Faculty of Physics, Astronomy
and Applied Computer Science

Positronium, an unstable atom consisting of an electron and a positron, is abundantly produced within the molecular voids of a patient?s body during positron emission tomography (PET) diagnosis. Its properties, such as its average lifetime between formation and annihilation into photons, dynamically respond to the submolecular architecture of the tissue and the partial pressure of oxygen molecules. However, the diagnostic information that positronium may deliver about early molecular alterations remains unavailable in clinics with state-of-the-art PET scanners. This study presents the first in vivo images of positronium lifetime in humans. We developed a dedicated J-PET system with multiphoton detection capability for imaging. The measurements of positronium lifetime were performed on a patient with a glioblastoma tumor in the brain. The patient was injected intratumorally with the 68Ga radionuclide attached to Substance-P, which accumulates in glioma cells, and intravenously with 68Ga attached to the PSMA-11 ligand, which is selective to glioma cells and salivary glands. The 68Ga radionuclide is routinely used in PET for detecting radiopharmaceutical accumulation and was applied for positronium imaging because it can emit an additional prompt gamma. The prompt gamma enables the determination of the time of positronium formation, while the photons from positronium annihilation were used to reconstruct the place and time of its decay. The determined positronium mean lifetime in glioblastoma cells is shorter than in salivary glands, which in turn is shorter than in healthy brain tissues, demonstrating for the first time that positronium imaging can be used to diagnose disease in vivo. This study also demonstrates that if current total-body PET systems were equipped with multiphoton detection capability and the 44Sc radionuclide was applied, it would be possible to perform positronium imaging at 6500 times greater sensitivity than achieved in this research. Therefore, it is anticipated that positronium imaging has the potential to bring a new quality of cancer diagnosis in clinics.

We have developed a compact detector for measuring beam particles using plastic scintillators readout through Multi-Pixel Photon Counters, which is employed for hypernuclear measurements in the WASA-FRS experiment at GSI. The Time-of-Flight resolution of the newly-developed detector has been investigated in relation to the overvoltage with respect to the breakdown voltage, a maximum counting rate of approximately 3*10^6/s per segment, and a maximum beam charge of Z = 6. The evaluated Time-of-Flight resolutions between the neighboring segments of the detector range from 44.6+-1.3 ps to 100.3+-3.6 ps (sigma) depending on the segment, overvoltage values, and beam intensity. It is also observed that the Time-of-Flight resolution is inversely correlated to the beam atomic charge (Z).

In this paper, an overview of kaonic atoms studies from the late 90s to nowadays at the DAFNE collider at INFN-LNF is presented. Experiments on kaonic atoms are an important tool to test and optimize phenomenological models on the low-energy strong interaction. Since its construction, the DAFNE collider has represented an ideal machine to perform kaonic atoms measurements, thanks to the unique beam of kaons coming from the Phi_s produced in the collider decays. The DEAR and SIDDHARTA experiments achieved the precise evaluation of the shift and width of the 2p -> 1s transition in kaonic hydrogen due to the strong interaction, and thus provided a measurement strictly linked to isospin-dependent antikaon-nucleon scattering lengths. To fully disentangle the iso-scalar and iso-vector scattering lengths, the measurement of kaonic deuterium is necessary as well. The SIDDHARTA-2 experiment is now taking data at the DAFNE collider with the aim to fulfill the need of this measurement, and therefore provide important information to the various phenomenological models on low-energy strong interactions with strangeness. The SIDDHARTA-2 Collaboration is also exploring the possibility to perform future kaonic atoms experiments, developing X-ray detector systems beyond the current stateof-art. These measurements are crucial for a deeper understanding of the kaon interactions with nuclei and for solving the kaon mass ''puzzle''.

Objective: The aim of this work is to investigate the feasibility of the JagiellonianPositron Emission Tomography (J-PET) scanner for intra-treatment proton beamrange monitoring. Approach: The Monte Carlo simulation studies with GATE and PET imagereconstruction with CASToR were performed in order to compare six J-PET scannergeometries (three dual-heads and three cylindrical). We simulated proton irradiationof a PMMA phantom with a Single Pencil Beam (SPB) and Spread-Out BraggPeak (SOBP) of various ranges. The sensitivity and precision of each scanner werecalculated, and considering the setup?s cost-effectiveness, we indicated potentiallyoptimal geometries for the J-PET scanner prototype dedicated to the proton beamrange assessment. Main results: The investigations indicate that the double-layer cylindrical andtriple-layer double-head configurations are the most promising for clinical application.We found that the scanner sensitivity is of the order of 10?5coincidences per primaryproton, while the precision of the range assessment for both SPB and SOBP irradiationplans was found below 1 mm. Among the scanners with the same number of detectormodules, the best results are found for the triple-layer dual-head geometry. Significance: We performed simulation studies demonstrating that the feasibilityof the J-PET detector for PET-based proton beam therapy range monitoring ispossible with reasonable sensitivity and precision enabling its pre-clinical tests in theclinical proton therapy environment. Considering the sensitivity, precision and cost-effectiveness, the double-layer cylindrical and triple-layer dual-head J-PET geometryconfigurations seem promising for the future clinical application. Experimental testsare needed to confirm these findings.

Silicon drift detectors (SDDs) stand as a groundbreaking technology with a diverse range of applications, particularly in the fields of physics and medical imaging. This paper provides an analysis of the performance of SDDs as detectors for X-ray radiation measurement, shedding light on their exceptional capabilities and potential in medical imaging. Compared to conventional detectors, SDDs have several notable advantages. Their high efficiency in capturing X-rays allows them to provide outstanding sensitivity and accuracy in detecting even low-energy X-rays. In addition, SDDs exhibit significantly low electronic-noise levels, contributing to better signal-to-noise ratio and better data quality. Furthermore, their high resolution enables exact spatial localization of radiation sources, which is essential for accurate diagnosis. This research is devoted to the evaluation of efficiency and potential application of SDDs in X-ray spectroscopy, with particular emphasis on their application in medical imaging. We focus on evaluating the performance characteristics of SDDs, such as their linearity, stability and sensitivity in detecting X-rays. The aim is to highlight the suitability of SDDs for a wide range of applications.

Hybrid in-beam PET/Compton camera imaging currently shows a promising approach to use of the quasi-real-time range verification technique in proton therapy. This work aims to assess the capability of utilizing a configuration of the Jagiellonian-positron emission tomography (J-PET) scanner made of plastic scintillator strips, so as to serve as a Compton camera for proton beam range verification. This work reports the production yield results obtained from the GATE/Geant4 simulations, focusing on an energy spectrum (4.2?4.6) MeV of prompt gamma (PG) produced from a clinical proton beam impinging on a water phantom. To investigate the feasibility of J-PET as a Compton camera, a geometrical optimisation was performed. This optimisation was conducted by a point spread function (PSF) study of an isotropic 4.44 MeV gamma source. Realistic statistics of 4.44 MeV PGs obtained from the prior step were employed, simulating interactions with the detector. A sufficient number of detected photons was obtained for the source position reconstruction after performing a geometry optimisation for the proposed J-PET detector. Furthermore, it was demonstrated that more precise calculation of the total deposited energy of coincident events plays a key role in improving the image quality of source distribution determination. A reasonable spatial resolution of 6.5 mm FWHM along the actual proton beam direction was achieved for the first imaging tests. This preliminary study has shown notable potential in using the J-PET application for in-beam PET/Compton camera imaging at quasi-real-time proton range monitoring in future clinical use.

Ultra-high dose rate (FLASH) proton radiotherapy is a promising treatment method for cancer patients. In our research, we want to compare the FLASH method with a conventional radiation method to show what effect they have on the biochemical structure of the tumour (3D model ? spheroids) and the secretion of extracellular vesicles (EVs) and their cargo. The use of a modern method of creating spheroids will enable us to create conditions that are better able to mimic the tumour microenvironment.

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is a powerful analytical technique with great application potential in biomolecular matter research. SIMS measurements performed on biological samples, due to their complex structure and the content of many small and large atomic molecular compounds, suffer very rich and complex mass spectra of particles, which characterise the content and physio-chemical properties of examined samples. The proper description and understanding of features appearing in the spectra and, consequently, the final data confirming or rejecting the hypothesis put forward in the experiment, largely depend on the experimenter?s correct understanding of the technique itself and its limitations, knowledge of the tested material and its appropriate preparation. These issues mean that obtaining the right answer to the questions posed in the research hypothesis requires not only the correct conduct of experiments but also the appropriate processing of post-experimental data. This study aims to demonstrate the impact of various analytical and experimental procedures applied to reach proper conclusions from TOF-SIM measurements. These are different types of data normalization, the selection of a so-called region of interest (ROI), the selection of representative secondary ions and specific quantification methods, including a combination of experimental parameters. All these aspects were checked and discussed based on the results of the analysis of pancreatic ? cells placed in a PBS solution on silicon wafers.

Background: Alongside the benefits of Total-Body imaging modalities, such as higher sensitivity, single-bed position, low dose imaging, etc., their final construction cost prevents worldwide utilization. The main aim of this study is to present a simulation-based comparison of the sensitivities of existing and currently developed tomographs to introduce a cost-efficient solution for constructing a Total-Body PET scanner based on plastic scintillators. Methods: For the case of this study, eight tomographs based on the uEXPLORER configuration with different scintillator materials (BGO, LYSO), axial field-of-view (97.4 cm and 194.8 cm), and detector configuration (full and sparse) were simulated. In addition, 8 J-PET scanners with different configurations, such as various axial field-of-view (200 cm and 250 cm), the different cross-sections of plastic scintillator, and the multiple numbers of the plastic scintillator layers (2, 3, and 4), based on J-PET technology have been simulated by GATE software. Furthermore, Biograph Vision has been simulated to compare the results with standard PET scans. Two types of simulations have been performed. The first one with a centrally located source with a diameter of 1mm and a length of 250 cm, and the second one with the same source inside a water-filled cylindrical phantom with a diameter of 20 cm and a length of 183 cm. Results: With regards to sensitivity, among all the proposed scanners, the ones constructed with BGO crystals give the best performance (? 350 cps/kBq at the center). The utilization of sparse geometry or LYSO crystals significantly lowers the achievable sensitivity of such systems. The J-PET design gives a similar sensitivity to the sparse LYSO crystal-based detectors while having full detector coverage over the body. Moreover, it provides uniform sensitivity over the body with additional gain on its sides and provides the possibility for high-quality brain imaging. Conclusion: Taking into account not only the sensitivity but also the price of the Total-Body PET tomographs, which till now was one of the main obstacles in their widespread clinical availability, the J-PET tomography system based on plastic scintillators could be a cost-efficient alternative for Total-Body PET scanners.

In positron emission tomography (PET) studies, convolutional neural networks (CNNs) may be applied directly to the reconstructed distribution of radioactive tracers injected into the patient's body, as a pattern recognition tool. Nonetheless, unprocessed PET coincidence data exist in tabular format. This paper develops the transformation of tabular data into -dimensional matrices, as a preparation stage for classification based on CNNs. This method explicitly introduces a nonlinear transformation at the feature engineering stage and then uses principal component analysis to create the images. We apply the proposed methodology to the classification of simulated PET coincidence events originating from NEMA IEC and anthropomorphic XCAT phantom. Comparative studies of neural network architectures, including multilayer perceptron and convolutional networks, were conducted. The developed method increased the initial number of features from 6 to 209 and gave the best precision results (79.8) for all tested neural network architectures; it also showed the smallest decrease when changing the test data to another phantom.

