann, Wolfgang; Toi, Masakazu; Im, Young-Hyuck; Conte, Pierfranco; Martin, Miguel; Pienkowski, Tadeusz; Pivot, Xavier; Burris, Howard; Petersen, Jennifer A.; Stanzel, Sven; Strasak, Alexander; Patre, Monika; Ellis, Paul

2017-01-01

Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) –targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study. Methods In the MARIANNE study, 1,095 patients with centrally assessed, HER2-positive, advanced breast cancer and no prior therapy for advanced disease were randomly assigned 1:1:1 to control (trastuzumab plus taxane), T-DM1 plus placebo, hereafter T-DM1, or T-DM1 plus pertuzumab at standard doses. Primary end point was progression-free survival (PFS), as assessed by independent review. Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane (median PFS: 13.7 months with trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab). Neither experimental arm showed PFS superiority to trastuzumab plus taxane. Response rate was 67.9% in patients who were treated with trastuzumab plus taxane, 59.7% with T-DM1, and 64.2% with T-DM1 plus pertuzumab; median response duration was 12.5 months, 20.7 months, and 21.2 months, respectively. The incidence of grade ≥ 3 adverse events was numerically higher in the control arm (54.1%) versus the T-DM1 arm (45.4%) and T-DM1 plus pertuzumab arm (46.2%). Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms, and health-related quality of life was maintained for longer in the T-DM1 arms. Conclusion T-DM1 showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast cancer. PMID:28056202

Characterization of Makrofol ® DE 1-1 for alpha particle radiography

NASA Astrophysics Data System (ADS)

El Ghazaly, M.; Aydarous, Abdulkadir; Al-Thomali, Talal A.

2017-09-01

Makrofol ® DE 1-1 (bisphenol-A polycarbonate) was investigated for alpha particle radiography. The edge spread function (ESF) was measured by razor-blade's edge. Makrofol ® DE 1-1 detectors were irradiated with perpendicular incident alpha particles of energy 2.5, 4 and 5.4 MeV, thereafter they were etched in 75% 6N KOH+25% C2H5OH at a temperature of 50 °C for different durations. The etched Makrofol®DE 1-1 detectors were imaged with an optical microscope equipped with a CCD camera. The results revealed that the green channel of the original RGB image provides the highest contrast comparing with red and blue channel by a factor of 27.6% of the original RGB image. The image contrast of alpha particle-irradiated Makrofol®DE 1-1 detector was found to be inversely related to the etching time since the alpha particle tracks proceed from a conical phase to spherical phase. The spatial resolution of alpha particle-irradiated Makrofol®DE 1-1 detector, in terms of line spread function, was found to deteriorate as the etching time increases for all examined alpha particle energies. The results revealed the potential capability of Makrofol®DE 1-1 detector as an efficient detector for alpha particle radiography such as autoradiography.

Neutron Radiation Characteristics of Plutonium Dioxide Fuel

NASA Technical Reports Server (NTRS)

Taherzadeh, M.

1972-01-01

The major sources of neutrons from plutonium dioxide nuclear fuel are considered in detail. These sources include spontaneous fission of several of the Pu isotopes, reactions with low Z impurities in the fuel, and reactions with O-18. For spontaneous fission neutrons a value of (1.95 plus or minus 0.07) X 1,000 n/s/q PuO2 is obtained. The neutron yield from (alpha, neutron) reactions with oxygen is calculated by integrating the reaction rate equation over all alpha particle energies and all center-of-mass angles. The results indicate a neutron emission rate of (1.42 plus or minus 0.32) X 10,000 n/s/q PuO2. The neutron yield from (alpha, neutron) reactions with low Z impurities in the fuel is presented in tabular form for one part per million of each impurity. The total neutron flux emitted from a particular fuel geometry is estimated by adding the neutron yield due to the induced fission to the other neutron sources.

Effect of alpha-particle irradiation on the electrical properties of n-type Ge

NASA Astrophysics Data System (ADS)

Roro, K. T.; Janse van Rensburg, P. J.; Auret, F. D.; Coelho, S.

2009-12-01

Deep-level transient spectroscopy was used to investigate the effect of alpha particle irradiation on the electrical properties of n-type Ge. The samples were irradiated with alpha particles at room temperature using an americium-241 (Am-241) radionuclide source. The main defects introduced were found to be electron traps with energy levels at EC-0.38, EC-0.21, EC-0.20, EC-0.15, and EC-0.10 eV, respectively. The main defects in alpha particle irradiation are similar to those introduced by MeV electron irradiation, where the main defect is the E-center. A quadratic increase in concentration as a function of dose is observed.

XRF-analysis of fine and ultrafine particles emitted from laser printing devices.

PubMed

Barthel, Mathias; Pedan, Vasilisa; Hahn, Oliver; Rothhardt, Monika; Bresch, Harald; Jann, Oliver; Seeger, Stefan

2011-09-15

In this work, the elemental composition of fine and ultrafine particles emitted by ten different laser printing devices (LPD) is examined. The particle number concentration time series was measured as well as the particle size distributions. In parallel, emitted particles were size-selectively sampled with a cascade impactor and subsequently analyzed by the means of XRF. In order to identify potential sources for the aerosol's elemental composition, materials involved in the printing process such as toner, paper, and structural components of the printer were also analyzed. While the majority of particle emissions from laser printers are known to consist of recondensated semi volatile organic compounds, elemental analysis identifies Si, S, Cl, Ca, Ti, Cr, and Fe as well as traces of Ni and Zn in different size fractions of the aerosols. These elements can mainly be assigned to contributions from toner and paper. The detection of elements that are likely to be present in inorganic compounds is in good agreement with the measurement of nonvolatile particles. Quantitative measurements of solid particles at 400 °C resulted in residues of 1.6 × 10(9) and 1.5 × 10(10) particles per print job, representing fractions of 0.2% and 1.9% of the total number of emitted particles at room temperature. In combination with the XRF results it is concluded that solid inorganic particles contribute to LPD emissions in measurable quantities. Furthermore, for the first time Br was detected in significant concentrations in the aerosol emitted from two LPD. The analysis of several possible sources identified the plastic housings of the fuser units as main sources due to substantial Br concentrations related to brominated flame retardants.

a Theoretical and Experimental Investigation of 1/F Noise in the Alpha Decay Rates of AMERICIUM-241.

NASA Astrophysics Data System (ADS)

Pepper, Gary T.

New experimental methods and data analysis techniques were used to investigate the hypothesis of the existence of 1/f noise in a alpha particle emission rates for ^{241}Am. Experimental estimates of the flicker floor were found to be almost two orders of magnitude less than Handel's theoretical prediction and previous measurements. The existence of a flicker floor for ^{57}Co decay, a process for which no charged particles are emitted, indicate that instrumental instability is likely responsible for the values of the flicker floor obtained. The experimental results and the theoretical arguments presented indicate that a re-examination of Handel's theory of 1/f noise is appropriate. Methods of numerical simulation of noise processes with a 1/f^{rm n} power spectral density were developed. These were used to investigate various statistical aspects of 1/f ^{rm n} noise. The probability density function for the Allan variance was investigated in order to establish confidence limits for the observations made. The effect of using grouped (correlated) data, for evaluating the Allan variance, was also investigated.

A Luminosity Function of Ly(alpha)-Emitting Galaxies at Z [Approx. Equal to] 4.5(Sup 1),(Sup 2)

NASA Technical Reports Server (NTRS)

Dawson, Steve; Rhoads, James E.; Malhotra, Sangeeta; Stern, Daniel; Wang, JunXian; Dey, Arjun; Spinrad, Hyron; Jannuzi, Buell T.

2007-01-01

We present a catalog of 59 z [approx. equal to] 4:5 Ly(alpha)-emitting galaxies spectroscopically confirmed in a campaign of Keck DEIMOS follow-up observations to candidates selected in the Large Are (LALA) narrowband imaging survey.We targeted 97 candidates for spectroscopic follow-up; by accounting for the variety of conditions under which we performed spectroscopy, we estimate a selection reliability of approx.76%. Together with our previous sample of Keck LRIS confirmations, the 59 sources confirmed herein bring the total catalog to 73 spectroscopically confirmed z [approx. equal to] 4:5 Ly(alpha)- emitting galaxies in the [approx. equal to] 0.7 deg(exp 2) covered by the LALA imaging. As with the Keck LRIS sample, we find that a nonnegligible fraction of the co rest-frame equivalent widths (W(sub lambda)(sup rest)) that exceed the maximum predicted for normal stellar populations: 17%-31%(93%confidence) of the detected galaxies show (W(sub lambda)(sup rest)) 12%-27% (90% confidence) show (W(sub lambda)(sup rest)) > 240 A. We construct a luminosity function of z [approx. equal to] 4.5 Ly(alpha) emission lines for comparison to Ly(alpha) luminosity function < 6.6. We find no significant evidence for Ly(alpha) luminosity function evolution from z [approx. equal to] 3 to z [approx. equal to] 6. This result supports the conclusion that the intergalactic me largely reionized from the local universe out to z [approx. equal to] 6.5. It is somewhat at odds with the pronounced drop in the cosmic star formation rate density recently measured between z approx. 3 an z approx. 6 in continuum-selected Lyman-break galaxies, and therefore potentially sheds light on the relationship between the two populations.

Intracellular bimodal nanoparticles based on quantum dots for high-field MRI at 21.1 T.

PubMed

Rosenberg, Jens T; Kogot, Joshua M; Lovingood, Derek D; Strouse, Geoffrey F; Grant, Samuel C

2010-09-01

Multimodal, biocompatible contrast agents for high magnetic field applications represent a new class of nanomaterials with significant potential for tracking of fluorescence and MR in vitro and vivo. Optimized for high-field MR applications-including biomedical imaging at 21.1 T, the highest magnetic field available for MRI-these nanoparticles capitalize on the improved performance of chelated Dy(3+) with increasing magnetic field coupled to a noncytotoxic Indium Phosphide/Zinc Sulfide (InP/ZnS) quantum dot that provides fluorescence detection, MR responsiveness, and payload delivery. By surface modifying the quantum dot with a cell-penetrating peptide sequence coupled to an MR contrast agent, the bimodal nanomaterial functions as a self-transfecting high-field MR/optical contrast agent for nonspecific intracellular labeling. Fluorescent images confirm sequestration in perinuclear vesicles of labeled cells, with no apparent cytotoxicity. These techniques can be extended to impart cell selectivity or act as a delivery vehicle for genetic or pharmaceutical interventions. 2010 Wiley-Liss, Inc.

Measurements of ultrafine particles from a gas-turbine burning biofuels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Allouis, C.; Beretta, F.; Minutolo, P.

2010-04-15

Measurements of ultrafine particles have been performed at the exhaust of a low emission microturbine for power generation. This device has been fuelled with liquid fuels, including a commercial diesel oil, a mixture of the diesel oil with a biodiesel and kerosene, and tested under different loads. Primarily attention has been focused on the measurements of the size distribution functions of the particles emitted from the system by using particle differential mobility analysis. A bimodal size distribution function of the particle emitted has been found in all the examined conditions. Burning diesel oil, the first mode of the size distributionmore » function of the combustion-formed particles is centered at around 2-3 nm, whereas the second mode is centered at about 20-30 nm. The increase of the turbine load and the addition of 50% of biodiesel has not caused changes in the shape of size distribution of the particles. A slightly decrease of the amount of particle formed has been found. By using kerosene the amount of emitted particles increases of more than one order of magnitude. Also the shape of the size distribution function changes with the first mode shifted towards larger particles of the order of 8-10 nm but with a lower emission of larger 20-30 nm particles. Overall, in this conditions, the mass concentration of particles is increased respect to the diesel oil operation. Particle sizes measured with the diesel oil have been compared with the results on a diesel engine operated in the same power conditions and with the same fuel. Measurements have showed that the mean sizes of the formed particles do not change in the two combustion systems. However, diesel engine emits a number concentration of particles more than two orders of magnitude higher in the same conditions of power and with the same fuel. By running the engine in more premixed-like conditions, the size distribution function of the particles approaches that measured by burning kerosene in the microturbine indicating that the distribution function of the sizes of the emitted particles can be strongly affected by combustion conditions. (author)« less

A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors.

