Search Results (143)

Background/Objectives: Liver fat represents an early metabolic lesion in the development of diabetes and its cardiometabolic complications. Diets high in free sugars, particularly from sugar-sweetened beverages (SSBs), are associated with abdominal obesity and increased cardiometabolic risk, prompting global guidelines to limit SSBs as a major public health strategy. Low-fat cow’s milk is promoted as the preferred caloric replacement strategy for SSBs due to its high nutritional value and cardiometabolic advantages. Fortified soymilk is a plant-based alternative with approved health claims for cholesterol and coronary heart disease risk reduction that offers an equivalent nutritional value to cow’s milk. However, given concerns about its classification as an ultra-processed food (UPF), it is unclear whether soymilk offers comparable metabolic health benefits to milk as part of clinical and public health strategies to reduce SSB intake. The Soy Treatment Evaluation for Metabolic (STEM) health trial seeks to evaluate the impact of replacing SSBs with either 2% soymilk or 2% cow’s milk on liver fat and other cardiometabolic risk factors in habitual adult consumers of SSBs with obesity. Methods: The STEM trial is a 24-week, pragmatic, 3-arm, parallel, randomized trial. We recruited adults with obesity (high BMI plus high waist circumference based on ethnic specific cut-offs) consuming ≥1 SSB/day. Participants were randomized to one of three groups based on their usual SSB intake at baseline (servings/day): continued SSB (355 mL can) intake; replacement with fortified, sweetened 2% soymilk (250 mL); or replacement with 2% cow’s milk (250 mL). The primary outcome is the change in intrahepatocellular lipid (IHCL) measured by ¹H-MRS at 24 weeks. Hierarchical testing will be done to reduce the familywise error rate. The superiority of cow’s milk to SSBs will be assessed first to establish assay sensitivity. If superiority is established, then the non-inferiority of soymilk to cow’s milk will be assessed using a pre-specified non-inferiority margin of 1.5% IHCL units (assessed by difference of means using a 90% confidence interval [CI]). Analyses will be conducted according to the intention-to-treat (ITT) principle using inverse probability weighting (IPW) for superiority testing and per-protocol analyses for non-inferiority testing, using ANCOVA adjusted for age, sex, metabolic dysfunction-associated steatotic liver disease (MASLD) status, medication use, intervention dose, and baseline levels. We hypothesize that soymilk will be non-inferior to cow’s milk (Clinicaltrials.gov NCT05191160). Results: Recruitment began in November 2021. A total of 3050 individuals were screened. We randomized 186 participants (62 per group) between 19 April 2022 and 16 April 2024. Participants are 57% male; with a mean [SD] age of 39.9 [11.8] years; BMI of 34.6 [6.1] kg/m², waist circumference of 112.6 [13.8] cm; IHCL of 10.0 [8.2] % with 64.1% meeting the criteria for MASLD; and SSBs intake of 2.3 [1.3] servings/day. Conclusions: Baseline characteristics were balanced across the study arms, with participants representing adults with a high-risk metabolic phenotype, and 64.1% meeting the criteria for MASLD. Findings will contribute to evidence on the cardiometabolic benefits of soymilk, informing clinical practice guidelines and public health policy. Full article

