Technical note: A small animal irradiation platform for investigating the dependence of the FLASH effect on electron beam parameters.

BACKGROUND: The recent rediscovery of the FLASH effect, a normal tissue sparing phenomenon observed in ultra-high dose rate (UHDR) irradiations, has instigated a surge of research endeavors aiming to close the gap between experimental observation and clinical treatment. However, the dependences of the FLASH effect and its underpinning mechanisms on beam parameters are not well known, and large-scale in vivo studies using murine models of human cancer are needed for these investigations. PURPOSE: To commission a high-throughput, variable dose rate platform providing uniform electron fields (≥15 cm diameter) at conventional (CONV) and UHDRs for in vivo investigations of the FLASH effect and its dependences on pulsed electron beam parameters. METHODS: A murine whole-thoracic lung irradiation (WTLI) platform was constructed using a 1.3 cm thick Cerrobend collimator forming a 15 × 1.6 cm2 slit. Control of dose and dose rate were realized by adjusting the number of monitor units and couch vertical position, respectively. Achievable doses and dose rates were investigated using Gafchromic EBT-XD film at 1 cm depth in solid water and lung-density phantoms. Percent depth dose (PDD) and dose profiles at CONV and various UHDRs were also measured at depths from 0 to 2 cm. A radiation survey was performed to assess radioactivation of the Cerrobend collimator by the UHDR electron beam in comparison to a precision-machined copper alternative. RESULTS: This platform allows for the simultaneous thoracic irradiation of at least three mice. A linear relationship between dose and number of monitor units at a given UHDR was established to guide the selection of dose, and an inverse-square relationship between dose rate and source distance was established to guide the selection of dose rate between 20 and 120 Gy·s-1 . At depths of 0.5 to 1.5 cm, the depth range relevant to murine lung irradiation, measured PDDs varied within ±1.5%. Similar lateral dose profiles were observed at CONV and UHDRs with the dose penumbrae widening from 0.3 mm at 0 cm depth to 5.1 mm at 2.0 cm. The presence of lung-density plastic slabs had minimal effect on dose distributions as compared to measurements made with only solid water slabs. Instantaneous dose rate measurements of the activated copper collimator were up to two orders of magnitude higher than that of the Cerrobend collimator. CONCLUSIONS: A high-throughput, variable dose rate platform has been developed and commissioned for murine WTLI electron FLASH radiotherapy. The wide field of our UHDR-enabled linac allows for the simultaneous WTLI of at least three mice, and for the average dose rate to be modified by changing the source distance, without affecting dose distribution. The platform exhibits uniform, and comparable dose distributions at CONV and UHDRs up to 120 Gy·s-1 , owing to matched and flattened 16 MeV CONV and UHDR electron beams. Considering radioactivation and exposure to staff, Cerrobend collimators are recommended above copper alternatives for electron FLASH research. This platform enables high-throughput animal irradiation, which is preferred for experiments using a large number of animals, which are required to effectively determine UHDR treatment efficacies.

AI-assisted clinical decision making (CDM) for dose prescription in radiosurgery of brain metastases using three-path three-dimensional CNN.

