183 results on '"Slater JM"'
Search Results
2. TU‐H‐CAMPUS‐TeP1‐03: Magnetically Focused Proton Irradiation of Small Volume Radiosurgery Targets
- Author
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McAuley, GA, primary, Slater, JM, additional, and Wroe, AJ, additional
- Published
- 2016
- Full Text
- View/download PDF
Catalog
3. SU-D-304-02: Magnetically Focused Proton Irradiation of Small Field Targets
- Author
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McAuley, GA, primary, Slater, JM, additional, Slater, JD, additional, and Wroe, AJ, additional
- Published
- 2015
- Full Text
- View/download PDF
4. SU-E-T-333: Immobilization for Proton Therapy - How Is It Different to Photon Therapy?
- Author
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Wroe, A, primary, Schulte, R, additional, Slater, JD, additional, and Slater, JM, additional
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- 2012
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5. MO-A-213AB-10: Scattering System Optimization for Proton Therapy
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Wroe, A, primary, Schulte, R, additional, Barnes, S, additional, McAuley, G, additional, Slater, JD, additional, and Slater, JM, additional
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- 2012
- Full Text
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6. Proton dosimetry intercomparison based on the ICRU report 59 protocol
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Vatnitsky, S, Moyers, M, Miller, D, Abell, G, Slater, JM, Pedroni, E, Coray, A, Mazal, A, Newhauser, W, Jaekel, O, Heese, J, Fukumura, A, Futami, Y, Verhey, L, Daftari, I, Grusell, Erik, Molokanov, A, Bloch, C, Vatnitsky, S, Moyers, M, Miller, D, Abell, G, Slater, JM, Pedroni, E, Coray, A, Mazal, A, Newhauser, W, Jaekel, O, Heese, J, Fukumura, A, Futami, Y, Verhey, L, Daftari, I, Grusell, Erik, Molokanov, A, and Bloch, C more...
- Abstract
BACKGROUND AND PURPOSE: A new protocol for calibration of proton beams was established by the ICRU in report 59 on proton dosimetry. In this paper we report the results of an international proton dosimetry intercomparison, which was held at Loma Linda University Medical Center. The goals of the intercomparison were, first, to estimate the level of consistency in absorbed dose delivered to patients if proton beams at various clinics were calibrated with the new ICRU protocol, and second, to evaluate the differences in absorbed dose determination due to differences in 60Co-based ionization chamber calibration factors. MATERIALS AND METHODS: Eleven institutions participated in the intercomparison. Measurements were performed in a polystyrene phantom at a depth of 10.27 cm water equivalent thickness in a 6-cm modulated proton beam with an accelerator energy of 155 MeV and an incident energy of approximately 135 MeV. Most participants used ionization chambers calibrated in terms of exposure or air kerma. Four ionization chambers had 60Co-based calibration in terms of absorbed dose-to-water. Two chambers were calibrated in a 60Co beam at the NIST both in terms of air kerma and absorbed dose-to-water to provide a comparison of ionization chambers with different calibrations. RESULTS: The intercomparison showed that use of the ICRU report 59 protocol would result in absorbed doses being delivered to patients at their participating institutions to within +/-0.9% (one standard deviation). The maximum difference between doses determined by the participants was found to be 2.9%. Differences between proton doses derived from the measurements with ionization chambers with N(K)-, or N(W) - calibration type depended on chamber type. CONCLUSIONS: Using ionization chambers with 60Co calibration factors traceable to standard laboratories and the ICRU report 59 protocol, a distribution of stated proton absorbed dose is achieved with a difference less than 3%. The ICRU protocol should b, Erratum in Radiother Oncol 1999 Sep;52(3):281. more...
- Published
- 1999
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7. Partial Breast Irradiation Delivered With Proton Beam: Results of a Phase II Trial.
- Author
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Bush DA, Slater JD, Garberoglio C, Do S, Lum S, and Slater JM
- Published
- 2011
8. A technique of partial breast irradiation utilizing proton beam radiotherapy: comparison with conformal X-ray therapy.
- Author
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Bush DA, Slater JD, Garberoglio C, Yuh G, Hocko JM, and Slater JM
- Abstract
PURPOSE:: To develop a breast immobilization system and clinical technique to deliver partial breast irradiation with a proton beam and compare dose distributions using proton therapy and conformal x-rays. METHODS:: A clinical technique to provide reproducible breast immobilization was developed. Breast immobilization begins by fitting each patient with a treatment brassiere. Patients are placed prone in a cylindrical polyvinyl chloride shell with the upper and lower body being supported and immobilized with Vac-Lok foam bead cushions. The upper chest and breast areas are immobilized with two-part expandable foam. After a treatment planning computed tomography scan, the lumpectomy cavity is outlined, and a clinical target volume is generated by adding 1cm in all dimensions. A three-dimensional treatment plan is developed with treatment typically given with 2 to 4 separate proton beams. The dose administered is 40 cobalt Gray equivalents (CGE) delivered in 10 daily fractions of 4 CGE with multiple fields treated each day. Proton and conformal x-ray plans were compared using dose-volume histogram analysis to determine volumes of normal breast tissue and skin treated with each technique. RESULTS:: An institutional review board-approved clinical trial was developed using this technique, and 20 patients have completed treatment. All subjects were able to undergo the immobilization procedure and daily treatments without significant discomfort, and no treatment interruptions were encountered. There was no evidence of respiratory motion identified on treatment planning CT images or on daily set-up radiographs. Acute toxicity has been limited to occasional radiation dermatitis (Radiation Therapy Oncology Group grade 1-2). Proton plans were compared with 2 methods of photon partial breast irradiation, including reduced tangential fields and five-field conformal techniques. Ten treatment plans with dose-volume histogram analysis revealed that the use of proton beams provided a significant reduction in doses to the ipsilateral breast and skin while eliminating doses to the heart and lung tissues. CONCLUSIONS:: A simple immobilization procedure provides accurate and reproducible breast positioning while simultaneously eliminating respiratory motion. The procedure has been well tolerated by the first 20 patients. Protons can provide substantial normal tissue protection compared with the use of conformal x-rays when used for partial breast treatment. We plan to continue enrollment and analyze long-term toxicity, local control, and survival. [ABSTRACT FROM AUTHOR] more...
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- 2007
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9. Fractionated proton radiation treatment for pediatric craniopharyngioma: preliminary report.
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Luu QT, Loredo LN, Archambeau JO, Yonemoto LT, Slater JM, and Slater JD
- Abstract
This retrospective preliminary review evaluated the efficacy and toxicity of fractionated proton radiotherapy in the management of pediatric craniopharyngioma. METHODS: Sixteen patients, aged 7-34 years, were treated with proton-beam radiation. All had undergone at least one tumor resection. Seven patients underwent repeat resection for recurrence; one had previous x-ray radiotherapy. A daily dose of 1.8 cobalt gray equivalent was used to give a total dose in the range of 50.4-59.4 cobalt gray equivalent. RESULTS: Local control was achieved in 14 of 15 patients. Twelve of 15 patients survived. There were few acute side effects. Long-term complications included newly diagnosed panhypopituitarism, a cerebrovascular accident from which the patient fully recovered, and an out-of-proton-field meningioma in the single patient who received previous radiotherapy. DISCUSSION: Fractionated proton radiotherapy is an effective treatment for children with craniopharyngioma. Longer follow-up is needed to evaluate late complications. [ABSTRACT FROM AUTHOR] more...
- Published
- 2006
10. Effect of therapeutic irradiation on the immune responses
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Slater, JM, primary, Ngo, E, additional, and Lau, BH, additional
- Published
- 1976
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11. Image-Guided Proton Therapy: A Comprehensive Review.
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Lane SA, Slater JM, and Yang GY
- Abstract
Image guidance for radiation therapy can improve the accuracy of the delivery of radiation, leading to an improved therapeutic ratio. Proton radiation is able to deliver a highly conformal dose to a target due to its advantageous dosimetric properties, including the Bragg peak. Proton therapy established the standard for daily image guidance as a means of minimizing uncertainties associated with proton treatment. With the increasing adoption of the use of proton therapy over time, image guidance systems for this modality have been changing. The unique properties of proton radiation present a number of differences in image guidance from photon therapy. This paper describes CT and MRI-based simulation and methods of daily image guidance. Developments in dose-guided radiation, upright treatment, and FLASH RT are discussed as well. more...
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- 2023
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12. Interaction of negatively and positively capped gold nanoparticle with different lipid model membranes.
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Sheridan AJ, Thompson KC, and Slater JM
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- Cetrimonium, Citrates, Gold, Lipid Bilayers chemistry, Metal Nanoparticles chemistry
- Abstract
The use of functionalised gold nanoparticles in biomedical applications is expanding. Here we explore the interaction of gold nanoparticles with lipid membranes using readily available equipment and basic techniques to explore how the charge on the nanoparticles, and the nature of the lipid, influences the interaction. Gold nanoparticles were synthesised with two different surface functionalisations, negatively charged citrate groups and positively charged cetyltrimethylammonium groups from CTAB, to determine how surface charge affects the interaction of the nanoparticles with the Zwitterionic lipid POPC and the anionic lipid POPG. It was observed that the surface pressure/area isotherms of POPG monolayers on exposure to citrate capped nanoparticles were not shifted to higher molecular areas as much as those of POPC, suggesting that the anionic headgroups of the POPG lipid repel the anionic surface charge of the citrate capped nanoparticles to some extent limiting inclusion. In contrast, the surface pressure/area isotherms of the POPG monolayers exposed to CTAB capped nanoparticles are shifted to higher molecular areas more than for the POPC monolayers. The interaction of anionic nanoparticles with lipid bilayers was measured by the mass change of the bilayer deposited on the surface of a quartz crystal microbalance (QCM) exposed to nanoparticles in an aqueous phase flow. The QCM frequency changes show that bilayers of unsaturated phosophocholine lipids readily took up particles, whereas for the saturated lipid DPPC significant uptake was only observed when the bilayer was warmed to above its gel-to-fluid transition temperature, T
m. This is possibly due to an increase in the molecular mobility and bilayer bending modulus, κ, of the bilayer., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier B.V.) more...- Published
- 2022
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13. Neurotrophin Pathway Receptors NGFR and TrkA Control Perineural Invasion, Metastasis, and Pain in Oral Cancer.
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Doan C, Aouizerat BE, Ye Y, Dang D, Asam K, Bhattacharya A, Howard T, Patel YK, Viet DT, Figueroa JD, Zhong JF, Thomas CM, Morlandt AB, Yu G, Callahan NF, Allen CT, Grandhi A, Herford AS, Walker PC, Nguyen K, Kidd SC, Lee SC, Inman JC, Slater JM, and Viet CT more...