Background/Objectives: FLASH radiotherapy (RT) has shown potential to reduce normal tissue toxicity compared with conventional (CONV) RT while maintaining tumor control. FLASH RT is characterized by ultra-high dose rate delivery, commonly using mean dose rates ≥ 40 Gy/s and sub-second delivery times. Most preclinical studies have used single-fraction regimens, leaving the feasibility and normal tissue impact of clinically relevant fractionation largely unexplored. We evaluated electron FLASH RT given in a standard five-fraction regimen to a porcine skin model, simulating adjuvant treatment workflow for high-risk cutaneous melanoma. Method: Three Yorkshire–Landrace swine received paired five-fraction electron irradiations to dorsolateral skin using either FLASH RT (mean dose rates 175–246 Gy/s) or CONV RT (8 Gy/min). Radiation was delivered with a 9-MeV electron beam; field diameters of 4, 7, or 10 cm; and doses of 5 × 6, 5 × 7, or 5 × 8 Gy. Dosimetry was validated with several dosimeters and real-time beam monitoring, confirming dose accuracy within 3%. Skin toxicity was assessed over 22–24 weeks using clinical grading, erythema spectrophotometry, and histopathologic evaluation. Results: FLASH RT was well tolerated at 5 × 6 Gy and 5 × 7 Gy, with no significant differences in peak radiation dermatitis, erythema index, or histologic damage compared with CONV RT. At 5 × 8 Gy, both modalities caused unacceptable toxicity, including moist desquamation and necrosis. No volume-dependent effects were observed. Conclusions: Although a FLASH-specific normal tissue sparing effect was not observed, this study demonstrates the technical feasibility and safety of delivering fractionated electron FLASH RT in a large animal model using a clinically relevant workflow. These findings support further investigation of physical beam parameters and biological modifiers, such as tissue oxygenation, and inform the clinical translation of fractionated FLASH RT for cutaneous malignancies. Full article

Percentage depth–dose (PDD) distributions are fundamental to characterizing radiation beams in radiotherapy. This review provides an overview of both methods and sensor technologies for measuring PDD in photon, electron, proton, and carbon-ion beams. We summarize conventional dosimetry techniques, including water-phantom scanning with ionization chambers (cylindrical and parallel-plate) and radiochromic film, and discuss their strengths (established accuracy, calibration traceability) and limitations (volume averaging, delayed readout). We then examine emerging sensor technologies designed to improve spatial resolution, speed, and radiation hardness: multi-layer ionization chambers and Faraday cups for one-shot PDD acquisition; scintillator-based detectors (liquid, plastic, and fiber-optic) enabling real-time and high-resolution depth–dose measurements; advanced semiconductor detectors including silicon carbide diodes; as well as novel approaches such as ionoacoustic range sensing for proton beams. For each modality and detector type, we emphasize clinical relevance, measurement accuracy, spatial resolution, radiation durability, and suitability for high dose-per-pulse environments (e.g., FLASH radiotherapy). Current challenges, such as detector response in regions of steep dose gradient, saturation or recombination at ultra-high dose rates, and energy-dependent sensitivity in mixed radiation fields, are analyzed in detail. We also highlight the limitations of each technique and discuss ongoing improvements and prospects for clinical implementation. In summary, no single detector technology fully satisfies all requirements for fast, high-accuracy, high-resolution, radiation-hard PDD measurement, but the integration of emerging sensor innovations into clinical dosimetry promises to enhance the precision and efficiency of radiotherapy quality assurance. Full article

This study investigated the ethanolic leaf extract of Brazilian pepper tree (Schinus terebinthifolius Raddi) for its metabolite composition and effects on growth performance and intestinal immune gene expression in Nile tilapia (Oreochromis niloticus). Ultra-performance liquid chromatography-electrospray ionization-mass spectrometry (UPLC-ESI-MS/MS) in positive and negative modes revealed a diverse profile of 33 peaks in each polarity, identifying key compounds such as phenolic acids (e.g., gallic acid and ferulic acid), flavonoids (e.g., myricetin-O-glucoside and quercetin 3-O-glucoside), gallotannins (e.g., glucogallin and pentagalloylglucose), and triterpenoids (e.g., masticadienoic acid). A 60-day feeding trial with four groups (control and three extract doses; 0.5%; T0.5%, 1%; T1% and 2%; T2%) demonstrated dose-dependent enhancements in growth metrics, where final body weight increased by up to 106.9 ± 3.6 g, weight gain% by 197.3 ± 3.5%, and the growth rate got more than doubled in T2% (2.4 ± 0.1), alongside improved feed conversion ratio (1.24 ± 0.01) at 30 days and condition factor (stabilized at 2.1 ± 0.0) at 60 days post-feeding. Viscero- and gastro-somatic indices declined insignificantly in most feed groups, indicating improved muscle growth. Biphasic patterns were observed in intestinal gene expression as follows: over 60 days, the IL-1β gene upregulated at low doses but returned to normal at high doses. The IL-10 gene upregulated progressively, promoting an anti-inflammatory balance. In fish fed medium and high doses (T1% and T2%), the IgM gene is upregulated, supporting humoral immunity. These outcomes, linked to the extract’s previously described antioxidants, anti-inflammatory, and antimicrobial bioactive compounds, suggest that S. terebinthifolius is a promising natural feed additive for sustainable tilapia aquaculture and warrants further validation for commercial application. Full article

