Abstract Mass spectrometry (MS)-based proteomics aims to characterize comprehensive proteomes in a fast and reproducible manner. Here we present the narrow-window data-independent acquisition (nDIA) strategy consisting of high-resolution MS1 scans with parallel tandem MS (MS/MS) scans of ~200 Hz using 2-Th isolation windows, dissolving the differences between data-dependent and -independent methods. This is achieved by pairing a quadrupole Orbitrap mass spectrometer with the asymmetric track lossless (Astral) analyzer which provides >200-Hz MS/MS scanning speed, high resolving power and sensitivity, and low-ppm mass accuracy. The nDIA strategy enables profiling of >100 full yeast proteomes per day, or 48 human proteomes per day at the depth of ~10,000 human protein groups in half-an-hour or ~7,000 proteins in 5 min, representing 3× higher coverage compared with current state-of-the-art MS. Multi-shot acquisition of offline fractionated samples provides comprehensive coverage of human proteomes in ~3 h. High quantitative precision and accuracy are demonstrated in a three-species proteome mixture, quantifying 14,000+ protein groups in a single half-an-hour run.
Particle therapy is supposed to be an advanced treatment modality compared to conventional radiotherapy because of the well-defined range of the ions. Prompt gamma rays, produced in nuclear reactions between ion and nuclei, can be utilized for real-time range verification to exploit the full potential of particle therapy. Several devices have been investigated in the field of Prompt Gamma Imaging (PGI), like Slit and Compton Cameras. The latter need very high detection efficiency as well as good time and energy resolution, requiring a versatile scintillation detector. In Positron Emission Tomography (PET), LSO and LYSO are known for their good time resolution, while the lower cost alternative BGO shows worse performance. In PGI however, where gamma rays have energies up to 10 MeV, the light output of a scintillator is up to 20 times larger compared to PET. This reduces the statistical contribution of the time resolution, which is the dominant part in case of BGO. Thus, BGO could be a reasonable alternative to LSO/LYSO for applications in PGI. Hence, experiments at the ELBE accelerator at HZDR (Germany) were performed using digital silicon photomultiplier (dSiPM) from Philips with monolithic BGO and LYSO crystals, and for completeness with GAGG, CeBr 3 , CsI, CaF 2 , and GSO. The time resolution of BGO compared to the other scintillators will be presented for a wide range of trigger- and validation levels as well as validation lengths of the dSiPM. Timing resolutions below 220 ps are obtained for BGO, while LYSO and CeBr 3 achieve about 170 ps.
Prompt gamma (PG) imaging has previously been demonstrated for use in proton range verification of a brain treatment with a homogeneous target region. In this study, the feasibility of PG imaging to detect anatomic change within a heterogeneous region is presented.A prompt gamma camera recorded several fractions of a patient treatment to the base of skull. An evaluation CT revealed a decrease in sinus cavity filling during the treatment course. Comparison of PG profiles between measurement and simulation was performed to investigate range variations between planned and measured pencil beam spot positions.For one field, an average over range of 3 mm due to the anatomic change could be detected for a subset of spots traversing the sinus cavity region. The two other fields appeared less impacted by the change but predicted range variations could not be detected. These results were partially consistent with the simulations of the evaluation CT.We report the first clinical application of PG imaging that detected some of the expected small regional proton range deviations due to anatomic change in a heterogeneous region. However, several limitations exist with the technology that may limit its sensitivity to detect range deviations in heterogeneous regions.We report on the first detection of range variations due to anatomic change in a heterogeneous region using PGI. The results confirm the feasibility of using PG-based range verification in highly heterogeneous target regions to identify deviations from the treatment plan.
Prompt gamma (PG) based range verification can potentially reduce the safety margins in proton therapy. A knife-edge slit camera has been developed in this context using analytical PG simulations as reference for absolute range verification during patient treatment. Geometrical deviations between measurement and simulation could be observed and have to be corrected for in order to improve the range retrieval of the system. A geometrical correction model is derived from Monte Carlo simulations in water. The influence of different parameters is tested and the model is validated in a dedicated benchmark experiment. We found that the geometrical correction improves the agreement between measured and simulated PG profiles resulting in an improved range retrieval and higher accuracy for absolute range verification. An intrinsic offset of 1.4 mm between measurement and simulation is observed in the experimental data and corrected in the PG simulation. In summary, the absolute range verification capabilities of a PG camera have been improved by applying a geometrical correction model.