- Subjects
- Humans, Neoplasm Invasiveness genetics, Neoplasm Recurrence, Local, Neoplastic Processes, Nerve Growth Factors, Nerve Tissue Proteins, Pain, Receptor Protein-Tyrosine Kinases, Receptor, Nerve Growth Factor, Receptor, trkA, Receptors, Nerve Growth Factor genetics, Squamous Cell Carcinoma of Head and Neck, Carcinoma, Squamous Cell genetics, Head and Neck Neoplasms, Mouth Neoplasms genetics
- Abstract
Oral squamous cell carcinoma (OSCC) patients suffer from poor survival due to metastasis or locoregional recurrence, processes that are both facilitated by perineural invasion (PNI). OSCC has higher rates of PNI than other cancer subtypes, with PNI present in 80% of tumors. Despite the impact of PNI on oral cancer prognosis and pain, little is known about the genes that drive PNI, which in turn drive pain, invasion, and metastasis. In this study, clinical data, preclinical, and in vitro models are leveraged to elucidate the role of neurotrophins in OSCC metastasis, PNI, and pain. The expression data in OSCC patients with metastasis, PNI, or pain demonstrate dysregulation of neurotrophin genes. TrkA and nerve growth factor receptor (NGFR) are focused, two receptors that are activated by NGF, a neurotrophin expressed at high levels in OSCC. It is demonstrated that targeted knockdown of these two receptors inhibits proliferation and invasion in an in vitro and preclinical model of OSCC, and metastasis, PNI, and pain. It is further determined that TrkA knockdown alone inhibits thermal hyperalgesia, whereas NGFR knockdown alone inhibits mechanical allodynia. Collectively the results highlight the ability of OSCC to co-opt different components of the neurotrophin pathway in metastasis, PNI, and pain., (© 2022 The Authors. Advanced Biology published by Wiley-VCH GmbH.) more...
- Published
- 2022
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14. Brain-Specific Relative Biological Effectiveness of Protons Based on Long-term Outcome of Patients With Nasopharyngeal Carcinoma.
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Zhang YY, Huo WL, Goldberg SI, Slater JM, Adams JA, Deng XW, Sun Y, Ma J, Fullerton BC, Paganetti H, Loeffler JS, Lu HM, and Chan AW
- Subjects
- Humans, Male, Middle Aged, Female, Adult, Aged, Follow-Up Studies, Radiotherapy Dosage, Magnetic Resonance Imaging, Radiation Tolerance, Carcinoma radiotherapy, Carcinoma diagnostic imaging, Carcinoma pathology, Organs at Risk radiation effects, Organs at Risk diagnostic imaging, Young Adult, Radiotherapy Planning, Computer-Assisted methods, Treatment Outcome, Proton Therapy methods, Relative Biological Effectiveness, Nasopharyngeal Neoplasms radiotherapy, Nasopharyngeal Neoplasms diagnostic imaging, Nasopharyngeal Neoplasms pathology, Monte Carlo Method, Radiotherapy, Intensity-Modulated methods, Nasopharyngeal Carcinoma radiotherapy, Nasopharyngeal Carcinoma diagnostic imaging, Nasopharyngeal Carcinoma pathology, Temporal Lobe diagnostic imaging, Temporal Lobe radiation effects
- Abstract
Purpose: Uncertainties in relative biological effectiveness (RBE) constitute a major pitfall of the use of protons in clinics. An RBE value of 1.1, which is based on cell culture and animal models, is currently used in clinical proton planning. The purpose of this study was to determine RBE for temporal lobe radiographic changes using long-term follow-up data from patients with nasopharyngeal carcinoma., Methods and Materials: Five hundred sixty-six patients with newly diagnosed nasopharyngeal carcinoma received double-scattering proton therapy or intensity modulated radiation therapy at our institutions. The 2 treatment cohorts were well matched. Proton dose distributions were simulated using Monte Carlo and compared with those obtained from the proton clinical treatment planning system. Late treatment effect was defined as development of enhancement of temporal lobe on T1-weighted magnetic resonance imaging, with or without accompanying clinical symptoms. The tolerance dose was calculated with receiving operator characteristic analysis and the Youden index. Tolerance curves, expressed as a cumulative dose-volume histogram, were generated using the cutoff points., Results: With a median follow-up period >5 years for both cohorts, 10% of proton patients and 4% of patients undergoing intensity modulated radiation therapy developed temporal lobe enhancement in unilateral temporal lobe. There was no significant difference in dose distributions between the Monte Carlo method and treatment planning system. The tolerance dose-volume levels were V10 (26.1%), V20 (21.9%), V30 (14.0%), V40 (7.7%), V50 (4.8%), and V60 (3.3%) for proton therapy (P < .03). Comparison of the two tolerance curves revealed that tolerance doses of proton treatments were lower than that of photon treatments at all dose levels. The dose tolerance at D1% was 58.56 Gy for protons and 69.07 Gy for photons. The RBE for temporal lobe enhancement from proton treatments were calculated to be 1.18., Conclusions: Using long-term clinical outcome of patients with nasopharyngeal carcinoma, our data suggest that the RBE for temporal lobe enhancement is 1.18 at D1%. A prospective study in a large cohort would be necessary to confirm these findings., (Copyright © 2021 Elsevier Inc. All rights reserved.) more...
- Published
- 2021
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15. Pseudoprogression in low-grade glioma.
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Slater JM and Shih HA
- Abstract
Competing Interests: Conflicts of Interest: Helen A. Shih: prIME Oncology (educational speaker), UpToDate (Writer), Cleveland Clinic (expert testimony). The other author has no conflicts of interest to declare. more...
- Published
- 2019
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16. Hypofractionated Proton Therapy in Early Prostate Cancer: Results of a Phase I/II Trial at Loma Linda University.
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Slater JM, Slater JD, Kang JI, Namihas IC, Jabola BR, Brown K, Grove R, Watt C, and Bush DA
- Abstract
Purpose: To determine whether a hypofractionated proton therapy regimen will control early-stage disease and maintain low rates of side effects similar to results obtained using standard-fraction proton therapy at our institution., Materials and Methods: A cohort of 146 patients with low-risk prostate cancer according to National Comprehensive Cancer Network guidelines (Gleason score <7, prostate-specific antigen [PSA] <10, tumor stage of T1-T2a) received 60 Gy (cobalt Gy equivalent) of proton therapy (20 fractions of 3.0 Gy per fraction) in 4 weeks, a dose biologically equivalent to standard fractionation (44-45 fractions of 1.8 Gy to a total of 79.2 to 81 Gy in 0 weeks). Patients were evaluated at least weekly during treatment, at which time documentation of treatment tolerance and acute reactions was obtained. Follow-up visits were conducted every 3 months for the first 1 years, every 6 months for the next 3 years, then annually. Follow-up visits consisted of history and physical examination, PSA measurements, and evaluation of toxicity., Results: The median follow-up time was 42 months (range, 3-96 months). Acute grade 2 urinary toxicity occurred in 16% (20/120) of the patients; acute grade 2 or higher gastrointestinal toxicity was seen in 1.7% (2/120). At 9 months, 1 patient had late grade 3 urinary toxicity, which resolved by 12 months; no grade 3 gastrointestinal toxicities occurred. The 3-year biochemical survival rate was 99.3% (144/145). The median time to PSA nadir was 30 months., Conclusion: Hypofractionated proton therapy of 60 Gy in 20 fractions was safe and effective for patients with low-risk prostate cancer., Competing Interests: Conflicts of Interest Statement: The authors have no relevant conflicts of interest to disclose., (©Copyright 2019 The Author(s).) more...
- Published
- 2019
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17. Experimental validation of magnetically focused proton beams for radiosurgery.
- Author
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McAuley GA, Teran AV, McGee PQ, Nguyen TT, Slater JM, Slater JD, and Wroe AJ
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- Monte Carlo Method, Water, Magnetic Phenomena, Protons, Radiosurgery methods
- Abstract
We performed experiments using a triplet of quadrupole permanent magnets to focus protons and compared their dose distributions with unfocused collimated beams using energies and field sizes typically employed in proton radiosurgery. Experiments were performed in a clinical treatment room wherein small-diameter proton beams were focused by a magnet triplet placed immediately upstream of a water tank. The magnets consisted of segments of Sm
2 Co17 rare-earth permanent magnetic material adhered into Halbach cylinders with nominal field gradients of 100, 150, 200, and 250 T m-1 . Unmodulated beams with initial diameters of 3 mm-20 mm were delivered using a single scattering system with nominal energies of 127 and 157 MeV (respective ranges of ~10 cm and 15 cm in water), commonly used for proton radiosurgery at our institution. For comparison, small-diameter unfocused collimated beams were similarly delivered. Transverse and depth dose distributions were measured using radiochromic film and a diode detector, respectively, and compared between the focused and unfocused beams (UNF). The focused beams produced low-eccentricity beam spots (defined by the 80% dose contour) at Bragg depth, with full width at 80% maximum dose values ranging from 3.8 to 7.6 mm. When initial focused beam diameters were larger than matching unfocused diameters (19 of 29 cases), the focused beams peak-to-entrance dose ratios were 13% to 73% larger than UNF. In addition, in 17 of these cases the efficiency of dose delivery to the target was 1.3× to 3.3× larger. Both peak-to-entrance dose ratios and efficiency tended to increase with initial beam diameter, while efficiency also tended to increase with magnet gradient. These experimental results are consistent with our previous Monte Carlo (MC) studies and suggest that a triplet of quadrupole Halbach cylinders could be clinically useful for irradiating small-field radiosurgical targets with fewer beams, lower entrance dose, and shorter treatment times. more...- Published
- 2019
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18. Limited effects of the maternal rearing environment on the behaviour and fitness of an insect herbivore and its natural enemy.
- Author
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Slater JM, Gilbert L, Johnson D, and Karley AJ
- Subjects
- Animals, Aphids growth & development, Female, Fertility, Host Specificity, Host-Parasite Interactions, Pisum sativum parasitology, Vicia faba parasitology, Wasps growth & development, Aphids parasitology, Aphids physiology, Herbivory, Pisum sativum physiology, Vicia faba physiology, Wasps physiology
- Abstract
The maternal rearing environment can affect offspring fitness or phenotype indirectly via 'maternal effects' and can also influence a mother's behaviour and fecundity directly. However, it remains uncertain how the effects of the maternal rearing environment cascade through multiple trophic levels, such as in plant-insect herbivore-natural enemy interactions. Pea aphids (Acyrthosiphon pisum) show differential fitness on host legume species, while generalist aphid parasitoids can show variable fitness on different host aphid species, suggesting that maternal effects could operate in a plant-aphid-parasitoid system. We tested whether the maternal rearing environment affected the behaviour and fitness of aphids by rearing aphids on two plant hosts that were either the same as or different from those experienced by the mothers. A similar approach was used to test the behaviour and fitness of parasitoid wasps in response to maternal rearing environment. Here, the host environment was manipulated at the plant or plant and aphid trophic levels for parasitoid wasps. We also quantified the quality of host plants for aphids and host aphids for parasitoid wasps. In choice tests, aphids and parasitoid wasps had no preference for the plant nor plant and aphid host environment on which they were reared. Aphid offspring experienced 50.8% higher intrinsic rates of population growth, 43.4% heavier offspring and lived 14.9% longer when feeding on bean plants compared to aphids feeding on pea plants, with little effect of the maternal rearing environment. Plant tissue nitrogen concentration varied by 21.3% in response to aphid mothers' rearing environment, and these differences correlated with offspring fitness. Maternal effects in parasitoid wasps were only observed when both the plant and aphid host environment was changed: wasp offspring were heaviest by 10.9-73.5% when both they and their mothers developed in bean-reared pea aphids. Also, parasitoid wasp fecundity was highest by 38.4% when offspring were oviposited in the maternal rearing environment. These findings indicate that maternal effects have a relatively small contribution towards the outcome of plant-aphid-parasitoid interactions., Competing Interests: The authors have declared that no competing interests exist. more...
