[Direct Positron Emission Imaging Using Ultrafast Timing Performance Detectors].

This is an explanatory paper on Sun Il Kwon et al., Nat. Photon. 15: 914-918, 2021 and some parts of this manuscript are translated from the paper. Medical imaging modalities such as X-ray computed tomography, Magnetic resonance imaging, positron emission tomography (PET), and single photon emission computed tomography, require image reconstruction processes, consequently constraining them to form cylindrical shapes. However, among them, only PET can use additional information, so called time of flight, on an event-by-event basis. If coincidence time resolution (CTR) of PET detectors improved to 30 ps, which corresponds to spatial resolution of 4.5 mm, directly localizing electron-positron annihilation point is possible, allowing us to circumvent image reconstruction processes and free us from the geometric constraint. We call this concept direct positron emission imaging (dPEI). We have developed ultrafast radiation detectors by focusing on Cherenkov photon detection. Furthermore, the CTR of 32 ps being equivalent to 4.8 mm spatial resolution is achieved by combining deep learning-based signal processing with the detectors. In this article, we explain how we developed the detectors and demonstrated the first dPEI using different types of phantoms, how we will tackle limitations to be addressed to make the dPEI more practical, and how dPEI will emerge as an imaging modality in nuclear medicine.

Improving image quality using the pause function combination to PROPELLER sequence in brain MRI: a phantom study.

While some MRI systems offer a "pause" function, combining it with the PROPELLER method for image quality improvement remains underexplored. This study investigated whether repositioning the head after pausing during PROPELLER imaging enhances image quality. All brain phantom images in this study were obtained using a 3.0 T MRI and acquired using the fast spin-echo T2WI-based PROPELLER with motion correction. By combining the angle of rotational motion of the head phantom and the number of repositioning after a pause, two studies including seven trials were performed. Increasing the rotation angle decreased the image quality; however, pausing the image and repositioning the head phantom to the original angle improved the image quality. A similar result was obtained by repositioning the angle closer to its original angle. Experiments with multiple head movements showed that pausing the scan and repositioning the phantom with each movement improved image quality.

Development of a novel delivery quality assurance system based on simultaneous verification of dose distribution and binary multi-leaf collimator opening in helical tomotherapy.

BACKGROUND: Intensity-modulated radiation therapy (IMRT) requires delivery quality assurance (DQA) to ensure treatment accuracy and safety. Irradiation techniques such as helical tomotherapy (HT) have become increasingly complex, rendering conventional verification methods insufficient. This study aims to develop a novel DQA system to simultaneously verify dose distribution and multi-leaf collimator (MLC) opening during HT. METHODS: We developed a prototype detector consisting of a cylindrical plastic scintillator (PS) and a cooled charge-coupled device (CCD) camera. Scintillation light was recorded using a CCD camera. A TomoHDA (Accuray Inc.) was used as the irradiation device. The characteristics of the developed system were evaluated based on the light intensity. The IMRT plan was irradiated onto the PS to record a moving image of the scintillation light. MLC opening and light distribution were obtained from the recorded images. To detect MLC opening, we placed a region of interest (ROI) on the image, corresponding to the leaf position, and analyzed the temporal change in the light intensity within each ROI. Corrections were made for light changes due to differences in the PS shape and irradiation position. The corrected light intensity was converted into the leaf opening time (LOT), and an MLC sinogram was constructed. The reconstructed MLC sinogram was compared with that calculated using the treatment planning system (TPS). Light distribution was obtained by integrating all frames obtained during IMRT irradiation. The light distribution was compared with the dose distribution calculated using the TPS. RESULTS: The LOT and the light intensity followed a linear relationship. Owing to MLC movements, the sensitivity and specificity of the reconstructed sinogram exceeded 97%, with an LOT error of - 3.9 ± 7.8%. The light distribution pattern closely resembled that of the dose distribution. The average dose difference and the pass rate of gamma analysis with 3%/3 mm were 1.4 ± 0.2% and 99%, respectively. CONCLUSION: We developed a DQA system for simultaneous and accurate verification of both dose distribution and MLC opening during HT.