Objective. The Jagiellonian positron emission tomography (J-PET) technology, based on plastic scintillators, has been proposed as a cost effective tool for detecting range deviations during proton therapy. This study investigates the feasibility of using J-PET for range monitoring by means of a detailed Monte Carlo simulation study of 95 patients who underwent proton therapy at the Cyclotron Centre Bronowice (CCB) in Krakow, Poland. Approach. Discrepancies between prescribed and delivered treatments were artificially introduced in the simulations by means of shifts in patient positioning and in the Hounsfield unit to the relative proton stopping power calibration curve. A dual-layer, cylindrical J-PET geometry was simulated in an in-room monitoring scenario and a triple-layer, dual-head geometry in an in-beam protocol. The distribution of range shifts in reconstructed PET activity was visualized in the beam's eye view. Linear prediction models were constructed from all patients in the cohort, using the mean shift in reconstructed PET activity as a predictor of the mean proton range deviation. Main results. Maps of deviations in the range of reconstructed PET distributions showed agreement with those of deviations in dose range in most patients. The linear prediction model showed a good fit, with coefficient of determination r2 = 0.84 (in-room) and 0.75 (in-beam). Residual standard error was below 1 mm: 0.33 mm (in-room) and 0.23 mm (in-beam). Significance. The precision of the proposed prediction models shows the sensitivity of the proposed J-PET scanners to shifts in proton range for a wide range of clinical treatment plans. Furthermore, it motivates the use of such models as a tool for predicting proton range deviations and opens up new prospects for investigations into the use of intra-treatment PET images for predicting clinical metrics that aid in the assessment of the quality of delivered treatment.

Objective. The Jagiellonian positron emission tomography (J-PET) technology, based on plastic scintillators, has been proposed as a cost effective tool for detecting range deviations during proton therapy. This study investigates the feasibility of using J-PET for range monitoring by means of a detailed Monte Carlo simulation study of 95 patients who underwent proton therapy at the Cyclotron Centre Bronowice (CCB) in Krakow, Poland. Approach. Discrepancies between prescribed and delivered treatments were artificially introduced in the simulations by means of shifts in patient positioning and in the Hounsfield unit to the relative proton stopping power calibration curve. A dual-layer, cylindrical J-PET geometry was simulated in an in-room monitoring scenario and a triple- layer, dual-head geometry in an in-beam protocol. The distribution of range shifts in reconstructed PET activity was visualized in the beam?s eye view. Linear prediction models were constructed from all patients in the cohort, using the mean shift in reconstructed PET activity as a predictor of the mean proton range deviation. Main results. Maps of deviations in the range of reconstructed PET distributions showed agreement with those of deviations in dose range in most patients. The linear prediction model showed a good fit, with coefficient of determination r2 = 0.84 (in-room) and 0.75 (in-beam). Residual standard error was below 1 mm: 0.33 mm (in-room) and 0.23 mm (in-beam). Significance. The precision of the proposed prediction models shows the sensitivity of the proposed J-PET scanners to shifts in proton range for a wide range of clinical treatment plans. Furthermore, it motivates the use of such models as a tool for predicting proton range deviations and opens up new prospects for investigations into the use of intra-treatment PET images for predicting clinical metrics that aid in the assessment of the quality of delivered treatment.

It was recently demonstrated that newly invented positronium imaging may be used for improving cancer diagnostics by providing additional information about tissue pathology with respect to the standardized uptake value currently available in positron emission tomography (PET). Positronium imaging utilizes properties of a positronium atoms, which are built from the electron and positron produced in the body during PET examinations. We hypothesized whether positronium imaging would be sensitive to in vitro discrimination of tumour-like three-dimensional structures (spheroids) build of melanoma cell lines with different cancer activity and biological properties. The lifetime of ortho-Positronium (o-Ps) was evaluated in melanoma spheroids from two cell lines (WM266-4 and WM115) differing in the stage of malignancy. Additionally, we considered such parameters: as cell size, proliferation rate and malignancy to evaluate their relationship with o-Ps lifetime. We demonstrate the pilot results for the o-Ps lifetime measurement in extracellular matrix free spheroids. With the statistical significance of two standard deviations, we demonstrated that the higher the degree of malignancy and the rate of proliferation of neoplastic cells the shorter the lifetime of ortho-positronium. In particular we observed following indications encouraging further research: (i) WM266-4 spheroids characterized with higher proliferation rate and malignancy showed shorter o-Ps lifetime compared to WM115 spheroids characterized by lower growth rate, (ii) Both cell lines showed a decrease in the lifetime of o-Ps after spheroid generation in 8th day comparing to 4th day in culture and the mean o-Ps lifetime is longer for spheroids formed from WM115 cells than these from WM266-4 cells, regardless spheroid age. The results of these study revealed that positronium is a promising biomarker that may be applied in PET diagnostics for the assessment of the degree of cancer malignancy.

Positronium is the simplest bound state, built of an electron and a positron. Studies of positronium in vacuum and its decays in medium tell us about quantum electrodynamics (QED) and about the structure of matter and biological processes of living organisms at the nanoscale, respectively. Spectroscopic measurements constrain our understanding of QED bound state theory. Searches for rare decays and measurements of the effect of gravitation on positronium are used to look for new physics phenomena. In biological materials positronium decays are sensitive to the intermolecular and intramolecular structure and to the metabolism of living organisms ranging from single cells to human beings. This leads to new ideas of positronium imaging in medicine using the fact that during positron emission tomography (PET) as much as 40% of positron annihilation occurs through the production of positronium atoms inside the patient?s body. A new generation of the high sensitivity and multiphoton total-body PET systems opens perspectives for clinical applications of positronium as a biomarker of tissue pathology and the degree of tissue oxidation.

Extracellular vesicles (EVs) are released by all cells, both in physiological and pathological conditions. Their molecular charge and composition emerge as possible biomarkers, but EVs may also be considered for other clinical applications. This review discusses the role of other features of EVs, such as their lipid components or composition of glycans that form the EV corona and regulate EV biodistribution and uptake by target cells. The importance of EV electric charge has been discussed as a new insight into EV fate and destination.

Background: The Jagiellonian Positron Emission Tomograph is the 3-layer prototype of the first scanner based on plastic scintillators, consisting of 192 half-metre-long strips with readouts at both ends. Compared to crystal-based detectors, plastic scintillators are several times cheaper and could be considered as a more economical alternative to crystal scintillators in future PETs. JPET is also a first multi-photon PET prototype. For the development of multi-photon detection, with photon characterized by the continuous energy spectrum, it is important to estimate the efficiency of J-PET as a function of energy deposition. The aim of this work is to determine the registration efficiency of the J-PET tomograph as a function of energy deposition by incident photons and the intrinsic efficiency of the J-PET scanner in detecting photons of different incident energies. In this study, 3-hit events are investigated, where 2-hits are caused by 511 keV photons emitted in e+e- annihilations, while the third hit is caused by one of the scattered photons. The scattered photon is used to accurately measure the scattering angle and thus the energy deposition. Two hits by a primary and a scattered photon are sufficient to calculate the scattering angle of a photon, while the third hit ensures the precise labeling of the 511 keV photons. Results: By comparing experimental and simulated energy distribution spectra, the registration efficiency of the J-PET scanner was determined in the energy deposition range of 70-270 keV, where it varies between 20 and 100%. In addition, the intrinsic efficiency of the J-PET was also determined as a function of the energy of the incident photons. Conclusion: A method for determining registration efficiency as a function of energy deposition and intrinsic efficiency as a function of incident photon energy of the J-PET scanner was demonstrated. This study is crucial for evaluating the performance of the scanner based on plastic scintillators and its applications as a standard and multi-photon PET systems. The method may be also used in the calibration of Compton-cameras developed for the ion-beam therapy monitoring and simultaneous multi-radionuclide imaging in nuclear medicine.

Purpose: Cardiac myxoma (CM), the most common cardiac tumor in adults, accounts for 50?75% of benign cardiac tumors. The diagnosis of CM is often elusive, especially in young stroke survivors and transthoracic echocardiography (TTE) is the initial technique for the differential diagnostics of CM. Less invasive cardiac computed tomography (CT) and magnetic resonance imaging (MRI) are not available for the majority of cardiac patients. Here, a robust imaging approach, ortho-Positronium (o-Ps) imaging, is presented to determine cardiac myxoma extracted from patients undergoing urgent cardiac surgery due to unexpected atrial masses. We aimed to assess if the o-Ps atom, produced copiously in intramolecular voids during the PET imaging, serves as a biomarker for CM diagnosing. Methods: Six perioperative CM and normal (adipose) tissue samples from patients, with primary diagnosis confirmed by the histopathology examination, were examined using positron annihilation lifetime spectroscopy (PALS) and micro-CT. Additionally, cell cultures and confocal microscopy techniques were used to picture cell morphology and origin. Results: We observed significant shortening in the mean o-Ps lifetime in tumor with compare to normal tissues: an average value of 1.92(02) ns and 2.72(05) ns for CM and the adipose tissue, respectively. Microscopic differences between tumor samples, confirmed in histopathology examination and micro-CT, did not influenced the major positronium imaging results. Conclusions: Our findings, combined with o-Ps lifetime analysis, revealed the novel emerging positronium imaging marker (o-PS) for cardiovascular imaging. This method opens the new perspective to facilitate the quantitative in vivo assessment of intracardiac masses on a molecular (nanoscale) level.

Pioneering investigations on the usage of positron-emission-tomography (PET) for the monitoring of ion beam therapy with light (protons, helium) and heavier (stable and radioactive neon, carbon and oxygen) ions started shortly after the first realization of planar and tomographic imaging systems, which were able to visualize the annihilation of positrons resulting from irradiation induced or implanted positron emitting nuclei. And while the first clinical experience was challenged by the utilization of instrumentation directly adapted from nuclear medicine applications, new detectors optimized for this unconventional application of PET imaging are currently entering the phase of (pre)clinical testing for more reliable monitoring of treatment delivery during irradiation. Moreover, recent advances in detector technologies and beam production open several new exciting opportunities which will not only improve the performance of PET imaging under the challenging conditions of in-beam applications in ion beam therapy, but will also likely expand its field of application. In particular, the combination of PET and Compton imaging can enable the most efficient utilization of all possible radiative emissions for both stable and radioactive ion beams, while positronium lifetime imaging may enable probing new features of the underlying tumour and normal tissue environment. Thereby, PET imaging will not only provide means for volumetric reconstruction of the delivered treatment and in-vivo verification of the beam range, but can also shed new insights for biological optimization of the treatment or treatment response assessment.

Background: Boron Neutron Capture Therapy (BNCT) is a two-step treatment that can be used in some types of cancers. It involves administering a compound containing boron atoms to the patient and irradiating the affected area of the body with a neutron beam. The success of the therapy depends mainly on the delivery of the boron isotope (10B) to the tumor using an appropriate boron carrier. One of the boron carriers used is boronophenylalanine (BPA). Therefore, in research on the use of boron carriers, it is also important to know the mechanisms of its uptake by cells. Aim: To study the expression of LAT family genes in two melanoma (high melanotic WM115 and low melanotic WM266-4) cell lines and melanocytes (HEMa-Lp) which are responsible for the transport the BPA into cells. Methods: To normalize data from the transcriptomic analysis, the ratio of the median method was used. This allowed the samples to be compared with each other. Comparison metrics included log-fold change (LFC) values. The heatmap of LFC values and the cluster map were created. These graphs show the similarities and differences between the samples. Results: Transcriptomic data show that in melanocytes, LFC for SLC7A5 (LAT1) and SLC3A2 (4Fhc) was higher than in melanoma cell lines, which corresponded with their melanin content. Conclusion: Our results indicate overexpression of BPA transporter genes in normal cells (melanocytes), which may suggest the highest level of these proteins in melanocytes compared to less melanotic melanoma. Therefore, for BNCT, the use of BPA as the 10B carrier will require additional qualifying tests of amino acid transporter expression for patients and specific tumors to develop a personalized BNCT.