- Published
- 2019
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19. A before-after study of hospital use in two frail populations receiving different home-based services over the same time in Vancouver, Canada.
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McGregor MJ, Cox MB, Slater JM, Poss J, McGrail KM, Ronald LA, Sloan J, and Schulzer M
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- Aged, Aged, 80 and over, British Columbia, Controlled Before-After Studies, Emergency Service, Hospital statistics & numerical data, Facilities and Services Utilization, Female, Frail Elderly, Home Care Services organization & administration, Hospitals statistics & numerical data, House Calls statistics & numerical data, Humans, Male, Outcome Assessment, Health Care, Patient Discharge statistics & numerical data, Primary Health Care statistics & numerical data, Retrospective Studies, Home Care Services statistics & numerical data, Hospitalization statistics & numerical data
- Abstract
Background: As individuals age, they are more likely to experience increasing frailty and more frequent use of hospital services. First, we explored whether initiating home-based primary care in a frail homebound cohort, influenced hospital use. Second, we explored whether initiating regular home care support for personal care with usual primary care, in a second somewhat less frail cohort, influenced hospital use., Methods: This was a before-after retrospective cohort study of two frail populations in Vancouver, Canada using administrative data to assess the influence of two different services started in two different cohorts over the same time period. The participants were 246 recipients of integrated home-based primary care and 492 recipients of home care followed between July 1st, 2008 and June 30th, 2013 before and after starting their respective services. Individuals in each group were linked to their hospital emergency department visit and discharge abstract records. The main outcome measures were mean emergency department visit and hospital admission rates per 1000 patient days for 21 months before versus the period after receipt of services, and the adjusted incidence rate ratios (IRRs) on these outcomes post receipt of service., Results: Before versus after starting integrated home-based primary care, emergency department visit rates per 1000 patient days (95% confidence intervals) were 4.1 (3.8, 4.4) versus 3.7 (3.3, 4.1), and hospital admissions rates were 2.3 (2.1, 2.5) versus 2.2 (1.9, 2.5). Before versus after starting home care, emergency department visit rates per 1000 patient days (95% confidence intervals) were 3.0 (2.8, 3.2) versus 4.0 (3.7, 4.3) visits and hospital admissions rates were 1.3 (1.2, 1.4) versus 1.9 (1.7, 2.1). Home-based primary care IRRs were 0.91 (0.72, 1.15) and 0.99 (0.76, 1.27) and home care IRRs were 1.34 (1.15, 1.56) and 1.46 (1.22, 1.74) for emergency department visits and hospital admissions respectively., Conclusions: After enrollment in integrated home-based primary care, emergency department visit and hospital admission rates stabilized. After starting home care with usual primary care, emergency department visit and hospital admission rates continued to rise. more...
- Published
- 2018
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20. Monte Carlo evaluation of magnetically focused proton beams for radiosurgery.
- Author
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McAuley GA, Heczko SL, Nguyen TT, Slater JM, Slater JD, and Wroe AJ
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- Humans, Magnetics, Monte Carlo Method, Phantoms, Imaging, Protons, Radiosurgery methods, Radiotherapy Planning, Computer-Assisted methods
- Abstract
The purpose of this project is to investigate the advantages in dose distribution and delivery of proton beams focused by a triplet of quadrupole magnets in the context of potential radiosurgery treatments. Monte Carlo simulations were performed using various configurations of three quadrupole magnets located immediately upstream of a water phantom. Magnet parameters were selected to match what can be commercially manufactured as assemblies of rare-earth permanent magnetic materials. Focused unmodulated proton beams with a range of ~10 cm in water were target matched with passive collimated beams (the current beam delivery method for proton radiosurgery) and properties of transverse dose, depth dose and volumetric dose distributions were compared. Magnetically focused beams delivered beam spots of low eccentricity to Bragg peak depth with full widths at the 90% reference dose contour from ~2.5 to 5 mm. When focused initial beam diameters were larger than matching unfocused beams (10 of 11 cases) the focused beams showed 16%-83% larger peak-to-entrance dose ratios and 1.3 to 3.4-fold increases in dose delivery efficiency. Peak-to-entrance and efficiency benefits tended to increase with larger magnet gradients and larger initial diameter focused beams. Finally, it was observed that focusing tended to shift dose in the water phantom volume from the 80%-20% dose range to below 20% of reference dose, compared to unfocused beams. We conclude that focusing proton beams immediately upstream from tissue entry using permanent magnet assemblies can produce beams with larger peak-to-entrance dose ratios and increased dose delivery efficiencies. Such beams could potentially be used in the clinic to irradiate small-field radiosurgical targets with fewer beams, lower entrance dose and shorter treatment times. more...
- Published
- 2018
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21. Changes to DPPC Domain Structure in the Presence of Carbon Nanoparticles.
- Author
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Sheridan AJ, Slater JM, Arnold T, Campbell RA, and Thompson KC
- Abstract
DPPC (dipalmitoylphosphatidylcholine) is a disaturated lipid capable of forming closely packed monolayers at the air-liquid interface of the lung and allows the surface tension within the alveoli to reduce to almost zero and thus prevent alveolar collapse. Carbon nanoparticles are formed in natural and man-made combustion events, including diesel engines, and are capable of reaching the alveolar epithelium during breathing. In this work, we have used Brewster angle microscopy and neutron reflectivity to study the effect of differing concentrations of carbon nanoparticles on the structure of DPPC monolayer as the monolayer is subject to compression and expansion. The results show that the inclusion of carbon nanoparticles within a DPPC monolayer affects the formation and structure of the lipid domains. The domains lose their circular structure and show a crenated structure as well as a reduction in overall size of the domains. This change in structure is also evident following expansion of the lipid monolayer, suggesting that some carbon nanoparticles may remain associated with the monolayer. This observation could have an important implication regarding the removal of nanosized airborne pollutants from the human lung. more...
- Published
- 2017
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22. Initial testing of a pixelated silicon detector prototype in proton therapy.
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Wroe AJ, McAuley G, Teran AV, Wong J, Petasecca M, Lerch M, Slater JM, and Rozenfeld AB
- Subjects
- Equipment Design, Monte Carlo Method, Radiometry instrumentation, Radiosurgery methods, Silicon, Proton Therapy instrumentation, Radiosurgery instrumentation
- Abstract
As technology continues to develop, external beam radiation therapy is being employed, with increased conformity, to treat smaller targets. As this occurs, the dosimetry methods and tools employed to quantify these fields for treatment also have to evolve to provide increased spatial resolution. The team at the University of Wollongong has developed a pixelated silicon detector prototype known as the dose magnifying glass (DMG) for real-time small-field metrology. This device has been tested in photon fields and IMRT. The purpose of this work was to conduct the initial performance tests with proton radiation, using beam energies and modulations typically associated with proton radiosurgery. Depth dose and lateral beam profiles were measured and compared with those collected using a PTW parallel-plate ionization chamber, a PTW proton-specific dosimetry diode, EBT3 Gafchromic film, and Monte Carlo simulations. Measurements of the depth dose profile yielded good agreement when compared with Monte Carlo, diode and ionization chamber. Bragg peak location was measured accurately by the DMG by scanning along the depth dose profile, and the relative response of the DMG at the center of modulation was within 2.5% of that for the PTW dosimetry diode for all energy and modulation combinations tested. Real-time beam profile measurements of a 5 mm 127 MeV proton beam also yielded FWHM and FW90 within ±1 channel (0.1 mm) of the Monte Carlo and EBT3 film data across all depths tested. The DMG tested here proved to be a useful device at measuring depth dose profiles in proton therapy with a stable response across the entire proton spread-out Bragg peak. In addition, the linear array of small sensitive volumes allowed for accurate point and high spatial resolution one-dimensional profile measurements of small radiation fields in real time to be completed with minimal impact from partial volume averaging., (© 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.) more...
- Published
- 2017
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23. Evaluation of the dosimetric properties of a diode detector for small field proton radiosurgery.
- Author
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McAuley GA, Teran AV, Slater JD, Slater JM, and Wroe AJ
- Subjects
- Computer Simulation, Humans, Linear Energy Transfer, Linear Models, Monte Carlo Method, Proton Therapy instrumentation, Radiosurgery instrumentation, Radiotherapy Dosage, Radiotherapy Planning, Computer-Assisted methods, Radiotherapy Planning, Computer-Assisted statistics & numerical data, Water, X-Ray Film, Proton Therapy methods, Radiometry instrumentation, Radiosurgery methods
- Abstract
The small fields and sharp gradients typically encountered in proton radiosurgery require high spatial resolution dosimetric measurements, especially below 1-2 cm diameters. Radiochromic film provides high resolution, but requires postprocessing and special handling. Promising alternatives are diode detectors with small sensitive volumes (SV) that are capable of high resolution and real-time dose acquisition. In this study we evaluated the PTW PR60020 proton dosimetry diode using radiation fields and beam energies relevant to radiosurgery applications. Energies of 127 and 157 MeV (9.7 to 15 cm range) and initial diameters of 8, 10, 12, and 20mm were delivered using single-stage scattering and four modulations (0, 15, 30, and 60mm) to a water tank in our treatment room. Depth dose and beam profile data were compared with PTW Markus N23343 ionization chamber, EBT2 Gafchromic film, and Monte Carlo simulations. Transverse dose profiles were measured using the diode in "edge-on" orientation or EBT2 film. Diode response was linear with respect to dose, uniform with dose rate, and showed an orientation-dependent (i.e., beam parallel to, or perpendicular to, detector axis) response of less than 1%. Diodevs. Markus depth-dose profiles, as well as Markus relative dose ratio vs. simulated dose-weighted average lineal energy plots, suggest that any LET-dependent diode response is negligible from particle entrance up to the very distal portion of the SOBP for the energies tested. Finally, while not possible with the ionization chamber due to partial volume effects, accurate diode depth-dose measurements of 8, 10, and 12 mm diameter beams were obtained compared to Monte Carlo simulations. Because of the small SV that allows measurements without partial volume effects and the capability of submillimeter resolution (in edge-on orientation) that is crucial for small fields and high-dose gradients (e.g., penumbra, distal edge), as well as negligible LET dependence over nearly the full the SOBP, the PTW proton diode proved to be a useful high-resolution, real-time metrology device for small proton field radiation measurements such as would be encountered in radiosurgery applications. more...
- Published
- 2015
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24. Single-Plane Magnetically Focused Elongated Small Field Proton Beams.