Dedicated phantom tools using traceable 68Ge/68Ga point-like sources for dedicated-breast PET and positron emission mammography scanners.

Since the early 2000s, many types of positron emission tomography (PET) scanners dedicated to breast imaging for the diagnosis of breast cancer have been introduced. However, conventional performance evaluation methods developed for whole-body PET scanners cannot be used for such devices. In this study, we developed phantom tools for evaluating the quantitative accuracy of positron emission mammography (PEM) and dedicated-breast PET (dbPET) scanners using novel traceable point-like 68Ge/68 Ga sources. The PEM phantom consisted of an acrylic cube (100 × 100 × 40 mm) and three point-like sources. The dbPET phantom comprised an acrylic cylinder (ø100 × 100 mm) and five point-like sources. These phantoms were used for evaluating the fundamental responses of clinical PEM and dbPET scanners to point-like inputs in a medium. The results showed that reasonable recovery values were obtained based on region-of-interest analyses of the reconstructed images. The developed phantoms using traceable 68Ge/68 Ga point-like sources were useful for evaluating the physical characteristics of PEM and dbPET scanners. Thus, they offer a practical, reliable, and universal measurement scheme for evaluating various types of PET scanners using common sets of sealed sources.

Molecular characterization of mouse CREB3 regulatory factor in Neuro2a cells.

We performed expression and functional analysis of mouse CREB3 regulatory factor (CREBRF) in Neuro2a cells by constructing several expression vectors. Overexpressed full-length (FL) CREBRF protein was stabilized by MG132; however, the intrinsic CREBRF expression in Neuro2a cells was negligible under all conditions. On the other hand, N- or C-terminal deletion of CREBRF influenced its stability. Cotransfection of CREBRF together with GAL4-tagged FL CREB3 increased luciferase reporter activity, and only the N-terminal region of CREBRF was sufficient to potentiate luciferase activity. Furthermore, this positive effect of CREBRF was also observed in cells expressing GAL4-tagged cleaved CREB3, although CREBRF hardly influenced the protein stability of NanoLuc-tagged cleaved CREB3 or intracellular localization of EGFP-tagged one. In conclusion, this study suggests that CREBRF, a quite unstable proteasome substrate, positively regulates the CREB3 pathway, which is distinct from the canonical ER stress pathway in Neuro2a cells.

Elucidation of brefeldin A-induced ER and Golgi stress responses in Neuro2a cells.

Brefeldin A (BFA) disrupts the structure of the Golgi apparatus to trigger ER stress signaling pathways. On the other hand, treatment with BFA induces the activation of CREB3, the protein structure of which is similar to that of ATF6. In this study, we established Neuro2a cells in which three different transcription factors, namely, ATF4, ATF3 and CREB3, were deficient using the CRISPR/Cas9 approach, and we investigated the BFA-induced ER and Golgi stress response in these cells. BFA treatment rapidly induced ATF4, ATF3, Herp and GADD153 protein expression in Neuro2a cells. ATF4-deficient Neuro2a cells exhibited significantly decreased mRNA and protein expression of ATF3 and Herp but not GADD153; however, cells deficient in ATF3 exhibited minimal effects on GADD34, GADD153 and Herp expression. The cleavage of CREB3 in Neuro2a cells was triggered by BFA; however, the expression of several ER and Golgi stress-related factors was hardly influenced by the CREB3 deficiency in these Neuro2a cells. This study shows that CREB3 minimally associates with typical ER stress-inducible responses in Neuro2a cells. Therefore, identification and characterization of the downstream transcriptional targets of CREB3 is required to clarify not only Golgi stress response but also its relationship with ER stress signaling pathways.

Ultrafast timing enables reconstruction-free positron emission imaging.