PubMed

Hudis, Clifford; Swanton, Charles; Janjigian, Yelena Y; Lee, Ray; Sutherland, Stephanie; Lehman, Robert; Chandarlapaty, Sarat; Hamilton, Nicola; Gajria, Devika; Knowles, James; Shah, Jigna; Shannon, Keith; Tetteh, Ernestina; Sullivan, Daniel M; Moreno, Carolina; Yan, Li; Han, Hyo Sook

2013-11-19

Trastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing breast and gastric cancers. However, patients may develop resistance through downstream signaling via the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to determine whether the combination with trastuzumab could inhibit compensatory signaling. Patients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule. A total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and 135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial. The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash, consistent with prior experience; one death unrelated to treatment was reported. There was one complete response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinib-based therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206. Results suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is associated with clinical activity, supporting further investigation. ClinicalTrials.gov; identifier: NCT00963547.

Human Epidermal Growth Factor Receptor 2 (HER-2/neu)-Directed Therapy for Rare Metastatic Epithelial Tumors with HER-2 Amplification

PubMed Central

Shin, Daniel Sanghoon; Sherry, Timothy; Kallen, Michael E.; Wong, Steven; Drakaki, Alexandra

2016-01-01

Case 1 A 67-year-old Asian female was diagnosed with locally advanced high-grade salivary duct carcinoma in June 2011. Molecular analysis revealed human epidermal growth factor receptor 2 (HER-2) amplification. She received adjuvant therapy with carboplatin/paclitaxel/ trastuzumab and maintenance of trastuzumab. Upon disease progression, trastuzumab could not be continued due to lack of financial coverage. Instead, she was treated with compassionate use of lapatinib from April 2013 and standard 5-fluorouracil. Her disease ultimately progressed and she expired later in 2013. Case 2 A 68-year-old Asian male was diagnosed with extramammary Paget's disease of the scrotum with HER-2 amplification in May 2011. He received 6 cycles of adjuvant trastuzumab/docetaxel/carboplatin followed by maintenance trastuzumab, which was changed to compassionate use of lapatinib as his insurance did not cover further administration of trastuzumab. He showed clinical benefits from single-agent lapatinib and a combination of lapatinib/capecitabine upon progression to the single-agent lapatinib. Ultimately, he was started on ado-trastuzumab emtansine, which was approved at that time by the FDA for HER-2-positive breast cancer progressed on trastuzumab. He is having clinical and radiographic complete response based on current imaging and normalization of his tumor markers. Conclusion HER-2-targeted therapy should be considered for tumors with HER-2 amplification. In our case series, we would like to emphasize this approach in other rare histologies. Specifically, our patient with extramammary Paget's disease of the scrotum represents the first reported case of a non-breast, non-gastric tumor with HER-2 overexpression with complete clinical and radiographic response to HER-2-targeted therapy PMID:27403128

Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study.

PubMed

von Minckwitz, Gunter; du Bois, Andreas; Schmidt, Marcus; Maass, Nicolai; Cufer, Tanja; de Jongh, Felix E; Maartense, Eduard; Zielinski, Christoph; Kaufmann, Manfred; Bauer, Wolfgang; Baumann, Klaus H; Clemens, Michael R; Duerr, Ralph; Uleer, Christoph; Andersson, Michael; Stein, Robert C; Nekljudova, Valentina; Loibl, Sibylle

2009-04-20

Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)-positive early and advanced breast cancer. In the German Breast Group 26/Breast International Group 03-05 trial, we investigated if trastuzumab treatment should be continued beyond progression. Patients with HER-2-positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine (2,500 mg/m(2) body-surface area on days 1 through 14 [1,250 mg/m(2) semi-daily]) alone or with continuation of trastuzumab (6 mg/kg body weight) in 3-week cycles. The primary end point was time to progression. We randomly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab. Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15.6 months of follow-up. Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the capecitabine-plus-trastuzumab group with an unadjusted hazard ratio of 0.69 (95% CI, 0.48 to 0.97; two-sided log-rank P = .0338). Overall survival rates were 20.4 months (95% CI, 17.8 to 24.7) in the capecitabine group and 25.5 months (95% CI, 19.0 to 30.7) in the capecitabine-plus-trastuzumab group (P = .257). Overall response rates were 27.0% with capecitabine and 48.1% with capecitabine plus trastuzumab (odds ratio, 2.50; P = .0115). Continuation of trastuzumab beyond progression was not associated with increased toxicity. Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2-positive breast cancer who experienced progression during trastuzumab treatment.

A Pharmacokinetics Phase 1 Bioequivalence Study of the Trastuzumab Biosimilar MYL-1401O vs EU-Trastuzumab and US-Trastuzumab.

PubMed

Waller, Cornelius F; Vutikullird, Apinya; Lawrence, Tracey E; Shaw, Andrew; Liu, Mark Shiyao; Baczkowski, Mark; Sharma, Rajiv; Barve, Abhijit; Goyal, Parag; Donnelly, Charles; Sengupta, Nilanjan; Pennella, Eduardo J

2018-06-21

Trastuzumab is a humanized monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2) oncoprotein and is an effective therapy for HER2-overexpressing breast cancer. MYL-1401O is a trastuzumab biosimilar. Here, we report results from a phase 1 study that investigated bioequivalence among MYL-1401O, reference EU-trastuzumab, and US-trastuzumab. This single-center, randomized, double-blind, three-arm, parallel-group, phase 1 study was conducted in healthy adult male volunteers. Subjects were randomized 1:1:1 to receive a single 8 mg kg -1 dose of MYL-1401O, EU-trastuzumab, or US-trastuzumab as a 90-minute intravenous infusion. Primary objective was to assess PK similarity among all three products. Primary endpoints assessed were peak serum concentration (Cmax), area under the serum concentration-time curve from time of dosing to time of last quantifiable concentration (AUC 0-last ), and AUC from time of dosing to infinity (AUC 0-∞ ). Secondary endpoints included time of Cmax (tmax), elimination rate constant (λz), half-life (t ½ ), safety, and immunogenicity. Of 132 subjects enrolled (44/treatment), 120 (MYL-1401O, n=42; EU-trastuzumab, n=41; US-trastuzumab, n=37) were included in the PK analysis. The 90% CIs of the ratios of geometric means for the primary endpoints were bounded within the predefined bioequivalence criterion of 80% to 125%. Secondary endpoints tmax, λz, and t ½ were similar among groups. All treatment-emergent adverse events were mild or moderate, similar across groups, and no serious adverse events were reported. No treatment-related antidrug antibodies were detected. MYL-1401O was well tolerated, and demonstrated PK and safety profiles similar to EU-trastuzumab and US-trastuzumab in healthy volunteers (ClinicalTrials.gov, NCT02594761). This article is protected by copyright. All rights reserved.

Power-dependent speciation of volatile organic compounds in aircraft exhaust

NASA Astrophysics Data System (ADS)

Beyersdorf, Andreas J.; Thornhill, K. Lee; Winstead, Edward L.; Ziemba, Luke D.; Blake, Donald R.; Timko, Michael T.; Anderson, Bruce E.

2012-12-01

As part of the third NASA Aircraft Particle Emissions Experiment (APEX-3, November 2005), whole air samples were collected to determine the emission rates of volatile organic compounds (VOCs) from aircraft equipped with three different gas-turbine engines (an Allison Engine 3007-A1E, a Pratt-Whitney 4158, and a Rolls-Royce RB211-535E4B). Samples were collected 1 m behind the engine exhaust plane of the engines while they were operated at powers ranging from idle up to 30% of maximum rated thrust. Exhaust emission indices (mass emitted per kilogram of fuel used) for CO and non-methane hydrocarbons (NMHCs) were calculated based on enhancements over background relative to CO2. Emissions of all NMHCs were greatest at low power with values decreasing by an order of magnitude with increasing power. Previous studies have shown that scaling idle hydrocarbon emissions to formaldehyde or ethene (which are typically emitted at a ratio of 1-to-1 at idle) reduces variability amongst engine types. NMHC emissions were found to scale at low power, with alkenes contributing over 50% of measured NMHCs. However, as the power increases hydrocarbon emissions no longer scale to ethene, as the aromatics become the dominant species emitted. This may be due in part to a shift in combustion processes from thermal cracking (producing predominantly alkenes) to production of new molecules (producing proportionally more aromatics) as power increases. The formation of these aromatics is an intermediate step in the production of soot, which also increases with increasing power. The increase in aromatics relative to alkenes additionally results in a decrease in the hydroxyl radical reactivity and ozone formation potential of aircraft exhaust. Samples collected 30 m downwind of the engine were also analyzed for NMHCs and carbonyl compounds (acetone, 2-butanone and C1-C9 aldehydes). Formaldehyde was the predominant carbonyl emitted; however, the ratio of ethene-to-formaldehyde varied between the aircraft, possibly due to the sampling of transient emissions such as engine start-up and power changes. A large portion of the measured emissions (27-42% by mass) in the plume samples was made up of hazardous air pollutants (HAPs) with oxygenated compounds being most significant.

Human Lung Cancer Risks from Radon – Part I - Influence from Bystander Effects - A Microdose Analysis

PubMed Central

Leonard, Bobby E.; Thompson, Richard E.; Beecher, Georgia C.

2010-01-01

Since the publication of the BEIR VI report in 1999 on health risks from radon, a significant amount of new data has been published showing various mechanisms that may affect the ultimate assessment of radon as a carcinogen, at low domestic and workplace radon levels, in particular the Bystander Effect (BE) and the Adaptive Response radio-protection (AR). We analyzed the microbeam and broadbeam alpha particle data of Miller et al. (1995, 1999), Zhou et al. (2001, 2003, 2004), Nagasawa and Little (1999, 2002), Hei et al. (1999), Sawant et al. (2001a) and found that the shape of the cellular response to alphas is relatively independent of cell species and LET of the alphas. The same alpha particle traversal dose response behavior should be true for human lung tissue exposure to radon progeny alpha particles. In the Bystander Damage Region of the alpha particle response, there is a variation of RBE from about 10 to 35. There is a transition region between the Bystander Damage Region and Direct Damage Region of between one and two microdose alpha particle traversals indicating that perhaps two alpha particle “hits” are necessary to produce the direct damage. Extrapolation of underground miners lung cancer risks to human risks at domestic and workplace levels may not be valid. PMID:21731539

Ra-224 labeling of calcium carbonate microparticles for internal α-therapy: Preparation, stability, and biodistribution in mice.

PubMed

Westrøm, Sara; Malenge, Marion; Jorstad, Ida Sofie; Napoli, Elisa; Bruland, Øyvind S; Bønsdorff, Tina B; Larsen, Roy H

2018-05-30

Internal therapy with α-emitters should be well suited for micrometastatic disease. Radium-224 emits multiple α-particles through its decay and has a convenient 3.6 days of half-life. Despite its attractive properties, the use of 224 Ra has been limited to bone-seeking applications because it cannot be stably bound to a targeting molecule. Alternative delivery systems for 224 Ra are therefore of considerable interest. In this study, calcium carbonate microparticles are proposed as carriers for 224 Ra, designed for local therapy of disseminated cancers in cavitary regions, such as peritoneal carcinomatosis. Calcium carbonate microparticles were radiolabeled by precipitation of 224 Ra on the particle surface, resulting in high labeling efficiencies for both 224 Ra and daughter 212 Pb and retention of more than 95% of these nuclides for up to 1 week in vitro. The biodistribution after intraperitoneal administration of the 224 Ra-labeled CaCO 3 microparticles in immunodeficient mice revealed that the radioactivity mainly remained in the peritoneal cavity. In addition, the systemic distribution of 224 Ra was found to be strongly dependent on the amount of administered microparticles, with a reduced skeletal uptake of 224 Ra with increasing dose. The results altogether suggest that the 224 Ra-labeled CaCO 3 microparticles have promising properties for use as a localized internal α-therapy of cavitary cancers. © 2018 Oncoinvent AS. Journal of Labelled Compounds and Radiopharmaceuticals Published by John Wiley & Sons, Ltd.