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McAuley GA, Slater JM, and Wroe AJ
- Subjects
- Computer Simulation, Humans, Monte Carlo Method, Proton Therapy instrumentation, Radiosurgery instrumentation, Radiosurgery methods, Radiotherapy Dosage, Proton Therapy methods
- Abstract
We previously performed Monte Carlo simulations of magnetically focused proton beams shaped by a single quadrapole magnet and thereby created narrow elongated beams with superior dose delivery characteristics (compared to collimated beams) suitable for targets of similar geometry. The present study seeks to experimentally validate these simulations using a focusing magnet consisting of 24 segments of samarium cobalt permanent magnetic material adhered into a hollow cylinder. Proton beams with properties relevant to clinical radiosurgery applications were delivered through the magnet to a water tank containing a diode detector or radiochromic film. Dose profiles were analyzed and compared with analogous Monte Carlo simulations. The focused beams produced elongated beam spots with high elliptical symmetry, indicative of magnet quality. Experimental data showed good agreement with simulations, affirming the utility of Monte Carlo simulations as a tool to model the inherent complexity of a magnetic focusing system. Compared to target-matched unfocused simulations, focused beams showed larger peak to entrance ratios (26% to 38%) and focused simulations showed a two-fold increase in beam delivery efficiency. These advantages can be attributed to the magnetic acceleration of protons in the transverse plane that tends to counteract the particle outscatter that leads to degradation of peak to entrance performance in small field proton beams. Our results have important clinical implications and suggest rare earth focusing magnet assemblies are feasible and could reduce skin dose and beam number while delivering enhanced dose to narrow elongated targets (eg, in and around the spinal cord) in less time compared to collimated beams., (© The Author(s) 2014.) more...
- Published
- 2015
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25. Evaluation of normal tissue exposure in patients receiving radiotherapy for pancreatic cancer based on RTOG 0848.
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Ling TC, Slater JM, Mifflin R, Nookala P, Grove R, Ly AM, Patyal B, Slater JD, and Yang GY
- Abstract
Background: Pancreatic cancer is a highly aggressive malignancy. Chemoradiotherapy (CRT) is utilized in many cases to improve locoregional control; however, toxicities associated with radiation can be significant given the location of the pancreas. RTOG 0848 seeks to evaluate chemoradiation using either intensity-modulated radiation therapy (IMRT) or 3D conformal photon radiotherapy (3DCRT) modalities as an adjuvant treatment. The purpose of this study is to quantify the dosimetric changes seen when using IMRT or 3D CRT photon modalities, as well as proton radiotherapy, in patients receiving CRT for cancer of the pancreas treated per RTOG 0848 guidelines., Materials: Ten patients with pancreatic head adenocarcinoma treated between 2010 and 2013 were evaluated in this study. All patients were simulated with contrast-enhanced CT imaging. Separate treatment plans using IMRT and 3DCRT as well as proton radiotherapy were created for each patient. All planning volumes were created per RTOG 0848 protocol. Dose-volume histograms (DVH) were calculated and analyzed in order to compare plans between the three modalities. The organs at risk (OAR) evaluated in this study are the kidneys, liver, small bowel, and spinal cord., Results: There was no difference between the IMRT and 3DCRT plans in dose delivered to the kidneys, liver, or bowel. The proton radiotherapy plans were found to deliver lower mean total kidney doses, mean liver doses, and liver D1/3 compared to the IMRT plans. The proton plans also gave less mean liver dose, liver D1/3, bowel V15, and bowel V50 in comparison to the 3DCRT., Conclusions: For patients receiving radiotherapy per ongoing RTOG 0848 for pancreatic cancer, there was no significant difference in normal tissue sparing between IMRT and 3DCRT treatment planning. Therefore, the choice between the two modalities should not be a confounding factor in this study. The proton plans also demonstrated improved OAR sparing compared to both IMRT and 3DCRT treatment plans. more...
- Published
- 2015
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26. Analysis of Intensity-Modulated Radiation Therapy (IMRT), Proton and 3D Conformal Radiotherapy (3D-CRT) for Reducing Perioperative Cardiopulmonary Complications in Esophageal Cancer Patients.
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Ling TC, Slater JM, Nookala P, Mifflin R, Grove R, Ly AM, Patyal B, Slater JD, and Yang GY
- Abstract
Background. While neoadjuvant concurrent chemoradiotherapy has improved outcomes for esophageal cancer patients, surgical complication rates remain high. The most frequent perioperative complications after trimodality therapy were cardiopulmonary in nature. The radiation modality utilized can be a strong mitigating factor of perioperative complications given the location of the esophagus and its proximity to the heart and lungs. The purpose of this study is to make a dosimetric comparison of Intensity-Modulated Radiation Therapy (IMRT), proton and 3D conformal radiotherapy (3D-CRT) with regard to reducing perioperative cardiopulmonary complications in esophageal cancer patients. Materials. Ten patients with esophageal cancer treated between 2010 and 2013 were evaluated in this study. All patients were simulated with contrast-enhanced CT imaging. Separate treatment plans using proton radiotherapy, IMRT, and 3D-CRT modalities were created for each patient. Dose-volume histograms were calculated and analyzed to compare plans between the three modalities. The organs at risk (OAR) being evaluated in this study are the heart, lungs, and spinal cord. To determine statistical significance, ANOVA and two-tailed paired t-tests were performed for all data parameters. Results. The proton plans showed decreased dose to various volumes of the heart and lungs in comparison to both the IMRT and 3D-CRT plans. There was no difference between the IMRT and 3D-CRT plans in dose delivered to the lung or heart. This finding was seen consistently across the parameters analyzed in this study. Conclusions. In patients receiving radiation therapy for esophageal cancer, proton plans are technically feasible while achieving adequate coverage with lower doses delivered to the lungs and cardiac structures. This may result in decreased cardiopulmonary toxicity and less morbidity to esophageal cancer patients. more...
- Published
- 2014
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27. The prognostic value of percentage of positive biopsy cores, percentage of cancer volume, and maximum involvement of biopsy cores in prostate cancer patients receiving proton and photon beam therapy.
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Slater JM, Bush DA, Grove R, and Slater JD
- Subjects
- Adult, Aged, Aged, 80 and over, Disease-Free Survival, Humans, Male, Middle Aged, Neoplasm Staging, Prognosis, Prostate pathology, Prostate-Specific Antigen, Prostatic Neoplasms mortality, Radiotherapy Dosage, Biopsy statistics & numerical data, Phototherapy, Prostatic Neoplasms pathology, Prostatic Neoplasms radiotherapy, Proton Therapy
- Abstract
Unlabelled: The purpose of this study was to compare the prognostic value of the percentage of positive biopsy cores (PPBC), the percentage of cancer volume (PCV), and the maximum involvement of biopsy cores (MIBC) as a prognostic factor in low- and intermediate-risk patients with clinically localized prostate cancer who received proton or photon beam therapy. Four hundred and fifty-nine patients with clinically localized prostate carcinoma who were treated with proton or photon beam therapy at Loma Linda University Medical Center were used for this analysis. Patients were treated with a median dose of 74.0 Gy (range 70.2-79.2) proton or combined proton/photon beam radiotherapy. Pathology reports were reviewed and PPBC, PCV, and MIBC were recorded. Analysis of biochemical no evidence of disease (bNED) outcome was assessed using Kaplan-Meier analyses. Cox regression multivariate analyses were performed to assess the impact of the biopsy factors on survival., Results: 285, 291, and 291 patients had biopsy information available for analysis, respectively. Survival analysis showed that a higher PPBC, PCV, and MIBC were each individually associated with an increased risk of biochemical failure on univariate analysis (p < 0.01). Only PPBC and PCV were associated with an increased risk of biochemical failure on multivariate analysis, adjusting for age, NCCN risk group, and dose (p < 0.01). When isolating the intermediate-risk group, only PPBC and PCV were statistically significant on multivariate analysis. Multivariate analysis of the intermediate-risk group comparing PPBC and PCV showed that PPBC was not a significant predictor of biochemical failure, while PCV was a significant predictor of biochemical failure (p = 0.37 and p = 0.03, respectively)., Conclusion: PPBC and PCV can potentially be used for additional risk stratification of intermediate-risk patients with PCV potentially being the most clinically relevant predictor bNED survival. MIBC was not found to have utility in the prognosis of low- and intermediate-risk patients. more...
- Published
- 2014
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28. Surgical and radiation therapy management of recurrent anal melanoma.
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Ling TC, Slater JM, Senthil M, Kazanjian K, Howard F, Garberoglio CA, Slater JD, and Yang GY
- Abstract
Background: Melanoma of the anorectal mucosa is a rare but highly aggressive tumor. Its presenting symptoms are frequently confused with hemorrhoids, thereby causing a delay in diagnosis. Anorectal melanoma carries with it a very poor prognosis. There is a paucity of data investigating management options for anorectal melanoma, and even fewer data reporting recurrent or refractory cases., Case Presentation: This case documents a 41-year-old female with a long history of hemorrhoids presenting with anorectal discharge. She was incidentally found have anorectal melanoma following surgical resection. Systemic diagnostic work-up demonstrated PET-avid lymphadenopathy in her right groin. She underwent right groin dissection. However, seven months later she recurred in her right groin and a new recurrent mass was found in her pelvis. She underwent a second groin dissection and resection of the pelvic recurrence. This was followed by a course of hypofractionated radiation therapy then systemic immunotherapy., Discussion: Surgery has been the mainstay of treatment. However, the extent of surgery has been the topic of investigation. Historically, radical resections have been performed but they result in high rates of post-operative morbidity. Newer studies have compared radical resection with wide local excisions and found comparable outcomes. Anorectal melanoma is frequently a systemic disease. The ideal systemic therapy regimen has not yet been determined but numerous studies show a benefit to multi-agent treatments. Radiation therapy is typically given in the post-operative or palliative setting., Conclusions: Anorectal mucosal melanoma is a very rare but aggressive disease with a poor prognosis. The overall treatment goal should strive to optimize quality of life and tumor control while minimizing treatment-related morbidities. more...
- Published
- 2014
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29. Palliative radiation therapy for primary gastric melanoma.
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Slater JM, Ling TC, Slater JD, and Yang GY
- Abstract
Introduction: Primary gastric melanoma is an exceedingly rare cause of upper gastrointestinal bleeding (GI bleeding). Prior reports of primary gastric melanoma have mostly been treated with surgery with utilization of radiation therapy being unreported. Radiation therapy has been used to palliate bleeding of other cancers including lung, bladder, cervix, and more recently primary gastric cancers., Case Presentation: This case documents an 87-year-old male who presented with fatigue and melena, and was found to have severe anemia. Endoscopy with biopsy revealed an isolated focus of melanoma. After discharge, he presented two days later and was found to have continued bleeding. Because he was deemed a poor surgical candidate he elected to undergo palliative radiation therapy for bleeding control., Discussion: The diagnosis of primary verses metastatic melanoma is a topic of debate. Case reports of patients with no known extra-gastric primary have undergone surgical treatment with varying outcomes. Patients with metastatic gastric melanoma have relied on chemotherapy and radiation in addition to surgery, with radiation being used in the palliative setting. The use of radiation to control bleeding in other cancers including primary gastric adenocarcinoma has been previously studied. This case documents the utilization of radiation therapy in bleeding due to primary gastric melanoma., Conclusions: Radiation therapy can provide adequate bleeding palliation in patients with primary gastric melanoma. more...
- Published
- 2014
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30. Correction: Changes in Mouse Thymus and Spleen after Return from the STS-135 Mission in Space.
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Gridley DS, Mao XW, Stodieck LS, Ferguson VL, Bateman TA, Moldovan M, Cunningham CE, Jones TA, Slater JM, and Pecaut MJ
- Abstract
[This corrects the article on p. e75097 in vol. 8.].
- Published
- 2013
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31. Changes in mouse thymus and spleen after return from the STS-135 mission in space.
