Optimum delineation of skin structure for dose calculation with the linear Boltzmann transport equation algorithm in radiotherapy treatment planning.

This study investigated the effectiveness of placing skin-ring structures to enhance the precision of skin dose calculations in patients who had undergone head and neck volumetric modulated arc therapy using the Acuros XB algorithm. The skin-ring structures in question were positioned 2 mm below the skin surface (skin A) and 1 mm above and below the skin surface (skin B) within the treatment-planning system. These structures were then tested on both acrylic cylindrical and anthropomorphic phantoms and compared with the Gafchromic EBT3 film (EBT3). The results revealed that the maximum dose differences between skins A and B for the cylindrical and anthropomorphic phantoms were approximately 12% and 2%, respectively. In patients 1 and 2, the dose differences between skins A and B were 9.2% and 8.2%, respectively. Ultimately, demonstrated that the skin-dose calculation accuracy of skin B was within 2% and did not impact the deep organs.

[Evaluation of Transmitted X-ray Spectrum, Lead Equivalent, and Uniformity of Radiation Protective Clothing Made of Lead-containing and Lead-free Materials].

PURPOSE: The purpose of this study was to evaluate the protective performance of several new radiation-protective clothing and to clarify issues of quality control. METHODS: The composition of the shielding elements was analyzed using X-ray fluorescence analysis, and the energy spectrum of transmitted X-rays was measured. Furthermore, the lead equivalent and uniformity were measured from the transmitted X-ray doses according to Japanese industrial standards (JIS). Uniformity was evaluated by transmitting X-ray images of each radiation protective clothing in addition to the conventional method. RESULTS: The energy spectrum showed K-absorption edges of lead, bismuth, tin, etc., which were detected in the composition analysis. The multi-layered protective material maintained higher shielding ability at high tube voltages. In addition, X-ray images of the radiation-protective clothing showed uneven density and dots, and the differences in uniformity measurement methods and points that didn't meet the required shielding capacity were seen. CONCLUSION: The current JIS does not allow accurate evaluation of the lead equivalent and uniformity, so visual evaluation of X-ray images is important. It is necessary to establish standardized standards for quality control performed by each facility.

The Usefulness of a Virtual Environment-Based Patient Setup Training System for Radiation Therapy.

In radiation therapy, patient setup is important for improving treatment accuracy. The six-axis couch semi-automatically adjusts the patient's position; however, adjusting the patient to twist is difficult. In this study, we developed and evaluated a virtual reality setup training tool for medical students to understand and improve their patient setup skills for radiation therapy. First, we set up a simulated patient in a virtual space to reproduce the radiation treatment room. A gyro sensor was attached to the patient phantom in real space, and the twist of the phantom was linked to the patient in the virtual space. Training was conducted for 24 students, and their operation records were analyzed and evaluated. The training's efficacy was also evaluated through questionnaires provided at the end of the training. The total time required for patient setup tests before and after training decreased significantly from 331.9 s to 146.2 s. As a result of the questionnaire regarding the usability of training to the trainee, most were highly evaluated. We found that training significantly improved students' understanding of the patient setup. With the proposed system, trainees can experience a simulated setup that can aid in deepening their understanding of radiation therapy treatments.

Evaluation of radiation protection effectivity in a cardiac angiography room using visualized scattered radiation distribution.

In this study, we devised a radiation protection tool specifically designed for healthcare professionals and students engaged in cardiac catheterization to easily monitor and evaluate scattered radiation distribution across diverse C-arm angles and arbitrary physician associated staff positions-scrub nurse and technologist positions. In this study, scattered radiation distributions in an angiography room were calculated using the Monte Carlo simulation of particle and heavy ion transport code system (PHITS) code. Four visualizations were performed under different C-arm angles with and without radiation protection: (1) a dose profile, (2) a 2D cross-section, (3) a 3D scattered radiation distribution, and (4) a 4D scattered radiation distribution. The simulation results detailing the scattered radiation distribution in PHITS were exported in Visualization Toolkit format and visualized through the open-source visualization application ParaView for analysis. Visualization of the scattered dose showed that dose distribution depends on the C-arm angle and the x-ray machine output parameters (kV, mAs s-1, beam filtration) which depend upon beam angulation to the patient body. When irradiating in the posterior-anterior direction, the protective curtain decreased the dose by 62% at a point 80 cm from the floor, where the physician's gonads are positioned. Placing the protection board close to the x-ray tube reduced the dose by 24% at a location 160 cm from the floor, where the lens of the eye is situated. Notably, positioning the protection board adjacent to the physician resulted in a 95.4% reduction in incident air kerma. These visualization displays can be combined to understand the spread and direction of the scattered radiation distribution and to determine where and how to operate and place radiation protection devices, accounting for the different beam angulations encountered in interventional cases. This study showed that scatter visualization could be a radiation protection teaching aid for students and medical staff in angiography rooms.

