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Circadian disturbance of clock gene expression is a risk factor for diseases such as obesity, cancer, and sleep disorders. To study these diseases, it is necessary to monitor and analyze the expression rhythm of clock genes in the whole body for a long duration. The bioluminescent reporter enzyme firefly luciferase and its substrate d-luciferin have been used to generate optical signals from tissues in vivo with high sensitivity. However, little information is known about the stability of d-luciferin to detect gene expression in living animals for a long duration. In the present study, we examined the stability of a luciferin solution over 21 days. l-Luciferin, which is synthesized using racemization of d-luciferin, was at high concentrations after 21 days. In addition, we showed that bioluminescence of Period1 (Per1) expression in the liver was significantly decreased compared with the day 1 solution, although locomotor activity rhythm was not affected. These results showed that d-luciferin should be applied to the mouse within, at most, 7 days to detect bioluminescence of Per1 gene expression rhythm in vivo.

Because the disruption of circadian clock gene is a risk factor in many diseases such as obesity and cancer, it is important to monitor and analyzed the expression of the rhythm of the clock gene throughout the body over a long period of time. Although we previously reported on a new gene expression analysis system tracking a target position on the body surface of freely moving mice, the experimental apparatus required a large space. We have therefore developed an in vivo recording system using a portable photomultiplier tube (PMT) system attached to an optical fibre. Directly connecting the target area with the device, we could easily measure the photon counts in a very small space. However, little information is known about the characteristics of optical fibres when exposed to twisting/looping in association with a moving mouse and the effect of the surface of optical fibre. In the present study, we report on the characteristics of optical fibres to detect gene expression rhythm in freely moving mice. Using this portable optical device directly connected with a target area, we were able to measure the circadian rhythm of clock gene expression over a prolonged period in freely moving mice in a small space.

BACKGROUND Synovitis, which is a hallmark of rheumatoid arthritis (RA), needs to be precisely quantified to determine the treatment plan. Time-intensity curve (TIC) shape analysis is an objective assessment method for characterizing the pixels as artery, inflamed synovium, or other tissues using dynamic contrast-enhanced MRI (DCE-MRI). PURPOSE/HYPOTHESIS To assess the feasibility of our original arterial mask subtraction method (AMSM) with mutual information (MI) for quantification of synovitis in RA. STUDY TYPE Prospective study. SUBJECTS Ten RA patients (nine women and one man; mean age, 56.8 years; range, 38-67 years). FIELD STRENGTH/SEQUENCE 3T/DCE-MRI. ASSESSMENT After optimization of TIC shape analysis to the hand region, a combination of TIC shape analysis and AMSM was applied to synovial quantification. The MI between pre- and postcontrast images was utilized to determine the arterial mask phase objectively, which was compared with human subjective selection. The volume of objectively measured synovitis by software was compared with that of manual outlining by an experienced radiologist. Simple TIC shape analysis and TIC shape analysis combined with AMSM were compared in slices without synovitis according to subjective evaluation. STATISTICAL TESTS Pearson's correlation coefficient, paired t-test and intraclass correlation coefficient (ICC). RESULTS TIC shape analysis was successfully optimized in the hand region with a correlation coefficient of 0.725 (P

Purpose: The authors propose a graphical representation of the relation between the effect on the tumor and the damage effect on an organ at risk (OAR) against the irradiation dose, as an aid for choosing an appropriate fractionation regimen. Methods: The graphical relation is depicted by the radiation effect on the tumorE 1 versus that on an OAR E 0. By observing the features of the E 1 vs E 0 relation curve, i.e., convex or concave shape, one can judge whether multifractionation is better or not. This method is applied to the linear-quadratic model (with α and β parameters) as an example. Further, the method is extended to the general case for nonuniform dose distribution to the OAR, which is frequently seen in clinical situations. Results: The criterion for selecting multi- or hypofractionation is based on the relation between the dose for the OAR and theα/β ratio of the OAR to the tumor. It is also shown that the graphical relation enables us to estimate the final effect after multifractionated treatment by plotting a tangent line on the curve. Conclusions: The graphical representation method is of use for improving planning in radiotherapy by determining the effective fractionation scheme.