Background/Objectives: Proton therapy has emerged as an advanced radiotherapy modality due to its unique physical dose distribution and its distinct radiobiological properties. The finite range of protons in tissue enables highly conformal dose delivery with minimal exit dose, significantly reducing irradiation of surrounding normal tissues compared to photon-based radiotherapy. Beyond these physical advantages, proton beams exhibit a spatially varying linear energy transfer that increases toward the distal edge of the spread-out Bragg peak, leading to clustered and complex DNA damage that is more difficult for cancer cells to repair. Methods: This review integrates experimental, computational, and clinical evidence to examine how proton-induced DNA damage, relative biological effectiveness, oxygen effects, and non-targeted responses contribute to tumor control and normal tissue sparing. Results: Comparative analyses with photon intensity-modulated radiotherapy demonstrate consistent reductions in acute and late toxicities across multiple tumor sites, particularly in pediatric patients and in tumors located near critical organs. The review also discusses emerging technologies, including pencil beam scanning, image-guided and adaptive proton therapy, compact accelerator systems, and ultra-high dose rate FLASH proton therapy, which collectively aim to enhance treatment precision, biological effectiveness, and accessibility. Conclusions: Together, these developments support proton therapy as a rapidly evolving modality with significant potential to improve therapeutic outcomes in modern oncology. Full article

Ultra-high dose-rate (FLASH) irradiation can transiently deplete oxygen and modulate radical-mediated chemistry in irradiated cells. Cellular antioxidants also contribute to mitigating oxidative damage in a manner dependent on linear energy transfer (LET), as suggested by recent experimental studies. In this work, we employed our multi-track Monte Carlo simulation framework (IONLYS-IRT) to investigate how LET influences transient radiation-induced oxygen depletion (ROD) in a cell-like aqueous environment under FLASH irradiation conditions. FLASH exposures were modeled as single, instantaneous pulses of protons with energies from 300 MeV to 150 keV, corresponding to LET values of ~0.3 to 71 keV/μm. Our simulations revealed a marked decline in oxygen depletion with increasing LET, in agreement with experimental observations. For an intracellular O₂ concentration of 30 μM, the oxygen consumption yield, G(–O₂), decreased from ~4.0 molecules/100 eV at low LET (~0.3 keV/μm) to ~1.6 molecules/100 eV at high LET (~71 keV/μm), representing a ~60% reduction. To assess whether ROD depends solely on LET or is also governed by ion track structure, we systematically compared multiple ion species (protons, ⁴He²⁺, ¹⁰B⁵⁺, ¹²C⁶⁺, ¹⁶O⁸⁺, ²⁰Ne¹⁰⁺, ²⁸Si¹⁴⁺, ³²S¹⁶⁺, and ⁴⁰Ar¹⁸⁺) at comparable LET values. At ~70 keV/μm, heavier ions produced significantly higher G(−O₂) values than protons—though still below those at low LET—suggesting that track structure plays a key role beyond LET alone. These findings highlight the dual importance of LET and ion-specific track structure in modulating ROD under FLASH conditions. Notably, enhanced ROD in surrounding normal tissues (low-LET plateau regions) may contribute to radioprotective effects, whereas reduced ROD in tumor tissues (high-LET Bragg peak regions) would be expected to preserve tumoricidal efficacy. Together, these results provide a mechanistic framework for optimizing proton and heavy-ion approaches in FLASH radiotherapy. Full article