Purpose: AI modeling physicians' clinical decision-making (CDM) can improve the efficiency and accuracy of clinical practice or serve as a surrogate to provide initial consultations to patients seeking secondary opinions. In this study, we developed an AI network to model radiotherapy CDM and used dose prescription as an example to demonstrate its feasibility. Materials/Methods: 152 patients with brain metastases treated by radiosurgery from 2017 to 2021 were included. CT images and tumor and organ-at-risk (OAR) contours were exported. Eight relevant clinical parameters were extracted and digitized, including age, numbers of lesions, performance status (ECOG), presence of symptoms, arrangement with surgery (pre- or post-surgery radiation therapy), re-treatment, primary cancer type, and metastasis to other sites. A 3D convolutional neural network (CNN) architecture was built using three encoding paths with the same kernel and filters to capture the different image and contour features. Specifically, one path was built to capture the tumor feature, including the size and location of the tumor, another path was built to capture the relative spatial relationship between the tumor and OARs, and the third path was built to capture the clinical parameters. The model combines information from three paths to predict dose prescription. The actual prescription in the patient record was used as ground truth for model training. The model performance was assessed by 19-fold-cross-validation, with each fold consisting of randomly selected 128 training, 16 validation, and 8 testing subjects. Result: The dose prescriptions of 152 patient cases included 48 cases with 1 × 24 Gy, 48 cases with 1 × 20-22 Gy, 32 cases with 3 × 9 Gy, and 24 cases with 5 × 6 Gy prescribed by 8 physicians. The AI model prescribed correctly for 124 (82 %) cases, including 44 (92 %) cases with 1 × 24 Gy, 36 (75 %) cases with 1 × 20-22 Gy, 25 (78 %) cases with 3 × 9 Gy, and 19 (79 %) cases with 5 × 6 Gy. Analysis of the failed cases showed the potential cause of practice variations across individual physicians, which were not accounted for in the model trained by the group data. Including clinical parameters improved the overall prediction accuracy by 20 %. Conclusion: To our best knowledge, this is the first study to demonstrate the feasibility of AI in predicting dose prescription in CDM in radiation therapy. Such CDM models can serve as vital tools to address healthcare disparities by providing preliminary consultations to patients in underdeveloped areas or as a valuable quality assurance (QA) tool for physicians to cross-check intra- and inter-institution practices.

Isofraxidin inhibits the proliferation and differentiation of the osteoblast MC3T3-E1 subclone 14 cell line.

Ankylosing spondylitis (AS) is an autoimmune inflammatory disease associated with joint inflammation and destruction. Current treatment modalities alleviate symptoms; however, they cannot cure the disease and are associated with significant side effects. Thus, we aimed to confirm the inhibitory effect of isofraxidin, a herbal extract, on pathological osteogenesis in ankylosing spondylitis to better treat patients affected by the disease. Mouse preosteoblast MC3T3-E1 subclone 14 cells were used in vitro to establish control and isofraxidin intervention groups. Cell viability was then determined using the MTT assay; the expression of osteogenic factors, including Runx2, OSX, collagen I, and ALP was measured using qRT-PCR and western blotting. Final osteogenic mineralization was performed by alizarin red staining. The results showed that isofraxidin could inhibit osteoblast viability; however, this effect was nullified at concentrations of 0-20 µM after adding 1% serum. Gene and protein expression of the osteogenic factors RUNX2, OSX, Collagen I, and ALP was inhibited, and a similar trend was exhibited at 7, 14, and 21 days after isofraxidin treatment. This trend was further verified by alizarin red staining of the final osteogenic mineralized nodules on days 7, 14, 21, and 35. Isofraxidin inhibits MC3T3-E1 subclone 14 proliferation and differentiation and may be considered a potential drug therapy for treating pathological osteogenesis in ankylosing spondylitis.

Triptolide attenuates inhibition of ankylosing spondylitis-derived mesenchymal stem cells on the osteoclastogenesis through modulating exosomal transfer of circ-0110634.

Background: Ankylosing spondylitis (AS) is featured by chronic inflammation of the sacroiliac joints and spine as well as pathological new bone formation. Osteoclastogenesis is a critical part in the development of bone formation. Circular RNAs (circRNAs) are recent research hotspot in the RNA field while rarely reported in osteoclastogenesis. Methods: AS mesenchymal stem cells (ASMSCs) and healthy donor mesenchymal stem cells (HDMSCs) were co-cultured with peripheral blood mononuclear cells (PBMCs). RT-qPCR was applied to detect the expression level of circ-0110634 in different exosomes. TRAP staining and TRAP activity detection were performed to identify the effect of circ-0110634 overexpression on osteoclastogenesis. Bioinformatics analysis and mechanism investigation were conducted to explore the downstream molecular mechanism of circ-0110634. Results: The effect of ASMSCs on PBMCs osteoclastogenesis is weaker than that of HDMSCs. Circ-0110634 had higher expression in ASMSCs exosomes than HDMSCs exosomes. Circ-0110634 overexpression suppressed the osteoclastogenesis. Circ-0110634 bound to both TNF receptor associated factor 2 (TRAF2) and tumor necrosis factor receptor II (TNFRII). Circ-0110634 also accelerated the dimerization of TRAF2 to induce TRAF2 ubiquitination and degradation. Circ-0110634 repressed the interplay between TRAF2 and TNFRII to inactivate the nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK) pathways. Triptolide promoted the osteoclastogenesis of ASMSCs exosomes-treated PBMCs via decreasing the exosomal transference of circ-0110634 in a dose-dependent manner. Consistently, triptolide treatment stimulated osteoclastogenesis to alleviate the arthritis of DBA/1 mice through suppressing circ-0110634. Conclusion: Our study confirmed that triptolide targets circ-0110634 to ease the burden of AS patients. The Translational potential of this article: This study suggests triptolide targets circ-0110634 to regulate osteoclastogenesis, which provides a novel potential target in triptolide treatment for AS patients.