Trastuzumab-induced cardiomyopathy.

PubMed

Guglin, Maya; Cutro, Raymond; Mishkin, Joseph D

2008-06-01

Trastuzumab is a recombinant humanized monoclonal antibody used for the treatment of advanced breast cancer. It improves survival and increases response to chemotherapy. The major side effect of trastuzumab is cardiotoxicity manifesting as a reduction in left ventricular systolic function, either asymptomatic or with signs and symptoms of heart failure. Although reversible in most cases, cardiotoxicity frequently results in the discontinuation of trastuzumab. The objective of this review is to summarize facts about trastuzumab-induced cardiotoxicity and to highlight the areas of future investigations. We searched PubMed for trials involving trastuzumab used as an adjuvant therapy for breast cancer, including the metastatic breast cancer setting, and focused on cardiotoxicity.

The solar-flare infrared continuum - Observational techniques and upper limits

NASA Technical Reports Server (NTRS)

Hudson, H. S.

1975-01-01

Exploratory observations at 20 microns and 350 microns have determined detection thresholds for solar flares in these wavelengths. In the 20-micron range, solar atmospheric fluctuations (the 'temperature field') set the basic limits on flare detectability at about 5 K; at 350 microns, extinction in the earth's atmosphere provides the basic limitation of about 30 K. These thresholds are low enough for the successful detection of several infrared-emitting components of large flares. The upper limits obtained for subflares indicate that the thickness of the H-alpha flare region does not exceed approximately 10 km. This result confirms the conclusion of Suemoto and Hiei (1959) regarding the small effective thickness of the H-alpha-emitting regions in solar flares.

Are life-saving anticancer drugs reaching all patients? Patterns and discrepancies of trastuzumab use in the European Union and the USA.

PubMed

Ades, Felipe; Senterre, Christelle; Zardavas, Dimitrios; de Azambuja, Evandro; Popescu, Razvan; Piccart, Martine

2017-01-01

The development of trastuzumab is considered to be one of the greatest improvements in breast cancer treatment in recent years. This study aims to evaluate changes in the uptake of trastuzumab over the last 12 years and to determine whether its use is proportional to patient needs in the European Union and the USA. Using national registry data, the number of new cases of HER2-positive breast cancer patients per year was estimated. The number of likely trastuzumab treatments per year was estimated using trastuzumab procurement data for each country. Western Europe and the USA show increasing procurement level of trastuzumab over the years studied, reaching proportional of use of trastuzumab few years after its marketing authorization in the early 2000's. After the approval in the adjuvant setting, in the year 2006, it was observed underuse of trastuzumab given the increase of the number of patients in need of treatment. Proportional use was shortly met after a couple of years. Few countries in Eastern Europe acquired the needed quantity of trastuzumab, with procurement levels starting to increase only after approval in the adjuvant setting in 2006. Significant differences in trastuzumab procurement are observed between Western Europe, the USA and Eastern Europe, with the latter geographic region acquiring insufficient amounts of the drug required to treat all patients in need.

Functional Imaging of HER2-Positive Metastatic Breast Cancer Using 64Cu-DOTA-Trastuzumab Positron Emission Tomography

PubMed Central

Mortimer, Joanne E.; Bading, James R.; Colcher, David M.; Conti, Peter S.; Frankel, Paul H.; Carroll, Mary I.; Tong, Shan; Poku, Erasmus; Miles, Joshua K.; Shively, John E.; Raubitschek, Andrew A.

2014-01-01

Women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are candidates for treatment with the anti-HER2 antibody trastuzumab. Assessment of HER2 status in recurrent disease is usually made by core needle biopsy of a single lesion which may not be representative of the larger tumor mass or other sites of disease. Our long-range goal is to develop positron emission tomography (PET) of radiolabeled trastuzumab for systemically assessing tumor HER2 expression and identifying appropriate use of anti-HER2 therapies. The purpose of this study was to evaluate PET-CT of 64Cu-DOTA-trastuzumab for detecting and measuring tumor uptake of trastuzumab in patients with HER2-positive metastatic breast cancer. Methods Eight women with biopsy-confirmed HER2-positive metastatic breast cancer and no anti-HER2 therapy for ≥ 4 mo underwent complete staging, including 18F-fluorodeoxyglucose (FDG)/PET-CT. For 6 of the 8 patients, 64Cu-DOTA-trastuzumab injection (364-512 MBq, 5 mg trastuzumab) was preceded by trastuzumab infusion (45 mg). PET-CT (PET scan duration 1 h) was performed 21-25 (“Day 1”) and 47-49 (“Day 2”) h after 64Cu-DOTA-trastuzumab injection. Scan fields of view were chosen based on 18F-FDG/PET-CT. Lesions visualized relative to adjacent tissue on PET were considered PET-positive; analysis was limited to lesions identifiable on CT. Radiolabel uptake in prominent lesions was measured as maximum single-voxel standardized uptake value (SUVmax). Results Liver uptake of 64Cu was reduced approximately 75% with the 45 mg trastuzumab pre-dose, without significant effect on tumor uptake. The study included 89 CT-positive lesions; detection sensitivity was 77, 89 and 93% for Day 1, Day 2 and 18F-FDG, respectively. On average, tumor uptake was similar for 64Cu-DOTA-trastuzumab and 18F-FDG [SUVmax (mean, range): Day 1 (8.1, 3.0-22.5, n=48); Day 2 (8.9, 0.9-28.9, n=38); 18F-FDG (9.7, 3.3-25.4, n=56)], but the extent of same-lesion uptake was not correlated between the 2 radiotracers. No toxicities were observed, and estimated radiation dose from 64Cu-DOTA-trastuzumab was similar to 18F-FDG. Conclusion 64Cu-DOTA-trastuzumab visualizes HER2-positive metastatic breast cancer with high sensitivity, and is effective in surveying disseminated disease. A 45 mg trastuzumab pre-dose provides a 64Cu-DOTA-trastuzumab biodistribution favorable for tumor imaging. 64Cu-DOTA-trastuzumab/PET-CT warrants further evaluation for assessing tumor HER2 expression and measuring delivery of trastuzumab-based therapy. PMID:24337604

Functional imaging of human epidermal growth factor receptor 2-positive metastatic breast cancer using (64)Cu-DOTA-trastuzumab PET.

PubMed

Mortimer, Joanne E; Bading, James R; Colcher, David M; Conti, Peter S; Frankel, Paul H; Carroll, Mary I; Tong, Shan; Poku, Erasmus; Miles, Joshua K; Shively, John E; Raubitschek, Andrew A

2014-01-01

Women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are candidates for treatment with the anti-HER2 antibody trastuzumab. Assessment of HER2 status in recurrent disease is usually made by core needle biopsy of a single lesion, which may not represent the larger tumor mass or other sites of disease. Our long-range goal is to develop PET of radiolabeled trastuzumab for systemically assessing tumor HER2 expression and identifying appropriate use of anti-HER2 therapies. The purpose of this study was to evaluate PET/CT of (64)Cu-DOTA-trastuzumab for detecting and measuring tumor uptake of trastuzumab in patients with HER2-positive metastatic breast cancer. Eight women with biopsy-confirmed HER2-positive metastatic breast cancer and no anti-HER2 therapy for 4 mo or longer underwent complete staging, including (18)F-FDG PET/CT. For 6 of the 8 patients, (64)Cu-DOTA-trastuzumab injection (364-512 MBq, 5 mg of trastuzumab) was preceded by trastuzumab infusion (45 mg). PET/CT (PET scan duration 1 h) was performed 21-25 (day 1) and 47-49 (day 2) h after (64)Cu-DOTA-trastuzumab injection. Scan fields of view were chosen on the basis of (18)F-FDG PET/CT. Tumor detection sensitivity and uptake analyses were limited to lesions identifiable on CT; lesions visualized relative to adjacent tissue on PET were considered PET-positive. Radiolabel uptake in prominent lesions was measured as maximum single-voxel standardized uptake value (SUVmax). Liver uptake of (64)Cu was reduced approximately 75% with the 45-mg trastuzumab predose, without significant effect on tumor uptake. The study included 89 CT-positive lesions. Detection sensitivity was 77%, 89%, and 93% for day 1, day 2, and (18)F-FDG, respectively. On average, tumor uptake was similar for (64)Cu-DOTA-trastuzumab and (18)F-FDG (SUVmax and range, 8.1 and 3.0-22.5 for day 1 [n = 48]; 8.9 and 0.9-28.9 for day 2 [n = 38]; 9.7 and 3.3-25.4 for (18)F-FDG [n = 56]), but same-lesion SUVmax was not correlated between the 2 radiotracers. No toxicities were observed, and estimated radiation dose from (64)Cu-DOTA-trastuzumab was similar to (18)F-FDG. (64)Cu-DOTA-trastuzumab visualizes HER2-positive metastatic breast cancer with high sensitivity and is effective in surveying disseminated disease. A 45-mg trastuzumab predose provides a (64)Cu-DOTA-trastuzumab biodistribution favorable for tumor imaging. (64)Cu-DOTA-trastuzumab PET/CT warrants further evaluation for assessing tumor HER2 expression and individualizing treatments that include trastuzumab.

Volatile properties of particles emitted by compressed natural gas and diesel buses during steady-state and transient driving modes.

PubMed

Jayaratne, E R; Meyer, N K; Ristovski, Z D; Morawska, L

2012-01-03

Volatile properties of particle emissions from four compressed natural gas (CNG) and four diesel buses were investigated under steady-state and transient driving modes on a chassis dynamometer. The exhaust was diluted utilizing a full-flow continuous volume sampling system and passed through a thermodenuder at controlled temperature. Particle number concentration and size distribution were measured with a condensation particle counter and a scanning mobility particle sizer, respectively. We show that while almost all the particles emitted by the CNG buses were in the nanoparticle size range, at least 85% and 98% were removed at 100 and 250 °C, respectively. Closer analysis of the volatility of particles emitted during transient cycles showed that volatilization began at around 40 °C, with the majority occurring by 80 °C. Particles produced during hard acceleration from rest exhibited lower volatility than those produced during other times of the cycle. On the basis of our results and the observation of ash deposits on the walls of the tailpipes, we suggest that these nonvolatile particles were composed mostly of ash from lubricating oil. Heating the diesel bus emissions to 100 °C removed ultrafine particle numbers by 69-82% when a nucleation mode was present and just 18% when it was not.

On determining dead layer and detector thicknesses for a position-sensitive silicon detector

NASA Astrophysics Data System (ADS)

Manfredi, J.; Lee, Jenny; Lynch, W. G.; Niu, C. Y.; Tsang, M. B.; Anderson, C.; Barney, J.; Brown, K. W.; Chajecki, Z.; Chan, K. P.; Chen, G.; Estee, J.; Li, Z.; Pruitt, C.; Rogers, A. M.; Sanetullaev, A.; Setiawan, H.; Showalter, R.; Tsang, C. Y.; Winkelbauer, J. R.; Xiao, Z.; Xu, Z.

2018-04-01

In this work, two particular properties of the position-sensitive, thick silicon detectors (known as the "E" detectors) in the High Resolution Array (HiRA) are investigated: the thickness of the dead layer on the front of the detector, and the overall thickness of the detector itself. The dead layer thickness for each E detector in HiRA is extracted using a measurement of alpha particles emitted from a 212Pb pin source placed close to the detector surface. This procedure also allows for energy calibrations of the E detectors, which are otherwise inaccessible for alpha source calibration as each one is sandwiched between two other detectors. The E detector thickness is obtained from a combination of elastically scattered protons and an energy-loss calculation method. Results from these analyses agree with values provided by the manufacturer.

Development and Testing of a 212Pb/212Bi Peptide for Targeting Metastatic Melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fisher, Darrell R.