Developing simulation-based learning application for radiation therapy students at pre-clinical stage.

INTRODUCTION: Simulation-based education has been particularly valuable as a preclinical training method that adequately prepares students for clinical practice, including simulation in educational programs enhances the quality of learning outcomes. However, relevant previous research has exhibited several crucial limitations, with most of them having focused solely on the setup procedures. This study aimed to outline the development of an educational application in radiationtherapy and emphasizes the essential factors that radiation therapist technologists(RTTs) must consider in the treatment room from the perspective of experienced RTTs. METHOD: We connected the virtual pendants to the linear accelerator components using C# programming and Unity. Customized scripts were assigned to specific linear accelerator (LINAC) functions, and the patient and RTT avatars were developed. We also included audio feedback for the realistic gantry movement sounds. RESULT: This study outlines various aspects of radiotherapy procedures duringtreatment, such as the simulation of patient positioning, treatment fields, and pendantfunctions, aimed toward enabling the effective use of virtual reality technology inradiation therapy. DISCUSSION: This study explores the potential of an avatar-based app for radiotherapy education, providing foundational data for future trials. CONCLUSION: Simulation learning is the most advantageous pre-clinical instrument for equipping students with the skills necessary for clinical practice. This study's resultsare expected to facilitate radiotherapy students' adoption of clinical replacement applications and improve collaborative partnerships and knowledge sharing. Notably, this application complements traditional learning methods, further enhancing the overall educational experience.

Directional vector visualization of scattered rays in mobile c-arm fluoroscopy.

Previous radiation protection-measure studies for medical staff who perform X-ray fluoroscopy have employed simulations to investigate the use of protective plates and their shielding effectiveness. Incorporating directional information enables users to gain a clearer understanding of how to position protective plates effectively. Therefore, in this study, we propose the visualization of the directional vectors of scattered rays. X-ray fluoroscopy was performed; the particle and heavy-ion transport code system was used in Monte Carlo simulations to reproduce the behavior of scattered rays in an X-ray room by reproducing a C-arm X-ray fluoroscopy system. Using the calculated results of the scattered-ray behavior, the vectors of photons scattered from the phantom were visualized in three dimensions. A model of the physician was placed on the directional vectors and dose distribution maps to confirm the direction of the scattered rays toward the physician when the protective plate was in place. Simulation accuracy was confirmed by measuring the ambient dose equivalent and comparing the measured and calculated values (agreed within 10%). The directional vectors of the scattered rays radiated outward from the phantom, confirming a large amount of backscatter radiation. The use of a protective plate between the patient and the physician's head part increased the shielding effect, thereby enhancing radiation protection for the physicians compared to cases without the protective plate. The use of directional vectors and the surrounding dose-equivalent distribution of this method can elucidate the appropriate use of radiation protection plates.

A novel approach to predict acute radiation dermatitis in patients with head and neck cancer using a model based on Bayesian probability.