Technical note: Characterization and practical applications of a novel plastic scintillator for online dosimetry for an ultrahigh dose rate (FLASH).

PURPOSE: Although flash radiation therapy (FLASH-RT) is a promising novel technique that has the potential to achieve a better therapeutic ratio between tumor control and normal tissue complications, the ultrahigh pulsed dose rates (UHPDR) mean that experimental dosimetry is very challenging. There is a need for real-time dosimeters in the development and implementation of FLASH-RT. In this work, we characterize a novel plastic scintillator capable of temporal resolution short enough (2.5 ms) to resolve individual pulses. METHODS: We characterized a novel plastic dosimeter for use in a linac converter to deliver 16-MeV electrons at 100-Gy/s UHPDR average dose rates. The linearity and reproducibility were established by comparing relative measurements with a pinpoint ionization chamber placed at 10-cm water-equivalent depth where the electrometer is not saturated by the high dose per pulse. The accuracy was established by comparing the plastic scintillator dose measurements with EBT-XD Gafchromic radiochromic films, the current reference dosimeter for UHPDR. Finally, the plastic scintillator was compared against EBT-XD films for online dosimetry of two in vitro experiments performed at UHPDR. RESULTS: Relative ion chamber measurements were linear with plastic scintillator response within ≤1% over 4-20 Gy and pulse frequencies (18-180 Hz). When characterized under reference conditions with NIST-traceability, the plastic scintillator maintained its dose response under UHPDR conditions and agreed with EBT-XD film dose measurements within 4% under reference conditions and 6% for experimental online dosimetry. CONCLUSION: The plastic scintillator shows a linear and reproducible response and is able to accurately measure the radiation absorbed dose delivered by 16-MeV electrons at UHPDR. The dose is measured accurately in real time with a greater level of precision than that achieved with a radiochromic film.

Radiation shielding and safety implications following linac conversion to an electron FLASH-RT unit.

PURPOSE: Due to their finite range, electrons are typically ignored when calculating shielding requirements in megavoltage energy linear accelerator vaults. However, the assumption that 16 MeV electrons need not be considered does not hold when operated at FLASH-RT dose rates (~200× clinical dose rate), where dose rate from bremsstrahlung photons is an order of magnitude higher than that from an 18 MV beam for which shielding was designed. We investigate the shielding and radiation protection impact of converting a Varian 21EX linac to FLASH-RT dose rates. METHODS: We performed a radiation survey in all occupied areas using a Fluke Biomedical Inovision 451P survey meter and a Wide Energy Neutron Detection Instrument (Wendi)-2 FHT 762 neutron detector. The dose rate from activated linac components following a 1.8-min FLASH-RT delivery was also measured. RESULTS: When operated at a gantry angle of 180° such as during biology experiments, the 16 MeV FLASH-RT electrons deliver ~10 µSv/h in the controlled areas and 780 µSv/h in the uncontrolled areas, which is above the 20 µSv in any 1-h USNRC limit. However, to exceed 20 µSv, the unit must be operated continuously for 92 s, which corresponds in this bunker and FLASH-RT beam to a 3180 Gy workload at isocenter, which would be unfeasible to deliver within that timeframe due to experimental logistics. While beam steering and dosimetry activities can require workloads of that magnitude, during these activities, the gantry is positioned at 0° and the dose rate in the uncontrolled area becomes undetectable. Likewise, neutron activation of linac components can reach 25 µSv/h near the isocenter following FLASH-RT delivery, but dissipates within minutes, and total doses within an hour are below 20 µSv. CONCLUSION: Bremsstrahlung photons created by a 16 MeV FLASH-RT electron beam resulted in consequential dose rates in controlled and uncontrolled areas, and from activated linac components in the vault. While our linac vault shielding proved sufficient, other investigators would be prudent to confirm the adequacy of their radiation safety program, particularly if operating in vaults designed for 6 MV.