2012-10-25

The purpose of this project is to develop a new radiolabeled peptide for imaging and treating metastatic melanoma. The immunoconjugate consists of a receptor-specific peptide that targets melanoma cells. The beta-emitter lead-212 (half-life = 10.4 hours) is linked by coordination chemistry to the peptide. After injection, the peptide targets melanoma receptors on the surfaces of melanoma cells. Lead-212 decays to the alpha-emitter bismuth-212 (half-life = 60 minutes). Alpha-particles that hit melanoma cell nuclei are likely to kill the melanoma cell. For cancer cell imaging, the lead-212 is replaced by lead-203 (half-life = 52 hours). Lead-203 emits 279 keV photons (80.1%more » abundance) that can be imaged and measured for biodistribution analysis, cancer imaging, and quantitative dosimetry.« less

Effective dose in SMAW and FCAW welding processes using rutile consumables.

PubMed

Herranz, M; Rozas, S; Idoeta, R; Alegría, N

2014-03-01

The shielded metal arc welding (SMAW) and flux cored arc welding (FCAW) processes use covered electrodes and flux cored wire as consumables. Among these consumables, ones containing rutile are the most widely used, and since they have a considerable natural radioactive content, they can be considered as NORM (naturally occurring radioactive material). To calculate the effective dose on workers during their use in a conservative situation, samples of slag and aerosols and particles emitted or deposited during welding were taken and measured by gamma, alpha and beta spectrometry. An analytical method was also developed for estimating the activity concentration of radionuclides in the inhaled air. (222)Rn activity concentration was also assessed. With all these data, internal and external doses were calculated. The results show that external doses are negligible in comparison with internal ones, which do not exceed 1 mSv yr(-1), either in this conservative situation or in any other more favourable one. Radionuclides after Rn in the radioactive natural series are emitted at the same activity concentration to the atmosphere, this being around 17 times higher than that corresponding to radionuclides before Rn. Taking into account these conclusions and the analytical method developed, it can be concluded that one way to assess the activity concentration of natural radionuclides in inhaled air and hence effective doses could be the early gamma-ray spectrometry of aerosols and particles sampled during the welding process.

Halogenated naphthyl methoxy piperidines for mapping serotonin transporter sites

DOEpatents

Goodman, Mark M.; Faraj, Bahjat

1999-01-01

Halogenated naphthyl methoxy piperidines having a strong affinity for the serotonin transporter are disclosed. Those compounds can be labeled with positron-emitting and/or gamma emitting halogen isotopes by a late step synthesis that maximizes the useable lifeterm of the label. The labeled compounds are useful for localizing serotonin transporter sites by positron emission tomography and/or single photon emission computed tomography.

Halogenated naphthyl methoxy piperidines for mapping serotonin transporter sites

DOEpatents

Goodman, M.M.; Faraj, B.

1999-07-06

Halogenated naphthyl methoxy piperidines having a strong affinity for the serotonin transporter are disclosed. Those compounds can be labeled with positron-emitting and/or gamma emitting halogen isotopes by a late step synthesis that maximizes the useable lifeterm of the label. The labeled compounds are useful for localizing serotonin transporter sites by positron emission tomography and/or single photon emission computed tomography.

Trastuzumab-induced cardiotoxicity.

PubMed

Moss, Lisa Stegall; Starbuck, Mandy Fields; Mayer, Deborah K; Harwood, Elaine Brooks; Glotzer, Jana

2009-11-01

To review trastuzumab-related cardiotoxic effects in the breast cancer adjuvant setting, present a system for pretreatment screening for cardiovascular risk factors, describe monitoring recommendations, provide a tool to facilitate adherence to monitoring guidelines, and discuss implications for patient education. Literature regarding cardiotoxicity and trastuzumab in breast cancer. Trastuzumab was approved in 2006 for use in the adjuvant setting. A small percentage of women (approximately 4%) developed heart failure during or after treatment. However, the trials excluded women with cardiac disease. Current screening for cardiotoxicity relies on sequential left ventricular function measurements with either echocardiography or multigated acquisition scanning at baseline and every three months. Treatment modifications are recommended if changes from baseline are detected. Long-term and late effects have yet to be determined. Although a small number of women experienced cardiotoxicity in the adjuvant setting, an increase may be seen because women with preexisting heart disease receive this treatment. Guidelines and tools will be helpful for appropriate and consistent screening of cardiac risk factors and disease prior to initiation of trastuzumab and for monitoring during and after administration. Nurses are instrumental in assessing, monitoring, and treating women receiving trastuzumab. Implementing guidelines to promote adherence to recommended monitoring is important in the early detection of cardiotoxicity in this population. Educating women about their treatment and side effects is an important aspect of care.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elihn, K.; Landstroem, L.; Alm, O.

Iron nanoparticles enclosed in carbon shells were formed by laser-assisted chemical vapor decomposition of ferrocene (Fe(C{sub 5}H{sub 5}){sub 2}) vapor in Ar gas atmosphere. The particle size dependence on the total ambient gas pressure and on laser fluence of the pulsed ArF excimer laser was examined and, e.g., an effective size decrease of the iron core was observed at elevated laser fluences. Characterizations of the iron and carbon microstructures were performed by x-ray diffraction and transmission electron microscopy, while relative iron deposition rates were measured by x-ray fluorescence spectroscopy. Both {alpha}-Fe and {gamma}-Fe phases were found for the single crystallinemore » iron cores, surrounded by graphitic (inner) and amorphous (outer) carbon layers. The temperature rise of the laser-excited particles was also determined by optical spectroscopy of the emitted thermal radiation, which allowed an estimation of the iron loss of the nanoparticles due to evaporation. The estimated and measured iron losses are in good agreement.« less

Magnetic iron oxide nanoparticles for the collection and direct measurement of adsorbed alpha-emitting radionuclides from environmental waters by liquid scintillation analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

O'Hara, Matthew J.; Addleman, R. Shane

Radioactive contamination in the environment, be it from accidental or intentional release, can create an urgent need to assess water and food supplies, the environment, and monitor human health. Alpha-emitting radionuclides represent the most ionizing, and therefore the most damaging, form of radiation when internalized. Additionally, because of its ease of energy attenuation in solids or liquids, alpha emissions cannot be reliably monitored using non-destructive means. In the event of such an emergency, rapid and efficient methods will be needed to screen scores of samples (food, water, and human excreta) within a short time window. Unfortunately, the assay of alpha-emittingmore » radionuclides using traditional radioanalytical methods is typically labor intensive and time consuming. The creation of analytical counting sources typically requires a series of chemical treatment steps to achieve well performing counting sources. In an effort to devise radioanalytical methods that are fast, require little labor, and minimize the use of toxic or corrosive agents, researchers at PNNL have evaluated magnetite (Fe3O4) nanoparticles as extracting agents for alpha-emitting radionuclides from chemically unmodified aqueous systems. It is demonstrated that bare magnetic nanoparticles exhibit high affinity for representative α-emitting radionuclides (241Am and 210Po) from representative aqueous matrices: river and ground water. Furthermore, use of the magnetic properties of these materials to concentrate the sorbed analyte from the bulk aqueous solution has been demonstrated. The nanoparticle concentrate can be either directly dispensed into scintillation cocktail, or first dissolved and then added to scintillation cocktail as a solution for alpha emission assay by liquid scintillation analysis. Despite the extreme quench caused by the metal oxide suspensions, the authors have demonstrated that quench correction features available on modern liquid scintillation analyzers can be employed to assure that quench-induced analytical biases can be avoided.« less

Explosive plasma flows in a solar flare

NASA Technical Reports Server (NTRS)

Zarro, Dominic M.; Canfield, Richard C.; Metcalf, Thomas R.; Strong, Keith T.

1988-01-01

Solar Maximum Mission soft X-ray data and Sacramento Peak Observatory H-alpha observations are combined in a study of the impulsive phase of a solar flare. A blue asymmetry, indicative of upflows, was observed in the coronal Ca XIX line during the soft X-ray rise phase. A red asymmetry, indicative of downflows, was observed simultaneously in chromospheric H-alpha emitted from bright flare kernels during the period of hard X-ray emission. Combining the velocity data with a measurement of coronal electron density, it is shown that the impulsive phase momentum of upflowing soft X-ray-emitting plasma equalled that of the downflowing H-alpha-emitting plasma to within one order of magnitude. In particular, the momentum of the upflowing plasma was 2 x 10 to the 21st g cm/s while that of the downflowing plasma was 7 x 10 to the 21st g cm/s, with a factor of 2 uncertainty on each value. This equality supports the explosive chromospheric evaporation model of solar flares, in which a sudden pressure increase at the footprint of a coronal loop produces oppositely directed flows in the heated plasma.

Thermal Optical Properties of Lunar Dust Simulants and Their Constituents

NASA Technical Reports Server (NTRS)

Gaier, James R.; Ellis, Shaneise; Hanks, Nichole

2011-01-01

The total reflectance spectra of lunar simulant dusts (< 20 mm particles) were measured in order to determine their integrated solar absorptance (alpha) and their thermal emittance (epsilon) for the purpose of analyzing the effect of dust on the performance of thermal control surfaces. All of the simulants except one had a wavelength-dependent reflectivity (p (lambda)) near 0.10 over the wavelength range of 8 to 25 microns and so are highly emitting at room temperature and lower. The 300 K emittance (epsilon) of all the lunar simulants except one ranged from 0.78 to 0.92. The exception was Minnesota Lunar Simulant 1 (MLS-1), which has little or no glassy component. In all cases the epsilon was lower for the < 20 micron particles than for larger particles reported earlier. There was considerably more variation in the lunar simulant reflectance in the solar spectral range (250 to 2500 nm) than in the thermal infrared. As expected, the lunar highlands simulants were more reflective in this wavelength range than the lunar mare simulants. The integrated solar absorptance (alpha) of the simulants ranged from 0.39 to 0.75. This is lower than values reported earlier for larger particles of the same simulants (0.41 to 0.82), and for representative mare and highlands lunar soils (0.74 to 0.91). Since the of some mare simulants more closely matched that of highlands lunar soils, it is recommended that and values be the criteria for choosing a simulant for assessing the effects of dust on thermal control surfaces, rather than whether a simulant has been formulated as a highlands or a mare simulant.

In situ chemical analyses of extraterrestrial bodies

NASA Technical Reports Server (NTRS)

Economou, Thanasis E.; Turkevich, Anthony L.

1988-01-01

One of the most important tasks on any sample return mission will have to be a quick sample characterization in order to guarantee a variety of collected samples. An alpha particle instrument with alpha, proton and X-ray modes can provide a quick and almost complete chemical analysis of Mars samples. This instrument is based on three interactions of the alpha particles from a radioactive source with matter: elastic scattering of the alpha particles by nuclei (alpha mode), (alpha,p) nuclear reaction with some light elements (proton mode), and excitation of the atomic structure of atoms by alpha particles, leading to emission of characteristic X-rays of the lunar surface at three sites during the Surveyor mission of 1967 to 1968. Since then the instrument has been improved and miniaturized substantially. As shown in the past, the alpha particle instrument can operate under Martian conditions without any degradation in the performance. The alpha and proton modes can provide vital information about the light elements, while the X-ray mode with its ambient temperature X-ray detector will be useful for the heavier elements. The excitation of the atomic structure is provided by the same alpha radioactive source that is used by alpha and proton modes or by an auxiliary X-ray source that is selected to enhance the sensitivity to some important geochemical elements.

An integrated circuit/microsystem/nano-enhanced four species radiation sensor for inexpensive fissionable material detection

NASA Astrophysics Data System (ADS)

Waguespack, Randy Paul

2011-12-01

Small scale radiation detectors sensitive to alpha, beta, electromagnetic, neutron radiation are needed to combat the threat of nuclear terrorism and maintain national security. There are many types of radiation detectors on the market, and the type of detector chosen is usually determined by the type of particle to be detected. In the case of fissionable material, an ideal detector needs to detect all four types of radiation, which is not the focus of many detectors. For fissionable materials, the two main types of radiation that must be detected are gamma rays and neutrons. Our detector uses a glass or quartz scintillator doped with 10B nanoparticles to detect all four types of radiation particles. Boron-10 has a thermal neutron cross section of 3,840 barns. The interaction between the neutron and boron results in a secondary charge particle in the form of an alpha particle to be emitted, which is detectable by the scintillator. Radiation impinging on the scintillator matrix produces varying optical pulses dependent on the energy of the particles. The optical pulses are then detected by a photomultiplier (PM) tube, creating a current proportional to the energy of the particle. Current pulses from the PM tube are differentiated by on-chip pulse height spectroscopy, allowing for source discrimination. The pulse height circuitry has been fabricated with discrete circuits and designed into an integrated circuit package. The ability to replace traditional PM tubes with a smaller, less expensive photomultiplier will further reduce the size of the device and enhance the cost effectiveness and portability of the detector.