Positron-electron annihilation in living organisms occurs in about 30% via the formation of a metastable ortho-positronium atom that annihilates into two 511 keV photons in tissues because of the pick-off and conversion processes. Positronium (Ps) annihilation lifetime and intensities can be used to determine the size and quantity of defects in a material's microstructure, such as voids or pores in the range of nanometers. This is particularly true for blood clots. Here we present pilot investigations of positronium properties in fibrin clots. The studies are complemented by the use of SEM Edax and micro-computed tomography (microCT) to evaluate the extracted thrombotic material's properties. microCT is a versatile characterization method offering in situ and in operando possibilities and is a qualitative diagnostic tool. With microCT the presence of pores, cracks, and structural errors can be verified, and hence the 3D inner structure of samples can be investigated.

Objectives: Extracellular vesicles (EVs) are heterogeneous membrane vesicles in diameter of 30-5000 nm, that transport proteins, non-coding RNAs (miRNAs), lipids and metabolites. Major populations include exosomes, ectosomes and apoptotic bodies. The purpose of this study was to compare the distribution of EVs obtained under different conditions of differential centrifugation, including ultracentrifugation, with the results developed based on a theoretical model. Methods: Immortalized endothelial cell line that expresses h-TERT (human telomerase) was used to release of EVs: microvascular TIME. EVs were isolated from the culture medium at different centrifugation parameters. The size distribution of the EVs was measured using TRPS technology on a qNano instrument. Surface markers were evaluated using flow cytometry. The isolated EV subpopulations were compared with the theoretical model developed by Livshits. Results: EVs isolated from endothelial cells show strong aggregating properties, which was confirmed by TEM, TRPS imaging and flow cytometry. Conclusions: Obtaining pure EV subpopulations is difficult because of the small differences in the diameter of ectosomes and exosomes, and the strong aggregating properties of EVs.

Introduction Cargo carried by extracellular vesicles (EVs) is considered a promising diagnostic marker, especially proteins. EVs can be divided according to their size and way of biogenesis into exosomes (diameter < 200 nm) and ectosomes (diameter > 200 nm). Exosomes are considered to be of endocytic origin, and ectosomes are produced by budding and shedding from the plasma membrane [1]. Methods The first step of this study was a characterization of the exosome sample. Using Tunable Resistive Pulse Sensing (qNano) size distribution and concentration were measured. The mean size of exosomes was 120?9.17 nm. In the present study, a nano liquid chromatography coupled with tandem mass spectrometry (nanoLC-MS/MS) was used to compare protein profiles of exosomes secreted by pancreatic beta cells (1.1B4) grown under normal glucose (NG, 5 mM D-glucose) and high glucose (HG, 25 mM D-glucose) conditions. The EV samples were lysed, and proteins were denatured, digested, and analyzed using a Q-Exactive mass spectrometer coupled with the UltiMate 3000 RSLC nano system. The nanoLC-MS/MS data were searched against the SwissProt Homo sapiens database using MaxQuant software and protein quantitation was done by the MaxLFQ algorithm. Statistical analysis was carried out with Perseus software. Further bioinformatic analysis was performed using the FunRich 3.1.4 software with the UniProt protein database and String [2]. Results As a result of the nanoLC-MS/MS analysis more than 1,000 proteins were identified and quantified in each sample. The average number of identified proteins in exosomes was 1,397. Label-free quantitative analysis showed that exosome composition differed significantly between those isolated under NG and HG conditions. Many pathways were down-regulated in HG, particularly the ubiquitin-proteasome pathway. In addition, a significant up-regulation of the Ras-proteins pathway was observed in HG. Conclusion Our description of exosomes protein content and its related functions provides the first insight into the EV interactome and its role in glucose intolerance development and diabetic complications. The results also indicate the applicability of EV proteins for further investigation regarding their potential as circulating in vivo biomarkers.

Background Lugol's solution is well known for its unique contrasting properties to biological samples in in microcomputed tomography imaging. On the other hand, iron oxide nanoparticles (IONPs), which have much lower attenuation capabilities to X-ray radiation show decent cell penetration and accumulation properties, are increasingly being used as quantitative contrast agents in biology and medicine. In our research, they were used to stain 3D cell structures called spheroids. Aim In this study, the micro computed tomography (microCT) technique was used to visualize and compare the uptake and accumulation of two contrast agents, Lugol's solution and iron (II, III) oxide nanoparticles (IONPs) in the in vitro human spheroid tumour model. Methods The metastatic human melanoma cell line WM266-4 was cultured, first under standard 2D conditions, and after reaching 90% confluence cells was seeded in a low adhesive plate, which allows spheroid formation. On the 7th day of growth, the spheroids were transferred to the tubes and stained with IONPs or Lugol's solution and subjected to microCT imaging. Results Our research allows visualization of the regions of absorption at the level of single cells, with relatively short incubation times - 24h - for Lugol's solution. IONPs proved to be useful only in high concentrations (1 mg/ml) and long incubation times (96h). Conclusions When comparing the reconstructed visualizations of the distribution of these stating agents, it is worth noting that Lugol's solution spreads evenly throughout the spheroids, whereas IONPs (regardless of their size 5 and 30 nm) accumulate only in the outer layer of the spheroid structure.

We develop a positronium imaging method for the Jagiellonian PET (J-PET) scanners based on the time-of-flight maximum likelihood expectation maximisation (TOF MLEM). The system matrix elements are calculated on-the-fly for the coincidences comprising two annihilation and one de-excitation photons that originate from the ortho-positronium (o-Ps) decay. Using the Geant4 library, a Monte Carlo simulation was conducted for four cylindrical 22Na sources of ?+ decay with diverse o-Ps mean lifetimes, placed symmetrically inside the two JPET prototypes. The estimated time differences between the annihilation and the positron emission were aggregated into histograms (one per voxel), updated by the weights of the activities reconstructed by TOF MLEM. The simulations were restricted to include only the o-Ps decays into back-to-back photons, allowing a linear fitting model to be employed for the estimation of the mean lifetime from each histogram built in the log scale. To suppress the noise, the exclusion of voxels with activity below 2% ? 10% of the peak was studied. The estimated o-Ps mean lifetimes were consistent with the simulation and distributed quasi-uniformly at high MLEM iterations. The proposed positronium imaging technique can be further upgraded to include various correction factors, as well as be modified according to realistic o-Ps decay models.

Objective: This paper reports on the implementation and shows examples of the use of the ProTheRaMon framework for simulating the delivery of proton therapy treatment plans and range monitoring using positron emission tomography (PET). ProTheRaMon offers complete processing of proton therapy treatment plans, patient CT geometries, and intra-treatment PET imaging, taking into account therapy and imaging coordinate systems and activity decay during the PET imaging protocol specific to a given proton therapy facility. We present the ProTheRaMon framework and illustrate its potential use case and data processing steps for a patient treated at the Cyclotron Centre Bronowice (CCB) proton therapy center in Krakow, Poland. Approach: The ProTheRaMon framework is based on GATE Monte Carlo software, the CASToR reconstruction package and in-house developed Python and bash scripts. The framework consists of five separated simulation and data processing steps, that can be further optimized according to the user's needs and specific settings of a given proton therapy facility and PET scanner design. Main results: ProTheRaMon is presented using example data from a patient treated at CCB and the J-PET scanner to demonstrate the application of the framework for proton therapy range monitoring. The output of each simulation and data processing stage is described and visualized. Significance: We demonstrate that the ProTheRaMon simulation platform is a high-performance tool, capable of running on a computational cluster and suitable for multi-parameter studies, with databases consisting of large number of patients, as well as different PET scanner geometries and settings for range monitoring in a clinical environment. Due to its modular structure, the ProTheRaMon framework can be adjusted for different proton therapy centers and/or different PET detector geometries. It is available to the community via github.

This review introduce extracellular vesicles (EVs) to a molecular imaging field. The idea of modern analyses based on the use of omics studies, using highthroughput methods to characterize the molecular content of a single biological system, vesicolomics seems to be the new approach to collect molecular data about EV content, to find novel biomarkers or therapeutic targets. The use of various imaging techniques, including those based on radionuclides as positron emission tomography (PET) or single photon emission computed tomography (SPECT), combining molecular data on EVs, opens up the new space for radiovesicolomics?a new approach to be used in theranostics.

Time-of-flight secondary ion mass spectrometry (TOF-SIMS) with the Bi3+ liquid metal ion gun was used to investigate the content of lipids and amino acids (AAs) in extracellular vesicles (EVs). We induced metabolic changes in human pancreatic beta-cells by stimulation with high glucose concentrations (35 mM) and tested the hypothesis of hyperglycemia (HG) has a detrimental effect on lipids and AAs in released EV subpopulations: ectosomes and exosomes. As a result of HG treatment, selected fatty acids (FAs) such as arachidonic, myristic and palmitic acids, changed their abundance in ectosomes and exosomes. Also, intensities of the characteristic peaks for cholesterol (m/z 95.09; 147.07; 161.11; 369.45) along with the molecular ion m/z 386.37 [C27H46O+] under HG conditions, both for ectosomes and exosomes, have changed significantly. Comparative analysis of HG EVs and normoglycemic (NG) ones showed statistically significant differences in the signal intensities of four AAs: valine (m/z 72.08 and 83.05), isoleucine (m/z 86.10), phenylalanine (m/z 120.08 and 132.05) and tyrosine (m/z 107.05 and 136.09). We confirmed that ToF-SIMS is a useful technique to study selected AAs and lipid profiles in various EV subpopulations. Our study is the first demonstration of changes in FAs and AAs in exosomes and ectosomes derived from ?-cells under the influence of HG.

The image of positronium properties created in the patient?s body during PET examination tells about the inter- and intra-molecular structure of the tissue and the concentration of bio-active molecules in the tissue [2?4]. In this article, we advocate the opinion that total-body PET systems, thanks to their high imaging sensitivity and high time resolution, open up the prospect of translating positronium imaging into clinics.

The entanglement of photons originating from electron-positron annihilation has not been experimentally proven. owever, the independent experiments performed so far unanimously confirm that the correlation between the linear polarizations of back-to-back photons from electron?positron annihilation is consistent with the assumption that these photons are entangled in the polarization. Yet, unexpectedly, recent experiments differ as regards the correlation of polarization direction of back-to-back photons after the decoherence induced by the scattering of one of these photons on the electron in the scattering material. In one of the experiments, the correlation before and after the decoherence of the photon state is the same, and in the other experiment, the scattering of one photon leads to a significant decrease in this correlation. Here we discuss this puzzle. Decoherent states were ensured provided by forcing one of the annihilation photons to scatter earlier before measuring the polarization correlation based on Compton kinematics. The comparison is made between the experimental setups used for the different measurements, and the results obtained are briefly discussed, highlighting the parameters that are important in performing such measurements. Finally, the main features of the J-PET detector are presented, along with the schemes for performing similar studies, so that the conclusive results can be used as remarks to solve the puzzle in question. Solving the decoherence puzzle will have crucial consequences for basic studies of entanglement, as well as for the proposed application of the photon polarization in positron emission tomography. If the correlation of the polarization of back-to-back photons from the electron?positron annihilation is the same before and after the scattering of these photons, then it will not be useful for the reduction of scatter fraction in positron emission tomography diagnostics.

Large-scale physics experiments running at high interaction rates place a high demand on the data acquisition system (DAQ) responsible for transporting the data from the detector to the storage. The antiProton ANihilation at DArmstadt (PANDA) at the facility for anti-proton and ion research (FAIR) is one such experiment of the future that will not use fixed hardware triggers; instead, the event selection is based on real-time feature extraction, filtering, and high-level correlations. A firmware framework for such real-time data processing has been developed and tested with hardware setup for a PANDA Forward Tracker (FT) prototype. The solution is applicable for other detector subsystems based on the so-called Trigger Readout Board (TRB) data read-out system.