X-ray and gamma-ray photons are widely used for imaging but require a mathematical reconstruction step, known as tomography, to produce cross-sectional images from the measured data. Theoretically, the back-to-back annihilation photons produced by positron-electron annihilation can be directly localized in three-dimensional space using time-of-flight information without tomographic reconstruction. However, this has not yet been demonstrated due to the insufficient timing performance of available radiation detectors. Here, we develop techniques based on detecting prompt Cerenkov photons, which when combined with a convolutional neural network for timing estimation resulted in an average timing precision of 32 picoseconds, corresponding to a spatial precision of 4.8 mm. We show this is sufficient to produce cross-sectional images of a positron-emitting radionuclide directly from the detected coincident annihilation photons, without using any tomographic reconstruction algorithm. The reconstruction-free imaging demonstrated here directly localizes positron emission, and frees the design of an imaging system from the geometric and sampling constraints that normally present for tomographic reconstruction.

Size of pelvic bone metastasis as a significant prognostic factor for metastatic prostate cancer patients.

INTRODUCTION: To investigate the potential prognostic value of image analysis of pelvic bone metastasis in newly diagnosed prostate cancer patients. METHODS: Data from 69 patients with both bone scintigraphy and pelvic CT images were selected for this analysis. Open source software (3D Slicer version 4.8.1.) was used for image analysis. Metastatic pelvic bone lesions were manually contoured, and radiomic features were extracted. As risk factors for overall survival (OS) and cause-specific survival (CSS), 105 radiomic features and clinical risk factors including age, initial prostate-specific antigen, Gleason score, TNM stage, lactate dehydrogenase (LDH), hemoglobin (Hb), alkaline phosphatase, extent of disease, visceral metastases, and radiotherapy were assessed by uni- and multivariate analyses. RESULTS: Median follow-up was 41 months (range 0-157 months). Five-year overall survival and cause-specific survival rate were 37.9% and 43.5%, respectively. After multivariate analysis, LDH, Hb, and "maximum 2D diameter" defined as maximum tumor size in the axial plane were detected as risk factors for OS. Gleason sum, LDH, and maximum 2D diameter were detected as risk factors for CSS. CONCLUSION: Maximum 2D diameter was detected as a significant prognostic factor for metastatic prostate cancer patients.

Traceable point-like 68Ge/68Ga source with a spherically symmetric positron absorber for PET scanners.

A novel traceable point-like 68Ge/68Ga source was developed for calibration of positron emission tomography (PET) scanners. The source was equipped with a spherically symmetric acrylic positron absorber. The physical characteristics of photons emitted from the point-like source were evaluated by Monte Carlo simulation, considering possible geometrical uncertainties. The calibration factor of a clinical PET/CT scanner was evaluated using four manufactured point-like sources as a practical application of the point-like source. The results were consistent with that determined by the conventional cross-calibration method. The traceable point-like 68Ge/68Ga source is expected to be a simple and practical tool for determining the calibration factor and evaluating the physical characteristics of PET scanners.

Effect of chest compression with kneeling on the bed in clinical situations.

AIM: Cardiopulmonary resuscitation is vital for survival after cardiac arrest, and chest compressions are an important aspect of this. When performing chest compression in a hospital setting, the rescuer often has to kneel on the bed to overcome inconvenient differences in height between the rescuer and the bed. However, as yet no study has evaluated the quality of chest compressions in this position. The aim of this study was to examine the impact on the quality of chest compressions while kneeling on the bed. METHODS: Fifteen female students performed 2-min chest compressions on a manikin placed on the floor and a bed. Measurement parameters included compression depth, heart rate, integrated electromyogram, and a visual analog scale. The parameters were measured every 30 s and were statistically compared between the conditions. RESULTS: Compression depth at 30, 60, 90, and 120 s differed significantly between the conditions. Heart rate values at 150 and 210 s of recovery significantly differed between the conditions. Integrated electromyogram values for the trapezius, rectus femoris, and biceps femoris differed between the floor and bed conditions during 2-min chest compressions, whereas the external oblique muscle significantly differed at 60 and 120 s. Visual analog scales for fatigue, effectiveness, and stability significantly differed between the conditions. CONCLUSION: Kneeling on the bed does not enable grounding of the toe, causing the upper body to be unstable and limiting generation of the power required for chest compression. Our results suggest that rotation every minute is necessary to maintain effective cardiopulmonary resuscitation while kneeling on the bed.