Toxicity of inhaled plutonium dioxide in beagle dogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muggenburg, M.A.; Guilmette, R.A.; Mewhinney, J.A.

This study was conducted to determine the biological effects of inhaled {sup 238}PuO{sub 2} over the life spans of 144 beagle dogs. The dogs inhaled one of two sizes of monodisperse aerosols of {sup 238}PuO{sub 2} to achieve graded levels of initial lung burden (ILB). The aerosols also contained {sup 169}Yb to provide a {gamma}-ray-emitting label for the {sup 238}Pu inhaled by each dog. Excreta were collected periodically over each dog`s life span to estimate plutonium excretion; at death, the tissues were analyzed radiochemically for plutonium activity. The tissue content and the amount of plutonium excreted were used to estimatemore » the ILB. These data for each dog were used in a dosimetry model to estimate the ILB. These data for each dog were used in a dosimetry model to estimate tissue doses. The lung, skeleton and liver received the highest {alpha}-particle doses, ranging from 0.16-68 Gy for the liver. At death, all dogs were necropsied, and all organs and lesions were sampled and examined by histopathology. Findings of non-neoplastic changes included neutropenia and lymphopenia that developed in a dose-related fashion soon after inhalation exposure. These effects persisted for up to 5 years in some animals, but no other health effects could be related to the blood changes observed. Radiation pneumonitis was observed among the dogs with the highest ILBs. Deaths from radiation pneumonitis occurred from 1.5 to 5.4 years after exposure. Tumors of the lung, skeleton and liver occurred beginning at about 3 years after exposure. These findings in dogs suggest that similar dose-related biological effects could be expected in humans accidentally exposed to {sup 238}PuO{sub 2}. 89 refs., 10 figs., 11 tab.« less

Trastuzumab emtansine: first global approval.

PubMed

Ballantyne, Anita; Dhillon, Sohita

2013-05-01

Genentech and ImmunoGen are collaborating on the development of trastuzumab emtansine, a HER2 antibody-drug conjugate that comprises Genentech's trastuzumab antibody linked to ImmunoGen's anti-mitotic agent, mertansine (a maytansine derivative; also known as DM1). The conjugate combines two strategies: the anti-HER2 activity of trastuzumab, and the targeted intracellular delivery of mertansine, a tubulin polymerisation inhibitor which interferes with mitosis and promotes apoptosis. The linker in trastuzumab emtansine is a non-reducible thioether linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC, designated MCC after conjugation). Trastuzumab emtansine (Kadcyla™) has been launched in the USA as second-line monotherapy for HER2-positive metastatic breast cancer, and has been filed for approval in the EU and Japan in this indication. Trastuzumab emtansine is in phase III development as first-line combination therapy or monotherapy for metastatic HER2-positive breast cancer, and as third-line monotherapy for metastatic HER2-positive breast cancer. Phase II development is underway for early-stage breast cancer and phase II/III development is underway in patients with HER2-positive gastric cancer. This article summarizes the milestones in the development of trastuzumab emtansine leading to this first approval for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination.

Barriers to the Use of Trastuzumab for HER2+ Breast Cancer and the Potential Impact of Biosimilars: A Physician Survey in the United States and Emerging Markets.

PubMed

Lammers, Philip; Criscitiello, Carmen; Curigliano, Giuseppe; Jacobs, Ira

2014-09-17

Trastuzumab in combination with chemotherapy has become a standard of care for patients with HER2+ breast cancer. The cost of therapy, however, can limit patient access to trastuzumab in areas with limited financial resources for treatment reimbursement. This study examined access to trastuzumab and identified potential barriers to its use in the United States, Mexico, Turkey, Russia and Brazil via physician survey. The study also investigated if the availability of a biosimilar to trastuzumab would improve access to and use of HER2 monoclonal antibody therapy. Across all countries, a subset of oncologists reported barriers to the use of trastuzumab in a neoadjuvant, adjuvant or metastatic setting. Common barriers to the use of trastuzumab included issues related to insurance coverage, drug availability and cost to the patient. Overall, nearly half of oncologists reported that they would increase the use of HER2 monoclonal antibody therapy across all treatment settings if a lower cost biosimilar to trastuzumab were available. We conclude that the introduction of a biosimilar to trastuzumab may alleviate cost-related barriers to treatment and could increase patient access to HER2-directed therapy in all countries examined.

ABP 980: promising trastuzumab biosimilar for HER2-positive breast cancer.

PubMed

Paplomata, Elisavet; Nahta, Rita

2018-03-01

Approval of the HER2-targeted antibody trastuzumab dramatically improved outcomes for patients with HER2-positive breast cancer. Multiple trastuzumab biosimilars, including ABP 980, are in clinical development. Biosimilars are not identical to the reference biologic, but exhibit equivalence and safety in analytical and clinical studies. Areas covered: A brief introduction to trastuzumab, overview of trastuzumab biosimilars, and detailed review of ABP 980 preclinical and clinical studies are included. We searched PubMed and 2016-2017 ASCO and ESMO conference proceedings for 'ABP 980' or 'trastuzumab biosimilar'. 'ABP 980 and breast cancer' or 'trastuzumab biosimilar and breast cancer' were used to search clinicaltrials.gov for phase III trials. Analytical studies of ABP 980 pharmacokinetics (PK) or pharmacodynamics (PD), phase I studies of ABP 980 safety and PK/PD, and phase III studies of clinical efficacy vs trastuzumab are included. Expert opinion: Questions remain regarding long-term impact of biosimilars on overall healthcare costs, insurance coverage of multiple approved biosimilars, and extensive clinical safety and efficacy follow-up. By producing a competitive market, trastuzumab biosimilars are anticipated to improve access to standard of care therapies, although real-world evidence remains to be obtained. Increased global access to HER2-targeted therapy may eventually alter the landscape of breast cancer and survival rates.

MiR-129-5p Sensitizes the Response of Her-2 Positive Breast Cancer to Trastuzumab by Reducing Rps6.

PubMed

Lu, Xiangdong; Ma, Jingjing; Chu, Jiahui; Shao, Qing; Zhang, Yao; Lu, Guangping; Li, Jun; Huang, Xiang; Li, Wei; Li, Yongfei; Ling, Yang; Zhao, Tao

2017-01-01

Trastuzumab is an important treatment used for patients with Her-2-positive breast cancer, but an increasing incidence of trastuzumab resistance has been observed clinically during the past decade. Aberrant microRNA (miR) expression levels are correlated with prognosis and response to trastuzumab in breast cancer. MiR-129-5p is downregulated in trastuzumab-resistant human breast cancer cells (JIMT-1), but its potential function and underlying mechanism remain unclear. Quantitative RT-PCR (qRT-PCR) was used to determine the expression levels of miR-129-5p and its potential target genes. The effects of miR-129-5p on cell responses to trastuzumab were analyzed by CCK-8 and flow cytometry assays in Her-2-positive breast cancer cells (SKBR-3 and JIMT-1). Bio-informatics analyses were performed to predict target genes of miR-129-5p, and luciferase assays were carried out to confirm the binding of miR-129-5p and rpS6. MiR-129-5p, which was downregulated and predicted to target rpS6 in trastuzumab-resistant breast cancer cells, enhanced the sensitivity of breast cancer cells to trastuzumab by reducing the expression of rpS6. Moreover, the overexpression of rpS6 reversed the sensitivity of cells to trastuzumab induced by miR-129-5p. MiR-129-5p sensitized Her-2-positive breast cancer to trastuzumab by downregulating rpS6. These findings provide novel insights into the common role of rpS6 and its related molecular mechanisms in mediating trastuzumab-resistance in Her-2-positive breast cancers. © 2017 The Author(s). Published by S. Karger AG, Basel.

Disparities in Use of Human Epidermal Growth Hormone Receptor 2-Targeted Therapy for Early-Stage Breast Cancer.

PubMed

Reeder-Hayes, Katherine; Peacock Hinton, Sharon; Meng, Ke; Carey, Lisa A; Dusetzina, Stacie B

2016-06-10

Trastuzumab is a key component of adjuvant therapy for stage I to III human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The rates and patterns of trastuzumab use have never been described in a population-based sample. The recent addition of HER2 information to the SEER-Medicare database offers an opportunity to examine patterns of trastuzumab use and to evaluate possible disparities in receipt of trastuzumab. We examined a national cohort of Medicare beneficiaries with incident stage I to III HER2-positive breast cancer diagnosed in 2010 and 2011 (n = 1,362). We used insurance claims data to track any use of trastuzumab in the 12 months after diagnosis as well as to identify chemotherapy drugs used in partnership with trastuzumab. We used modified Poisson regression analysis to evaluate the independent effect of race on likelihood of receiving trastuzumab by controlling for clinical need, comorbidity, and community-level socioeconomic status. Overall, 50% of white women and 40% of black women received some trastuzumab therapy. Among women with stage III disease, 74% of whites and 56% of blacks received trastuzumab. After adjustment for tumor characteristics, poverty, and comorbidity, black women were 25% less likely to receive trastuzumab within 1 year of diagnosis than white women (risk ratio, 0.745; 95% CI, 0.60 to 0.93). Approxemately one half of patients 65 years of age and older with stage I to III breast cancer do not receive trastuzumab-based therapy, which includes many with locally advanced disease. Significant racial disparities exist in the receipt of this highly effective therapy. Further research that identifies barriers to use and increases uptake of trastuzumab could potentially improve recurrence and survival outcomes in this population, particularly among minority women. © 2016 by American Society of Clinical Oncology.

Fabrication, characterization and simulation of 4H-SiC Schottky diode alpha particle detectors for pyroprocessing actinide monitoring

NASA Astrophysics Data System (ADS)

Garcia, Timothy Richard

Pyroprocessing is a method of using high-temperature molten salts and electric fields to separate and collect fuel isotopes of used nuclear fuel. It has been has been tested in the U.S. at Idaho National Laboratory as a key step in closing the nuclear fuel cycle. One technical problem with the pyroprocessing method is a lack of knowledge regarding the actinide concentrations in the salt bath during operation, since on-line techniques for measuring these concentrations are not presently available. 4H-SiC Schottky diode detectors can potentially fulfill this need. Such detectors would operate in contact with the molten salt, and measure concentrations via alpha-particle spectroscopy. This work seeks to fabricate and characterize 4H-SiC Schottky diode detectors at high temperature, model the alpha particle spectrum expected in a molten salt, and model the operation of the detectors to confirm the physics of operation is as expected. In this work, 4H-SiC Schottky diode detectors were fabricated at OSU Nanotech West. After fabrication, these detectors were characterized using both I-V curves and Am-241 alpha-particle energy spectra. All measurements were made as a function of temperature, from room temperature up to 500°C. The average energy required to create an electron-hole pair was observed to decrease with an increase of temperature, due to a decrease of both the 4H-SiC bandgap and non-linear energy loss terms. Furthermore, the FWHM of the spectra was observed to be dependent on the leakage current at a certain temperature, and not dependent on the temperature itself. Secondly, the alpha particle energy spectrum in the pyroprocessing environment was modeled using SRIM. The molten salt was modeled in 3 different geometries, with or without a protective cover material on top of the detector. Due to the loss of alpha-particle energy in the molten salt itself, a high-energy alpha emitter may completely cover the spectrum from a lower-energy alpha emitter. Each of the geometries simulated showed a different sensitivity to the lower-energy alpha emitter. Regardless of which geometry was modeled, it was observed that it is possible to measure both the emission energy of the alpha particles, as well as the concentration of the alpha emitter in the liquid. Lastly, Sentaurus TCAD was used to simulate the detection of alpha-particle charge collection in situations that are relevant to the molten salt alpha particle energy spectra. The effect of electric field negation was investigated, as well as velocity saturation. Finally, the dependence of charge recombination on temperature, alpha particle energy, and angle of incidence was investigated. These simulations captured the measurements performed at room temperature. With changed angle of incidence, the change in the amount of charge collected was less than 1 percent, indicating a weak dependence. Also, the amount of charge lost to Auger recombination was seen to increase with temperature. This disagrees with observations from experiment, indicating that the temperature dependence of one or more parameters of the model may not be accurate.

