Development and verification of an analytical algorithm to predict absorbed dose distributions in ocular proton therapy using Monte Carlo simulations

Proton beam radiotherapy is an effective and non-invasive treatment for uveal melanoma. Recent research efforts have focused on improving the dosimetric accuracy of treatment planning and overcoming the present limitation of relative analytical dose calculations. Monte Carlo algorithms have been shown to accurately predict dose per monitor unit (D/MU) values, but this has yet to be shown for analytical algorithms dedicated to ocular proton therapy, which are typically less computationally expensive than Monte Carlo algorithms. The objective of this study was to determine if an analytical method could predict absolute dose distributions and D/MU values for a variety of treatment fields like those used in ocular proton therapy. To accomplish this objective, we used a previously validated Monte Carlo model of an ocular nozzle to develop an analytical algorithm to predict three-dimensional distributions of D/MU values from pristine Bragg peaks and therapeutically useful spread-out Bragg peaks (SOBPs). Results demonstrated generally good agreement between the analytical and Monte Carlo absolute dose calculations. While agreement in the proximal region decreased for beams with less penetrating Bragg peaks compared with the open-beam condition, the difference was shown to be largely attributable to edge-scattered protons. A method for including this effect in any future analytical algorithm was proposed. Comparisons of D/MU values showed typical agreement to within 0.5%. We conclude that analytical algorithms can be employed to accurately predict absolute proton dose distributions delivered by an ocular nozzle. © 2010 Institute of Physics and Engineering in Medicine

Monte Carlo calculations and measurements of absorbed dose per monitor unit for the treatment of uveal melanoma with proton therapy

The treatment of uveal melanoma with proton radiotherapy has provided excellent clinical outcomes. However, contemporary treatment planning systems use simplistic dose algorithms that limit the accuracy of relative dose distributions. Further, absolute predictions of absorbed dose per monitor unit are not yet available in these systems. The purpose of this study was to determine if Monte Carlo methods could predict dose per monitor unit (D/MU) value at the center of a proton spread-out Bragg peak (SOBP) to within 1% on measured values for a variety of treatment fields relevant to ocular proton therapy. The MCNPX Monte Carlo transport code, in combination with realistic models for the ocular beam delivery apparatus and a water phantom, was used to calculate dose distributions and D/MU values, which were verified by the measurements. Measured proton beam data included central-axis depth dose profiles, relative cross-field profiles and absolute D/MU measurements under several combinations of beam penetration ranges and range-modulation widths. The Monte Carlo method predicted D/MU values that agreed with measurement to within 1% and dose profiles that agreed with measurement to within 3% of peak dose or within 0.5 mm distance-to-agreement. Lastly, a demonstration of the clinical utility of this technique included calculations of dose distributions and D/MU values in a realistic model of the human eye. It is possible to predict D/MU values accurately for clinical relevant range-modulated proton beams for ocular therapy using the Monte Carlo method. It is thus feasible to use the Monte Carlo method as a routine absolute dose algorithm for ocular proton therapy. © 2008 Institute of Physics and Engineering in Medicine

Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function

Phosphodiesterase-5 (PDE5) inhibitors (sildenafil, tadalafil, and vardenafil) are agents currently in clinical use for nonmalignant conditions. We report the use of PDE5 inhibitors as modulators of the antitumor immune response. In several mouse tumor models, PDE5 inhibition reverses tumor-induced immunosuppressive mechanisms and enables a measurable antitumor immune response to be generated that substantially delays tumor progression. In particular, sildenafil, down-regulates arginase 1 and nitric oxide synthase–2 expression, thereby reducing the suppressive machinery of CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) recruited by growing tumors. By removing these tumor escape mechanisms, sildenafil enhances intratumoral T cell infiltration and activation, reduces tumor outgrowth, and improves the antitumor efficacy of adoptive T cell therapy. Sildenafil also restores in vitro T cell proliferation of peripheral blood mononuclear cells from multiple myeloma and head and neck cancer patients. In light of the recent data that enzymes mediating MDSC-dependent immunosuppression in mice are active also in humans, these findings demonstrate a potentially novel use of PDE5 inhibitors as adjuncts to tumor-specific immune therapy

Benchmark measurements and simulations of dose perturbations due to metallic spheres in proton beams