Identification of a Novel RAMA/RON3 Rhoptry Protein Complex in Plasmodium falciparum Merozoites.

Malaria causes a half a million deaths annually. The parasite intraerythrocytic lifecycle in the human bloodstream is the major cause of morbidity and mortality. Apical organelles of merozoite stage parasites are involved in the invasion of erythrocytes. A limited number of apical organellar proteins have been identified and characterized for their roles during erythrocyte invasion or subsequent intraerythrocytic parasite development. To expand the repertoire of identified apical organellar proteins we generated a panel of monoclonal antibodies against Plasmodium falciparum schizont-rich parasites and screened the antibodies using immunofluorescence assays. Out of 164 hybridoma lines, 12 clones produced monoclonal antibodies yielding punctate immunofluorescence staining patterns in individual merozoites in late schizonts, suggesting recognition of merozoite apical organelles. Five of the monoclonal antibodies were used to immuno-affinity purify their target antigens and these antigens were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two known apical organelle protein complexes were identified, the high-molecular mass rhoptry protein complex (PfRhopH1/Clags, PfRhopH2, and PfRhopH3) and the low-molecular mass rhoptry protein complex (rhoptry-associated proteins complex, PfRAP1, and PfRAP2). A novel complex was additionally identified by immunoprecipitation, composed of rhoptry-associated membrane antigen (PfRAMA) and rhoptry neck protein 3 (PfRON3) of P. falciparum. We further identified a region spanning amino acids Q221-E481 within the PfRAMA that may associate with PfRON3 in immature schizonts. Further investigation will be required as to whether PfRAMA and PfRON3 interact directly or indirectly.

Antibodies against a Plasmodium falciparum RON12 inhibit merozoite invasion into erythrocytes.

Proteins coating Plasmodium merozoite surface and secreted from its apical organelles are considered as promising vaccine candidates for blood-stage malaria. The rhoptry neck protein 12 of Plasmodium falciparum (PfRON12) was recently reported as a protein specifically expressed in schizonts and localized to the rhoptry neck of merozoites. Here, we assessed its potential as a vaccine candidate. We expressed a recombinant PfRON12 protein by a wheat germ cell-free system to obtain anti-PfRON12 antibody. Immunoblot analysis of schizont lysates detected a single band at approximately 40 kDa under reducing conditions, consistent with the predicted molecular weight. Additionally, anti-PfRON12 antibody recognized a single band around 80 kDa under non-reducing conditions, suggesting native PfRON12 forms a disulfide-bond-mediated multimer. Immunofluorescence assay and immunoelectron microscopy revealed that PfRON12 localized to the rhoptry neck of merozoites in schizonts and to the surface of free merozoites. The biological activity of anti-PfRON12 antibody was tested by in vitro growth inhibition assay (GIA), and the rabbit antibodies significantly inhibited merozoite invasion of erythrocytes. We then investigated whether PfRON12 is immunogenic in P. falciparum-infected individuals. The sera from P. falciparum infected individuals in Thailand and Mali reacted with the recombinant PfRON12. Furthermore, human anti-PfRON12 antibodies affinity-purified from Malian serum samples inhibited merozoite invasion of erythrocytes in vitro. Moreover, pfron12 is highly conserved with only 4 non-synonymous mutations in the coding sequence from approximately 200 isolates deposited in PlasmoDB. These results suggest that PfRON12 might be a potential blood-stage vaccine candidate antigen against P. falciparum.

Cherenkov radiation-based three-dimensional position-sensitive PET detector: A Monte Carlo study.

