Active roles for inhibitory B kinases and in nuclear factor- B-mediated chemoresistance to doxorubicin

Chemotherapy agents have been shown to induce the transcription factor NF-κB and subsequent chemoresistance in fibrosarcomas and other cancers. The mechanism of NF-κB-mediated chemoresistance remains unclear, with a previous report suggesting that doxorubicin induces this response independent of the inhibitory κB kinases (IKKs). Other studies have indicated that IKKβ, but not IKKα, is required. Mouse embryo fibroblasts (MEF) devoid of IKKα, IKKβ, or both subunits (DKO) were treated with doxorubicin. The absence of either IKKα or IKKβ or both kinases resulted in impaired induction of NF-κB DNA-binding activity in response to doxorubicin. To provide a valid clinical correlate, HT1080 human fibrosarcoma cells were transfected with small interference RNAs (siRNAs) specific for IKKα or IKKβ and then subsequently treated with doxorubicin. Knockdown of IKKα severely impaired the ability of doxorubicin to initiate NF-κB DNA-binding activity. However, a decrease in either IKKα or IKKβ resulted in decreased phosphorylation of p65 in response to doxorubicin. The inhibition of doxorubicin-induced NF-κB activation by the knockdown of either catalytic subunit resulted in increased cleaved caspase 3 and cleaved PARP, and increased apoptosis when compared to doxorubicin alone. The results of this study validate current approaches aimed at NF-κB inhibition to improve clinical therapies. Moreover, we demonstrate that IKKα plays a critical role in NF-κB-mediated chemoresistance in response to doxorubicin and may serve as a potential target in combinational strategies to improve chemotherapeutic response

A feasibility study of ortho-positronium decays measurement with the J-PET scanner based on plastic scintillators

We present a study of the application of the Jagiellonian Positron Emission Tomograph (J-PET) for the registration of gamma quanta from decays of ortho-positronium (o-Ps). The J-PET is the first positron emission tomography scanner based on organic scintillators in contrast to all current PET scanners based on inorganic crystals. Monte Carlo simulations show that the J-PET as an axially symmetric and high acceptance scanner can be used as a multi-purpose detector well suited to pursue research including e.g. tests of discrete symmetries in decays of ortho-positronium in addition to the medical imaging. The gamma quanta originating from o-Ps decay interact in the plastic scintillators predominantly via the Compton effect, making the direct measurement of their energy impossible. Nevertheless, it is shown in this paper that the J-PET scanner will enable studies of the o-Ps$\to3\gamma$ decays with angular and energy resolution equal to $\sigma(\theta) \approx 0.4^{\circ}$ and $\sigma(E) \approx 4.1$ keV, respectively. An order of magnitude shorter decay time of signals from plastic scintillators with respect to the inorganic crystals results not only in better timing properties crucial for the reduction of physical and instrumental background, but also suppresses significantly the pileups, thus enabling compensation of the lower efficiency of the plastic scintillators by performing measurements with higher positron source activities

Processing optimization with parallel computing for the J-PET tomography scanner

The Jagiellonian-PET (J-PET) collaboration is developing a prototype TOF-PET detector based on long polymer scintillators. This novel approach exploits the excellent time properties of the plastic scintillators, which permit very precise time measurements. The very fast, FPGA-based front-end electronics and the data acquisition system, as well as, low- and high-level reconstruction algorithms were specially developed to be used with the J-PET scanner. The TOF-PET data processing and reconstruction are time and resource demanding operations, especially in case of a large acceptance detector, which works in triggerless data acquisition mode. In this article, we discuss the parallel computing methods applied to optimize the data processing for the J-PET detector. We begin with general concepts of parallel computing and then we discuss several applications of those techniques in the J-PET data processing.Comment: 8 page

Calculation of time resolution of the J-PET tomograph using the Kernel Density Estimation

In this paper we estimate the time resolution of the J-PET scanner built from plastic scintillators. We incorporate the method of signal processing using the Tikhonov regularization framework and the Kernel Density Estimation method. We obtain simple, closed-form analytical formulas for time resolutions. The proposed method is validated using signals registered by means of the single detection unit of the J-PET tomograph built out from 30 cm long plastic scintillator strip. It is shown that the experimental and theoretical results, obtained for the J-PET scanner equipped with vacuum tube photomultipliers, are consistent.Comment: 25 pages, 11 figure

Multichannel FPGA based MVT system for high precision time (20~ps~RMS) and charge measurement