Evaluation of Trastuzumab-induced early cardiac dysfunction using two-dimensional Strain Echocardiography.

PubMed

Emren, Sadik Volkan; Tuluce, Selcen Yakar; Levent, Fatih; Tuluce, Kamil; Kalkan, Toygar; Yildiz, Yasar; Alacacioğlu, Ahmet; Kucukzeybek, Yüksel; Akyol, Murat; Salman, Tarık

2015-12-01

Trastuzumab, a chemotherapeutic agent used in the treatment of breast cancer. has been shown to induce subclinical left ventricular (LV) dysfunction during a three to six month period as evidenced by strain echocardiographic examination without any change occurring in the ejection fraction of LV. The present study evaluated the presence of subclinical LV dysfunction using strain echocardiography 1 day and 7 days after the initiation of trastuzumab therapy. The patients with breast cancer receiving adjuvant trastuzumab therapy underwent 2-dimensional, tissue Doppler, and strain echocardiographic examination at baseline and 1 day and 7 days after therapy. LV global longitudinal strain (GLS), global circumferential strain (GCS) values, and other echocardiographic parameters were calculated. A total of 40 females, mean age 50+/-10 years, were evaluated. Of these patients, 97% received anthracycline and 73% received radiotherapy before the initiation of trastuzumab therapy. No change was observed in any of the echocardiographic parameters 1 day after the initiation of trastuzumab therapy (p>0.05). The LV ejection fraction, tissue Doppler parameters, and GCS values did not show any changes 7 days after the initiation of therapy, whereas significant decreases were observed in GLS value (19.2+/-4.0% vs. 17.2+/-3.4, p=0.001) and systolic annular velocity of the lateral LV wall (S' velocity) (10.5+/-3.2 vs. 8.6+/-2.2, p=0.002). Trastuzumab therapy is associated with subclinical LV dysfunction as early as 7 days after initiation of the therapy as evidenced by the decreases in GLS value of LV and systolic annular velocity of the lateral LV wall.

Subcutaneous Trastuzumab for HER2-positive Breast Cancer – Evidence and Practical Experience in 7 German Centers

PubMed Central

Jackisch, C.; Müller, V.; Dall, P.; Neumeister, R.; Park-Simon, T.-W.; Ruf-Dördelmann, A.; Seiler, S.; Tesch, H.; Ataseven, B.

2015-01-01

A subcutaneous formulation of trastuzumab to treat patients with HER2-positive breast cancer is available since August 2013. The subcutaneous formulation is administered as a fixed dose of 600 mg over a period of up to 5 minutes. The HannaH trial compared subcutaneous with intravenous administration and found comparable pharmacokinetics, efficacy and tolerability for both administration forms of trastuzumab in the neoadjuvant setting. The randomized crossover study PrefHer reported a clear preference from the patientʼs point of view for subcutaneous over intravenous administration of trastuzumab. The accompanying time-and-motion study reported a reduction concerning the total time spent for the institution as well as for the patient receiving trastuzumab s. c.. The experience of 7 German centers largely corresponded with the results of these studies. Patients expressed a clear preference for subcutaneous trastuzumab administration, with the time saved by the subcutaneous administration route cited as the greatest benefit. Although the existing reimbursement terms mean that centers will receive a lower remuneration, the centersʼ overall evaluation of the subcutaneous administration route for trastuzumab was overwhelmingly positive. The greatest benefit cited by the centers was the flexibility in scheduling patient appointments. This increased flexibility improved conditions in some centers which were experiencing pressures due to a shortage of staff, particularly at peak times. The general consensus, however, was that the remuneration systems for oncological treatments urgently need to be amended to ensure that the real costs of treatment are covered, even if the administration route has changed. PMID:26166837

Economic evaluations of trastuzumab in HER2-positive metastatic breast cancer: a systematic review and critique.

PubMed

Parkinson, Bonny; Pearson, Sallie-Anne; Viney, Rosalie

2014-01-01

Published economic evaluations of trastuzumab for the treatment of HER2-positive metastatic breast cancer have arrived at different conclusions regarding the cost-effectiveness of trastuzumab, despite comparative efficacy being demonstrated by a small set of randomised controlled trials (RCTs). This article aims to provide insight into the quality of the evaluations and explore the possible drivers of the conflicting conclusions. A systematic literature review was conducted to identify all published economic evaluations that compared the incremental costs and outcomes of trastuzumab versus a comparator. Fifteen economic evaluations were identified. In the evaluations that estimated efficacy using an RCT, the key drivers of the conclusions regarding cost-effectiveness were: the approach used to estimate overall survival in the control group given crossover to trastuzumab following progression in the trials; the inclusion of treatment beyond progression; inclusion of wastage due to unused vial portions, adverse events, and the cost of HER2 testing. Four evaluations used non-randomised approaches to estimate efficacy, thus introducing the potential for confounding. As a result these evaluations reported relatively optimistic estimates of comparative effectiveness. Finally the evaluations used different thresholds to determine whether treatment with trastuzumab was cost-effective. There were numerous drivers of the different conclusions regarding the cost-effectiveness of trastuzumab, many of which are due to judgements made by the authors when translating data from RCTs. Many of the potential drivers were not identified by the published systematic reviews of economic evaluations and perhaps more remain unidentified because of inconsistent and limited reporting.

Pilot study of 68Ga-DOTA-F(ab')2-trastuzumab in patients with breast cancer.

PubMed

Beylergil, Volkan; Morris, Patrick G; Smith-Jones, Peter M; Modi, Shanu; Solit, David; Hudis, Clifford A; Lu, Yang; O'Donoghue, Joseph; Lyashchenko, Serge K; Carrasquillo, Jorge A; Larson, Steven M; Akhurst, Timothy J

2013-12-01

68Ga-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-F(ab')2-trastuzumab [68Ga-DOTA-F(ab')2-trastuzumab] has been developed at our institution as a positron imaging reagent for assessing human epidermal growth factor receptor 2 (HER2) expression status by in-vivo imaging. Initial studies on animals demonstrated promising results in the monitoring of treatment response to heat shock protein 90-targeted drugs that inhibit the client protein HER2. We report here our initial clinical experience in the assessment of the toxicity, pharmacokinetics, biodistribution, and dosimetry profile of 68Ga-DOTA-F(ab')2-trastuzumab with PET/computed tomography using a mean of 236 MBq/5 mg administered intravenously. A group of 16 women with breast cancer were enrolled in this study. The one patient who did not receive 68Ga-DOTA-F(ab')2-trastuzumab was excluded from analysis. Both HER2-negative (n=7) and HER2-positive (n=8) cases were studied. Among the latter, seven had undergone trastuzumab treatment previously and one had not. It was determined that 68Ga-DOTA-F(ab')2-trastuzumab was well tolerated, with a T½ of ≈ 3.6 ± 0.9 h; the critical organ was the kidney, with a mean dose of 0.383 cGy/37 MBq; and tumor targeting was seen in 4/8 patients with HER2-positive disease. The reagent is safe, and assessments through additional studies in a better-defined group of patients, using larger administered masses of antibodies, with a better immunoreactive fraction are needed.

Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941.

PubMed

Junttila, Teemu T; Akita, Robert W; Parsons, Kathryn; Fields, Carter; Lewis Phillips, Gail D; Friedman, Lori S; Sampath, Deepak; Sliwkowski, Mark X

2009-05-05

Herceptin (trastuzumab) is the backbone of HER2-directed breast cancer therapy and benefits patients in both the adjuvant and metastatic settings. Here, we describe a mechanism of action for trastuzumab whereby antibody treatment disrupts ligand-independent HER2/HER3 interactions in HER2-amplified cells. The kinetics of dissociation parallels HER3 dephosphorylation and uncoupling from PI3K activity, leading to downregulation of proximal and distal AKT signaling, and correlates with the antiproliferative effects of trastuzumab. A selective and potent PI3K inhibitor, GDC-0941, is highly efficacious both in combination with trastuzumab and in the treatment of trastuzumab-resistant cells and tumors.

Occupational exposure to ultrafine particles among airport employees--combining personal monitoring and global positioning system.

PubMed

Møller, Karina Lauenborg; Thygesen, Lau Caspar; Schipperijn, Jasper; Loft, Steffen; Bonde, Jens Peter; Mikkelsen, Sigurd; Brauer, Charlotte

2014-01-01

Exposure to ultrafine particles (UFP) has been linked to cardiovascular and lung diseases. Combustion of jet fuel and diesel powered handling equipment emit UFP resulting in potentially high exposure levels among employees working at airports. High levels of UFP have been reported at several airports, especially on the apron, but knowledge on individual exposure profiles among different occupational groups working at an airport is lacking. The aim of this study was to compare personal exposure to UFP among five different occupational groups working at Copenhagen Airport (CPH). 30 employees from five different occupational groups (baggage handlers, catering drivers, cleaning staff and airside and landside security) at CPH were instructed to wear a personal monitor of particle number concentration in real time and a GPS device. The measurements were carried out on 8 days distributed over two weeks in October 2012. The overall differences between the groups were assessed using linear mixed model. Data showed significant differences in exposure levels among the groups when adjusted for variation within individuals and for effect of time and date (p<0.01). Baggage handlers were exposed to 7 times higher average concentrations (geometric mean, GM: 37×103 UFP/cm(3), 95% CI: 25-55 × 10(3) UFP/cm(3)) than employees mainly working indoors (GM: 5 × 10(3) UFP/cm(3), 95% CI: 2-11 × 103 UFP/cm(3)). Furthermore, catering drivers, cleaning staff and airside security were exposed to intermediate concentrations (GM: 12 to 20 × 10(3) UFP/cm(3)). The study demonstrates a strong gradient of exposure to UFP in ambient air across occupational groups of airport employees.

Tyrosine sulfation in precursors of collagen V.

PubMed

Fessler, L I; Brosh, S; Chapin, S; Fessler, J H

1986-04-15

Radioactive labeling of p-collagens V, collagens V, and, to a small extent, of procollagen V occurred when [35S]sulfate was incubated with tendons or primary tendon cell cultures, or blood vessels and crops of 17- to 19-day-old chick embryos, or with lung slices from neonatal rats. Most or all of this label is in the form of 1 or more sulfated tyrosine residues/chain of p alpha 1(V), alpha 1(V), p alpha 1'(V), alpha 1'(V), p alpha 2(V), and alpha 2(V), and it remains attached through purification by dialysis, ammonium sulfate precipitation, CsCl-GdnCl2 equilibrium buoyant density and velocity sedimentations, ion-exchange chromatography, and sodium dodecyl sulfate gel electrophoresis. Radioactive tyrosine sulfate was identified in alkaline hydrolysates of these collagen V chains, after labeling the tissues with either [35S]sulfate or [3H]tyrosine, by electrophoretic and chromatographic comigration with a tyrosine sulfate standard. Tunicamycin A1, which inhibits the attachment of N-linked complex carbohydrate, did not interfere with the sulfation process. The tyrosine sulfate is located in a noncollagenous domain, which is probably adjacent to the amino end of the collagen helix, and is retained throughout the physiological proteolytic processing of procollagens V. After digestion with Staphylococcus aureus V8 protease, 35S-labeled p alpha 1(V) and alpha 1(V) chains gave the same map of labeled peptides, and this differed from the map given by p alpha 1'(V) and alpha 1'(V) chains. Little sulfation of p alpha 2(V) and alpha 2(V) chains occurs. The implications of these observations for the structure and properties of procollagens V and their derivatives are considered.

Mutagenicity of airborne particulates in the rubber industry.