PURPOSE: Cherenkov radiation has recently received attention due to its prompt emission phenomenon, which has the potential to improve the timing performance of radiation detectors dedicated to positron emission tomography (PET). In this study, a Cherenkov-based three-dimensional (3D) position-sensitive radiation detector was proposed, which is composed of a monolithic lead fluoride (PbF2 ) crystal and a photodetector array of which the signals can be readout independently. METHODS: Monte Carlo simulations were performed to estimate the performance of the proposed detector. The position- and time resolution were evaluated under various practical conditions. The radiator size and various properties of the photodetector, e.g., readout pitch and single photon timing resolution (SPTR), were parameterized. The single photon time response of the photodetector was assumed to be a single Gaussian for the simplification. The photo detection efficiency of the photodetector was ideally 100% for all wavelengths. Compton scattering was included in simulations, but partly analyzed. To estimate the position at which a γ-ray interacted in the Cherenkov radiator, the center-of-gravity (COG) method was employed. In addition, to estimate the depth-of-interaction (DOI) principal component analysis (PCA), which is a multivariate analysis method and has been used to identify the patterns in data, was employed. The time-space distribution of Cherenkov photons was quantified to perform PCA. To evaluate coincidence time resolution (CTR), the time difference of two independent γ-ray events was calculated. The detection time was defined as the first photon time after the SPTR of the photodetector was taken into account. RESULTS: The position resolution on the photodetector plane could be estimated with high accuracy, by using a small number of Cherenkov photons. Moreover, PCA showed an ability to estimate the DOI. The position resolution heavily depends on the pitch of the photodetector array and the radiator thickness. If the readout pitch were ideally 0 and practically 3 mm, a full-width at half-maximum (FWHM) of 0.348 and 1.92 mm was achievable with a 10-mm-thick PbF2 crystal, respectively. Furthermore, first-order correlation could be observed between the primary principal component and the true DOI. To obtain a coincidence timing resolution better than 100-ps FWHM with a 20-mm-thick PbF2 crystal, a photodetector with SPTR of better than σ = 30 ps was necessary. CONCLUSIONS: From these results, the improvement of SPTR allows us to achieve CTR better than 100-ps FWHM, even in the case where a 20-mm-thick radiator is used. Our proposed detector has the potential to estimate the 3D interaction position of γ-rays in the radiator, using only time and space information of Cherenkov photons.

Evaluation of spatial dependence of point spread function-based PET reconstruction using a traceable point-like 22Na source.

BACKGROUND: The point spread function (PSF) of positron emission tomography (PET) depends on the position across the field of view (FOV). Reconstruction based on PSF improves spatial resolution and quantitative accuracy. The present study aimed to quantify the effects of PSF correction as a function of the position of a traceable point-like 22Na source over the FOV on two PET scanners with a different detector design. METHODS: We used Discovery 600 and Discovery 710 (GE Healthcare) PET scanners and traceable point-like 22Na sources (<1 MBq) with a spherical absorber design that assures uniform angular distribution of the emitted annihilation photons. The source was moved in three directions at intervals of 1 cm from the center towards the peripheral FOV using a three-dimensional (3D)-positioning robot, and data were acquired over a period of 2 min per point. The PET data were reconstructed by filtered back projection (FBP), the ordered subset expectation maximization (OSEM), OSEM + PSF, and OSEM + PSF + time-of-flight (TOF). Full width at half maximum (FWHM) was determined according to the NEMA method, and total counts in regions of interest (ROI) for each reconstruction were quantified. RESULTS: The radial FWHM of FBP and OSEM increased towards the peripheral FOV, whereas PSF-based reconstruction recovered the FWHM at all points in the FOV of both scanners. The radial FWHM for PSF was 30-50 % lower than that of OSEM at the center of the FOV. The accuracy of PSF correction was independent of detector design. Quantitative values were stable across the FOV in all reconstruction methods. The effect of TOF on spatial resolution and quantitation accuracy was less noticeable. CONCLUSIONS: The traceable 22Na point-like source allowed the evaluation of spatial resolution and quantitative accuracy across the FOV using different reconstruction methods and scanners. PSF-based reconstruction reduces dependence of the spatial resolution on the position. The quantitative accuracy over the entire FOV of the PET system is good, regardless of the reconstruction methods, although it depends slightly on the position.