In this review article, we present arguments demonstrating that the advent of high sensitivity total-body PET systems and the invention of the method of positronium imaging, open realistic perspectives for the application of positronium as a biomarker forin-vivo assessment of the degree of hypoxia. Hypoxia is a state or condition, in which the availability of oxygen is not sufficient to support physiological processes in tissue and organs. Positronium is a meta-stable atom formed from electron and positron which is copiously produced in the intramolecular spaces in the living organisms undergoing positron emission tomography (PET). Properties of positronium, such as e.g., lifetime, depend on the size of intramolecular spaces and the concentration in them of oxygen molecules. Therefore, information on the partial pressure of oxygen (pO2) in the tissue may be derived from the positronium lifetime measurement. The partial pressure of oxygen differs between healthy and cancer tissues in the range from 10 to 50 mmHg. Such differences of pO2 result in the change of ortho-positronium lifetime e.g., in water by about 2?7 ps. Thus, the application of positronium as a biomarker of hypoxia requires the determination of the mean positronium lifetime with the resolution in the order of2 ps. We argue that such resolution is in principle achievable for organ-wise positronium imaging with the total-body PET systems.

Extracellular vesicles (EVs) are nano- and micro-sized double-layered membrane entities derivedfrom most cell types and released into biological fluids. Biological properties (cell-uptake, biocompatibility), and chemical (composition, structure) or physical (size, density) characteristics make EVs a good candidate for drug delivery systems (DDS). Recent advances in the field of EVs (e.g., scaling-up production, purification) and developments of new imaging methods (total-body positron emission tomography [PET]) revealed benefits ofradio labeled EVs in diagnostic and interventional medicine as a potential DDs in theranostics.

Positron emission tomography (PET) imaging is the most quantitative modality for assessing diseaseactivity at the molecular and cellular levels, and therefore, it allows monitoring its course and determining the efficacy of various therapeutic interventions. In this scientific communication, we describe the unparalleled and revolutionary impact of PET imaging on researchand day to day practice of medicine. We emphasize thecritical importance of the development and synthesis of novel radiotracers (starting from the enormous impactof F-Fluorodeouxyglucose (FDG) introduced by investigators at the University of Pennsylvania (PENN)) and PET instrumentation. These innovations have led to the total-body PET systems enabling dynamic and parametric molecular imaging of all organs in the body simultaneously. We also present our perspectives for future development of molecular imaging by multiphoton PET systems that will enable users to extract substantial information (owing to the evolving role of positronium imaging) about the related molecular and biological bases of various disorders, which are unachievable by the current PET imaging techniques.

In vivo assessment of cancer and precise location of altered tissues at initial stages of molecular disorders are important diagnostic challenges. Positronium is copiously formed in the free molecular spaces in the patient?s body during positron emission tomography (PET). The positronium properties vary according to the size of inter- and intramolecular voids and the concentration of molecules in them such as, e.g., molecular oxygen, O2; therefore, positronium imaging may provide information about disease progression during the initial stages of molecular alterations. Current PET systems do not allow acquisition of positronium images. This study presents a new method that enables positronium imaging by simultaneous registration of annihilation photons and deexcitation photons from pharmaceuticals labeled with radionuclides. The first positronium imaging of a phantom built from cardiac myxoma and adipose tissue is demonstrated. It is anticipated that positronium imaging will substantially enhance the specificity of PET diagnostics.

We perform a parametric study of the newly developed time-of-flight (TOF) image reconstruction algorithm, proposed for the real-time imaging in total-body Jagiellonian PET (J-PET) scanners. The asymmetric 3D filtering kernel is applied at each most likely position of electron-positron annihilation, estimated from the emissions of back-to-back gamma-photons. The optimisation of its parameters is studied using Monte Carlo simulations of a 1-mm spherical source, NEMA IEC and XCAT phantoms inside the ideal J-PET scan- ner. The combination of high-pass filters which included the TOF filtered back-projection (FBP), resulted in spatial resolution, 1.5 times higher in the axial direction than for the conventional 3D FBP. For real- istic 10-minute scans of NEMA IEC and XCAT, which require a trade-offbetween the noise and spatial resolution, the need for Gaussian TOF kernel components, coupled with median post-filtering, is demon- strated. The best sets of 3D filter parameters were obtained by the Nelder-Mead minimisation of the mean squared error between the resulting and reference images. The approach allows training the recon- struction algorithm for custom scans, using the IEC phantom, when the temporal resolution is below 50 ps. The image quality parameters, estimated for the best outcomes, were systematically better than for the non-TOF FBP.

Charged lepton system symmetry under combined charge, parity, and time-reversal transformation (CPT) remain scarcely tested. Despite stringent quantum-electrodynamic limits, discrepancies in predictions for the electron-positron bound state (positronium atom) motivate further investigation, including fundamental symmetry tests. While CPT noninvariance effects could be manifested in non-vanishing angular correlations between final-state photons and spin of annihilating positronium, measurements were previously limited by the knowledge of the latter. Here, we demonstrate tomographic reconstruction techniques applied to three-photon annihilations of ortho-positronium atoms to estimate their spin polarisation without a magnetic field or polarised positronium source. We use a plastic-scintillator-based positron-emission-tomography scanner to record ortho-positronium (o-Ps) annihilations with a single-event estimation of o-Ps spin and determine the complete spectrum of an angular correlation operator sensitive to CPT-violating effects. We find no violation at the precision level of 10^{-4}, with an over threefold improvement on the previous measurement.

The purpose of the presented research is the estimation of the performance characteristics of the economic total-body Jagiellonian-PET system (TB-J-PET) constructed from plastic scintillators. The characteristics are estimated according to the NEMANU-2-2018 standards utilizing the GATE package. The simulated detector consists of 24 modules, each built out of 32 plastic scintillator strips (each with a cross-section of 6 mm times 30 mm and length of 140 or 200 cm) arranged in two layers in regular 24-sided polygon circumscribing a circle with a diameter of 78.6 cm. For the TB-J-PET with an axial field-of-view (AFOV) of 200 cm, a spatial resolution (SRs) of 3.7mm (transversal) and 4.9mm (axial) are achieved. The noise equivalent count rate (NECR) peak of 630 kcps is expected at 30 kBq cc^-1. Activity concentration and the sensitivity at the center amount to 38 cps kBq^-1. The scatter fraction (SF) is estimated to 36.2 %. The values of SF and SR are comparable to those obtained for the state-of-the-art clinical PET scanners and the first total-body tomographs: uExplorer and PennPET.With respect to the standard PET systemswithAFOVin the range from16 to 26 cm, the TBJ-PET is characterized by an increase inNECRapproximately by a factor of 4 and by the increase of the whole-body sensitivity by a factor of 12.6 to 38. The time-of-flight resolution for the TB-J-PETis expected to be at the level ofCRT=240 ps fullwidth at half-maximum. For the TB-J-PETwith an AFOVof 140 cm, an image quality of the reconstructed images of a NEMAIEC phantom was presented with a contrast recovery coefficient and a background variability parameters. The increase of the whole-body sensitivity andNECRestimated for the TB-J-PET with respect to current commercial PETsystems makes the TB-J-PET a promising cost-effective solution for the broad clinical applications of total-body PET scanners. TB-J-PETmay constitutes an economic alternative for the crystal TB-PET scanners, since plastic scintillators are much cheaper than BGO or LYSO crystals and the axial arrangement of the strips significantly reduces the costs of readout electronics and SiPMs.

The J-PET tomograph is constructed from plastic scintillator strips arranged axially in concentric cylindrical layers. It enables investigations of positronium decays by measurement of the time, position, polarization and energy deposited by photons in the scintillators, in contrast to studies conducted so far with crystal and semiconductor based detection systems where the key selection of events is based on the measurement of the photons energies. In this article we show that the J-PET tomography system constructed solely from plastic scintillator detectors is capable of exclusive measurements of the decays of ortho-positronium atoms. We present the first positronium production results and its lifetime distribution measurements. The obtained results prove the capability of the J-PET tomograph for (i) fundamental studies of positronium decays (in particular test of discrete symmetries in purely leptonic systems), (ii) positron annihilation lifetime spectroscopy, as well as (iii) molecular imaging diagnostics and (iv) observation of entanglement

One of the directions in today's development of PET scanners is to increase their axial field of view (AFOV). Currently limited to several centimeters, AFOV of the clinically available PET tomographs results in a very low sensitivity (~1%) and requires an extended time for a scan of a whole human body. While these drawbacks are addressed in the so-called, Total Body PET concept (scanner with a significantly elongated field of view), it creates new challenges not only in the mechanical construction but also in image reconstruction and event selection. The possibility of taking into account of large-angle variety of lines of responses (LORs) contributes positively to the sensitivity of the tomograph. However, at the same time, the most oblique LORs have an unfavorable influence on the spatial resolution due to the parallax error and large contribution to the scatter fraction. This forces to determine a new factor -acceptance angle - which is a maximum azimuthal angle for which the LORs are still taken into image reconstruction. Correct determination of such factors is imperative to maximize the performance of a Total Body PET system since it introduces a trade-off between the two main characteristics of scanners: sensitivity and spatial resolution. This work has been dedicated to the estimation of the optimal acceptance angle for the proposed by the Jagiellonian PET (J-PET) Collaboration Total Body tomograph. J-PET Collaboration introduces a novel, cost-effective approach to PET systems development with the use of organic scintillators. This simulation study provides evidence that the 45-degree acceptance angle cut can be an appropriate choice for the investigated scanner.

Built on top of the Geant4 toolkit, GATE is collaboratively developed for more than 15 years to design Monte Carlo simulations of nuclear-based imaging systems. It is, in particular, used by researchers and industrials to design, optimize, understand and create innovative emission tomography systems. In this paper, we reviewed the recent developments that have been proposed to simulate modern detectors and provide a comprehensive report on imaging systems that have been simulated and evaluated in GATE. Additionally, some methodological developments that are not specific for imaging but that can improve detector modeling and provide computation time gains, such as Variance Reduction Techniques and Artificial Intelligence integration, are described and discussed.

In this paper we introduce a semi-analytic algorithm for 3-dimensional image reconstruction for positron emission tomography (PET). The method consists of the back-projection of the acquired data into the most likely image voxel according to time-of-flight (TOF) information, followed by the filtering step in the image space using an iterative optimization algorithm with a total variation (TV) regularization. TV regularization in image space is more computationally efficient than usual iterative optimization methods for PET reconstruction with a full system matrix that uses TV regularization. The efficiency comes from the one-time TOF back-projection step that might also be described as a reformatting of the acquired data. An important aspect of our work concerns the evaluation of the filter operator of the linear transform mapping an original radioactive tracer distribution into the TOF back-projected image. We obtain concise, closed-form analytical formula for the filter operator. The proposed method is validated with the Monte Carlo simulations of the NEMA IEC phantom using a one-layer, 50 cm-long cylindrical device called Jagiellonian PET scanner. The results show a better image quality compared with the reference TOF maximum likelihood expectation maximization algorithm.

A precise characterization of therapeutic proton pencil beams is essential for commissioning of any treatment planning system (TPS). The dose profile characterization includes measurement of the beam lateral dose profile in the beam core and far from the beam core, in the so called low-dose envelope, and requires a sophisticated detection system with a few orders of magnitude dynamic range. We propose to use a single-quantum sensitive MINIPIX TIMEPIX detector, along with an in-house designed holder to perform measurements of the pencil beam dose profile in air and in water. We validated the manufacturer calibration of the MINIPIX TIMEPIX detector in proton beams of various energies and compared the deposited energy spectra to Monte Carlo (MC) simulations. The precision of the lateral dose profile measurements has been systematically validated against Krakow proton facility commissioning data and dose profile simulations performed with MC codes GATE/Geant4 and FRED. We obtained an excellent agreement between MINIPIX TIMEPIX measurements and simulations demonstrating the feasibility of the system for a simple characterization and validation of proton pencil beams. The proposed approach can be implemented at any proton therapy facility to acquire experimental data needed to commission and validate analytical and MC based TPS.