PURPOSE: In this study, we aimed to establish a method for predicting the probability of each acute radiation dermatitis (ARD) grade during the head and neck Volumetric Modulated Arc Therapy (VMAT) radiotherapy planning phase based on Bayesian probability. METHODS: The skin dose volume >50 Gy (V50), calculated using the treatment planning system, was used as a factor related to skin toxicity. The empirical distribution of each ARD grade relative to V50 was obtained from the ARD grades of 119 patients (55, 50, and 14 patients with G1, G2, and G3, respectively) determined by head and neck cancer specialists. Using Bayes' theorem, the Bayesian probabilities of G1, G2, and G3 for each value of V50 were calculated with an empirical distribution. Conversely, V50 was obtained based on the Bayesian probabilities of G1, G2, and G3. RESULTS: The empirical distribution for each graded patient group demonstrated a normal distribution. The method predicted ARD grades with 92.4 % accuracy and provided a V50 value for each grade. For example, using the graph, we could predict that V50 should be ≤24.5 cm3 to achieve G1 with 70 % probability. CONCLUSIONS: The Bayesian probability-based ARD prediction method could predict the ARD grade at the treatment planning stage using limited patient diagnostic data that demonstrated a normal distribution. If the probability of an ARD grade is high, skin care can be initiated in advance. Furthermore, the V50 value during treatment planning can provide radiation oncologists with data for strategies to reduce ARD.

Dose estimation for cone-beam computed tomography in image-guided radiation therapy for pelvic cancer using adult mesh-type reference computational phantoms.

The use of cone-beam computed tomography (CBCT) is expanding owing to its installation in linear accelerators for radiation therapy, and the imaging dose induced by this system has become the center of attention. Here, the dose to patients caused by the CBCT imager was investigated. Organ doses and effective doses for male and female mesh-type reference computational phantoms (MRCPs) and pelvis CBCT mode, routinely used for pelvic irradiation, were estimated using the Particle and Heavy Ion Transport Code System. The simulation results were confirmed based on the point-dose measurements. The estimated organ doses for male MRCPs with/without raised arms and for female MRCPs with/without raised arms were 0.00286-35.6 mGy, 0.00286-35.1 mGy, 0.00933-39.5 mGy, and 0.00931-39.0 mGy, respectively. The anticipated effective doses for male MRCPs with/without raised arms and female MRCPs with/without raised arms irradiated by pelvis CBCT mode were 4.25 mSv, 4.16 mSv, 7.66 mSv, and 7.48 mSv, respectively. The results of this study will be useful for patients who undergo image-guided radiotherapy with CBCT. However, because this study only covered one type of cancer with one type of imager, and image quality was not considered, more studies should be conducted to estimate the radiation dose from imaging devices in radiation therapy.

Effects of gastric inhibitory polypeptide (GIP) immunoneutralization on mouse motor coordination and memory.

Gastric inhibitory polypeptide (GIP) is a regulatory peptide expressed in the mammalian upper small intestine, and both GIP and its receptor (GIPR) are expressed in the cortex and hippocampus regions of the brain as well. While learning and memory deficits have been observed in GIPR-/- mice, the effects of peripheral GIP immunoneutralization on motor-coordination, learning, and memory have not been examined. In the present study, adult GIPR-/- mice (KO) and age-matched wild-type C57BL/6 J mice (WT) received weekly vehicle PBS injections for 12 weeks, while a third group of wild-type mice were injected weekly for 12 weeks with 30 mg/kg body weight humanized GIP-mAb (AB) to assess the possibility of long-term effects of peripheral GIP antagonism on rodent memory and behavior. All mice groups then underwent a battery of tests that evaluated motor behavior, body coordination, and memory. Performance deficits in several memory studies after 12 weeks of treatment were demonstrated in KO, but not in AB or WT mice. Body coordination performance showed no significant differences among the 3 groups. A similar short-term study (3 injections over 9 days) was also conducted and the results were similar to those from the long-term study. Thus, short-term and long-term peripheral GIP antagonism by GIP-mAb did not appear to affect learning and memory in mice, consistent with the notion that the GIP-mAb does not cross the blood brain barrier. Furthermore, our studies indicate that GIP signaling in the brain appears to involve local neurocrine pathways.

Long-Term Deficits in Behavior Performances Caused by Low- and High-Linear Energy Transfer Radiation.