In-situ range verification of ion beams during dose delivery is a key for further improving the precision and reducing side effects of radiotherapy with particle beams. The detection and analysis of the emission point, time or energy of prompt gamma rays can provide corresponding means. Prompt gamma-ray imaging (PGI) has already been used for range verification in patient treatments with proton beams. The prompt gamma-ray timing (PGT) technique promises range verification at lower hardware expense with simpler detection systems superseding heavy collimators. After proving the principle, this technique is now being translated to the treatment room. The paper presents latest experimental results obtained with clinically applicable PGT hardware in irradiations of acrylic glass (PMMA) targets in pencil beam scanning (PBS) mode with proton beams at clinical dose rates. The data were acquired with multiple PGT detection units while the distal layer of an artificial 1 Gy dose cube treatment plan was repeatedly delivered to a solid PMMA target without and with a cylindrical air cavity of 5, 10, or 20 mm depth inside. The corresponding local range shifts were clearly detected and visualized by analyzing position or variance of the prompt gamma-ray timing peaks in PGT spectra assigned to the individual PBS spots. In this context, a major challenge concerning all prompt-gamma based techniques is examined and discussed: collecting the event statistics that is needed for range verification of single pencil beam spots at an accuracy level of a few millimeters.
Particle therapy in oncology is advantageous compared to classical radiotherapy due to its well-defined penetration depth. In the so-called Bragg peak, the highest dose is deposited; the tissue behind the cancerous area is not exposed. Different factors influence the range of the particle and thus the target area, e.g. organ motion, mispositioning of the patient or anatomical changes. In order to avoid over-exposure of healthy tissue and under-dosage of cancerous regions, the penetration depth of the particle has to be monitored, preferably already during the ongoing therapy session. The verification of the ion range can be performed using prompt gamma emissions, which are produced by interactions between projectile and tissue, and originate from the same location and time of the nuclear reaction. The prompt gamma emission profile and the clinically relevant penetration depth are correlated. Various imaging concepts based on the detection of prompt gamma rays are currently discussed: collimated systems with counting detectors, Compton cameras with (at least) two detector planes, or the prompt gamma timing method, utilizing the particle time-of-flight within the body. For each concept, the detection system must meet special requirements regarding energy, time, and spatial resolution. Nonetheless, the prerequisites remain the same: the gamma energy region (2 to 10 MeV), high counting rates and the stability in strong background radiation fields. The aim of this work is the comparison of different scintillation crystals regarding energy and time resolution for optimized prompt gamma detection.
Compton camera prototype for a position-sensitive detection of prompt γ rays from proton-induced nuclear reactions is being developed in Garching. The detector system allows to track the Comptonscattered electrons. The camera consists of a monolithic LaBr3:Ce scintillation absorber crystal, read out by a multi-anode PMT, preceded by a stacked array of 6 double-sided silicon strip detectors acting as scatterers. The LaBr3:Ce crystal has been characterized with radioactive sources. Online commissioning measurements were performed with a pulsed deuteron beam at the Garching Tandem accelerator and with a clinical proton beam at the OncoRay facility in Dresden. The determination of the interaction point of the photons in the monolithic crystal was investigated.
We evaluate the quantitative performance of the newly released Asymmetric Track Lossless (Astral) analyzer. Using data independent acquisition, the Thermo Scientific™ Orbitrap™ Astral™ mass spectrometer quantifies 5 times more peptides per unit time than state-of-the-art Thermo Scientific™ Orbitrap™ mass spectrometers, which have long been the gold standard for high resolution quantitative proteomics. Our results demonstrate that the Orbitrap Astral mass spectrometer can produce high quality quantitative measurements across a wide dynamic range. We also use a newly developed extra-cellular vesicle enrichment protocol to reach new depths of coverage in the plasma proteome, quantifying over 5,000 plasma proteins in a 60-minute gradient with the Orbitrap Astral mass spectrometer.
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