Purpose: In accurate proton spot-scanning therapy, continuous target tracking by fluoroscopic x ray during irradiation is beneficial not only for respiratory moving tumors of lung and liver but also for relatively stationary tumors of prostate. Implanted gold markers have been used with great effect for positioning the target volume by a fluoroscopy, especially for the cases of liver and prostate with the targets surrounded by water-equivalent tissues. However, recent studies have revealed that gold markers can cause a significant underdose in proton therapy. This paper focuses on prostate cancer and explores the possibility that multiple-field irradiation improves the underdose effect by markers on tumor-control probability (TCP). Methods: A Monte Carlo simulation was performed to evaluate the dose distortion effect. A spherical gold marker was placed at several characteristic points in a water phantom. The markers were with two different diameters of 2 and 1.5 mm, both visible on fluoroscopy. Three beam arrangements of single-field uniform dose (SFUD) were examined: one lateral field, two opposite lateral fields, and three fields (two opposite lateral fields + anterior field). The relative biological effectiveness (RBE) was set to 1.1 and a dose of 74 Gy (RBE) was delivered to the target of a typicalmore » prostate size in 37 fractions. The ratios of TCP to that without the marker (TCP{sub r}) were compared with the parameters of the marker sizes, number of fields, and marker positions. To take into account the dependence of biological parameters in TCP model, {alpha}/{beta} values of 1.5, 3, and 10 Gy (RBE) were considered. Results: It was found that the marker of 1.5 mm diameter does not affect the TCPs with all {alpha}/{beta} values when two or more fields are used. On the other hand, if the marker diameter is 2 mm, more than two irradiation fields are required to suppress the decrease in TCP from TCP{sub r} by less than 3%. This is especially true when multiple (two or three) markers are used for alignment of a patient. Conclusions: It is recommended that 1.5-mm markers be used to avoid the reduction of TCP as well as to spare the surrounding critical organs, as long as the markers are visible on x-ray fluoroscopy. When 2-mm markers are implanted, more than two fields should be used and the markers should not be placed close to the distal edge of any of the beams.« less

Purpose: To make clear the spatial distribution of dose enhancement around gold nanoparticles (GNPs) located near the proton Bragg peak, and to evaluate the potential of GNPs as a radio sensitizer. Methods: The dose enhancement by electrons emitted from GNPs under proton irradiation was estimated by Geant4 Monte Carlo simulation toolkit in two steps. In an initial macroscopic step, 100 and 195 MeV proton beams were incident on a water cube, 30 cm on a side. Energy distributions of protons were calculated at four depths, 50% and 75% proximal to the Bragg peak, 100% peak, and 75% distal to the peak (P50, P75, Peak, and D75, respectively). In a subsequent microscopic step, protons with the energy distribution calculated above were incident on a 20 nm diameter GNP in a nanometer-size water box and the spatial distribution of dose around the GNP was determined for each energy distribution. The dose enhancement factor (DEF) was also deduced. Results: The dose enhancement effect was spread to several tens of nanometers in the both depth and radial directions. The enhancement area increased in the order of P50, P75, Peak, and D75 for both cases with 100 and 195 MeV protons. In every position around the Bragg peak, the 100 MeV beam resulted in a higher dose enhancement than the 195 MeV beam. At P75, the average and maximum DEF were 3.9 and 17.0 for 100 MeV, and 3.5 and 16.2 for 195 MeV, respectively. These results indicate that lower energy protons caused higher dose enhancement in this incident proton energy range. Conclusion: The dose enhancement around GNPs spread as the position in the Bragg peak region becomes deeper and depends on proton energy. It is expected that GNPs can be used as a radio sensitizer with consideration of the location and proton beam energy.