Research conducted in the framework of the J-PET project aims to develop a cost-effective total-body positron emission tomography scanner. As a first step on the way to construct a full-scale J-PET tomograph from long strips of plastic scintillators, a 24-strip prototype was built and tested. The prototype consists of detection modules arranged axially forming a cylindrical diagnostic chamber with an inner diameter of 360 mm and an axial field-of-view of 300 mm. Promising perspectives for a low-cost construction of a total-body PET scanner are opened due to an axial arrangement of strips of plastic scintillators, which have a small light attenuation, superior timing properties, and the possibility of cost-effective increase of the axial field-of-view. The presented prototype comprises dedicated solely digital front-end electronic circuits and a triggerless data acquisition system which required development of new calibration methods including time, thresholds and gain synchronization. The system and elaborated calibration methods including first results of the 24-module J-PET prototype are presented and discussed. The achieved coincidence resolving time equals to CRT = 490 +- 9 ps. This value can be translated to the position reconstruction accuracy s(Dl) = 18 mm which is fairly position-independent Keywords: positron emission tomography, plastic scintillators, J-PET.

Study of certain angular correlations in the three-photon annihilations of the triplet state of positronium, the electron?positron bound state, may be used as a probe of potential CP and CPT-violating effects in the leptonic sector. We present the perspectives of CP and CPT tests using this process recorded with a novel detection system for photons in the positron annihilation energy range, the Jagiellonian Positron Emission Tomography (J-PET). We demonstrate the capability of this system to register three-photon annihilations with an unprecedented range of kinematical configurations and to measure the CPT-odd correlation between positronium spin and annihilation plane orientation with a precision improved by at least an order of magnitude with respect to present results. We also discuss the means to control and reduce detector asymmetries in order to allow J-PET to set the first measurement of the correlation between positronium spin and momentum of the most energetic annihilation photon which has never been studied to date.

Total-body PET opens new diagnostic paradigm with prospects for personalized disease treatment, yet the high cost of the current crystal-based PET technology limits dissemination of total-body PET in hospitals and even in the research clinics. The J-PET tomography system is based on axially arranged low-cost plastic scintillator strips. It constitutes a realistic cost-effective solution of a total-body PET for broad clinical applications. High sensitivity of total-body J-PET and trigger-less data acquisition enable multi-photon imaging, opening possibilities for multi-tracer and positronium imaging, thus promising quantitative enhancement of specificity in cancer and inflammatory diseases assessment. An example of dual tracer analysis, becoming possible with total-body J-PET system, could be a concurrent application of FDA-approved 82Rb-Chloride and [18F]FDG, allowing simultaneous assessment of myocardium metabolic rate and perfusion of the cardiovascular system.

The aim of the performed technical attenuation length measurement is to compare light attenuation of a few commercially available plastic scintillator strips and to select the best scintillator type for the total-body Jagiellonian Positron Emission Tomograph (J-PET) construction. Few models of plastic scintillators obtained from different manufacturers were tested. All strips had the same rectangular cross section and dimensions 6 mm x 24 mm x 1000 mm with all surfaces polished. The light attenuation length was measured by exciting the scintillator strip at different positions with an ultraviolet lamp emitting at 365 nm and reading light signal collected at one side of the strip by a silicon photodiode. Among measured plastic scintillators, EJ-200 possesses the highest technical light attenuation length and is suitable for construction of total-body J-PET scanner.

Three-dimensional (3D) spheroids mimic important properties of tumors and may soon become a reasonable substitute for animal models and human tissue, eliminating numerous problems related to in vivo and ex vivo experiments and pre-clinical drug trials. Currently, various imaging methods including X-ray microtomography (micro-CT), exist but their spatial resolution is limited. Here, we visualized and provided a morphological analysis of spheroid cell cultures using micro-CT and compared it to that of confocal microscopy. An approach is proposed that can potentially open new diagnostic opportunities to determine the morphology of cancer cells cultured in 3D structures instead of using actual tumors. Spheroids were formed from human melanoma cell lines WM266-4 and WM115 seeded at different cell densities using the hanging drop method. Micro-CT analysis of spheroid showed that spheroid size and shape differed depending on the cell line, initial cell number, and duration of culture. The melanoma cell lines used in this study can successfully be cultured as 3D spheroids and used to substitute human and animal models in pre-clinical studies. The micro-CT allows for high-resolution visualization of the spheroids structure.

The idea of a very sensitive positron emission tomography (PET) system covering a large portion of the body of a patient already dates back to the early 1990s. In the period 2000-2010, only some prototypes with long axial field of view (FOV) have been built, which never resulted in systems used for clinical research. One of the reasons was the limitations in the available detector technology, which did not yet have sufficient energy resolution, timing resolution or countrate capabilities for fully exploiting the benefits of a long axial FOV design. PET was also not yet as widespread as it is today: the growth in oncology, which has become the major application of PET, appeared only after the introduction of PET-CT (early 2000).The detector technology used in most clinical PET systems today has a combination of good energy and timing resolution with higher countrate capabilities and has now been used since more than a decade to build time-of-flight (TOF) PET systems with fully 3D acquisitions. Based on this technology, one can construct total body PET systems and the remaining challenges (data handling, fast image reconstruction, detector cooling) are mostly related to engineering. The direct benefits of long axial FOV systems are mostly related to the higher sensitivity. For single organ imaging, the gain is close to the point source sensitivity which increases linearly with the axial length until it is limited by solid angle and attenuation of the body. The gains for single organ (compared to a fully 3D PET 20-cm axial FOV) are limited to a factor 3-4. But for long objects (like body scans), it increases quadratically with scanner length and factors of 10?40 × higher sensitivity are predicted for the long axial FOV scanner. This application of PET has seen a major increase (mostly in oncology) during the last 2 decades and is now the main type of study in a PET centre. As the technology is available and the full body concept also seems to match with existing applications, the old concept of a total body PET scanner is seeing a clear revival. Several research groups are working on this concept and after showing the potential via extensive simulations; construction of these systems has started about 2 years ago. In the first phase, two PET systems with long axial FOV suitable for large animal imaging were constructed to explore the potential in more experimental settings. Recently, the first completed total body PET systems for human use, a 70-cm-long system, called PennPET Explorer, and a 2-m-long system, called uExplorer, have become reality and first clinical studies have been shown. These results illustrate the large potential of this concept with regard to low-dose imaging, faster scanning, whole-body dynamic imaging and follow-up of tracers over longer periods. This large range of possible technical improvements seems to have the potential to change the current clinical routine and to expand the number of clinical applications of molecular imaging. The J-PET prototype is a prototype system with a long axial FOV built from axially arranged plastic scintillator strips.This paper gives an overview of the recent technical developments with regard to PET scanners with a long axial FOV covering at least the majority of the body (so called total body PET systems). After explaining the benefits and challenges of total body PET systems, the different total body PET system designs proposed for large animal and clinical imaging are described in detail. The axial length is one of the major factors determining the total cost of the system, but there are also other options in detector technology, design and processing for reducing the cost these systems. The limitations and advantages of different designs for research and clinical use are discussed taking into account potential applications and the increased cost of these systems.

In living organisms the positron-electron annihilation (occurring during the PET imaging) proceeds in about 30% via creation of a metastable ortho-positronium atom. In the tissue, due to the pick-off and conversion processes, over 98% of ortho-positronia annihilate into two 511~keV photons. In this article we assess the feasibility for reconstruction of the mean ortho-positronium lifetime image based on annihilations into two photons. The main objectives of this work include: (i) estimation of the sensitivity of the total-body PET scanners for the ortho-positronium mean lifetime imaging using 2gamma annihilations, and (ii) estimation of the spatial and time resolution of the ortho-positronium image as a function of the coincidence resolving time (CRT) of the scanner. Simulations are conducted assuming that radiopharmaceutical is labelled with 44Sc isotope emitting one positron and one prompt gamma. The image is reconstructed on the basis of triple coincidence events. The ortho-positronium lifetime spectrum is determined for each voxel of the image. Calculations were performed for cases of total-body detectors build of (i) LYSO scintillators as used in the EXPLORER PET, and (ii) plastic scintillators as anticipated for the cost-effective total-body J-PET scanner. To assess the spatial and time resolution the three cases were considered assuming that CRT is equal to 140ps, 50ps and 10ps. The estimated total-body PET sensitivity for the registration and selection of image forming triple coincidences is larger by a factor of 12.2 (for LYSO PET) and by factor of 4.7 (for plastic PET) with respect to the sensitivity for the standard 2gamma imaging by LYSO PET scanners with AFOV=20cm.

Time-Over-Threshold (TOT) technique is being used widely due to its implications in developing the multi channel readouts mainly when fast signal processing is required. Using TOT technique as a measure of energy loss instead of charge integration methods significantly reduces the signals readout cost by combining the time and energy information. Therefore, this approach can potentially be used in J-PET tomograph which is build from plastic scintillators characterized by fast light signals. The drawback in adopting this technique is lying in the non-linear correlation between input energy loss and TOT of the signal. The main motivation behind this work is to develop the relationship between TOT and energy loss and validate it with the J-PET tomograph. The experiment was performed using the 22Na beta emitter source placed in the center of the J-PET tomograph. One can obtain primary photons of two different energies: 511 keV photon from the annihilation of positron (direct annihilation or through the formation of para-Positronim atom or pick-off process of ortho-Positronium atoms), and 1275 keV prompt photon. This allows to study the correlation between TOT values and energy loss for energy range up to 1000 keV. As the photon interacts dominantly via Compton scattering inside the plastic scintillator, there is no direct information of primary photon energy. However, using the J-PET geometry one can measure the scattering angle of the interacting photon. Since, 22Na source emits photons of two different energies, it is required to know unambiguously the energy of incident photons and its corresponding scattering angle for the estimation of energy deposition. In this work, the relationship between Time Over Threshold and energy loss by interacting photons inside the plastic scintillators used in J-PET scanner is established for a energy deposited range 100-1000 keV.

In this article a new method for the reconstruction of hit-position and hit-time of photons in long scintillator detectors is investigated. This research is motivated by the recent development of the positron emission tomography scanners based on plastic scintillators. The proposed method constitutes a new way of signal processing in Multi-Voltage-Technique. It is based on the determination of the degree of similarity between the registered signals and the synchronized model signals stored in a library. The library was established for a set of well defined hit-positions along the length of the scintillator. The Mahalanobis distance was used as a measure of similarity between the two compared signals. The method was validated on the experimental data measured using two-strips J-PET prototype with dimensions of 5x9x300 mm. The obtained Time-of-Flight (TOF) and spatial resolutions amount to 325 ps (FWHM) and 25 mm (FWHM), respectively. The TOF resolution was also compared to the results of an analogous study done using Linear Fitting method. The best TOF resolution was obtained with this method at four pre-defined threshold levels which was comparable to the resolution achieved from the Mahalanobis distance at two pre-defined threshold levels. Although the algorithm of Linear Fitting method is much simpler to apply than the Mahalanobis method, the application of the Mahalanobis distance requires a lower number of applied threshold levels and, hence, decreases the costs of electronics used in PET scanner.

J-PET Framework is an open-source software platform for data analysis, written in C++ and based on the ROOT package. It provides a common environment for implementation of reconstruction, calibration and filtering procedures, as well as for user-level analyses of Positron Emission Tomography data. The library contains a set of building blocks that can be combined by users with even little programming experience, into chains of processing tasks through a convenient, simple and well-documented API. The generic input-output interface allows processing the data from various sources: low-level data from the tomography acquisition system or from diagnostic setups such as digital oscilloscopes, as well as high-level tomography structures e.g. sinograms or a list of lines-of-response. Moreover, the environment can be interfaced with Monte Carlo simulation packages such as GEANT and GATE, which are commonly used in the medical scientific community.