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Gridley DS, Mao XW, Stodieck LS, Ferguson VL, Bateman TA, Moldovan M, Cunningham CE, Jones TA, Slater JM, and Pecaut MJ
- Subjects
- Animals, DNA Fragmentation, Feeding Behavior, Female, Gene Expression Profiling, Gene Expression Regulation, Mice, Models, Biological, Oncogene Proteins genetics, Oncogene Proteins metabolism, Organ Size, Signal Transduction, Spleen anatomy & histology, Thymus Gland anatomy & histology, Weightlessness, Space Flight, Spleen physiology, Thymus Gland physiology
- Abstract
Our previous results with flight (FLT) mice showed abnormalities in thymuses and spleens that have potential to compromise immune defense mechanisms. In this study, the organs were further evaluated in C57BL/6 mice after Space Shuttle Atlantis returned from a 13-day mission. Thymuses and spleens were harvested from FLT mice and ground controls housed in similar animal enclosure modules (AEM). Organ and body mass, DNA fragmentation and expression of genes related to T cells and cancer were determined. Although significance was not obtained for thymus mass, DNA fragmentation was greater in the FLT group (P<0.01). Spleen mass alone and relative to body mass was significantly decreased in FLT mice (P<0.05). In FLT thymuses, 6/84 T cell-related genes were affected versus the AEM control group (P<0.05; up: IL10, Il18bp, Il18r1, Spp1; down: Ccl7, IL6); 15/84 cancer-related genes had altered expression (P<0.05; up: Casp8, FGFR2, Figf, Hgf, IGF1, Itga4, Ncam1, Pdgfa, Pik3r1, Serpinb2, Sykb; down: Cdc25a, E2F1, Mmp9, Myc). In the spleen, 8/84 cancer-related genes were affected in FLT mice compared to AEM controls (P<0.05; up: Cdkn2a; down: Birc5, Casp8, Ctnnb1, Map2k1, Mdm2, NFkB1, Pdgfa). Pathway analysis (apoptosis signaling and checkpoint regulation) was used to map relationships among the cancer-related genes. The results showed that a relatively short mission in space had a significant impact on both organs. The findings also indicate that immune system aberrations due to stressors associated with space travel should be included when estimating risk for pathologies such as cancer and infection and in designing appropriate countermeasures. Although this was the historic last flight of NASA's Space Shuttle Program, exploration of space will undoubtedly continue. more...
- Published
- 2013
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32. Proton beam scattering system optimization for clinical and research applications.
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Wroe AJ, Schulte RW, Barnes S, McAuley G, Slater JD, and Slater JM
- Subjects
- Computer Simulation, Equipment Design, Equipment Failure Analysis, Radiotherapy Dosage, Scattering, Radiation, Computer-Aided Design, Models, Theoretical, Proton Therapy, Radiotherapy, High-Energy instrumentation, Radiotherapy, High-Energy methods
- Abstract
Purpose: To develop and test a method for optimizing and constructing a dual scattering system in passively scattered proton therapy., Methods: A beam optics optimization algorithm was developed to optimize the thickness of the first scatterer (S1) and the profile (of both the high-Z material and Lexan) of the second scatterer (S2) to deliver a proton beam matching a given set of parameters, including field diameter, fluence, flatness, and symmetry. A new manufacturing process was also tested that allows the contoured second scattering foil to be created much more economically and quickly using Cerrobend casting. Two application-specific scattering systems were developed and tested using both experimental and Monte Carlo techniques to validate the optimization process described., Results: A scattering system was optimized and constructed to deliver large uniform irradiations of radiobiology samples at low dose rates. This system was successfully built and tested using film and ionization chambers. The system delivered a uniform radiation field of 50 cm diameter (to a dose of ± 7% of the central axis) while the depth dose profile could be tuned to match the specifications of the particular investigator using modulator wheels and range shifters. A second scattering system for intermediate field size (4 cm < diameter < 10 cm) stereotactic radiosurgery and radiation therapy (SRS and SRT) treatments was also developed and tested using GEANT4. This system improved beam efficiency by over 70% compared with existing scattering systems while maintaining field flatness and depth dose profile. In both cases the proton range uniformity across the radiation field was maintained, further indicating the accuracy of the energy loss formalism in the optimization algorithm., Conclusions: The methods described allow for rapid prototyping of scattering foils to meet the demands of both research and clinical beam delivery applications in proton therapy. more...
- Published
- 2013
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33. Monte Carlo simulation of single-plane magnetically focused narrow proton beams.
- Author
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McAuley GA, Barnes SR, Slater JM, and Wroe AJ
- Subjects
- Magnetic Phenomena, Monte Carlo Method, Proton Therapy methods
- Abstract
We present Monte Carlo simulations of magnetically focused proton beams shaped by a single quadrapole magnet. Such beams are narrowly focused in one longitudinal plane but fan out in the perpendicular plane producing elongated elliptical beam spots (a 'screwdriver' shape). The focused beams were compared to passively collimated beams (the current standard of delivery for small radiosurgery beams). Beam energies considered were relevant to functional radiosurgery and standard radiosurgery clinical applications. Three monoenergetic beams (100, 125, and 150 MeV) and a modulated beam were simulated. Monoenergetic magnetically focused beams demonstrated 28 to 32% lower entrance doses, 31 to 47% larger central peak to entrance depth dose ratios, 26 to 35% smaller integral dose, 25 to 32% smaller estimated therapeutic ratios, 19 to 37% smaller penumbra volumes, and 38 to 65% smaller vertical profile lateral penumbras at Bragg depth, compared to the collimated beams. Focused modulated beams showed 31% larger central peak to entrance dose ratio, and 62 to 65% smaller vertical lateral penumbras over the plateau of the spread out Bragg peak. These advantages can be attributed to the directional acceleration of protons in the transverse plane due to the magnetic field. Such beams can be produced using commercially available assemblies of permanent rare earth magnets that do not require electric power or cryrogenic cooling. Our simulations suggest that these magnets can be inexpensively incorporated into the beam line to deliver reduced dose to normal tissue, and enhanced dose to elongated elliptical targets with major and minor axes on the order of a few centimeters and millimeters, respectively. Such beams may find application in novel proton functional and standard radiosurgery treatments in and around critical structures. more...
- Published
- 2013
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34. Space-relevant radiation modifies cytokine profiles, signaling proteins and Foxp3+ T cells.
- Author
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Gridley DS, Rizvi A, Makinde AY, Luo-Owen X, Mao XW, Tian J, Slater JM, and Pecaut MJ
- Subjects
- Animals, Body Weight radiation effects, Cytokines biosynthesis, Female, Interleukin-2 Receptor alpha Subunit metabolism, Leukocytes cytology, Leukocytes radiation effects, Mice, Mice, Inbred C57BL, Signal Transduction radiation effects, Spleen cytology, T-Lymphocytes, Regulatory cytology, Transforming Growth Factor beta1 blood, Vascular Endothelial Growth Factor A blood, Cytokines metabolism, Extraterrestrial Environment, Forkhead Transcription Factors metabolism, JNK Mitogen-Activated Protein Kinases metabolism, T-Lymphocytes, Regulatory metabolism, T-Lymphocytes, Regulatory radiation effects, p38 Mitogen-Activated Protein Kinases metabolism
- Abstract
Purpose: The major goal was to evaluate effects of various radiation regimens on leukocyte populations relatively long-term after whole-body irradiation., Materials and Methods: C57BL/6 mice were exposed to-low-dose/low-dose rate (LDR) (57)Co γ-rays (0.01 Gy, 0.03 cGy/h), with and without acute 2 Gy proton (1 Gy/min) or γ-ray (0.9 Gy/min) irradiation; analyses were done on days 21 and 56 post-exposure., Results: Numerous radiation-induced changes were noted at one or both time points. Among the most striking differences (P < 0.05) were: (i) High percentage of CD4(+)CD25(+)Foxp3(+) T cells in spleens from the Proton vs. LDR, Gamma and LDR + Proton groups (day 56); (ii) high interleukin-2 (IL-2) in spleen supernatants from the LDR and LDR + Proton groups vs. 0 Gy (day 56), whereas IL-10 was high in the LDR + Gamma group vs. 0 Gy (day 56); (iii) difference in transforming growth factor-β1 (TGF-β1) in spleen supernatants from Proton and LDR + Proton groups vs. Gamma and LDR + Gamma groups (both days); (iv) low TGF-β1 in blood from LDR + Proton vs. LDR + Gamma group (day 21); and (v) high level of activated cJun N-terminal kinase (JNK) in CD4(+) T cells from LDR + Proton vs. LDR + Gamma group (day 21)., Conclusions: The findings demonstrate that at least some immune responses to acute 2 Gy radiation were dependent on radiation quality time of assessment, and pre-exposure to LDR γ-rays. more...
- Published
- 2013
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35. Analysis of a metalloporphyrin antioxidant mimetic (MnTE-2-PyP) as a radiomitigator: prostate tumor and immune status.
- Author
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Mehrotra S, Pecaut MJ, Freeman TL, Crapo JD, Rizvi A, Luo-Owen X, Slater JM, and Gridley DS
- Subjects
- Animals, Blood Cell Count, Male, Metalloporphyrins chemistry, Mice, Mice, Inbred C57BL, Molecular Mimicry, Organ Size, Prostatic Neoplasms immunology, Prostatic Neoplasms pathology, Radiation Injuries, Experimental prevention & control, Spleen drug effects, Spleen pathology, Spleen radiation effects, Superoxide Dismutase chemistry, Tumor Burden drug effects, Tumor Burden radiation effects, Whole-Body Irradiation, Xenograft Model Antitumor Assays, Antioxidants administration & dosage, Metalloporphyrins administration & dosage, Prostatic Neoplasms radiotherapy, Radiation-Protective Agents administration & dosage
- Abstract
Due to radiation-induced immune depression and development of pathologies such as cancer, there is increasing urgency to identify radiomitigators that are effective when administered after radiation exposure. The main goal of this study was to determine the radiomitigation capacity of MnTE-2-PyP[Mn(III) tetrakis (N-ethylpyridinium-2-yl) porphyrin], a superoxide dismutase (SOD) mimetic, and evaluate leukocyte parameters in spleen and blood. C57BL/6 mice were total-body exposed to 2 Gy γ-rays (Co-60), i.e., well below a lethal dose, followed by subcutaneous implantation of 5 × 10(5) RM-9 prostate tumor cells and initiation of MnTE-2-PyP treatment (day 0); interval between each procedure was 1-2 h. The drug was administered daily (12 times). Tumor progression was monitored and immunological analyses were performed on a subset per group on day 12. Animals treated with MnTE-2-PyP alone had significantly slower tumor growth compared to mice that did not receive the drug (P < 0.05), while radiation alone had no effect. Treatment of tumor-bearing mice with MnTE-2-PyP alone significantly increased spleen mass relative to body mass; the numbers of splenic white blood cells (WBC) and lymphocytes (B and T), as well as circulating WBC, granulocytes, and platelets, were high compared to one of more of the other groups (P < 0.05). The results show that MnTE-2-PyP slowed RM-9 tumor progression and up-regulated immune parameters, but mitigation of the effects of 2 Gy total-body irradiation were minimal. more...
- Published
- 2012
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36. Fractionated proton radiotherapy for benign cavernous sinus meningiomas.