Simple Analysis of the Computed Tomography Features of Gastric Schwannoma.

OBJECTIVE: The objective of this study was to assess the computed tomography (CT) findings of gastric schwannoma (GS) and identify the difference between large (> 5 cm) and small (≤ 5 cm) GS. MATERIALS AND METHODS: CT findings of 38 pathologically proven cases of GSs were retrospectively reviewed. The CT evaluation of GS included categorical variables (location, contour, growth pattern, enhancement pattern, necrosis, ulceration, calcification, and lymph nodes) and continuous variables (size, CT value of 3 phases, and enhancement degree). The lesion was divided into 2 groups (large [> 5 cm] and small [≤ 5 cm] GS) according to the tumor size. The Fisher exact test was used for categorical variables and the Student t or Mann-Whitney U test for continuous variables. RESULTS: Of the 38 patients, there were 32 women and 6 men. The median age was 54.5 years (range 39-79). Most of patients (65.8%, [25 of 38]) had nonspecific gastrointestinal symptoms such as abdominal or gastric pain, fullness and discomfort, bleeding, and melena. The tumors were mainly located in the stomach body (71.1% [27 of 38]), and the mean diameter was 3.7 cm (range 1.5 cm-10.3 cm), of which included large (> 5 cm) (n = 8) and small (≤ 5 cm) (n = 30). All of the GSs were benign, 9 of whom had palpable perigastric lymph nodes, which confirmed by pathology for the reactive inflammatory hyperplasia. Growth pattern, pattern of enhancement, necrosis, calcification, surface ulceration, and lymph node in the CT images were found to be significant variables for differentiating large (> 5 cm) and small (≤ 5 cm) GS (P < .05). CONCLUSION: GSs were predominantly located at the gastric body and occurred most frequently in women between the ages of 40-70 years, and showed gradual enhancement after contrast enhancement. Palpable perigastric lymph nodes could not be considered as malignant factor of GS. There 7 computed CT criteria are significant difference between large (> 5 cm) and small (≤ 5 cm) GS.

Diffractive Imaging of C_{60} Structural Deformations Induced by Intense Femtosecond Midinfrared Laser Fields.

Theoretical studies indicated that C_{60} exposed to linearly polarized intense infrared pulses undergoes periodic cage structural distortions with typical periods around 100 fs (1 fs=10^{-15} s). Here, we use the laser-driven self-imaging electron diffraction technique, previously developed for atoms and small molecules, to measure laser-induced deformation of C_{60} in an intense 3.6 µm laser field. A prolate molecular elongation along the laser polarization axis is determined to be (6.1±1.4)% via both angular- and energy-resolved measurements of electrons that are released, driven back, and diffracted from the molecule within the same laser field. The observed deformation is confirmed by density functional theory simulations of nuclear dynamics on time-dependent adiabatic states and indicates a nonadiabatic excitation of the h_{g}(1) prolate-oblate mode. The results demonstrate the applicability of laser-driven electron diffraction methods for studying macromolecular structural dynamics in four dimensions with atomic time and spatial resolutions.

The roles of photo-carrier doping and driving wavelength in high harmonic generation from a semiconductor.