Efforts to protect astronauts from harmful galactic cosmic radiation (GCR) require a better understanding of the effects of GCR on human health. In particular, little is known about the lasting effects of GCR on the central nervous system (CNS), which may lead to behavior performance deficits. Previous studies have shown that high-linear energy transfer (LET) radiation in rodents leads to short-term declines in a variety of behavior tests. However, the lasting impact of low-, medium- and high-LET radiation on behavior are not fully defined. Therefore, in this study C57BL/6 male mice were irradiated with 100 or 250 cGy of γ rays (LET ∼0.3 KeV/µm), 10 or 100 cGy of 1H at 1,000 MeV/n (LET ∼0.2 KeV/µm), 28Si at 300 MeV/n (LET ∼69 KeV/µm) or 56Fe at 600 MeV/n (LET of ∼180 KeV/µm), and behavior metrics were collected at 5 and 9 months postirradiation to analyze differences among radiation qualities and doses. A significant dose effect was observed on recognition memory and activity levels measured 9 months postirradiation, regardless of radiation source. In contrast, we observed that each ion species had a distinct effect on anxiety, motor coordination and spatial memory at extended time points. Although 28Si and 56Fe are both regarded as high-LET particles, they were shown to have different detrimental effects on behavior. In summary, our findings suggest that GCR not only affects the CNS in the short term, but also has lasting damaging effects on the CNS that can cause sustained declines in behavior performance.

Neurofibromatosis type 1 alternative splicing is a key regulator of Ras/ERK signaling and learning behaviors in mice.

Appropriate activation of the Ras/extracellular signal-regulated kinase (ERK) protein signaling cascade within the brain is crucial for optimal learning and memory. One key regulator of this cascade is the Nf1 Ras GTPase activating protein (RasGAP), which attenuates Ras/ERK signaling by converting active Ras is bound to guanosine triphosphate, activating Ras into inactive Ras is bound to guanosine diphosphate, inactivating Ras. A previous study using embryonic stem cells and embryonic stem cell-derived neurons indicated that Nf1 RasGAP activity is modulated by the highly regulated alternative splicing of Nf1 exon 23a. In this study, we generated Nf123aIN/23aIN mice, in which the splicing signals surrounding Nf1 exon 23a were manipulated to increase exon inclusion. Nf123aIN/23aIN mice are viable and exon 23a inclusion approaches 100% in all tissues, including the brain, where the exon is normally almost completely skipped. Ras activation and phosphorylation of ERK1/2 downstream of Ras are both greatly increased in Nf123aIN/23aIN mouse brain lysates, confirming that exon 23a inclusion inhibits Nf1 RasGAP activity in vivo as it does in cultured cells. Consistent with the finding of altered Ras/ERK signaling in the brain, Nf123aIN/23aIN mice showed specific deficits in learning and memory compared with Nf1+/+ mice. Nf123aIN/23aIN mice performed poorly on the T-maze and Morris water maze tests, which measure short- and long-term spatial memory, respectively. In addition, Nf123aIN/23aIN mice showed abnormally elevated context-dependent fear and a diminished ability to extinguish a cued fear response, indicating defective associative fear learning. Therefore, the regulated alternative splicing of Nf1 is an important mechanism for fine-tuning Ras/ERK signaling as well as learning and memory in mice.

A Fulminant Case of Granulomatosis with Polyangiitis with Meningeal and Parenchymal Involvement.

Central nervous system (CNS) involvement, such as pachymeningitis and/or cerebrovascular events, is rare in patients with granulomatosis with polyangiitis (GPA). Furthermore, the details of pathological examinations of cases have rarely been described. We describe a case of GPA that manifested as an isolated paranasal sinus disease that invaded the subarachnoid space and caused a hemorrhagic venous infarction. We also describe the pathological characteristics of the biopsied brain material from the successful decompressive craniectomy. In particular, granulomatous inflammation with geographic necrosis and multinucleated giant cells were observed in the perivascular area of the thickened dura mater and leptomeninges. Small vessels in the meninges were involved in the granulomatous lesions, and the lumens of the veins were often occluded. In the cerebral cortices and white matter in these areas, hemorrhagic infarction was widely observed. We suggest that our findings represent a novel mechanism of CNS involvement in GPA. Moreover, we believe that the emergency decompressive craniectomy and partial lobectomy for the cerebral infarction in this patient with GPA likely contributed to his survival.