- Author
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Slater JD, Loredo LN, Chung A, Bush DA, Patyal B, Johnson WD, Hsu FP, and Slater JM
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Dose Fractionation, Radiation, Female, Follow-Up Studies, Humans, Male, Meningeal Neoplasms mortality, Meningeal Neoplasms pathology, Meningioma mortality, Meningioma pathology, Protons adverse effects, Radiotherapy Planning, Computer-Assisted methods, Tumor Burden, Young Adult, Cavernous Sinus, Meningeal Neoplasms radiotherapy, Meningioma radiotherapy, Proton Therapy
- Abstract
Purpose: To evaluate the efficacy of fractionated proton radiotherapy for a population of patients with benign cavernous sinus meningiomas., Methods and Materials: Between 1991 and 2002, 72 patients were treated at Loma Linda University Medical Center with proton therapy for cavernous sinus meningiomas. Fifty-one patients had biopsy or subtotal resection; 47 had World Health Organization grade 1 pathology. Twenty-one patients had no histologic verification. Twenty-two patients received primary proton therapy; 30 had 1 previous surgery; 20 had more than 1 surgery. The mean gross tumor volume was 27.6 cm(3); mean clinical target volume was 52.9 cm(3). Median total doses for patients with and without histologic verification were 59 and 57 Gy, respectively. Mean and median follow-up periods were 74 months., Results: The overall 5-year actuarial control rate was 96%; the control rate was 99% in patients with grade 1 or absent histologic findings and 50% for those with atypical histology. All 21 patients who did not have histologic verification and 46 of 47 patients with histologic confirmation of grade 1 tumor demonstrated disease control at 5 years. Control rates for patients without previous surgery, 1 surgery, and 2 or more surgeries were 95%, 96%, and 95%, respectively., Conclusions: Fractionated proton radiotherapy for grade 1 cavernous sinus meningiomas achieves excellent control rates with minimal toxicities, regardless of surgical intervention or use of histologic diagnosis. Disease control for large lesions can be achieved by primary fractionated proton therapy., (Copyright © 2012 Elsevier Inc. All rights reserved.) more...
- Published
- 2012
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37. Comparison of proton and electron radiation effects on biological responses in liver, spleen and blood.
- Author
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Gridley DS, Freeman TL, Makinde AY, Wroe AJ, Luo-Owen X, Tian J, Mao XW, Rightnar S, Kennedy AR, Slater JM, and Pecaut MJ
- Subjects
- Animals, Blood Cell Count methods, Blood Cells cytology, Blood Cells metabolism, Dose-Response Relationship, Radiation, Gene Expression radiation effects, Killer Cells, Natural cytology, Killer Cells, Natural metabolism, Killer Cells, Natural radiation effects, Leukocytes cytology, Leukocytes metabolism, Leukocytes radiation effects, Liver metabolism, Male, Mice, Mice, Inbred ICR, Oxidative Stress radiation effects, Spleen metabolism, Time Factors, Whole-Body Irradiation methods, Blood Cells radiation effects, Electrons, Liver radiation effects, Protons, Radiation, Ionizing, Spleen radiation effects
- Abstract
Purpose: To determine whether differences exist between proton and electron radiations on biological responses after total-body exposure., Materials and Methods: ICR mice (n=45) were irradiated to 2 Gray (Gy) using fully modulated 70 MeV protons (0.5 Gy/min) and 21 MeV electrons (3 Gy/min). At 36 h post-irradiation liver gene expression, white blood cell (WBC), natural killer (NK) cell and other analyses were performed., Results: Oxidative stress-related gene expression patterns were strikingly different for irradiated groups compared to 0 Gy (P<0.05). Proton radiation up-regulated 15 genes (Ctsb, Dnm2, Gpx5, Il19, Il22, Kif9, Lpo, Nox4, Park7, Prdx4, Prdx6, Rag2, Sod3, Srxn1, Xpa) and down-regulated 2 genes (Apoe, Prdx1). After electron irradiation, 20 genes were up-regulated (Aass, Ctsb, Dnm2, Gpx1, Gpx4, Gpx5, Gpx6, Gstk1, Il22, Kif9, Lpo, Nox4, Park7, Prdx3, Prdx4, Prdx5, Rag2, Sod1, Txnrd3, Xpa) and 1 was down-regulated (Mpp4). Of the modified genes, only 11 were common to both forms of radiation. Comparison between the two irradiated groups showed that electrons significantly up-regulated three genes (Gstk1, Prdx3, Scd1). Numbers of WBC and major leukocyte types were low in the irradiated groups (P<0.001 vs. 0 Gy). Hemoglobin and platelet counts were low in the electron-irradiated group (P<0.05 vs. 0 Gy). However, spleens from electron-irradiated mice had higher WBC and lymphocyte counts, as well as enhanced NK cell cytotoxicity, compared to animals exposed to protons (P<0.05). There were no differences between the two irradiated groups in body mass, organ masses, and other assessed parameters, although some differences were noted compared to 0 Gy., Conclusion: Collectively, the data demonstrate that at least some biological effects induced by electrons may not be directly extrapolated to protons. more...
- Published
- 2011
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38. Expression of genes involved in mouse lung cell differentiation/regulation after acute exposure to photons and protons with or without low-dose preirradiation.
- Author
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Tian J, Zhao W, Tian S, Slater JM, Deng Z, and Gridley DS
- Subjects
- Adult Stem Cells cytology, Adult Stem Cells metabolism, Adult Stem Cells radiation effects, Animals, Biomarkers metabolism, Dose-Response Relationship, Radiation, Female, Lung radiation effects, Mice, Mice, Inbred C57BL, Organ Specificity, Time Factors, Cell Differentiation genetics, Cell Differentiation radiation effects, Lung cytology, Lung metabolism, Photons adverse effects, Protons adverse effects, Transcriptome radiation effects
- Abstract
The goal of this study was to compare the effects of acute 2 Gy irradiation with photons (0.8 Gy/min) or protons (0.9 Gy/min), both with and without pre-exposure to low-dose/low-dose-rate γ rays (0.01 Gy at 0.03 cGy/h), on 84 genes involved in stem cell differentiation or regulation in mouse lungs on days 21 and 56. Genes with a ≥1.5-fold difference in expression and P < 0.05 compared to 0 Gy controls are emphasized. Two proteins specific for lung stem cells/progenitors responsible for local tissue repair were also compared. Overall, striking differences were present between protons and photons in modulating the genes. More genes were affected by protons than by photons (22 compared to 2 and 6 compared to 2 on day 21 and day 56, respectively) compared to 0 Gy. Preirradiation with low-dose-rate γ rays enhanced the acute photon-induced gene modulation on day 21 (11 compared to 2), and all 11 genes were significantly downregulated on day 56. On day 21, seven genes (aldh2, bmp2, cdc2a, col1a1, dll1, foxa2 and notch1) were upregulated in response to most of the radiation regimens. Immunoreactivity of Clara cell secretory protein was enhanced by all radiation regimens. The number of alveolar type 2 cells positive for prosurfactant protein C in irradiated groups was higher on day 56 (12.4-14.6 cells/100) than on day 21 (8.5-11.2 cells/100) (P < 0.05). Taken together, these results showed that acute photons and protons induced different gene expression profiles in the lungs and that pre-exposure to low-dose-rate γ rays sometimes had modulatory effects. In addition, proteins associated with lung-specific stem cells/progenitors were highly sensitive to radiation. more...
- Published
- 2011
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39. Analysis of white blood cell counts in mice after gamma- or proton-radiation exposure.
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Maks CJ, Wan XS, Ware JH, Romero-Weaver AL, Sanzari JK, Wilson JM, Rightnar S, Wroe AJ, Koss P, Gridley DS, Slater JM, and Kennedy AR
- Subjects
- Animals, Dose-Response Relationship, Radiation, Endpoint Determination, Female, Leukocyte Count, Mice, Mice, Inbred ICR, Relative Biological Effectiveness, Gamma Rays adverse effects, Leukocytes cytology, Leukocytes radiation effects, Protons adverse effects
- Abstract
In the coming decades human space exploration is expected to move beyond low-Earth orbit. This transition involves increasing mission time and therefore an increased risk of radiation exposure from solar particle event (SPE) radiation. Acute radiation effects after exposure to SPE radiation are of prime importance due to potential mission-threatening consequences. The major objective of this study was to characterize the dose-response relationship for proton and γ radiation delivered at doses up to 2 Gy at high (0.5 Gy/min) and low (0.5 Gy/h) dose rates using white blood cell (WBC) counts as a biological end point. The results demonstrate a dose-dependent decrease in WBC counts in mice exposed to high- and low-dose-rate proton and γ radiation, suggesting that astronauts exposed to SPE-like radiation may experience a significant decrease in circulating leukocytes. more...
- Published
- 2011
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40. Sequentially-induced responses define tumour cell radiosensitivity.
- Author
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Williams JR, Zhang Y, Zhou H, Gridley DS, Koch CJ, Slater JM, Dicello JF, and Little JB
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- Apoptosis radiation effects, Ataxia Telangiectasia Mutated Proteins, Cell Cycle radiation effects, Cell Cycle Proteins genetics, Chromosome Aberrations, Colorectal Neoplasms genetics, Cyclin-Dependent Kinase Inhibitor p21 genetics, DNA-Binding Proteins genetics, Dose-Response Relationship, Radiation, Genes, p53, Genotype, Glioblastoma genetics, Humans, Models, Theoretical, Protein Serine-Threonine Kinases genetics, Relative Biological Effectiveness, Tumor Suppressor Proteins genetics, Colorectal Neoplasms radiotherapy, Glioblastoma radiotherapy, Radiation Tolerance genetics
- Abstract
Purpose: Our aim was to define dose-dependent and genotype-dependent components of radiosensitivity by resolving patterns of radiation-induced clonal inactivation into specific responses., Methods: In a set of 10 tumour cells with varying expression of radiosensitivity and genotype, we identified doses at which all tumour cells change in their rate of clonogenic inactivation. We tested intervening dose-segments as to whether inactivation was constant, expressing inactivation as a log-linear function of dose. We compared these segments to components proposed in the Hit-target (HT) model and the Linear-quadratic (LQ) model. Temporal changes in redistribution in cell-cycle prevalence and apoptosis were examined as essential components of cellular radiosensitivity., Results: We identified four distinct responses induced sequentially in all cells independent of genotype. Rates of inactivation within each response varied with expression of genotype and identified: (i) A hypersensitive component H (0.0-0.10 Gy); (ii) a resistant component R (0.1-0.2 Gy); (iii) an induced repair response alpha* (0.2 Gy and higher); and (iv) a more sensitive component omega* (3.0 Gy and higher). The H, alpha* and omega* components were fitted well by log-linear patterns, the R response did not., Conclusions: Four distinct, sequentially-induced responses comprise cellular radiosensitivity. H and R responses are associated with low dose hyper-radiosensitivity and early apoptosis, while the alpha* and omega* responses share characteristics of the HT and LQ models and are associated with post-repair apoptosis. Radiation induces these four responses at the same doses in all cells, but the rate of inactivation over each response depends on genotype. more...
- Published
- 2011
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41. Microdosimetric comparison of scanned and conventional proton beams used in radiation therapy.