Purpose: To evaluate density inhomogeneities which can effect dose distributions for real-time image gated spot-scanning proton therapy (RGPT), a dose calculation system, using treatment planning system VQA (Hitachi Ltd., Tokyo) spot position data, was developed based on Geant4. Methods: A Geant4 application was developed to simulate spot-scanned proton beams at Hokkaido University Hospital. A CT scan (0.98 × 0.98 × 1.25 mm) was performed for prostate cancer treatment with three or four inserted gold markers (diameter 1.5 mm, volume 1.77 mm3) in or near the target tumor. The CT data was read into VQA. A spot scanning plan was generated and exported to text files, specifying the beam energy and position of each spot. The text files were converted and read into our Geant4-based software. The spot position was converted into steering magnet field strength (in Tesla) for our beam nozzle. Individual protons were tracked from the vacuum chamber, through the helium chamber, steering magnets, dose monitors, etc., in a straight, horizontal line. The patient CT data was converted into materials with variable density and placed in a parametrized volume at the isocenter. Gold fiducial markers were represented in the CT data by two adjacent voxels (volume 2.38 mm3). 600,000 proton histories were tracked for each target spot. As one beam contained about 1,000 spots, approximately 600 million histories were recorded for each beam on a blade server. Two plans were considered: two beam horizontal opposed (90 and 270 degree) and three beam (0, 90 and 270 degree). Results: We are able to convert spot scanning plans from VQA and simulate them with our Geant4-based code. Our system can be used to evaluate the effect of dose reduction caused by gold markers used for RGPT. Conclusion: Our Geant4 application is able to calculate dose distributions for spot scanned proton therapy.

Purpose: In the real‐time tumor‐tracking radiotherapysystem, fiducial markers are detected by X‐ray fluoroscopy. The fluoroscopic parameters should be optimized as low as possible in order to reduce unnecessary imagingdose. However, the fiducial markers could not be recognized due to effect of statistical noise in low doseimaging.Image processing is envisioned to be a solution to improve image quality and to maintain tracking accuracy. In this study, a recursive image filter adapted to target motion is proposed. Methods: A fluoroscopysystem was used for the experiment. A spherical gold marker was used as a fiducial marker. About 450 fluoroscopic images of the marker were recorded. In order to mimic respiratory motion of the marker, the images were shifted sequentially. The tube voltage, current and exposure duration were fixed at 65 kV, 50 mA and 2.5 msec as low doseimaging condition, respectively. The tube current was 100 mA as high doseimaging. A pattern recognition score (PRS) ranging from 0 to 100 and image registration error were investigated by performing template pattern matching to each sequential image. The results with and without image processing were compared. Results: In low doseimaging, theimage registration error and the PRS without the image processing were 2.15±1.21 pixel and 46.67±6.40, respectively. Those with the image processing were 1.48±0.82 pixel and 67.80±4.51, respectively. There was nosignificant difference in the image registration error and the PRS between the results of low doseimaging with the image processing and that of high doseimaging without the image processing.Conclusions: The results showed that the recursive filter was effective in order to maintain marker tracking stability and accuracy in low dosefluoroscopy.

Purpose: In spot-scanning proton therapy, the interplay effect between tumor motion and beam delivery leads to deterioration of the dose distribution. To mitigate the impact of tumor motion, gating in combination with repainting is one of the most promising methods that have been proposed. This study focused on a synchrotron-based spot-scanning proton therapy system integrated with real-time tumor monitoring. The authors investigated the effectiveness of gating in terms of both the delivered dose distribution and irradiation time by conducting simulations with patients’ motion data. The clinically acceptable range of adjustable irradiation control parameters was explored. Also, the relation between the dose error and the characteristics of tumor motion was investigated. Methods: A simulation study was performed using a water phantom. A gated proton beam was irradiated to a clinical target volume (CTV) of 5 × 5 × 5 cm3, in synchronization with lung cancer patients’ tumor trajectory data. With varying parameters of gate width, spot spacing, and delivered dose per spot at one time, both dose uniformity and irradiation time were calculated for 397 tumor trajectory data from 78 patients. In addition, the authors placed an energy absorber upstream of the phantom and varied the thickness to examine the effect of changing the size of the Bragg peak and the number of required energy layers. The parameters with which 95% of the tumor trajectory data fulfill our defined criteria were accepted. Next, correlation coefficients were calculated between the maximum dose error and the tumor motion characteristics that were extracted from the tumor trajectory data. Results: With the assumed CTV, the largest percentage of the data fulfilled the criteria when the gate width was ±2 mm. Larger spot spacing was preferred because it increased the number of paintings. With a prescribed dose of 2 Gy, it was difficult to fulfill the criteria for the target with a very small effective depth (the sum of an assumed energy absorber's thickness and the target depth in the phantom) because of the sharpness of the Bragg peak. However, even shallow targets could be successfully irradiated by employing an adequate number of paintings and by placing an energy absorber of sufficient thickness to make the effective target depth more than 12 cm. The authors also observed that motion in the beam direction was the main cause of dose distortion, followed by motion in the lateral plane perpendicular to the scan direction. Conclusions: The results suggested that by properly adjusting irradiation control parameters, gated proton spot-scanning beam therapy can be robust to target motion. This is an important first step toward establishing treatment plans in real patient geometry.