Effects of the estrous cycle and ovarian hormones on central expression of interleukin-1 evoked by stress in female rats.

Exposure to stressors such as foot shock (FS) leads to increased expression of multiple inflammatory factors, including the proinflammatory cytokine interleukin-1 (IL-1) in the brain. Studies have indicated that there are sex differences in stress reactivity, suggesting that the fluctuations in gonadal steroid levels across the estrous cycle may play a regulatory role in the stress-induced cytokine expression. The present studies were designed to investigate the role of 17-ß-estradiol (E2) and progesterone (Pg) in regulating the cytokine response within the paraventricular nucleus (PVN) of the hypothalamus through analysis of gene expression with real-time RT-PCR. Regularly cycling female rats showed a stress-induced increase in PVN IL-1 levels during the diestrous, proestrous, and estrous stages. During the metestrous stage, no change in IL-1 levels was seen following FS; however, estrogen receptor (ER)-ß levels did increase. Ovariectomy resulted in an increase in PVN IL-1 levels, which was attenuated by treatment with estradiol benzoate (10 or 50 µg), indicating an E2-mediated anti-inflammatory effect. Ovariectomized rats treated with Pg (500 or 1,250 µg) showed no alteration in IL-1 levels, but Pg did up-regulate ER-ß gene expression. The results from the current study implicate a potential mechanism through which high availability of endogenous Pg during the metestrous stage increases ER-ß sensitivity, which in turn attenuates the PVN IL-1 response to stress. Thus, the interaction between gonadal steroid hormones and their central receptors may exert a powerful inhibitory effect on neuroimmune consequences of stress throughout the estrous cycle.

Attractiveness of illness-associated odorant cues in female rats is modulated by ovarian hormones, but not associated with pro-inflammatory cytokine levels.

Odorant cues released by rodents play a key role in mate preference/selection. The goal of the following series of studies was to determine the impact of acute illness, and the potential role of the inflammatory response, on the release of illness-associated odor cues from female rats. Adult female Sprague-Dawley rats were injected with lipopolysaccharide (LPS, 100 µg/kg) and their soiled bedding was used as a stimulus to naïve male odor recipients. While odored bedding from sick males elicited a robust avoidance response evidenced by decreased sniffing, avoidance and burying behavior, odored bedding from sick females elicited only a reduction in sniffing, indicating a reduction in odor attractiveness. Odor cues from ovariectomized, but not sham-operated females decreased sniffing behavior and increased avoidance in male odor recipients. Acute estradiol benzoate (EB, 20 µg/kg) replacement into ovariectomized females restored the investigatory response of male recipients toward odor cues, while LPS administration into ovariectomized oil or EB treated females had little impact on odor attractiveness. Measurement of cytokines in both brain (the paraventricular nucleus of the hypothalamus) and blood from female odor donors indicated increased expression of TNF-α, IL-1ß, and IL-6 following LPS, which was not affected by EB treatment. These findings illustrate a critical sexual dimorphism by demonstrating that acute illness reduces the attractiveness of female odor, whereas odor cues from sick males are highly aversive. Moreover, the attractiveness of female odor appears to be associated with circulating ovarian hormone levels, but not central or peripheral inflammatory cytokines.

Sickness-related odor communication signals as determinants of social behavior in rat: a role for inflammatory processes.

Infected animals are avoided by conspecifics, suggesting that the inflammatory cascade may play a significant role in odor communication. Injection of male rats with the bacterial mimetic, lipopolysaccharide (LPS, 100 microg/kg, i.p.), decreased investigation through a wire-mesh partition between healthy male partners. This avoidance response was observed in adult males in response to soiled bedding collected from sick rats, regardless of whether LPS was injected peripherally (100 microg/kg, i.p.) or centrally (0.25 or 2.5 microg, icv). The release of sickness-related odor cues was dose-dependently blocked by icv infusion of the anti-inflammatory cytokine, interleukin-10 (IL-10; 20 or 200 ng), and reproduced by icv infusion of pro-inflammatory cytokine, IL-1beta (5 or 50 ng). Subcutaneous pretreatment with either estradiol benzoate (20 microg/kg) or testosterone propionate (50 or 500 microg/kg) to adult males that were administered LPS inhibited release of aversive odor cues, but these hormones alone did not influence odor properties. Importantly, the avoidance response to sickness-related odor was not associated with changes in plasma corticosterone, testosterone, or IL-6 levels of odor donors. However, plasma IL-1beta concentrations of sick animals was in fact predictive of aversive responses in conspecifics, suggesting that the inflammatory cascade, but not plasma steroid hormones, is likely to mediate aversive properties in odor that functions to signal illness state to conspecifics.