Kaonic atoms measure the antikaon-nucleus interaction at almost zero relative energy, allowing one to determine basic low-energy quantum chromodynamics (QCD) quantities, namely, the antikaon-nucleon (KN) scattering lengths. The latter are important for extracting the sigma terms which are built on the symmetry breaking part of the Hamiltonian, thereby providing a measure of chiral and SU(3) symmetries breaking. After discussing the sigma terms and their relations to the kaonic atoms, we describe the most precise measurement in the literature of kaonic hydrogen, performed at LNF-INFN by the SIDDHARTA experiment. Kaonic deuterium is still to be measured, and two experiments are planned. The first, SIDDHARTA-2 at LNF-INFN was installed on DAFNE in spring 2019 and will collect data in 2020. The second, E57 at J-PARC, will become operative in 2021.

In this paper we describe a single-node, double precision Field Programmable Gate Array (FPGA) implementation of the Conjugate Gradient algorithm in the context of Lattice Quantum Chromodynamics. As a benchmark of our proposal we invert numerically the Dirac-Wilson operator on a 4-dimensional grid on three Xilinx hardware solutions: Zynq Ultrascale+ evaluation board, the Alveo U250 accelerator and the largest device available on the market, the VU13P device. In our implementation we separate software/hardware parts in such a way that the entire multiplication by the Dirac operator is performed in hardware, and the rest of the algorithm runs on the host. We find out that the FPGA implementation can offer a performance comparable with that obtained using current CPU or Intel?s many core Xeon Phi accelerators. A possible multiple node FPGA-based system is discussed and we argue that power-efficient High Performance Computing (HPC) systems can be implemented using FPGA devices only.

The Jagiellonian Positron Emission Tomograph (J-PET) setup, besides being the first PET scanner built with plastic scintillators is currently used to conduct a broad range of experiments involving ortho-positronium (o-Ps) decays into three photons. We present results of studies of o-Ps->3g decays performed in J-PET with a view to search for angular correlations between the photons' momenta and positronium spin direction which would violate the combined CPT symmetry, scarcely tested in leptonic systems. To date, the most precise CPT test using ortho-positronium decays reached the precision of 3×10-3 whereas effects limiting the sensitivity are only expected at the level of 10-9. In the discussed J-PET measurement, ortho-positronium atoms are created by positrons from a 22Na source thermalizing in an extensive-size cylindrical target of mesoporous silica and decay positions are reconstructed using a trilateration-based technique. Decay photons are recorded by 192 strips of plastic scintillators with high timing resolution. Such a setup allows for registration of an unprecedented spectrum of geometrical configurations of o-Ps->3g decays including also correlations with positronium spin. With an angular resolution and o-Ps polarization control improved with respect to previous measurements, J-PET aims at achieving the sensitivity of CPT test at a precision level of at least 10-4.

The aim of the research was to develop polystyrene scintillator for use in the novel time-of-flight Jagiellonian Positron Emission Tomography (J-PET) scanner being elaborated for the whole-body imaging. To achieve this goal, polystyrene based plastic scintillators with the different chemical compositions were produced and characterized. Light output, decay time and emission spectra were measured to develop best composition of polystyrene scintillator.

A detection system of the conventional PET tomograph is set-up to record data from e+e- annihilation into two photons, each with energy of 511 keV, and to give information about the spatial density distribution of a radiopharmaceutical in the patients body. Dedicated positron emission mammography (PEM) systems provide a potentially high sensitivity, high-resolution, low attenuation, and lower cost alternative to whole body PET. We have designed, built, and performed initial evaluation of a large field-of-view Jagiellonian Positron Emission Mammography (J-PEM) system. This 3D system is based on novel idea of applying plastic scintillators to detect annihilation photons and improving spatial resolution by utilization of wavelength shifters (WLS). In addition, this device is being developed in view of classification of malignancy based on the possibility of positronium mean lifetime imaging. Here we present the first results from the simulations as motivation for our investigation.

The Jagiellonian Positron Emission Tomograph (J-PET) is a multidisciplinary device aiming to perform studies in medical field as well as to test the fundamental symmetries. The plastic scintillators offer very good time resolution. Although, due to the low atomic number of the plastic material, the incident photons interact mainly via the Compton effect. Thus instead of full energy deposition by the photon, there is a range of energy depositions depending on its scattering angle. For the positron annihilation lifetime spectroscopy studies, it is necessary to distinguish the photons emitted from different processes. Therefore, it becomes crucial to find a method to disentangle the photons of different energies. In the present work, the control spectra are discussed which can unambiguously categorize the photons of different energies and origins, which are essential for the studies based on the positronium lifetime

A novel concept for tomography of the human body developed by the Jagiellonian Positronium EmissionTomography (J-PET) project provides the possibility to combine metabolic information collected by standardPET with structural information obtained from positronium lifetime. This results in a morphometric image. Tothis end, there is a need to develop software compatible with the J-PET Framework for fast online analysis duringimaging. PALS Avalanche is a software developed on UNIX system and based on ROOT software, which allows oneto decompose positronium annihilation lifetime spectra in the form of a set of single time differences and histogram.Performance of the PALS Avalanche will be tested by analysing simulated PAL spectra.

Positron Annihilation Lifetime Spectroscopy (PALS) is a technique based on the analysis of the lifetime of positronium emitted from implanted or delivered positronium donors. This technique employs the lifetime and intensity dependence on the structure of analyzed material. Due to this specific features, PALS might be used in further research protocols and clinical studies for cancer diagnostic purposes. This article reports the progress in the study design, main objectives of the study, protocols of measurement sand data analysis and further perspective of this study. The main goal of this work was to show the effectiveness of this method and progress in its development. For this purpose, colorectal cancer was examined.

The Jagiellonian Positron Emission Tomograph (J-PET) is a novel PET device that, in contrast to commercial PET scanners, is based on plastic scintillator strips. Modular J-PET is the latest prototype that consists of 24 modules arranged in a cylinder. In this study, 6 point-like sources defined in the NEMA spatial resolution standard were simulated twice with total activities of 60 kBq and 60 MBq, respectively. Results of simulations were processed with the GOJA software and reconstructed with the QETIR package

The Positron Emission Tomography (PET) is one of the most popular imaging techniques of the human body. During the PET scans, a positron from the beta+ emitter given to the patient, directly or after forming a positronium, annihilates with an electron from the patient, with emission of photons. Registration of produced photons allows one to reconstruct the distribution of radioisotopes in the patient's body, further interpreted as the metabolic image. The imaging of metabolism can be improved by measurement of the time difference between registration of the two photons in coincidence (Time-of-Flight (TOF))[1]. In the case of the TOF-PET scanners, the time resolution of the detection system and its calibration is crucial. The Jagiellonian Positron Emission Tomograph (J-PET) detector is an example of the TOF-PET system, constructed at the Jagiellonian University in Kraków, which is based on plastic scintillators and very fast electronics

In contrast to standard 2D cell cultures, spheroids are three-dimensional (3D) models which can mimic natural conditions of cancer growth and metabolism. Their complex structure can be investigated and analyzed using fluorescence microscopy and micro-tomographic imaging (micro-CT) as a new technique. In this study, we show application of two different melanoma cell lines (WM115 and WM266) with different biological characteristics to form spheroids by a hanging drop method.

Vacuum chambers are necessary for the physics experiments planned to be carried out with the use of the J-PET detector. Two chambers manufactured and used for particular runs of experiments had generally cylindrical shapes, while the radioactive source was placed in the center of each chamber. The highly porous material, used as a target in which positrons positronium atoms annihilate, was placed in the immediate vicinity of the source. Such orientation ensures the axially symmetrical response of J-PET scintillators and allows to carry out correct calibration. The variation of material used for manufacturing of the chambers (aluminum/plastic), allows to observe the detector response with various rates of absorption and scattering of annihilation quanta. Such determination is necessary for proper analysis of multi-quanta annihilation, which will be needed for planned experiments.

Physical and biological range uncertainties limit the clinical potential of Proton Beam Therapy (PBT). In this proceedings, we report on two research projects, which we are conducting in parallel and which both tackle the problem of range uncertainties. One aims at developing software tools and the other at developing detector instrumentation. Regarding the first, we report on our development and pre-clinical application of a GPU-accelerated Monte Carlo (MC) simulation toolkit Fred. Concerning the letter, we report on our investigations of plastic scintillator based PET detectors for particle therapy delivery monitoring. We study the feasibility of Jagiellonian-PET detector technology for proton beam therapy range monitoring by means of MC simulations of the beta+ activity induced in a phantom by proton beams and present preliminary results of PET image reconstruction. Using a GPU-accelerated Monte Carlo simulation toolkit Fred and plastic scintillator based PET detectors we aim to improve patient treatment quality with protons.

The purpose of the presented investigations is to design, construct and establish the characteristic performance of the Jagiellonian Positron Emission Mammography(J-PEM), being designed for the detection and diagnosis of breast cancer. Its construction is based on a novel idea of PET tomography based on plastic scintillators and wavelength shifter (WLS) and a new concept of positronium imaging. We have prepared a simulation program based on Monte Carlo methods for optimizing the geometry and material of the J-PEM prototype. Here we present the first results from the simulations and a brief review of the state of art of breast imaging modalities and their characteristics motivating our investigation.

A detection system of the conventional PET tomograph is set-up to record data from e+ e- annihilation into two photons with energy of 511 keV, and it gives information on the density distribution of a radiopharmaceutical in the body of the object. In this paper we explore the possibility of performing the three gamma photons imaging based on ortho- positronium annihilation, as well as the possibility of positronium average lifetime imaging with the J-PET tomograph constructed from plastic scintillators. For this purposes simulations of the ortho-positronium formation and its annihilation into three photons were performed taking into account distributions of photons' momenta as predicted by the theory of quantum electrodynamics and the response of the J-PET tomograph. In order to test the proposed ortho-positronium lifetime image reconstruction method, we concentrate on the decay of the ortho-positronium into three photons and applications of radiopharmaceuticals labeled with isotopes emitting a prompt gamma quantum. The proposed method of imaging is based on the determination of hit-times and hit-positions of registered photons which enables the reconstruction of the time and position of the annihilation point as well as the lifetime of the ortho-positronium on an event-by-event basis. We have simulated the production of the positronium in a cylindrical phantom composed of a set of different materials in which the ortho-positronium lifetime varied from 2 ns to ~2.9 ns, as expected for ortho-positronium created in the human body. The presented reconstruction method for total-body J-PET like detector allows to achieve a mean lifetime resolution of about 40 ps. Recent Positron Annihilation Lifetime Spectroscopy measurements of cancerous and healthy uterine tissues show that this sensitivity may allow to study the morphological changes in cell structures.

In recent years, computational capacity of single Field Programmable Gate Array (FPGA) devices as well as their versatility have increased signifcantly. Adding to that fact, the High Level Synthesis frameworks allowing to program such processors in a high-level language like C++, makes modern FPGA devices a serious candidate as building blocks of a general-purpose High Performance Computing solution. In this contribution we describe benchmarks which we performed using a kernel from the Lattice QCD code, a highly compute-demanding HPC academic code for elementary particle simulations on the newest device from Xilinx, the U250 accelerator card. We describe the architecture of our solution and benchmark its performance on a single FPGA device running in two modes: using either external or embedded memory. We discuss both approaches in detail and provide assessment for the necessary memory throughput and the minimal amount of resources needed to deliver optimal performance depending on the available hardware. Our considerations can be used as guidelines for estimating the performance of some larger, manynode systems.

In positron emission tomography, as much as 40% of positron annihilation occurs through the production of positronium atoms inside the patient's body. The decay of these positronium atoms is sensitive to metabolism and could provide information about disease progression. New research is needed to take full advantage of what positronium decays reveal.