Monte Carlo simulations are increasingly used for dose calculations in proton therapy due to its inherent accuracy. However, dosimetric deviations have been found using Monte Carlo code when high density materials are present in the proton beamline. The purpose of this work was to quantify the magnitude of dose perturbation caused by metal objects. We did this by comparing measurements and Monte Carlo predictions of dose perturbations caused by the presence of small metal spheres in several clinical proton therapy beams as functions of proton beam range and drift space. Monte Carlo codes MCNPX, GEANT4 and Fast Dose Calculator (FDC) were used. Generally good agreement was found between measurements and Monte Carlo predictions, with the average difference within 5% and maximum difference within 17%. The modification of multiple Coulomb scattering model in MCNPX code yielded improvement in accuracy and provided the best overall agreement with measurements. Our results confirmed that Monte Carlo codes are well suited for predicting multiple Coulomb scattering in proton therapy beams when short drift spaces are involved. © 2013 Elsevier Ltd. All rights reserved

Comparison of observed with model hadron charge ratio of secondary cosmic rays

The validity of previous comparisons between model results and observations of the neutral to charged ratio of hadrons in the atmosphere is re-examined. The authors then select the most appropriate published data plus data taken by the authors at Chacaltaya and compare them with model results.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/48864/2/jgv2i4pL61.pd

Adiponectin inhibits tumor necrosis factor-α-induced vascular inflammatory response via caveolin-mediated ceramidase recruitment and activation.

RATIONALE: Anti-inflammatory and vascular protective actions of adiponectin are well recognized. However, many fundamental questions remain unanswered. OBJECTIVE: The current study attempted to identify the adiponectin receptor subtype responsible for adiponectin\u27s vascular protective action and investigate the role of ceramidase activation in adiponectin anti-inflammatory signaling. METHODS AND RESULTS: Adiponectin significantly reduced tumor necrosis factor (TNF)α-induced intercellular adhesion molecule-1 expression and attenuated TNFα-induced oxidative/nitrative stress in human umbilical vein endothelial cells. These anti-inflammatory actions were virtually abolished by adiponectin receptor 1 (AdipoR1-), but not AdipoR2-, knockdown (KD). Treatment with adiponectin significantly increased neutral ceramidase (nCDase) activity (3.7-fold; P87% of adiponectin-induced nCDase activation was lost. Whereas adiponectin treatment failed to inhibit TNFα-induced intercellular adhesion molecule-1 expression, treatment with sphingosine-1-phosphate or SEW (sphingosine-1-phosphate receptor agonist) remained effective in Cav1-KD cells. AdipoR1 and Cav1 colocalized and coprecipitated in human umbilical vein endothelial cells. Adiponectin treatment did not affect this interaction. There is weak basal Cav1/nCDase interaction, which significantly increased after adiponectin treatment. Knockout of AdipoR1 or Cav1 abolished the inhibitory effect of adiponectin on leukocyte rolling and adhesion in vivo. CONCLUSIONS: These results demonstrate for the first time that adiponectin inhibits TNFα-induced inflammatory response via Cav1-mediated ceramidase recruitment and activation in an AdipoR1-dependent fashion

C1q/tumor necrosis factor-related protein-3, a newly identified adipokine, is a novel antiapoptotic, proangiogenic, and cardioprotective molecule in the ischemic mouse heart.

BACKGROUND: Obesity and diabetes mellitus adversely affect postischemic heart remodeling via incompletely understood mechanisms. C1q/tumor necrosis factor-related protein-3 (CTRP3) is a newly identified adipokine exerting beneficial metabolic regulation, similar to adiponectin. The aim of the present study was to determine whether CTRP3 may regulate postischemic cardiac remodeling and cardiac dysfunction, and, if so, to elucidate the underlying mechanisms. METHODS AND RESULTS: Male adult mice were subjected to myocardial infarction (MI) via left anterior descending coronary artery occlusion. Both the effect of MI on endogenous CTRP3 expression/production and the effect of exogenous CTRP3 (adenovirus or recombinant CTRP3) replenishment on MI injury were investigated. MI significantly inhibited adipocyte CTRP3 expression and reduced the plasma CTRP3 level, reaching a nadir 3 days after MI. CTRP3 replenishment improved survival rate (P CONCLUSION: CTRP3 is a novel antiapoptotic, proangiogenic, and cardioprotective adipokine, the expression of which is significantly inhibited after MI