PubMed

Barański, B; Indulski, J; Janik-Spiechowicz, E; Palus, J

1989-12-01

The aim of this work was to evaluate the mutagenic activity of airborne particulate matter in the rubber industry. Air was sucked through Whatman glass-fibre filters with Staplex pumps and adsorbed substances and fume particles were extracted with acetone or toluene for 2 h in a ultrasonic cleaner. After separation of the insoluble solid phase by filtration, solvent was evaporated at a temperature of 70 degrees C in an argon atmosphere. The residue was stored at -20 degrees C. Mutagenicity was determined by the Salmonella plate incorporation assay with the tester strain TA98 and activity is related either to the weight of aerosol (rev mg-1) or to the volume of atmospheric sample (rev m-3). The fumes emitted from the tyre tread line, calender feeding, and tyre vulcanizing processes, showed the highest mutagenic activity (55-211 rev mg-1, + S9). At these and at other workplaces (extruder mill, carbon black station, mixer loading), mutagenic activity related to the volume of air was in the range of 22-158 rev m-3, + S9. The results indicate the need to reduce and monitor mutagenic contamination in order to increase the safety of work in the rubber industry.

Effect of Photon Hormesis on Dose Responses to Alpha Particles in Zebrafish Embryos.

PubMed

Ng, Candy Yuen Ping; Cheng, Shuk Han; Yu, Kwan Ngok

2017-02-11

Photon hormesis refers to the phenomenon where the biological effect of ionizing radiation with a high linear energy transfer (LET) value is diminished by photons with a low LET value. The present paper studied the effect of photon hormesis from X-rays on dose responses to alpha particles using embryos of the zebrafish ( Danio rerio ) as the in vivo vertebrate model. The toxicity of these ionizing radiations in the zebrafish embryos was assessed using the apoptotic counts at 20, 24, or 30 h post fertilization (hpf) revealed through acridine orange (AO) staining. For alpha-particle doses ≥ 4.4 mGy, the additional X-ray dose of 10 mGy significantly reduced the number of apoptotic cells at 24 hpf, which proved the presence of photon hormesis. Smaller alpha-particle doses might not have inflicted sufficient aggregate damages to trigger photon hormesis. The time gap T between the X-ray (10 mGy) and alpha-particle (4.4 mGy) exposures was also studied. Photon hormesis was present when T ≤ 30 min, but was absent when T = 60 min, at which time repair of damage induced by alpha particles would have completed to prevent their interactions with those induced by X-rays. Finally, the drop in the apoptotic counts at 24 hpf due to photon hormesis was explained by bringing the apoptotic events earlier to 20 hpf, which strongly supported the removal of aberrant cells through apoptosis as an underlying mechanism for photon hormesis.

A Psychometric Examination of English and Spanish Versions of the Revised Conflict Tactics Scales

ERIC Educational Resources Information Center

Connelly, Cynthia D.; Newton, Rae R.; Aarons, Gregory A.

2005-01-01

The psychometric properties of the Revised Conflict Tactics Scales (CTS2) are examined for English-speaking (n = 211) and Spanish-speaking (n = 194) Latino women. Internal consistency of total scale scores is satisfactory (Cronbach's alpha of .70 to .84). However, subscale alphas range from .46 to .80. Confirmatory factor analyses support five…

Polystyrene-Core, Silica-Shell Scintillant Nanoparticles for Low-Energy Radionuclide Quantification in Aqueous Media.

PubMed

Janczak, Colleen M; Calderon, Isen A C; Mokhtari, Zeinab; Aspinwall, Craig A

2018-02-07

β-particle emitting radionuclides are useful molecular labels due to their abundance in biomolecules. Detection of β-emission from 3 H, 35 S, and 33 P, important biological isotopes, is challenging due to the low energies (E max ≤ 300 keV) and short penetration depths (≤0.6 mm) in aqueous media. The activity of biologically relevant β-emitters is usually measured in liquid scintillation cocktail (LSC), a mixture of energy-absorbing organic solvents, surfactants, and scintillant fluorophores, which places significant limitations on the ability to acquire time-resolved measurements directly in aqueous biological systems. As an alternative to LSC, we developed polystyrene-core, silica-shell nanoparticle scintillators (referred to as nanoSCINT) for quantification of low-energy β-particle emitting radionuclides directly in aqueous solutions. The polystyrene acts as an absorber for energy from emitted β-particles and can be loaded with a range of hydrophobic scintillant fluorophores, leading to photon emission at visible wavelengths. The silica shell serves as a hydrophilic shield for the polystyrene core, enabling dispersion in aqueous media and providing better compatibility with water-soluble analytes. While polymer and inorganic scintillating microparticles are commercially available, their large size and/or high density complicates effective dispersion throughout the sample volume. In this work, nanoSCINT nanoparticles were prepared and characterized. nanoSCINT responds to 3 H, 35 S, and 33 P directly in aqueous solutions, does not exhibit a change in scintillation response between pH 3.0 and 9.5 or with 100 mM NaCl, and can be recovered and reused for activity measurements in bulk aqueous samples, demonstrating the potential for reduced production of LSC waste and reduced total waste volume during radionuclide quantification. The limits of detection for 1 mg/mL nanoSCINT are 130 nCi/mL for 3 H, 8 nCi/mL for 35 S, and <1 nCi/mL for 33 P.

Alteration of gene expression in MDA-MB-453 breast cancer cell line in response to continuous exposure to Trastuzumab.

PubMed

Sharieh, Elham Abu; Awidi, Abdulla S; Ahram, Mamoun; Zihlif, Malek A

2016-01-10

Development of resistance against cancer therapeutic agents is a common problem in cancer management. Trastuzumab resistance is one of the challenges in management of HER-2-positive breast cancer patients resulting in breast cancer progression, metastasis, and patient poor outcome. The aim of this study is to determine the alteration in gene expression in response to Trastuzumab resistance after long-term exposure to Trastuzumab. The Trastuzumab-resistant MDA-MB-453 (MDA-MB-453/TR) cell line was developed by exposing cells to 10 μM Trastuzumab continuously for 6 months. Sensitivity toward Trastuzumab was tested using cell viability assays. The acquisition of an epithelial-to mesenchymal transition (EMT) phenotype was also observed in parallel with the development of resistance. Based on the real-time-based PCR array technology, several genes were altered affecting multiple networks. The most up-regulated genes were TGF-β1 and EGF, and IGFBP-3. These genes are known to have a critical role in Trastuzumab resistance in breast cancer cell lines and/or in the acquisition of EMT. They are also recognized for their role in cancer progression and metastasis. These alterations indicate that the development of Trastuzumab resistance is multifactorial and involves a development of a mesenchymal like phenotype. Copyright © 2015 Elsevier B.V. All rights reserved.

Viral transduction of the HER2-extracellular domain expands trastuzumab-based photoimmunotherapy for HER2-negative breast cancer cells.

PubMed

Shimoyama, Kyoko; Kagawa, Shunsuke; Ishida, Michihiro; Watanabe, Shinichiro; Noma, Kazuhiro; Takehara, Kiyoto; Tazawa, Hiroshi; Hashimoto, Yuuri; Tanabe, Shunsuke; Matsuoka, Junji; Kobayashi, Hisataka; Fujiwara, Toshiyoshi

2015-02-01

The prognosis of HER2-positive breast cancer has been improved by trastuzumab therapy, which features high specificity and limited side effects. However, trastuzumab-based therapy has shortcomings. Firstly, HER2-targeted therapy is only applicable to HER2-expressing tumors, which comprise only 20-25% of primary breast cancers. Secondly, many patients who initially respond to trastuzumab ultimately develop disease progression. To overcome these problems, we employed virus-mediated HER2 transduction and photoimmunotherapy (PIT) which involves trastuzumab conjugated with a photosensitizer, trastuzumab-IR700, and irradiation of near-infrared light. We hypothesized that the gene transduction technique together with PIT would expand the range of tumor entities suitable for trastuzumab-based therapy and improve its antitumor activity. The HER2-extracellular domain (ECD) was transduced by the adenoviral vector, Ad-HER2-ECD, and PIT with trastuzumab-IR700 was applied in the HER2-negative cancer cells. Ad-HER2-ECD can efficiently transduce HER2-ECD into HER2-negative human cancer cells. PIT with trastuzumab-IR700 induced direct cell membrane destruction of Ad-HER2-ECD-transduced HER2-negative cancer cells. Novel combination of viral transduction of a target antigen and an antibody-based PIT would expand and potentiate molecular-targeted therapy even for target-negative or attenuated cancer cells.

Alpha Particle Detection Using Alpha-Induced Air Radioluminescence: A Review and Future Prospects for Preliminary Radiological Characterisation for Nuclear Facilities Decommissioning

PubMed Central

Crompton, Anita J.; Jenkins, Alex

2018-01-01

The United Kingdom (UK) has a significant legacy of nuclear installations to be decommissioned over the next 100 years and a thorough characterisation is required prior to the development of a detailed decommissioning plan. Alpha radiation detection is notoriously time consuming and difficult to carry out due to the short range of alpha particles in air. Long-range detection of alpha particles is therefore highly desirable and this has been attempted through the detection of secondary effects from alpha radiation, most notably the air-radioluminescence caused by ionisation. This paper evaluates alpha induced air radioluminescence detectors developed to date and looks at their potential to develop a stand-off, alpha radiation detector which can be used in the nuclear decommissioning field in daylight conditions to detect alpha contaminated materials. PMID:29597340

[Primary safety analysis of trastuzumab after adjuvant chemotherapy in 30 Chinese Her2-positive early breast cancer patients].

PubMed

Zhou, Ning-Ning; Teng, Xiao-Yu; Liu, Dong-Geng; Xu, Ran; Guan, Zhong-Zhen

2008-12-01

It has been proved that trastuzumab has clinical activity in early and advanced breast cancer with Her2-overexpression. This study was to analyze the safety of trastuzumab after adjuvant chemotherapy in 30 Chinese Her2-positive early breast cancer patients. Trastuzumab was administrated after adjuvant chemotherapy every 21 days. The initial dose was 8 mg/kg, and the subsequent dose was 6 mg/kg, for four to 35 cycles (medium 18 cycles). The side effects of these patients, especially cardiotoxicity, were analyzed. Thirty patients with Her2-positive early breast cancer were entered into the study. The average treatment period was one year (range nine weeks to two years). Two patients had shivering and fever during the first infusion with trastuzumab. Left ventricular ejection fraction (LVEF) level dropped in 18 cases after treatment with trastuzumab, half of which decreased more then 10%û however, no cardiac failure was observed. The post-surgical treatment of trastuzumab in Chinese patients with Her2-positive early breast cancer shows a satisfactory safety profile. However, the potential cardiotoxicity of trastuzumab should be carefully monitored during therapy.

Trastuzumab Alters the Expression of Genes Essential for Cardiac Function and Induces Ultrastructural Changes of Cardiomyocytes in Mice

PubMed Central

ElZarrad, M. Khair; Mukhopadhyay, Partha; Mohan, Nishant; Hao, Enkui; Dokmanovic, Milos; Hirsch, Dianne S.; Shen, Yi; Pacher, Pal; Wu, Wen Jin

2013-01-01

Treatment with trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of Human Epidermal Growth Factor Receptor 2 (HER2), very successfully improves outcomes for women with HER2-positive breast cancer. However, trastuzumab treatment was recently linked to potentially irreversible serious cardiotoxicity, the mechanisms of which are largely elusive. This study reports that trastuzumab significantly alters the expression of myocardial genes essential for DNA repair, cardiac and mitochondrial functions, which is associated with impaired left ventricular performance in mice coupled with significant ultrastructural alterations in cardiomyocytes revealed by electron microscopy. Furthermore, trastuzumab treatment also promotes oxidative stress and apoptosis in myocardium of mice, and elevates serum levels of cardiac troponin-I (cTnI) and cardiac myosin light chain-1 (cMLC1). The elevated serum levels of cMLC1 in mice treated with trastuzumab highlights the potential that cMLC1 could be a useful biomarker for trastuzumab-induced cardiotoxicity. PMID:24255707

Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.