We present a quantum information theoretic version of the Klein-Nishina formula. This formulation singles out the quantity, the a priori visibility, that quantifies the ability to deduce the polarisation property of single photons. The Kraus-type structure allows a straightforward generalisation to the multiphoton cases, relevant in the decay of positronium which is utilized e.g. for metabolic PETimaging (Positron- Emission- Tomograph). Predicted by theory but never experimentally proven, the two- or three-photon states should be entangled. We provide an experimentally feasible method to witness entanglement for these processes via MUBs (Mutually Unbiased Bases), exploiting Bohr?s complementarity. Last but not least we present explicit cases exemplifying the interrelation of geometry and entanglement including relations to its potentiality for teleportation schemes or Bell inequality violations or in future for detecting cancer in human beings.

J-PET is a detector optimized for registration of photons from the electron-positron annihilation via plastic scintillators where photons interact predominantly via Compton scattering. Registration of both primary and scattered photons enables to determinate the linear polarization of the primary photon on the event by event basis with a certain probability. Here we present quantitative results on the feasibility of such polarization measurements of photons from the decay of positronium with the J-PET and explore the physical limitations for the resolution of the polarization determination of 511keV photons via Compton scattering. For scattering angles of about 82 degree (where the best contrast for polarization measurement is theoretically predicted) we find that the single event resolution for the determination of the polarization is about 40 degree (predominantly due to properties of the Compton effect). However, for samples larger than ten thousand events the J-PET is capable of determining relative average polarization of these photons with the precision of about few degrees. The obtained results open new perspectives for studies of various physics phenomena such as quantum entanglement and tests of discrete symmetries in decays of positronium and extend the energy range of polarization measurements by five orders of magnitude beyond the optical wavelength regime.

A novel approach to tomographic data processing has been developed and evaluated using the Jagiellonian PET (J- PET) scanner as an example. We propose a system in which there is no need for powerful, local to the scanner processing facility, capable to reconstruct images on the fly. Instead we introduce a Field Programmable Gate Array (FPGA) System-on-Chip (SoC) platform connected directly to data streams coming from the scanner, which can perform event building, filtering, coincidence search and Region-Of-Response (ROR) reconstruction by the programmable logic and visualization by the integrated processors. The platform significantly reduces data volume converting raw data to a list-mode representation, while generating visualization on the fly.

The Jagiellonian Positron Emission Tomograph (J-PET) is the first PET device built from plastic scintillators. It is a multi-purpose detector designed for medical imaging and for studies of properties of positronium atoms in porous matter and in living organisms. In this article we report on the commissioning of the J-PET detector in view of studies of positronium decays. We present results of analysis of the positron lifetime measured in the porous polymer. The obtained results prove that J-PET is capable of performing simultaneous imaging of the density distribution of annihilation points as well as positron annihilation lifetime spectroscopy.

This article reports on the feasibility of testing of the symmetry under reversal in time in a purely leptonic system constituted by positronium atoms using the J-PET detector. The present state of T symmetry tests is discussed with an emphasis on the scarcely explored sector of leptonic systems. Two possible strategies of searching for manifestations of T violation in non-vanishing angular correlations of final state observables in the decays of metastable triplet states of positronium available with J-PET are proposed and discussed. Results of a pilot measurement with J-PET and assessment of its performance in reconstruction of three-photon decays are shown along with an analysis of its impact on the sensitivity of the detector for the determination of T -violation sensitive observables.

A novel whole-body positron emission tomography (PET) system based on plastic scintillators is developed by the J-PET Collaboration. It consists of plastic scintillator strips arranged axially in the form of a cylinder, allowing the cost-effective construction of the total-body PET system. In order to determine the properties of the scanner prototype and optimize its geometry, advanced computer simulations were performed using the GATE (Geant4 application for tomographic emission) software. The spatial resolution, sensitivity, scatter fraction and noise equivalent count rate were estimated according to the National Electrical Manufacturers Association norm, as a function of the length of the tomograph, the number of detection layers, the diameter of the tomographic chamber and for various types of applied readout. For the single-layer geometry with a diameter of 85 cm, a strip length of 100 cm, a cross-section of 4 mm × 20 mm and silicon photomultipliers with an additional layer of wavelength shifter as the readout, the spatial resolution (full width at half maximum) in the centre of the scanner is equal to 3 mm (radial, tangential) and 6 mm (axial). For the analogous double-layer geometry with the same readout, diameter and scintillator length, with a strip crosssection of 7 mm × 20 mm, a noise equivalent count rate peak of 300 kcps was reached at 40 kBq cc?1 activity concentration, the scatter fraction is estimated to be about 35% and the sensitivity at the centre amounts to 14.9 cps kBq?1. Sensitivity profiles were also determined.

This article presents the results of the kaonic helium-4 measurement conducted by the SIDDHARTA-2 experiment, aiming to provide crucial insights into the low-energy strong interaction in the strangeness sector. High-precision X-ray spectroscopy is used to examine the interaction between negatively charged kaons and nuclei in atomic systems. The SIDDHARTA-2setup was optimized through the kaonic helium-4 measurement in preparation for the challenging kaonic deuterium measurement. The kaonic helium-4 measurement at a new density of 2.25 g/l is reported, providing the absolute and relative yields for the L-series transitions, which are essential data for understanding kaonic atom cascade processes.

The positronium system, a bound state of an electron and a positron, is suitable for testing the predictions of quantum electrodynamics (QED) as well as symmetry invariance. The Ps triple state, the ortho-Positronium (o-Ps), which mainly decays to three photons, is further studied to search for decays into 4gamma and 5gamma, the former C-violating decay and the latter never observed. The J-PET is a multi-purpose detector optimized for the detection of photons from positron?electron annihilation and can be used in a broad scope of interdisciplinary investigation. The large acceptance and high angular resolution of the J-PET detector will push the present limits in these forbidden and rare decays. The aim is to reach a sensitivity below O(10^?6) while reducing the uncertainties, thus increasing the sensitivity.

The positronium, a bound state of electron and positron, is a unique system to perform highly precise tests, due to no hadronic background and precise Quantum Electrodynamics (QED) predictions. Being a system of lepton and antilepton, its properties are precisely described by QED in the Standard Model (SM). The final events topology can be simulated using Monte Carlo techniques. The J-PET detector is a multi-purpose, large acceptance system that is very well-suitable to the studies of positronium decay due to its excellent angular (1?) and timing resolutions. We present preliminary results on the feasibility of searching for Dark Matter (DM) candidates in the decay o-Ps -> invisible with the J-PET, which is wellsuited for the detection of positronium-decay products. Toy Monte Carlo simulations have been prepared to incorporate DM decay models to the oPs decay expectations in order to assess the detector capabilities to search for such an elusive component of our Universe.

Positronium is a suitable leptonic system to test Charge-Parity (CP) discrete symmetry involving the correlations of photons momenta originating from ortho-positronium (o-Ps) annihilation. The photon?photon interaction in the final state due to the vacuum polarization may mimic CP symmetry violation of the order of 10^?9, while weak interaction effects lead to a violation of the order of 10^?14 according to the Standard Model prediction. So far, the experimental limits on CP symmetry violation in the o-Ps decay are set at the level of 10^?4. One of the unique features of the J-PET detector is its ability to measure the polarization direction of the annihilation photons without the magnetic field. The J-PET detector can be used to explore discrete symmetry by looking for probable non-zero expectation values of the symmetry-odd operators, constructed from spin of ortho-Positronium and momentum, and polarization vectors of gamma quanta resulting from o-Ps annihilation. In this work, the J-PET detector experimental and analysis method to improve the sensitivity level at least by one order for CP discrete symmetry studies in the o-Ps decay via symmetry odd operator (e_i k_j), where e_i and k_j are reconstructed polarization and momentum vectors of photons from the o-Ps decays, respectively, will be presented.

Positronium (Ps) is a bound state of electron and positron governed by electromagnetic interactions. Precise measurement of its decay rate is an important observational parameter to test theoretical predictions derived from Non-Relativistic Quantum Electrodynamics (NRQED). In this work, we present a new method for measuring the decay rate of Ps atoms, which has the potential to improve the precision and thus the description of the behavior of particles in bound states and to provide insight into the non-relativistic regime of QED.

J-PET is a photon detector built of plastic scintillators, which already has been commissioned for CPT studies in the decays of positronium. In the first experiment, J-PET has achieved a sensitivity to CPT violation at a level of 10^{-4}, and now it aims to reach a level of 10^{-5}. This will be done by enhancing the three-photon registration efficiency for ortho-positronium decays using a new layer of densely packed plastic scintillators termed Modular J-PET. We present the simulation studies performed for different experimental detection setups to be used for the next CPT test with the Modular J-PET detector.

The positronium atom, a bound state of electron and positron, is a suitable leptonic test site for Charge-Parity (CP) discrete symmetry research. According to the Standard Model, the photon?photon interaction in the final state due to the vacuum polarization may mimic CP violation of the order of 10^-9, while weak interaction effects lead to a violation of the order of 10^-14. So far, the experimental limits on CP symmetry violation in the decay of o-Ps are set at the level of 10^-3. The J-PET detector can be used to explore discrete symmetries by looking for probable non-zero expectation values of the symmetry-odd operators, constructed from spin of ortho-Positronium (o-Ps) and momentum, and polarization vectors of gamma quanta resulting from o-Ps annihilation. The upgraded version of the J-PET detector, with an additional fourth layer of detection modules increases signal acceptance, which allows to triple the efficiency of quanta detection for CP discrete symmetry studies.

We report on the progress in the development of positronium imaging and quantum entanglement imaging achieved thus far by the J-PET collaboration. Positronium (a bound state of electron and positron) is copiously produced in the human body during positron emission tomography. Its properties depend on the size of the intra-molecular voids and concentration in them of molecules as e.g. molecular oxygen. Therefore, positronium may serve as a biomarker of tissue pathology and hypoxia. Recently, the positronium imaging method was developed and the first positronium images of phantoms comprised of tumor cardiac myxoma and healthy adipose tissues were created by means of the J-PET tomograph. A significant difference in mean positronium lifetime in cardiac myxoma and adipose tissues opens promising perspectives for the application of positronium as a cancer diagnostic indicator. It is also important to note that photons originating from the decay of positronium are quantum entangled in polarisation. Thus, it can be hypothesized that by measuring the degree of entanglement of photons from positronium annihilation, additional information can be obtained about the molecular environment in which the positronium is formed. J-PET is the first PET system enabling the determination of linear polarisation of annihilation photons. The measurements performed with the J-PET detector confirm that the distribution of relative angle between the polarization of 511 keV back-toback photons is consistent with the assumption that these photons are quantum entangled. These results open up prospects for the study of quantum entanglement of photons from positronium annihilation in living organisms.

Quantum technology, such as the quantum computers, has attracted significant attention in recent years. In nuclear medicine, powerful and highly sensitive molecular imaging modalities such as PET (Positron Emission Tomography), SPECT (Single Photon Emission CT) and MRI (Magnetic Resonance Imaging) provide accurate morphological and functional information. Exploiting certain aspects of quantum mechanics may bring further improvements in sensitivity, spatial resolution and enable novel capabilities in the field of biomedical imaging and sensing. In this workshop, the possibilities of biomedical applications inspired by quantum technology were discussed. The following exciting topics were covered: quantum entanglement in PET, dynamic nuclear polarization toward more sensitive MRI, quantum sensors based on the 229mTh nuclear clock, plans of an advanced high-energy gamma-ray source at CERN, laser-assisted radiation detection, solid-state quantum sensors such as those based on nitrogen vacancy centers in diamond, quantum sensing using cascade multi photons, and a laser-based radioactive isotope analysis.