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Dicello JF, Gersey BB, Gridley DS, Coutrakon GB, Lesyna D, Pisacane VL, Robertson JB, Schulte RW, Slater JD, Wroe AJ, and Slater JM
- Subjects
- Radiotherapy Dosage, Particle Accelerators, Protons, Radiometry
- Abstract
Multiple groups have hypothesised that the use of scanning beams in proton therapy will reduce the neutron component of secondary radiation in comparison with conventional methods with a corresponding reduction in risks of radiation-induced cancers. Loma Linda University Medical Center (LLUMC) has had FDA marketing clearance for scanning beams since 1988 and an experimental scanning beam has been available at the LLUMC proton facility since 2001. The facility has a dedicated research room with a scanning beam and fast switching that allows its use during patient treatments. Dosimetric measurements and microdosimetric distributions for a scanned beam are presented and compared with beams produced with the conventional methods presently used in proton therapy. more...
- Published
- 2011
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42. Low-dose γ-rays modify CD4(+) T cell signalling response to simulated solar particle event protons in a mouse model.
- Author
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Rizvi A, Pecaut MJ, Slater JM, Subramaniam S, and Gridley DS
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Cell Survival radiation effects, Cytokines biosynthesis, Dose-Response Relationship, Radiation, Female, Humans, JNK Mitogen-Activated Protein Kinases metabolism, Lymphocyte Activation radiation effects, Lymphocyte Specific Protein Tyrosine Kinase p56(lck) metabolism, Mice, Mice, Inbred C57BL, Models, Animal, NF-kappa B metabolism, Protons adverse effects, Signal Transduction radiation effects, Space Simulation, ZAP-70 Protein-Tyrosine Kinase metabolism, p38 Mitogen-Activated Protein Kinases metabolism, CD4-Positive T-Lymphocytes radiation effects, Gamma Rays adverse effects, Solar Activity
- Abstract
Purpose: Astronauts on missions are exposed to low-dose/low-dose-rate (LDR) radiation and could receive high doses during solar particle events (SPE). This study investigated T cell function in response to LDR radiation and simulated SPE (sSPE) protons, alone and in combination., Materials and Methods: C57BL/6 mice received LDR γ-radiation (⁵⁷Co) to a total dose of 0.01 Gray (Gy) at 0.179 mGy/h, either with or without subsequent exposure to 1.7 Gy sSPE protons delivered over 36 h. Mice were euthanised on days 4 and 21 post-exposure. T cells with cluster of differentiation 4 (CD4(+)) were negatively isolated from spleens and activated with anti-CD3 antibody. Cells and supernatants were evaluated for survival/signalling proteins and cytokines., Results: The most striking effects were noted on day 21. In the survival pathway, nuclear factor-kappaB (NF-κB; total and active forms) and p38 mitogen activated protein kinase (p38MAPK; total) were significantly increased and cJun N-terminal kinase (JNK; total and active) was decreased when mice were primed with LDR γ-rays prior to sSPE exposure (P < 0.001). Evaluation of the T cell antigen receptor (TCR) signalling pathway revealed that LDR γ-ray exposure normalised the high sSPE proton-induced level of lymphocyte specific protein tyrosine kinase (Lck; total and active) on day 21 (P < 0.001 for sSPE vs. LDR + sSPE), while radiation had no effect on active zeta-chain-associated protein kinase 70 (Zap-70). There was increased production of interleukin-2 (IL-2) and IL-4 and decreased transforming growth factor-β1 in the LDR + sSPE group compared to the sSPE group., Conclusion: The data demonstrate, for the first time, that protracted exposure to LDR γ-rays can significantly modify the effects of sSPE protons on critical survival/signalling proteins and immunomodulatory cytokines produced by CD4(+) T cells. more...
- Published
- 2011
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43. Low-dose photon and simulated solar particle event proton effects on Foxp3+ T regulatory cells and other leukocytes.
- Author
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Gridley DS, Luo-Owen X, Rizvi A, Makinde A, Pecaut M, Mao XW, and Slater JM
- Subjects
- Animals, Body Weight radiation effects, Computer Simulation, Dose-Response Relationship, Radiation, Leukocytes metabolism, Mice, Mice, Inbred C57BL, Radiation Dosage, Skin cytology, Skin immunology, Skin metabolism, Skin radiation effects, T-Lymphocytes, Regulatory metabolism, Forkhead Transcription Factors metabolism, Leukocytes radiation effects, Photons adverse effects, Protons adverse effects, Solar Activity, T-Lymphocytes, Regulatory radiation effects
- Abstract
Radiation is a major factor in the spaceflight environment that has carcinogenic potential. Astronauts on missions are continuously exposed to low-dose/low-dose-rate (LDR) radiation and may receive relatively high doses during a solar particle event (SPE) that consists primarily of protons. However, there are very few reports in which LDR photons were combined with protons. In this study, C57BL/6 mice were exposed to 1.7 Gy simulated SPE (sSPE) protons over 36 h, both with and without pre-exposure to 0.01 Gray (Gy) LDR g-rays at 0.018 cGy/h. Apoptosis in skin samples was determined by immunohistochemistry immediately post-irradiation (day 0). Spleen mass relative to body mass, white blood cells (WBC), major leukocyte populations, lymphocyte subsets (T, Th, Tc, B, NK), and CD4(+)CD25(+)Foxp3+ T regulatory (Treg) cells were analyzed on days 4 and 21. Apoptosis in skin samples was evident in all irradiated groups; the LDR+sSPE mice had the greatest expression of activated caspase-3. On day 4 post-irradiation, the sSPE and LDR+sSPE groups had significantly lower WBC counts in blood and spleen compared to non-irradiated controls (p < 0.05 vs. 0 Gy). CD4(+)CD25(+)Foxp3(+) Treg cell numbers in spleen were decreased at day 4, but proportions were increased in the sSPE and LDR+sSPE groups (p < 0.05 vs. 0 Gy). By day 21, lymphocyte counts were still low in blood from the LDR+sSPE mice, especially due to reductions in B, NK, and CD8(+) T cytotoxic cells. The data demonstrate, for the first time, that pre-exposure to LDR photons did not protect against the adverse effects of radiation mimicking a large solar storm. The increased proportion of immunosuppressive CD4+CD25(+) Foxp3(+) Treg and persistent reduction in circulating lymphocytes may adversely impact immune defenses that include removal of sub-lethally damaged cells with carcinogenic potential, at least for a period of time post-irradiation. more...
- Published
- 2010
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44. Tumor response to radiotherapy is dependent on genotype-associated mechanisms in vitro and in vivo.
- Author
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Williams JR, Zhang Y, Zhou H, Gridley DS, Koch CJ, Dicello JF, Slater JM, and Little JB
- Subjects
- Animals, Cell Line, Tumor, Genotype, Humans, Mice, Xenograft Model Antitumor Assays, Neoplasms genetics, Neoplasms radiotherapy, Radiation Tolerance genetics
- Abstract
Background: We have previously shown that in vitro radiosensitivity of human tumor cells segregate non-randomly into a limited number of groups. Each group associates with a specific genotype. However we have also shown that abrogation of a single gene (p21) in a human tumor cell unexpectedly sensitized xenograft tumors comprised of these cells to radiotherapy while not affecting in vitro cellular radiosensitivity. Therefore in vitro assays alone cannot predict tumor response to radiotherapy.In the current work, we measure in vitro radiosensitivity and in vivo response of their xenograft tumors in a series of human tumor lines that represent the range of radiosensitivity observed in human tumor cells. We also measure response of their xenograft tumors to different radiotherapy protocols. We reduce these data into a simple analytical structure that defines the relationship between tumor response and total dose based on two coefficients that are specific to tumor cell genotype, fraction size and total dose., Methods: We assayed in vitro survival patterns in eight tumor cell lines that vary in cellular radiosensitivity and genotype. We also measured response of their xenograft tumors to four radiotherapy protocols: 8 x 2 Gy; 2 x 5 Gy, 1 x 7.5 Gy and 1 x 15 Gy. We analyze these data to derive coefficients that describe both in vitro and in vivo responses., Results: Response of xenografts comprised of human tumor cells to different radiotherapy protocols can be reduced to only two coefficients that represent 1) total cells killed as measured in vitro 2) additional response in vivo not predicted by cell killing. These coefficients segregate with specific genotypes including those most frequently observed in human tumors in the clinic. Coefficients that describe in vitro and in vivo mechanisms can predict tumor response to any radiation protocol based on tumor cell genotype, fraction-size and total dose., Conclusions: We establish an analytical structure that predicts tumor response to radiotherapy based on coefficients that represent in vitro and in vivo responses. Both coefficients are dependent on tumor cell genotype and fraction-size. We identify a novel previously unreported mechanism that sensitizes tumors in vivo; this sensitization varies with tumor cell genotype and fraction size. more...
- Published
- 2010
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45. A metalloporphyrin antioxidant alters cytokine responses after irradiation in a prostate tumor model.
- Author
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Makinde AY, Rizvi A, Crapo JD, Pearlstein RD, Slater JM, and Gridley DS
- Subjects
- Animals, Cell Line, Tumor, Combined Modality Therapy, Dose-Response Relationship, Drug, Dose-Response Relationship, Radiation, Male, Mice, Mice, Inbred C57BL, Radiation Dosage, Treatment Outcome, Antioxidants administration & dosage, Cytokines metabolism, Disease Models, Animal, Metalloporphyrins administration & dosage, Prostatic Neoplasms metabolism, Prostatic Neoplasms therapy, Radiotherapy, Conformal methods
- Abstract
The goal of this study was to evaluate cytokine secretion capacity in a mouse model of prostate cancer, both with and without metalloporphyrin antioxidant and radiation treatment. C57BL/6 mice with subcutaneous RM-9 tumors were treated daily for 12 days with MnTE-2-PyP(5+) [Mn (III) tetrakis (N-ethylpyridinium-2-yl) porphyrin], beginning 1 day after injection of RM-9 cells; a 10-Gy tumor-localized dose of (60)Co gamma rays was administered in a single fraction on day 7. Spleen, tumors and plasma were collected on day 12. T cells in the spleen were activated with anti-CD3 antibody and supernatants were collected. Twenty-two cytokines were quantified in spleen supernatants, five in tumor homogenates, and three in plasma using multiplex bead array technology and ELISA. The presence of a tumor had significant effects on many of the cytokines quantified (P < 0.05). Tumor-induced depression was evident for eight spleen cytokines (TNF-alpha, G-CSF, GM-CSF, IFN-gamma, IL10, IP-10, MIP-1alpha and mKC), whereas only three were enhanced (IL1beta, IL6 and MCP-1). Radiotherapy resulted in enhanced splenocyte capacity to produce IL4 and IL13 and increased IL4, MCP-1 and VEGF in tumors (P < 0.05). Addition of MnTE-2-PyP(5+) to radiation decreased the concentrations of IL4, IL13 and TGF-beta1 in spleen supernatants and IL4 and VEGF in tumors (P < 0.05 compared to radiation alone). Some differences were also noted in plasma cytokines. Overall, the findings suggest that administration of MnTE-2-PyP(5+) together with radiotherapy may enhance anti-tumor immune responsiveness and decrease the risk for radiation-induced normal tissue toxicities. more...
- Published
- 2010
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46. Metalloporphyrin antioxidants ameliorate normal tissue radiation damage in rat brain.