Identification of Plasmodium falciparum reticulocyte binding protein homologue 5-interacting protein, PfRipr, as a highly conserved blood-stage malaria vaccine candidate.

Genetic variability in Plasmodium falciparum malaria parasites hampers current malaria vaccine development efforts. Here, we hypothesize that to address the impact of genetic variability on vaccine efficacy in clinical trials, conserved antigen targets should be selected to achieve robust host immunity across multiple falciparum strains. Therefore, suitable vaccine antigens should be assessed for levels of polymorphism and genetic diversity. Using a total of one hundred and two clinical isolates from a region of high malaria transmission in Uganda, we analyzed extent of polymorphism and genetic diversity in four recently reported novel blood-stage malaria vaccine candidate proteins: Rh5 interacting protein (PfRipr), GPI anchored micronemal antigen (PfGAMA), rhoptry-associated leucine zipper-like protein 1 (PfRALP1) and Duffy binding-like merozoite surface protein 1 (PfMSPDBL1). In addition, utilizing the wheat germ cell-free system, we expressed recombinant proteins for the four candidates based on P. falciparum laboratory strain 3D7 sequences, immunized rabbits to obtain specific antibodies (Abs) and performed functional growth inhibition assay (GIA). The GIA activity of the raised Abs was demonstrated using both homologous 3D7 and heterologous FVO strains in vitro. Both pfripr and pfralp1 are less polymorphic but the latter is comparatively more diverse, with varied number of regions having insertions and deletions, asparagine and 6-mer repeats in the coding sequences. Pfgama and pfmspdbl1 are polymorphic and genetically diverse among the isolates with antibodies against the 3D7-based recombinant PfGAMA and PfMSPDBL1 inhibiting merozoite invasion only in the 3D7 but not FVO strain. Moreover, although Abs against the 3D7-based recombinant PfRipr and PfRALP1 proteins potently inhibited merozoite invasion of both 3D7 and FVO, the GIA activity of anti-PfRipr was much higher than that of anti-PfRALP1. Thus, PfRipr is regarded as a promising blood-stage vaccine candidate for next-generation vaccines against P. falciparum.

Relationship between weight of rescuer and quality of chest compression during cardiopulmonary resuscitation.

BACKGROUND: According to the guidelines for cardiopulmonary resuscitation (CPR), the rotation time for chest compression should be about 2 min. The quality of chest compressions is related to the physical fitness of the rescuer, but this was not considered when determining rotation time. The present study aimed to clarify associations between body weight and the quality of chest compression and physical fatigue during CPR performed by 18 registered nurses (10 male and 8 female) assigned to light and heavy groups according to the average weight for each sex in Japan. METHODS: Five-minute chest compressions were then performed on a manikin that was placed on the floor. Measurement parameters were compression depth, heart rate, oxygen uptake, integrated electromyography signals, and rating of perceived exertion. Compression depth was evaluated according to the ratio (%) of adequate compressions (at least 5 cm deep). RESULTS: The ratio of adequate compressions decreased significantly over time in the light group. Values for heart rate, oxygen uptake, muscle activity defined as integrated electromyography signals, and rating of perceived exertion were significantly higher for the light group than for the heavy group. CONCLUSION: Chest compression caused increased fatigue among the light group, which consequently resulted in a gradual fall in the quality of chest compression. These results suggested that individuals with a lower body weight should rotate at 1-min intervals to maintain high quality CPR and thus improve the survival rates and neurological outcomes of victims of cardiac arrest.

Microfocus X-ray imaging of the internal geometry of brachytherapy seeds.

Precise and reliable geometrical data on the internal structure of seeds are indispensable for dosimetric calculation in brachytherapy. We used a novel microfocus X-ray imaging technique for observing the internal structure of brachytherapy seeds. Two popular (125)I seed models were evaluated. Obtained high precision images enabled us to observe the internal structure of seeds qualitatively. Geometrical size parameters were evaluated quantitatively with uncertainty of 0.01-0.04 mm (k=2).