Positron Emission Tomography PET plays a fundamental role in medical diagnosis and oncological research. Due to exceptional performance of PET scanners and continuous advancement, their clinical availability is spreading [1]. The development of Total-Body PET technology is one of the most recent trends in the medical imaging field. Having large axial field of view (AFOV), they provide greater detection area and therefore an increased sensitivity [2]. Nevertheless, alongside many advantages over traditional PET tomographs they are more susceptible to the parallax error, which causes degradation of axial resolution. This is caused by the contribution of most oblique lines of response (LORs) in the acquired data. To overcome this problem the application of a cut ? angular acceptance criterion ? over such LORs has been recommended. Nonetheless, it causes a significant loss of scanner?s sensitivity [3].Jagiellonian PET (J-PET) collaboration from Krakow, Poland is currently developing novel PET tomographs based on the organic, plastic scintillators [4, 1]. Such unique design allows not only for the introduction of cost efficient Total-Body system, but also is able to solve challenges connected with such tomographs. The main aim of this study is to present a novel solution to overcoming the aforementioned problem of degradation in axial resolution in Total-Body scanners by introducing DOI capable detectors based on the J-PET technology.

Discrete symmetry under combined transformation of charge, parity and time reversal (CPT) can be tested in the decays of positronium atom, the lightest bound system built of charged leptons. Jagiellonian Positron Emission Tomograph (J-PET) device constructed from plastic scintillators, detects the photons originating from electron positron annihilation. This feature enables J-PET to study CPT symmetry in the three photon annihilations of the triplet state of positronium. Signs of violation of the CPT symmetry can be sought as a non-vanishing expectation value of an angular correlation operator that is odd under CPT transformation. A technique to estimate the spin of ortho-positronium and momenta of annihilation photons for single recorded ortho-positronium annihilation events allows J-PET to measure the expectation value of a CPT symmetry odd angular correlation operator. J-PET measures a broad range of kinematical configurations of ortho-positronium annihilation to three photons and is the first experiment to determine the full range of the CPT-odd angular correlation.

We present results on CPT symmetry tests in decays of positronium performed with the precision at the level of 10?4, and positronium images determined with the prototype of the J-PET tomograph. The first full-scale prototype apparatus consists of 192 plastic scintillator strips readout from both ends with vacuum tube photomultipliers. Signals produced by photomultipliers are probed in the amplitude domain and are digitized by FPGA-based readout boards in triggerless mode. In this contribution we report on the first two- and three-photon positronium images and tests of CPT symmetry in positronium decays.

During the positron emission tomography about 40% of positrons annihilations occur through the creation of positronium which may be trapped within and between molecules. Positronium decays in the patient body are sensitive to the nanostructure and metabolism of the tissues. This phenomenon is not used in the present PET diagnostics, yet it is in principle possible to use environment modified properties of positronium as diagnostic biomarkers for cancer therapy. First in-vitro studies show differences of positronium mean lifetime and production probability in the healthy and cancerous tissues, indicating that they may be used as indicators for in-vivo cancer classification. Here we present a method of positronium lifetime imaging in which the lifetime and position of positronium atoms is determined on an event-by-event basis. The method requires application of beta+ decaying isotope emitting prompt gamma (e.g. 44 Sc). We discuss the possibility of determining the time and position of positronium annihilation from the back-to-back photons originating from the interaction of positronium with the surrounding atoms and bio-active molecules. The prompt gamma is used for the determination of the time of the formation of positronium. We estimate that with the total-body PET scanners the sensitivity of the positronium lifetime imaging, which requires coincident registration of the back-to-back annihilation photons and the prompt gamma is comparable to the sensitivities for the metabolic imaging with standard PET scanners.

Positron Annihilation Lifetime Spectroscopy (PALS) allows examining structure of materials in nano and sub-nanometer scale. This technique is based on the lifetime and intensity of ortho-positronium atoms in free volumes of given structures. It is mostly used for studies in material sciences, but it can also be used for in vivo imaging of the cell morphology as proposed in [1], [2]. Cancer cells are characterized by an altered macro structure in comparison to normal cells, thus the main objective of these studies is to compare if these differences can be detected on sub-nanometer level with PALS technique. First studies on standard PAL spectrometers conducted by Jean [3],[4] and J-PET collaboration [5], [6], give promising results showing differences between normal and cancer tissues. This perspective will allow for simultaneous determination of early and advanced stages of carcinogenesis, by observing changes in biomechanical parameters between normal and tumour cells, and standard PET examination, which can be performed with the Jagiellonian Positron Emission Tomograph (J-PET), a multi-purpose detector used for investigations with positronium atoms in life-sciences as well as for development of medical diagnostics. Results of first PALS measurement of cardiac myxoma, with J-PET detector is presented in this paper. Obtained o-Ps lifetime for tumor tissue is equal to 2.03(01)[ns] and its intensity 25.7(1)%.

The precise measurements of the Compton scatterings of photons originating from the decay of positronium atoms can reveal information about their polarizations. J-PET detector is constructed of 192 plastic scintillators and is unique to study the scattering correlations of the annihilation photons with an angular precision of several degrees. In this work, we present the first experimental evidence showing the feasibility of measuring the photons relative polarization using the J-PET detector.

A problem of range uncertainty is currently one the most challenging in proton radiotherapy. To tackle that issue, the new, affordable, modular, lightweight, portable and reconfigurable technology of plastic scintillator based positron emission tomography was investigated. Monte Carlo simulation study was performed to evaluate the feasibility of the J-PET technology for proton beam range monitoring. Various configurations (single-layer, multi-layer, full ring, dual-head) were considered. 3D PET images were reconstructed using open-source CASToR software and the expected detector signal, as a function of detector acceptance and efficiency, was estimated. A relationship between the dose and activity profiles was investigated. Experimental validation of the presented results is currently under the preparation.

The purpose of the reported research is (i) the elaboration of the new imaging method based on the in-vivo measurement of properties of positronium produced inside patient during positron emission tomography, and determination of correlations between properties of positronium inside the cancer tissues and histopathological characteristics of cancers, as well as (ii) exploration of possibilities of the determination of the linear polarization of annihilation photons and development of novel prognostic indicators for cancer diagnostics based on the quantum information from (multipartite) entanglement of photons originating from the positronium decay.During PET diagnosis positronium may be trapped inside free volumes between and within molecules of the examined patient. Currently, in the PET technique, the phenomenon of positronium production is neither recorded nor used for imaging. Yet in about 40% cases, the electron-positron annihilation proceeds in the tissue via creation of positronium. The properties of positronium (such as e.g. mean lifetime or ratio of decay rates into two and three photons) depend on the size of the free volumes between atoms and there are indications that they are correlated with the stage of the development of metabolic disorders of the human tissues. Therefore, an image of properties of positronium formed inside the human body may deliver new information complementary to SUV index and useful for the diagnosis.Moreover, recent theoretical studies have proven that the entanglement in the three-photon state from the decay of ortho-positronium survives surprisingly also for mixed scenarios expected in human tissues. Hence, detecting entanglement of photons originating from positronium may enable the extraction of quantum properties of the surrounding tissue environment.We discuss (i) results of the feasibility studies of the positronium mean-lifetime image reconstruction with the total-body PET scanner from plastic scintillators, as well as (ii) results of pilot studies of the mean lifetime of positronium in the healthy and tumorous tissues operated from the patients. Performed experiments show that properties of positronium atoms in uterine tissues operated from human patients reveals meaningful differences between healthy and tumorous tissues. We also discuss results of the feasibility studies of the polarization of annihilation photons with the J-PET tomograph in which annihilation photons interact predominantly via Compton scattering. Registration of both primary and scattered photons enables to determinate the linear polarization of the primary photon on the event by event basis and hence enables to witness the entanglement of annihilation photons in polarization based on Mutually Unbiased Bases. The performed simulations indicate that in the future with the total-body PET and improved time resolution it shall be feasible to reconstruct images of positronium properties in-vivo during the routine PET diagnosis.

Currently a positron emission tomography (PET) based on novel, cutting-edge technology is developed by the Jagiellonian-PET (J-PET) collaboration. In this contribution, the principle of plastic scintillator based detector system, J-PET and the investigation of its feasibility for proton beam therapy range monitoring will be presented. Results of Monte Carlo simulation studies aiming at the characterization of secondary radiation induced by a proton beam in a PMMA phantom and detected by the J-PET scanner will be shown. Accounting for detector acceptance and PET-gamma detection efficiency in the plastics the diagnostic J-PET scanner can acquire 1.7×10?5 PET gammas per primary proton. The J-PET detector configurations and signal acquisition during and after the therapy is discussed.

As a relatively simple and purely leptonic state positronium consti-tutes a unique system to study discrete symmetries with precision limited onlyby the effects due to the weak interaction and photon-photon scattering. Theexperimental tests in the positronium decays were performed only on theC,CPandCPTsymmetries with sensitivity much smaller than the predictions whichopens a large window to search for phenomena beyond the Standard Model. Inthis article we present capability of the J-PET detector to improve the current precision of discrete symmetries tests in the decays of positronium atom.

The new ADAM?s tool demonstrates suitable performances to test, in realistic patient-like conditions, tracking systems based on soft tissue detection.

The Jagiellonian Positron Emission Tomograph (J-PET) is a novel device based on organic scintillators being developed at Jagiellonian University in Kraków, Poland. J-PET is an axially symmetric and high acceptance scanner that can be used as a multi-purpose detector system. It is well suited to pursue tests of discrete symmetries in decays of positronium in addition to medical imaging. J-PET enables measurement of both momenta and polarization vectors of annihilation photons. The latter is a unique feature of the J-PET detector which allows study of the time reversal symmetry violation operator constructed solely from the annihilation photons momenta before and after scattering within the detector.

The Jagiellonian Positron Emission Tomograph (J-PET) is a multi-purpose detector being developed to provide an economical alternative of com-mercially available PETs as well as to perform the tests on the discrete sym-metries and entanglement. It is composed of 192 plastic scintillators axiallyarranged in three cylindrical layers. In the framework of J-PET detector, Time-Over-Threshold (TOT) approach is adopted for the signal readouts in order toutilize the excellent time resolution of the plastic scintillators. In this paper, wepresent a method elaborated for establishing a relation between TOT and energyloss.

Symmetries under the parity transformation (P), charge-conjugation (C) and time reversal (T) are of fundamental importance in nuclear and elementary particle physics. Studies of the observables violating the combined CP symmetry constitute precise tests of the Standard Model. However, CP violation was observed to date only for systems involving quarks, raising the importance of searches its manifestations e.g. in purely leptonic systems. The 3? decay of spin-aligned ortho-positronium atoms (o-Ps) can be used to test CP invariance in such a purely leptonic system. The Jagiellonian Positron Emission Tomograph (J-PET) detection system enables experimental tests of CP and CPT through measurement of the expectation values of angular correlation operators odd under these transformations and constructed from (i) spin vector of the ortho-positronium atom, (ii) co-planar momentum vectors of photons originating from the decay of the positronium atom, and (iii) linear polarization direction of annihilation photons. Precise experimental symmetry tests with J-PET are possible thanks to a dedicated reconstruction technique of 3? ortho-positronium decays and a positronium production chamber including a highly porous aerogel target, whose setup allows for determining the orthopositronium spin polarization without the use of an external magnetic field.

Results of porting parts of the Lattice Quantum Chromodynamics code to modern FPGA devices are presented. A single-node, double precision implementation of the Conjugate Gradient algorithm is used to invert numerically the Dirac-Wilson operator on a 4-dimensional grid on a Xilinx Zynq evaluation board. The code is divided into two software/hardware parts in such a way that the entire multiplication by the Dirac operator is performed in programmable logic, and the rest of the algorithm runs on the ARM cores. Optimized data blocks are used to efficiently use data movement infrastructure allowing to reach intervals of 1 clock cycle. We show that the FPGA implementation can offer a comparable performance compared to that obtained using Intel Xeon Phi KNL.