Proton FLASH radiotherapy represents a promising innovation in the treatment of abdominal cancers, offering the potential to expand the therapeutic window by delivering ultra-high dose rates (UHDR) that spare normal tissue while maintaining tumor control. This approach is particularly beneficial for gastrointestinal (GI) tumors, where radiation dose escalation is often limited by the radiosensitivity of nearby organs. This review explores recent preclinical, planning, and technical developments in proton FLASH for abdominal sites and outlines the challenges and future directions for clinical translation. We reviewed the available published literature on proton FLASH radiotherapy, with a focus on abdominal applications. Recent preclinical studies in abdominal models have shown encouraging, though inconsistent, evidence of reduced toxicity with proton FLASH. Parallel advances in treatment planning have also demonstrated technical feasibility in achieving UHDR across complex abdominal geometries. However, key challenges remain, including variability in biological responses, lack of standardized dose-rate definitions, delivery system constraints, and the absence of robust clinical data. Although only limited clinical trials are currently underway, proton FLASH may enable safer hypofractionation, reirradiation, and dose escalation strategies in the future. Its successful clinical translation will require coordinated advances in biology, physics, and technology, supported by rigorous preclinical validation and carefully designed clinical trials. Full article

Background/Objectives: The PEER beamline at the ANSTO Australian Synchrotron has been developed to enable VHEE FLASH radiotherapy studies, both dosimetric and biological. Featuring a 100 MeV electron linac, it delivers single or multi-pulse irradiations consisting of 100 ps bunches with a 2 ns spacing, resulting in average dose-rates and instantaneous dose-rates as high as ${10}^8$ Gy/s and ${10}^9$ Gy/s, respectively. Much work has been conducted to realise a stable accelerator facility, complete with the tooling and diagnostics required to undertake such studies. However, to truly confirm its suitability required a successful biological benchmarking. Methods: Three cell lines were irradiated utilising real-time dosimetry to compare linear quadratic cell survival curves with other facilities. Also, mouse cadavers were transported and irradiated, mimicking live animals, to assess the feasibility and logistics of small animal experiments. Results: By comparing the trends of the linear quadratic model, evident in the $\alpha$ and $\beta$ parameters, the PEER cell survival results were shown to be in agreement with VHEE results from the ARES beamline at DESY, Hamburg, Germany. Evident in the survival trends, VHEE produced more cell sparing in all cell lines compared to 2 Gy/s X-rays delivered on the IMBL, another beamline at the Australian Synchrotron. The results of the mouse cadaver irradiations showed that PEER can safely and efficiently irradiate small animals. Conclusions: The PEER beamline is shown to possess suitable capabilities, including real-time dosimetry, repeatable alignment, and linac diagnostics, rendering it suitable for future in vivo VHEE UHDR FLASH radiotherapy investigations. Full article

FLASH radiotherapy requires real-time, non-invasive beam monitoring systems capable of operating under ultra-high dose rate (UHDR) conditions without perturbing the therapeutic beam. In this work, we characterized the extraction system of Supersonic Gas Curtain-based Ionization Profile Monitor (SGC-IPM) for its capabilities as a transverse beam profile and position monitor for FLASH protons. The monitor utilizes a tilted gas curtain intersected by the incident beam, leading to the generation of ions that are extracted through a tailored electrostatic field, and detected using a two stage microchannel plate (MCP) coupled to a phosphor screen and CMOS camera. CST Studio Suite was employed to conduct electrostatic and particle tracking simulations evaluating the ability of the extraction system to measure both beam profile and position. The ion interface, at the interaction region of proton beam and gas curtain, was modeled with realistic proton beam parameters and uniform gas curtain density distributions. The ion trajectory was tracked to evaluate the performance across multiple beam sizes. The simulations suggest that the extraction system can reconstruct transverse beam profiles for different proton beam sizes. Simulations also supported the system’s capability as a beam position monitor within the boundary defined by the beam size, the dimensions of the extraction system, and the height of the gas curtain. Some simulation results were benchmarked against experimental data of 28 MeV proton beam with 70 nA average beam current. This study will further help to optimize the design of the extraction system to facilitate the integration of SGC-IPM in medical accelerators. Full article