High-harmonic generation from gases produces attosecond bursts and enables high-harmonic spectroscopy to explore electron dynamics in atoms and molecules. Recently, high-harmonic generation from solids has been reported, resulting in novel phenomena and unique control of the emission, absent in gas-phase media. Here we investigate high harmonics from semiconductors with controllable induced photo-carrier densities, as well as the driving wavelengths. We demonstrate that the dominant generation mechanism can be identified by monitoring the variation of the harmonic spectra with the carrier density. Moreover, the harmonic spectral dependence on the driving wavelength is reported and a different dependence from the well-known one in gas-phase media is observed. Our study provides distinct control of the harmonic process from semiconductors, sheds light on the underlying mechanism and helps optimize the harmonic properties for future solid-state attosecond light sources.

[Diagnostic value of CT pulmonary artery imaging for idiopathic pulmonary artery hypertension].

OBJECTIVE: To evaluate the diagnostic value of CT pulmonary artery (CTPA) imaging with idiopathic pulmonary artery hypertension (IPAH). METHODS: A total of 20 patients with right heart catheterization (RHC) proven IPAH were retrospectively analyzed between January 2012 and November 2015.The imaging was analyzed including pulmonary parenchyma, pulmonary interstitial, mediastinal lymph nodes, pericardium and pleural cavity on the CTPA examination.Cardiovascular parameters were measured in CTPA including right ventricle biggest short axis diameter (RVD), left ventricle biggest short axis diameter (LVD), main pulmonary artery diameter (MPAD), right pulmonary artery diameter (RPAD), left pulmonary artery diameter (LPAD), right low pulmonary artery diameter (RLPAD), ascending aorta diameter (AAD) and descending aorta diameter (DAD), and parameters were calculated including the ratio of the main pulmonary and ascending aorta diameter (rPA), the ratio of the ascending and descending aorta diameter (rAD), the ratio of the right ventricular and left ventricular short axis diameter (RV/LV). The relationship between sex, pulmonary, lymph nodes, pericardium, pleural and pulmonary arrery pressure (PAP) was analyzed by Spearman rank correlation analysis.All the parameters between mild-moderate (4 cases) and severe (16 cases) PAH were analyzed by independent sample t test.PAP of different age (<50 years and≥50 years) groups was analyzed by Pearson correlation analysis. RESULTS: Of 20 cases, 7 cases showed patch exudative change, 5 cases showed"mosaic pattern"inhomogeneous perfusion, 3 cases displayed ill-defined centrilobular nodules, 6 cases manifested mediastinal lymphadenopathy, 10 cases had pericardial effusion including 4 cases of pleural effusion, 4 cases of dilated bronchial artery, 1 cases of secondary right pulmonary artery embolism.When comparing the presence or absence of pleural effusion, these was statistical difference of PAP (r=0.445, P=0.049). LVD, LPAD, RPAD, AAD, DAD and rPA were statistically different between mild-moderate and severe PAH (t values were 3.194, -3.393, -7.771, 10.299, 11.394 and -12.715, respectively, P<0.05). PAP was statistically different between different age groups (r=-0.481, P=0.032). CONCLUSION: CTPA is a very important examination for the diagnosis of IPAH.The changes of lung, mediastinum, percardium, pleural cavity and the cardiovascular parameters can help diognose and evaluate IPAH.

Diffraction using laser-driven broadband electron wave packets.

Directly monitoring atomic motion during a molecular transformation with atomic-scale spatio-temporal resolution is a frontier of ultrafast optical science and physical chemistry. Here we provide the foundation for a new imaging method, fixed-angle broadband laser-induced electron scattering, based on structural retrieval by direct one-dimensional Fourier transform of a photoelectron energy distribution observed along the polarization direction of an intense ultrafast light pulse. The approach exploits the scattering of a broadband wave packet created by strong-field tunnel ionization to self-interrogate the molecular structure with picometre spatial resolution and bond specificity. With its inherent femtosecond resolution, combining our technique with molecular alignment can, in principle, provide the basis for time-resolved tomography for multi-dimensional transient structural determination.

Size-dependent high-order harmonic generation in rare-gas clusters.