In this article it is presented an FPGA based $M$ulti-$V$oltage $T$hreshold (MVT) system which allows of sampling fast signals ($1-2$ ns rising and falling edge) in both voltage and time domain. It is possible to achieve a precision of time measurement of $20$ ps RMS and reconstruct charge of signals, using a simple approach, with deviation from real value smaller than 10$\%$. Utilization of the differential inputs of an FPGA chip as comparators together with an implementation of a TDC inside an FPGA allowed us to achieve a compact multi-channel system characterized by low power consumption and low production costs. This paper describes realization and functioning of the system comprising 192-channel TDC board and a four mezzanine cards which split incoming signals and discriminate them. The boards have been used to validate a newly developed Time-of-Flight Positron Emission Tomography system based on plastic scintillators. The achieved full system time resolution of $\sigma$(TOF) $\approx 68$ ps is by factor of two better with respect to the current TOF-PET systems.Comment: Accepted for publication in JINST, 10 pages, 8 figure

Search for the eta-mesic 4He with WASA-at-COSY detector

An exclusive measurement of the excitation function for the dd->3Heppi- reaction was performed at the Cooler Synchrotron COSY-Juelich with the WASA-at-COSY detection system. The data were taken during a slow acceleration of the beam from 2.185 GeV/c to 2.400 GeV/c crossing the kinematic threshold for the eta meson production in the dd->4He-eta reaction at 2.336 GeV/c. The corresponding excess energy with respect to the 4He-eta system varied from -51.4MeV to 22MeV. The integrated luminosity in the experiment was determined using the dd->3Hen reaction. The shape of the excitation function for the dd->3Heppi- was examined. No signal of the 4He-eta bound state was observed. An upper limit for the cross-section for the bound state formation and decay in the process dd->(4He-eta)bound->3Heppi- was determined on the 90% confidence level and it varies from 20nb to 27nb for the bound state width ranging from 5MeV to 35MeV, respectively.Comment: 8 pages, 9 figure

Radiation Sterilization of Anthracycline Antibiotics in Solid State

The impact of ionizing radiation generated by a beam of electrons of 25–400 kGy on the stability of such analogs of anthracycline antibiotics as daunorubicin (DAU), doxorubicin (DOX), and epidoxorubicin (EPI) was studied. Based on EPR results, it was established that unstable free radicals decay exponentially with the half-time of 4 days in DAU and DOX and 7 days in EPI after irradiation. Radiation-induced structural changes were analyzed with the use of spectrophotometric methods (UV-Vis and IR) and electron microscope imaging (SEM). A chromatographic method (HPLC-DAD) was applied to assess changes in the contents of the analogs in the presence of their impurities. The study showed that the structures of the analogs did not demonstrate any significant alterations at the end of the period necessary for the elimination of unstable free radicals. The separation of main substances and related substances (impurities and potential degradation products) allowed determining that no statistically significant changes in the content of particular active substances occurred and that their conversion due to the presence of free radicals resulting from exposure to an irradiation of 25 kGy (prescribed to ensure sterility) was not observed

Time resolution of the plastic scintillator strips with matrix photomultiplier readout for J-PET tomograph

Recent tests of a single module of the Jagiellonian Positron Emission Tomography system (J-PET) consisting of 30 cm long plastic scintillator strips have proven its applicability for the detection of annihilation quanta (0.511 MeV) with a coincidence resolving time (CRT) of 0.266 ns. The achieved resolution is almost by a factor of two better with respect to the current TOF-PET detectors and it can still be improved since, as it is shown in this article, the intrinsic limit of time resolution for the determination of time of the interaction of 0.511 MeV gamma quanta in plastic scintillators is much lower. As the major point of the article, a method allowing to record timestamps of several photons, at two ends of the scintillator strip, by means of matrix of silicon photomultipliers (SiPM) is introduced. As a result of simulations, conducted with the number of SiPM varying from 4 to 42, it is shown that the improvement of timing resolution saturates with the growing number of photomultipliers, and that the 2 x 5 configuration at two ends allowing to read twenty timestamps, constitutes an optimal solution. The conducted simulations accounted for the emission time distribution, photon transport and absorption inside the scintillator, as well as quantum efficiency and transit time spread of photosensors, and were checked based on the experimental results. Application of the 2 x 5 matrix of SiPM allows for achieving the coincidence resolving time in positron emission tomography of $\approx$ 0.170 ns for 15 cm axial field-of-view (AFOV) and $\approx$ 0.365 ns for 100 cm AFOV. The results open perspectives for construction of a cost-effective TOF-PET scanner with significantly better TOF resolution and larger AFOV with respect to the current TOF-PET modalities.Comment: To be published in Phys. Med. Biol. (26 pages, 17 figures