- Author
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Pearlstein RD, Higuchi Y, Moldovan M, Johnson K, Fukuda S, Gridley DS, Crapo JD, Warner DS, and Slater JM
- Subjects
- Animals, Apoptosis drug effects, Apoptosis radiation effects, Blood-Brain Barrier drug effects, Blood-Brain Barrier radiation effects, Brain metabolism, Brain pathology, Brain Injuries metabolism, Brain Injuries pathology, Brain Injuries prevention & control, Cell Line, Tumor, Cells, Cultured, DNA Breaks, Double-Stranded, Heme Oxygenase (Decyclizing) metabolism, Humans, Male, Neuroglia cytology, Neuroglia drug effects, Neuroglia radiation effects, Neurons cytology, Neurons drug effects, Neurons radiation effects, Radiation Injuries, Experimental metabolism, Radiation Injuries, Experimental pathology, Radiation Tolerance drug effects, Rats, Rats, Sprague-Dawley, Superoxide Dismutase metabolism, Antioxidants pharmacology, Brain drug effects, Brain radiation effects, Metalloporphyrins pharmacology, Radiation Injuries, Experimental prevention & control, Radiation-Protective Agents pharmacology
- Abstract
Purpose: We examined the effects of manganese (III) meso-tetrakis (diethyl-2-5-imidazole) porphyrin, a metalloporphyrin antioxidant (MPA), on neural tissue radiation toxicity in vivo and on tumour cell radiosensitivity in vitro., Materials and Methods: MPA was administered directly into the right lateral ventricle of young adult, male Sprague-Dawley rats (0 or 3.4 microg) 3 h before treatment with a single fraction, 100 Gy radiation dose delivered to the left brain hemisphere. The effects of treatment on radiation responses were assessed at different time points following irradiation., Results: MPA treatment prior to brain irradiation protected against acute radiation-induced apoptosis and ameliorated delayed damage to the blood-brain barrier and radiation necrosis, but without producing a discernible increase in tissue superoxide disumtase (SOD) activity. In vitro, MPA pretreatment protected against radiation-induced apoptosis in primary neuronal cultures and increased clonogenic survival of irradiated rat glioma C6 cells, but had no discernible effect on radiation-induced DNA double-strand breaks. MPA, a low molecular weight SOD mimic, significantly increased mitochondrial SOD activity in C6 cells, but not total cellular SOD activity. MPA up-regulated C6 expression of heme-oxygenase 1 (HO-1), an endogenous radioprotectant, but had no effect on HO-1 levels in human astrocytoma U-251 cells, human prostatic carcinoma LNCaP cells, or primary rat brain microvascular endothelial cells in vitro, nor on brain tissue HO-1 expression levels in vivo., Conclusions: Metalloporphyrin antioxidants merit further exploration as adjunctive radioprotectants for cranial radiotherapy/radiosurgery applications, although the potential for tumour protection must be carefully considered. more...
- Published
- 2010
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47. Spaceflight modulates expression of extracellular matrix, adhesion, and profibrotic molecules in mouse lung.
- Author
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Tian J, Pecaut MJ, Slater JM, and Gridley DS
- Subjects
- Animals, Female, Gene Expression Regulation, Mice, Mice, Inbred C57BL, Space Flight, Cell Adhesion Molecules metabolism, Extracellular Matrix Proteins metabolism, Lung physiopathology, Pulmonary Fibrosis etiology, Pulmonary Fibrosis physiopathology, Weightlessness adverse effects
- Abstract
NASA has reported pulmonary abnormalities in astronauts on space missions, but the molecular changes in lung tissue remain unknown. The goal of the present study was to explore the effects of spaceflight on expression of extracellular matrix (ECM), cell adhesion, and pro-fibrotic molecules in lungs of mice flown on Space Shuttle Endeavour (STS-118). C57BL/6Ntac mice housed in animal enclosure modules during a 13-day mission in space (FLT) were killed within hours after return; ground controls were treated similarly for comparison (GRD). Analysis of genes associated with ECM and adhesion molecules was performed according to quantitative RT-PCR. The data revealed that FLT lung samples had statistically significant transcriptional changes, i.e., at least 1.5-fold, in 25 out of 84 examined genes (P < 0.05); 15 genes were upregulated and 10 were downregulated. The genes that were upregulated by more than twofold were Ctgf, Mmp2, Ncam1, Sparc, Spock1, and Timp3, whereas the most downregulated genes were Lama1, Mmp3, Mmp7, vcam-1, and Sele. Histology showed profibrosis-like changes occurred in FLT mice, more abundant collagen accumulation around blood vessels, and thicker walls compared with lung samples from GRD mice. Immunohistochemistry was used to compare expression of six selected proteins associated with fibrosis. Immunoreactivity of four proteins (MMP-2, CTGF, TGF-beta1, and NCAM) was enhanced by spaceflight, whereas, no difference was detected in expression of MMP-7 and MMP-9 proteins between the FLT and GRD groups. Taken together, the data demonstrate that significant changes can be readily detected shortly after return from spaceflight in the expression of factors that can adversely influence lung function. more...
- Published
- 2010
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48. Response of extracellular matrix regulators in mouse lung after exposure to photons, protons and simulated solar particle event protons.
- Author
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Tian J, Pecaut MJ, Coutrakon GB, Slater JM, and Gridley DS
- Subjects
- Animals, Collagen metabolism, Extracellular Matrix Proteins metabolism, Female, Gamma Rays, Leukocyte Common Antigens metabolism, Leukocytes metabolism, Lung pathology, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 9 metabolism, Mice, Mice, Inbred C57BL, RNA, Messenger metabolism, Tissue Inhibitor of Metalloproteinase-1 metabolism, Tissue Inhibitor of Metalloproteinase-2 metabolism, Transforming Growth Factor beta1 metabolism, Cosmic Radiation, Extracellular Matrix Proteins radiation effects, Lung metabolism, Lung radiation effects, Photons, Protons
- Abstract
This study compared the effects of photons (gamma rays), protons and simulated solar particle event protons (sSPE) on the expression of profibrotic factors/extracellular matrix (ECM) regulators in lung tissue after whole-body irradiation. TGF-beta1, matrix metalloproteinase 2 and 9 (MMP-2, -9), and tissue inhibitor of metalloproteinase 1 and 2 (TIMP-1, -2) were assessed on days 4 and 21 in lungs from C57BL/6 mice exposed to 0 Gy or 2 Gy photons (0.7 Gy/min), protons (0.9 Gy/min) and sSPE (0.056 Gy/h). RT-PCR, histological and immunohistochemical techniques were used. The most striking changes included (1) up-regulation of TGF-beta1 by photons and sSPE, but not protons, at both times, (2) MMP-2 enhancement by photons and sSPEs, (3) TIMP-1 up-regulation by photons at both times, and (4) more collagen accumulation after exposure to either photons or sSPE than after exposure to protons. The findings demonstrate that expression of important ECM regulators was highly dependent upon the radiation regimen as well as the time after exposure. The data further suggest that irradiation during an SPE may increase an astronaut's risk for pulmonary complications. The greater perturbations after photon exposure compared to proton exposure have clinical implications and warrant further investigation. more...
- Published
- 2009
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49. Effects of spaceflight on innate immune function and antioxidant gene expression.
- Author
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Baqai FP, Gridley DS, Slater JM, Luo-Owen X, Stodieck LS, Ferguson V, Chapes SK, and Pecaut MJ
- Subjects
- Animals, Cytokines metabolism, Female, Leukocyte Count, Lipopolysaccharides pharmacology, Liver pathology, Lymphocyte Activation immunology, Lymphocyte Count, Mice, Oligonucleotide Array Sequence Analysis, Organ Size, RNA, Messenger metabolism, Spleen drug effects, Spleen metabolism, Spleen pathology, Thymus Gland pathology, Up-Regulation, Gene Expression, Immunity physiology, Myoglobin genetics, Oxidative Stress genetics, Space Flight
- Abstract
Spaceflight conditions have a significant impact on a number of physiological functions due to psychological stress, radiation, and reduced gravity. To explore the effect of the flight environment on immunity, C57BL/6NTac mice were flown on a 13-day space shuttle mission (STS-118). In response to flight, animals had a reduction in liver, spleen, and thymus masses compared with ground (GRD) controls (P < 0.005). Splenic lymphocyte, monocyte/macrophage, and granulocyte counts were significantly reduced in the flight (FLT) mice (P < 0.05). Although spontaneous blastogenesis of splenocytes in FLT mice was increased, response to lipopolysaccharide (LPS), a B-cell mitogen derived from Escherichia coli, was decreased compared with GRD mice (P < 0.05). Secretion of IL-6 and IL-10, but not TNF-alpha, by LPS-stimulated splenocytes was increased in FLT mice (P < 0.05). Finally, many of the genes responsible for scavenging reactive oxygen species were upregulated after flight. These data indicate that exposure to the spaceflight environment can increase anti-inflammatory mechanisms and change the ex vivo response to LPS, a bacterial product associated with septic shock and a prominent Th1 response. more...
- Published
- 2009
- Full Text
- View/download PDF
50. Low-dose, low-dose-rate proton radiation modulates CD4(+) T cell gene expression.
- Author
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Gridley DS, Pecaut MJ, Rizvi A, Coutrakon GB, Luo-Owen X, Makinde AY, and Slater JM
- Subjects
- Animals, CD4-Positive T-Lymphocytes metabolism, DNA biosynthesis, DNA blood, Dose-Response Relationship, Radiation, Female, Gene Expression Profiling, Leukocyte Count, Mice, Mice, Inbred C57BL, Spleen cytology, Spleen metabolism, Spleen radiation effects, CD4-Positive T-Lymphocytes radiation effects, Gene Expression Regulation radiation effects, Protons
- Abstract
Purpose: To evaluate cluster of differentiation 4(+) (CD4(+)) T cell gene expression and related parameters after whole-body exposure to proton radiation as it occurs in the spaceflight environment., Materials and Methods: C57BL/6 mice were irradiated to total doses of 0, 0.01, 0.05, and 0.1 gray (Gy) at 0.1 cGy/h. On day 0 spleens were harvested from a subset in the 0, 0.01 and 0.1 Gy groups; (CD4(+)) T cells were isolated; and expression of 84 genes relevant to T helper (Th) cell function was determined using reverse transcriptase-polymerase chain reaction (RT-PCR). Remaining mice were euthanized on days 0, 4, and 21 for additional analyses., Results: Genes with >2-fold difference and p < 0.05 compared to 0 Gy were noted. After 0.01 Gy, five genes were up-regulated (Ccr5, Cd40, Cebpb, Igsf6, Tnfsf4) and three were down-regulated (Il4ra, Mapk8, Nfkb1). After 0.1 Gy there were nine up-regulated genes (Ccr4, Cd40, Cebpb, Cxcr3, Socs5, Stat4, Tbx21, Tnfrsf4, Tnfsf4); none were down-regulated. On day 0 after 0.01 Gy, CD4(+) T cell counts and CD4:CD8 ratio were low in the spleen (p < 0.05). Spontaneous DNA synthesis in both spleen and blood was lowest in the 0.01 Gy group on day 0; on days 4 and 21 all p values were >0.1., Conclusion: The data show that the pattern of gene expression in CD4(+) T cells after protracted low-dose proton irradiation was significantly modified and highly dependent upon total dose. The findings also suggest that low-dose radiation, especially 0.01 Gy, may enhance CD4(+) T cell responsiveness. more...
- Published
- 2009
- Full Text
- View/download PDF
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