High-order harmonic generation (HHG) is investigated in rare-gas clusters as a function of the cluster size using 0.8 and 1.3 µm femtosecond lasers. A characteristic, species-dependent knee structure in the single particle response is observed. A 1D recollision model qualitatively reproduces this behavior and associates it to the degree of delocalization of the initial wave function. Small clusters are observed to have a higher efficiency than monomers but rapidly lose this advantage as the size increases. The implications of these findings on the HHG mechanism in clusters are discussed.

Imaging ultrafast dynamics of molecules with laser-induced electron diffraction.

We introduce a laser-induced electron diffraction method (LIED) for imaging ultrafast dynamics of small molecules with femtosecond mid-infrared lasers. When molecules are placed in an intense laser field, both low- and high-energy photoelectrons are generated. According to quantitative rescattering (QRS) theory, high-energy electrons are produced by a rescattering process where electrons born at the early phase of the laser pulse are driven back to rescatter with the parent ion. From the high-energy electron momentum spectra, field-free elastic electron-ion scattering differential cross sections (DCS), or diffraction images, can be extracted. With mid-infrared lasers as the driving pulses, it is further shown that the DCS can be used to extract atomic positions in a molecule with sub-angstrom spatial resolution, in close analogy to the standard electron diffraction method. Since infrared lasers with pulse duration of a few to several tens of femtoseconds are already available, LIED can be used for imaging dynamics of molecules with sub-angstrom spatial and a few-femtosecond temporal resolution. The first experiment with LIED has shown that the bond length of oxygen molecules shortens by 0.1 Å in five femtoseconds after single ionization. The principle behind LIED and its future outlook as a tool for dynamic imaging of molecules are presented.

Imaging ultrafast molecular dynamics with laser-induced electron diffraction.

Establishing the structure of molecules and solids has always had an essential role in physics, chemistry and biology. The methods of choice are X-ray and electron diffraction, which are routinely used to determine atomic positions with sub-ångström spatial resolution. Although both methods are currently limited to probing dynamics on timescales longer than a picosecond, the recent development of femtosecond sources of X-ray pulses and electron beams suggests that they might soon be capable of taking ultrafast snapshots of biological molecules and condensed-phase systems undergoing structural changes. The past decade has also witnessed the emergence of an alternative imaging approach based on laser-ionized bursts of coherent electron wave packets that self-interrogate the parent molecular structure. Here we show that this phenomenon can indeed be exploited for laser-induced electron diffraction (LIED), to image molecular structures with sub-ångström precision and exposure times of a few femtoseconds. We apply the method to oxygen and nitrogen molecules, which on strong-field ionization at three mid-infrared wavelengths (1.7, 2.0 and 2.3 µm) emit photoelectrons with a momentum distribution from which we extract diffraction patterns. The long wavelength is essential for achieving atomic-scale spatial resolution, and the wavelength variation is equivalent to taking snapshots at different times. We show that the method has the sensitivity to measure a 0.1 Å displacement in the oxygen bond length occurring in a time interval of ∼5 fs, which establishes LIED as a promising approach for the imaging of gas-phase molecules with unprecedented spatio-temporal resolution.

Laser-induced electron diffraction for probing rare gas atoms.

Recently, using midinfrared laser-induced electron diffraction (LIED), snapshots of a vibrating diatomic molecule on a femtosecond time scale have been captured [C.I. Blaga et al., Nature (London) 483, 194 (2012)]. In this Letter, a comprehensive treatment for the atomic LIED response is reported, a critical step in generalizing this imaging method. Electron-ion differential cross sections (DCSs) of rare gas atoms are extracted from measured angular-resolved, high-energy electron momentum distributions generated by intense midinfrared lasers. Following strong-field ionization, the high-energy electrons result from elastic rescattering of a field-driven wave packet with the parent ion. For recollision energies ≥100 eV, the measured DCSs are indistinguishable for the neutral atoms and ions, illustrating the close collision nature of this interaction. The extracted DCSs are found to be independent of laser parameters, in agreement with theory. This study establishes the key ingredients for applying LIED to femtosecond molecular imaging.