The implementation of FLASH Radiotherapy (FLASH-RT), characterized by ultra-high dose rates (UHDRs) frequently exceeding ${10}^6$ Gy/s in microsecond pulses, imposes stringent requirements on real-time dosimetry. Conventional ionization chambers suffer severe ion recombination and space-charge limitations under these conditions. This review summarizes the state of SSD technologies—including conventional standard silicon diodes, advanced SiC diodes, Low-Gain Avalanche Detectors (LGADs), and pixel detectors—and compares their performance, linearity, and dynamic range in UHDR environments. Particular attention is devoted to operational modes (integrating vs. counting), saturation mechanisms, and readout electronics, which frequently dominate detector behavior at FLASH conditions. We discuss the experimental results from recent UHDR beamlines and highlight emerging concepts that will shape future clinical translation. Full article

The global cancer burden continues to increase worldwide. Among the various treatment options, radiotherapy (RT), which employs high-energy ionizing radiation to destroy cancer cells, is one of the primary modalities for cancer. However, increasing the absorbed dose to the target volume also increases the risk of damage to surrounding healthy tissues. This radiation-induced toxicity to normal tissues limits the desirable dosage that can be delivered to the tumor, thereby constraining the effectiveness of radiation therapy in achieving tumor control. FLASH radiotherapy (FLASH-RT) has emerged as a promising technique due to its biological advantages. FLASH-RT involves the delivery of radiation at an ultra-high dose rate (≥40 Gy/s). Unlike conventional RT, FLASH-RT achieves comparable tumor control rates while significantly reducing damage to surrounding normal tissues, a phenomenon known as the FLASH effect. Although the mechanism behind the FLASH effect is not fully understood, this approach shows considerable promise for future cancer treatment. The development of specialized treatment planning systems (TPS) becomes imperative to facilitate the clinical implementation of FLASH-RT from experimental studies. These systems must account for the unique characteristics of FLASH-RT, including ultra-high dose rate delivery and its distinctive radiobiological effects. Critical reassessment and optimization of treatment planning protocols are essential to fully leverage the therapeutic potential of the FLASH effect. This review examines key considerations for the TPS development of electron and proton FLASH-RT, including electron and proton FLASH techniques, biological models, crucial beam parameters, and dosimetry, providing essential insights for optimizing TPS and advancing the clinical implementation of this promising therapeutic modality. Full article

Background/Objectives: Dietary inorganic nitrate (NO₃⁻), primarily sourced from vegetables such as beetroot, has been shown to enhance nitric oxide (NO) bioavailability, with emerging evidence suggesting its potential to modulate autonomic function. However, the effects of NO₃⁻ supplementation on cardiac autonomic recovery post-exercise in hypertensive postmenopausal women remain poorly understood. Using data from a previously conducted randomised controlled trial, this study investigated the effects of acute (800 mg) and seven-day (400 mg/day) beetroot juice NO₃⁻ supplementation on ultra-short-term post-exercise cardiac parasympathetic recovery in hypertensive older women. Methods: In a triple-blind, placebo-controlled crossover design, fourteen postmenopausal women (59 ± 4 y) with hypertension completed two intervention arms (NO₃⁻ and placebo). Ultra-short-term heart rate variability (HRV) indices (SDNN, RMSSD, HF) were assessed across 5 min post-exercise recovery using 60 s windows. Plasma NO₂⁻ and NO₃⁻ concentrations were measured via chemiluminescence. Results: Both acute and seven-day NO₃⁻ supplementation significantly increased plasma NO₂⁻ and NO₃⁻ concentrations compared to placebo (p < 0.001). Cardiac vagal recovery, assessed via SDNN and RMSSD, was significantly enhanced in both conditions, with greater and more sustained improvements observed after the seven-day protocol. HF power was significantly higher, but only after seven-day supplementation (p = 0.009). Conclusions: Inorganic NO₃⁻ supplementation enhances post-exercise cardiac parasympathetic reactivation in hypertensive postmenopausal women. Notably, the seven-day intake (400 mg/day) protocol elicited superior autonomic benefits compared to an acute high dose. These findings highlight the potential of NO₃⁻ as a non-pharmacological strategy for improving cardiovascular autonomic recovery in high-risk populations. Full article