PubMed

Slamon, D J; Leyland-Jones, B; Shak, S; Fuchs, H; Paton, V; Bajamonde, A; Fleming, T; Eiermann, W; Wolter, J; Pegram, M; Baselga, J; Norton, L

2001-03-15

The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide alone (138 women) or with trastuzumab (143 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 vs. 4.6 months; P<0.001), a higher rate of objective response (50 percent vs. 32 percent, P<0.001), a longer duration of response (median, 9.1 vs. 6.1 months; P<0.001), a lower rate of death at 1 year (22 percent vs. 33 percent, P=0.008), longer survival (median survival, 25.1 vs. 20.3 months; P=0.01), and a 20 percent reduction in the risk of death. The most important adverse event was cardiac dysfunction of New York Heart Association class III or IV, which occurred in 27 percent of the group given an anthracycline, cyclophosphamide, and trastuzumab; 8 percent of the group given an anthracycline and cyclophosphamide alone; 13 percent of the group given paclitaxel and trastuzumab; and 1 percent of the group given paclitaxel alone. Although the cardiotoxicity was potentially severe and, in some cases, life-threatening, the symptoms generally improved with standard medical management. Trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2.

Long-term survival in trastuzumab-treated patients with HER2-positive metastatic breast cancer: real-world outcomes and treatment patterns in a whole-of-population Australian cohort (2001-2016).

PubMed

Daniels, Benjamin; Kiely, Belinda E; Lord, Sarah J; Houssami, Nehmat; Lu, Christine Y; Ward, Robyn L; Pearson, Sallie-Anne

2018-05-07

Patients treated with trastuzumab for HER2-positive metastatic breast cancer (HER2+MBC) are living longer, but there is little information on their outcomes and treatment experience beyond the median survival from clinical trials and real-world observational studies. We aim to describe the real-world treatment patterns and overall survival (OS) for women surviving five or more years from initiation of trastuzumab for HER2+MBC. This is a retrospective, whole-of-population cohort study of women initiating trastuzumab for HER2+MBC between 2001 and 2011, followed to 2016. We defined long-term survivors (LTS) as those patients surviving ≥ 5 years from trastuzumab initiation. We used dispensing claims to describe timing of cancer treatments used by LTS and to estimate time on and off HER2-targeted therapies, and OS from trastuzumab initiation for HER2+MBC. Of 4177 women initiating trastuzumab for HER2+MBC, 1082 (26%) survived ≥ 5 years. Median age for LTS was 54 years (IQR 46-63). At a median follow-up of 9.4 years, 36% of LTS died; their conditional probability of surviving an additional 5 years was 55%. Median time on trastuzumab and all HER2-targeted therapy was 58.9 months (27.6-88.1) and 69.1 months (35.6-124.5), respectively. 85% of LTS had a period off HER2 therapy, lasting a median of 30.4 months (8.2-NR). LTS generally receive HER2-targeted therapies for periods of time longer than in clinical trials, but most LTS also had breaks in treatment. More research is needed to understand the effects of long-term treatment and to identify patients who may be able to safely discontinue HER2-targeted therapy.

Alpha-tocopherol disappearance rates from plasma depend on lipid concentrations: Studies using deuterium labeled collard greens in younger and older adults

USDA-ARS?s Scientific Manuscript database

Little is known about alpha-tocopherol's bioavailability as a constituent of food or its dependence on a subject's age. To evaluate the alpha-tocopherol bioavailability from food, we used collard greens grown in deuterated water (2H collard greens) as a source of deuterium-labeled (2H) alpha-tocophe...

Efficacy and safety analysis of trastuzumab and paclitaxel based regimen plus carboplatin or epirubicin as neoadjuvant therapy for clinical stage II-III, HER2-positive breast cancer patients: a phase 2, open-label, multicenter, randomized trial

PubMed Central

Yang, Wentao; Xu, Binghe; Huang, Tao; Yang, Hongjian; Zheng, Hong; Wang, Yongsheng; Song, Erwei; Zhang, Jin; Cui, Shude; Pang, Da; Tang, Lili; Lei, Yutao; Geng, Cuizhi; Shao, Zhiming

2015-01-01

This trial was designed to compare the efficacy and safety between epirubicin (E) and carboplatin (C) in combination with paclitaxel (P) and trastuzumab (H) in neoadjuvant setting. In 13 Chinese cancer centers, 100 patients with HER2-positive, locally advanced breast cancer were 1:1 randomized to receive medication as follows: trastuzumab and paclitaxel weekly combined with carboplatin weekly for PCH group, or epirubicin every 3 weeks for PEH group. Patients were given 4 to 6 cycles of chemotherapy. The primary endpoint was pathologic complete response (pCR) rate, which was no significant difference in PCH and PEH regimen (39.1% vs. 48.8%; p=0.365). However, PEH regimen achieved higher pCR in luminal-B (HER2-poitive) subgroup (55.0% vs. 24.0%; p = 0.033), but not in ERBB2+ subgroup (42.9% vs. 57.1%; p = 0.355). PEH regimen showed a favorable efficacy in PIK3CA mutated subgroup (69.2% vs.23.5%, p=0.012). No significant difference was observed in the subgroup analysis of TP53 mutation status, PTEN expression, FCGR2A SNP and FCGR3A SNP. Both regimens as neoadjuvant chemotherapy achieve similar efficacy and safety. PEH might improve pCR rate, especially in the luminal-B subtype and PIK3CA mutation subtype. PEH is feasible and less likely to increase the incidence of acute cardiac events compared to PCH. PMID:26084292

Size distribution of particle-phase molecular markers during a severe winter pollution episode.

PubMed

Kleeman, Michael J; Riddle, Sarah G; Jakober, Chris A

2008-09-01

Airborne particulate matter was collected using filter samplers and cascade impactors in six size fractions below 1.8 microm during a severe winter air pollution event at three sites in the Central Valley of California. The smallest size fraction analyzed was 0.056 < Dp <0.1 microm particle diameter, which accounts for the majority of the mass in the ultrafine (PM0.1) size range. Separate samples were collected during the daytime (10 a.m. to 6 p.m. PST) and nighttime (8 p.m. to 8 a.m. PST) to characterize diurnal patterns. Each sample was extracted with organic solvents and analyzed using gas chromatography mass spectrometry for molecular markers that can be used for size-resolved source apportionment calculations. Colocated impactor and filter measurements were highly correlated (R8 > 0.8) for retene, benzo[ghi]flouranthene, chrysene, benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[e]pyrene, benzo[a]pyrene, perylene, indeno[1,2,3-cd]pyrene, benzo[ghi]perylene, coronene, MW302 polycyclic aromatic hydrocarbon (PAHs), 17beta(H)-21alpha(H)-30-norhopane, 17alpha(H)-21beta(H)-hopane, alphabetabeta-20R-C29-ethylcholestane, levoglucosan, and cholesterol. Of these compounds, levoglucosan was present in the highest concentration (60-2080 ng m(-3)) followed by cholesterol (6-35 ng m(-3)), PAHs (2-38 ng m(-3)), and hopanes and steranes (0-2 ng m(-3)). Nighttime concentrations were higher than daytime concentrations in all cases. Organic compound size distributions were generally similar to the total carbon size distributions during the nighttime but showed greater variability during the daytime. This may reflect the dominance of fresh emission in the stagnant surface layer during the evening hours and the presence of aged organic aerosol at the surface during the daytime when the atmosphere is better mixed. All of the measured organic compound particle size distributions had a single mode that peaked somewhere between 0.18 and 0.56 microm, but the width of each distribution varied by compound. Cholesterol generally had the broadest particle size distribution, while benzo[ghi]perylene and 17alpha(H)-21beta(H)-29-norhopane generally had sharper peaks. The difference between the size distributions of the various particle-phase organic compounds reflects the fact that these compounds exist in particles emitted from different sources. The results of the current study will prove useful for size-resolved source apportionment exercises.

Monte Carlo simulation of age-dependent radiation dose from alpha- and beta-emitting radionuclides to critical trabecular bone and bone marrow targets

NASA Astrophysics Data System (ADS)

Dant, James T.; Richardson, Richard B.; Nie, Linda H.

2013-05-01

Alpha (α) particles and low-energy beta (β) particles present minimal risk for external exposure. While these particles can induce leukemia and bone cancer due to internal exposure, they can also be beneficial for targeted radiation therapies. In this paper, a trabecular bone model is presented to investigate the radiation dose from bone- and marrow-seeking α and β emitters to different critical compartments (targets) of trabecular bone for different age groups. Two main issues are addressed with Monte Carlo simulations. The first is the absorption fractions (AFs) from bone and marrow to critical targets within the bone for different age groups. The other issue is the application of 223Ra for the radiotherapy treatment of bone metastases. Both a static model and a simulated bone remodeling process are established for trabecular bone. The results show significantly lower AFs from radionuclide sources in the bone volume to the peripheral marrow and the haematopoietic marrow for adults than for newborns and children. The AFs from sources on the bone surface and in the bone marrow to peripheral marrow and haematopoietic marrow also varies for adults and children depending on the energy of the particles. Regarding the use of 223Ra as a radionuclide for the radiotherapy of bone metastases, the simulations show a significantly higher dose from 223Ra and its progeny in forming bone to the target compartment of bone metastases than that from two other more commonly used β-emitting radiopharmaceuticals, 153Sm and 89Sr. There is also a slightly lower dose from 223Ra in forming bone to haematopoietic marrow than that from 153Sm and 89Sr. These results indicate a higher therapy efficiency and lower marrow toxicity from 223Ra and its progeny. In conclusion, age-related changes in bone dimension and cellularity seem to significantly affect the internal dose from α and β emitters in the bone and marrow to critical targets, and 223Ra may be a more efficient radiopharmaceutical for the treatment of bone metastases than 153Sm and 89Sr, if the diffusion of 219Rn to the bone marrow is insignificant.

Decay studies of a long lived high spin isomer of /sup 210/Bi

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tuggle, D.G.

1976-08-01

A source of approximately 30 ..mu..g of pure (> 90%) /sup 210m/Bi (J..pi.. = 9-) was prepared by irradiating /sup 209/Bi in a nuclear reactor. After chemical separations to remove /sup 210/Po from the irradiated bismuth sample were completed, the /sup 210/Bi was electromagnetically separated from the /sup 209/Bi by a series of two isotope separations to create the source mentioned above. This source was then used to conduct alpha, conversion electron, gamma, gamma-gamma coincidence, and alpha-gamma coincidence spectroscopic studies of the decay of /sup 210m/Bi. The partial half life for the alpha decay of /sup 210m/Bi was measured asmore » 3.0 x 10/sup 6/ yr. A lower limit of 10/sup 13/ years was set for the partial half life for the decay of /sup 210m/Bi to /sup 210/Po. Alpha decay of /sup 210m/Bi to 8 excited states of /sup 206/Tl was observed. A lower limit of 10/sup -4/% was set for the branching ratio of the parity forbidden alpha decay of /sup 210/Bi to the /sup 206/Ti ground state. Theoretical decay rates for the alpha decays of /sup 210m/Bi, /sup 210/Bi, /sup 211/Po, and /sup 211m/Po were calculated using the method developed by Hans Mang. A comparison of the calculated and experimentally measured alpha decay rates of /sup 210m/Bi showed good agreement for the relative alpha decay rates.« less

Characterization of the Oum Er Rbia (Morocco) high basin karstic water sources by using solid state nuclear track detectors and radon as a natural tracer.

PubMed

Khalil, N; Misdaq, M A; Berrazzouk, S; Mania, J

2002-06-01

Uranium and thorium contents as well as radon alpha-activities per unit volume were evaluated inside different water samples by using a method based on calculating the CR-39 and LR-115 type II solid state nuclear track detectors (SSNTDs) detection efficiencies for the emitted alpha-particles and measuring the resulting track density rates. The validity of the SSNTD technique utilized was checked by analysing uranyl nitrate (UO2(NO3)26H2O) standard solutions. A relationship between water radon concentration and water transmission of different water sources belonging to two regions of the Middle Atlas (Morocco) water reservoir was found. The influence of the water flow rate as well as the permeability and fracture system of the host rocks of the sources studied was investigated.