Acute illness induces the release of aversive odor cues from adult, but not prepubertal, male rats and suppresses social investigation by conspecifics.

The present study examined odorant communication during acute illness provoked by injection of lipopolysaccharide (LPS; 100 microg/kg) and how these effects vary between prepubertal and adult conspecifics. Exposure to odor of LPS-treated adult male rats produced increased avoidance in both sexes of adults and prepubertal male partners. This response was not found when they were exposed to odor of LPS-treated prepubertal males. Even a 2.5-fold higher load of LPS in prepubertal males failed to produce aversive odor cues, suggesting that the difference in the odor is not a simple issue of dose/body volume. Both estradiol benzoate (20 microg/kg) and testosterone propionate (500 microg/kg), but not dihydrotestosterone (500 microg/kg) pretreatment in prepubertal males administered LPS restored the expression of aversive odor. These hormone treatments per se did not influence odor properties of prepubertal males, indicating that estrogen receptors may play a key regulatory role in the expression of aversive odor in LPS-treated prepubertal rats. These data suggest that the expression of sickness-related odor emerges through puberty, and likely involves a complex interaction between inflammation and sex steroids across development.

An epoch-making application of discharge plasma phenomenon to gene-transfer.

We discovered an epoch-making gene transfer method utilizing discharge plasma. Although an electroporation method is commonly used in present gene transfer experiments, it cannot transfer genes into primary cells sufficiently. The atmospheric pressure discharge plasma employed in this study was originally used for surface treatment of non-biological materials. We hypothesized that it could provide a suitable effect on the surface of target cells and applied it to gene transfer into various types of cells. The plasma technology succeeded in the efficient transfer of green fluorescence protein (GFP) plasmid into post-mitotic neuronal cells obtained from cerebral cortices of rats, into which an electroporation with conventional equipment cannot transfer genes sufficiently, as the cells were attached. After the transfection of rat pheochromocytoma PC12 cells with the GFP gene by plasma treatment, the cells retained their function, that is, nerve growth factor-induced differentiation. Furthermore, gene transfer with the plasma technology was also applicable to other types of cell lines such as HeLa cells and Chinese hamster lung (CHL) cells as adherent cell lines, and Jurkat cells as a suspended cell line, and another type of primary cell, human umbilical vein endothelial cells (HUVEC). In conclusion, the plasma method is an epoch-making gene transfer technology which efficiently transfers genes into primary cells into which electroporation cannot transfer genes. Moreover, the method is able to universally transfer genes into various types of cells as the function of the cells was maintained.

Identification of a selective ERK inhibitor and structural determination of the inhibitor-ERK2 complex.

Selective inhibition of extracellular signal-regulated kinase (ERK) represents a potential approach for the treatment of cancer and other diseases; however, no selective inhibitors are currently available. Here, we describe an ERK-selective inhibitor, FR180204, and determine the structural basis of its selectivity. FR180204 inhibited the kinase activity of ERK1 and ERK2, with K(i) values 0.31 and 0.14microM, respectively. Lineweaver-Burk analysis of the binding interaction revealed that FR180204 acted as competitive inhibitor of ATP. In mink lung epithelial Mv1Lu cells, FR180204 inhibited TGFbeta-induced luciferase-expression. X-ray crystal structure analysis of the human ERK2/FR180204 complex revealed that Q105, D106, L156, and C166, which form the ATP-binding pocket on ERK, play important roles in the drug/protein interaction. These results suggest that FR180204 is an ERK-selective and cell-permeable inhibitor, and could be useful for elucidating the roles of ERK as well as for drug development.