Purpose: Molecular imaging is one of the important modalities in delineating tumors particularly in radiotherapy treatment planning. If the real‐time tumor position can be detected using molecular imaging during radiotherapy, it may be helpful for gated irradiation. A feasibility study on a beam gating system for radiotherapy using real‐time molecular imaging was conducted by the prototype and simulating a parallel plane PET system. Methods: Assuming that the motion of the positron source is constrained to the central plane, the source position can be calculated from a cross point of the Line of Response (LOR) and the central plane between detector surfaces. If a positron source is located at the ISO center, distribution of the cross points might be blurred due to random/scattered coincidence. Center Located Ratio (CLR) was defined as a ratio of LORs passing through the ISO center divided by the entire LORs. When dislocation for perpendicular direction is occurred, a distribution of cross points will be spread out and associated decrease of CLR value will be expected. Results: The behavior between real measurement and simulation was similar on proto‐type experiments, however, the Result from simulation for demonstrator might be different from actual measurement. RTRT system recognizes the position of a gold marker in the rate of 30 fps using two X‐ray television systems. It is shown that 15,000 events per second will be needed for an appropriate gating irradiation to recognize discrepancy over 2mm of time resolution in the parallel plane PET system demonstrator. Conclusion: A feasibility study was carried out to verify the potential for gating irradiation of tumors with real‐time molecular imaging using a parallel plane PET system. For an parallel plane PET system demonstrator, the possibility of detecting the tumor position with an accuracy of 2 mm from the ISO center with 500 events. This research was a part of the “Innovation COE Program for Future Drug Discovery and Medical Care” project and partially supported by the Grant‐in‐Aid for Project for Developing Innovation Systems of the Japanese Ministry of Education, Culture, Sports, Science and Technology.

Purpose: To mitigate the impact of tumor motion in spot‐scanning proton beam therapy, the gating technique has been considered as a powerful tool. Although residual tumor motion of a few millimeters of gate volume can still cause a dose error, the error can be minimized by repainting. However, a larger number of paintings also results in the prolongation of treatment time. We propose a method which improves the dose uniformity while minimally increasing the number of paintings. Methods: Lateral beam tracking was applied in conjunction with gating. A simulation study was performed using the VQA treatment planning system (Hitachi Ltd., Japan) to assess the effectiveness of this method. A gated proton beam provided by a synchrotron was irradiated to spherical clinical target volumes (CTVs) with a diameter of 5 cm located at 10 cm and 15 cm depth in a heterogeneous phantom. The system delay time was 66 ms. Gate width was set to 2 mm. Rigid motion was assumed for CTVs which were shifted in synchronization with 20 patients' tumor trajectory data. A dose of 2 Gy was prescribed with the minimum repainting scheme. The cases that fulfilled the ICRU 50 criteria (CTVmax 95%) were accepted. Results: When only gating was used, 12 and 16 out of 20 cases were accepted for targets at 10 cm and 15 cm depth, respectively. On the other hand, when beam tracking was also applied, all cases were accepted for both target depths. Conclusion: The results suggest that the application of lateral beam tracking in gate volume can improve the dose uniformity without (or minimally) increasing the number of paintings. A simulation including non‐rigid patient motion will be considered in the future.