Objective: Chest computed tomography (CT) is a key component of the diagnostic assessment of people with cystic fibrosis (PwCF) and is increasingly replacing chest radiography. Due to improvements in life expectancy, radiation exposure has become a growing concern in PwCF. Photon-counting CT (PCCT) has the potential to reduce the risk of radiation-induced malignancies while maintaining diagnostic accuracy. This study aimed to compare the radiation dose and image quality of low-dose high-resolution (LD-HR) and ultra-low-dose high-resolution (ULD-HR) CT protocols using PCCT in PwCF. Methods: This retrospective study included 72 PwCF, with 36 undergoing a LD-HR chest CT protocol and 36 receiving an ULD-HR protocol on a PCCT. The radiation dose and image quality were assessed by comparing the effective dose and signal-to-noise ratio (SNR). Three blinded radiologists evaluated the overall image quality, sharpness, noise, and assessability of the bronchi, bronchial wall thickening, and bronchiolitis using a five-point Likert scale. Results: The ULD-HR PCCT protocol reduced radiation exposure by approximately 65% compared with the LD-HR PCCT protocol (median effective dose: 0.19 vs. 0.55 mSv, p < 0.001). While LD-HR images were consistently rated higher than ULD-HR images (p < 0.001), both protocols maintained diagnostic significance (median image quality rating of “4-good”). The average SNR of the lung parenchyma was significantly lower with ULD-HR PCCT compared to LD-HR PCCT (p < 0.001). Conclusions: ULD-HR PCCT significantly reduced radiation exposure while maintaining good diagnostic image quality in PwCF. The effective dose of ULD-HR PCCT is only twice that of a two-plane chest X-ray, making it a viable low-radiation alternative for routine imaging in PwCF. Full article

Objectives: Ultra-high dose-rate FLASH radiotherapy has demonstrated strong potential in reducing normal tissue toxicity while maintaining effective tumor control. However, its underlying radiobiological mechanisms remain unclear, highlighting the need for novel approaches to probe the effects of radiation during and immediately after delivery. This study presents the first exploration of 3D PET imaging of positron-emitting nuclei (PENs) generated by a FLASH proton beam. Methods: A home-built 12-panel preclinical small-animal PET system was employed for recording coincidence events. A 142.4 MeV FLASH proton beam with a 100 ms delivery time was directed into a solid water phantom. PET coincidence signals were recorded during the first 1 s and up to 11 min. The system’s capability for 3D localization was also assessed, and Monte Carlo simulations were performed for validation. Results: The PET system successfully recorded coincidence data within the first second, including the 100 ms beam delivery interval. Detector dead-time effects under the high beam flux were observed, leading to underestimated event counts. Following irradiation, the measured activity and decay behavior were consistent with simulations. The PET system accurately reconstructed the spatial distribution of PEN activities, with discrepancies in measured versus calculated line profiles ranging from 3.35–6.85%. Reconstructed PET images enabled reliable 3D localization with sub-millimeter accuracy in both lateral and depth dimensions. Conclusions: Our findings demonstrate that a multi-detector PET system is a promising tool for investigating the radiation effects of FLASH beams. Full article

Background: FLASH radiotherapy delivers ultra-high dose rates with normal tissue sparing, but mechanisms remain unclear. We present a streamlined workflow for establishing a LINAC-based electron FLASH (eFLASH) platform in low-resource settings without requiring vendor-proprietary hardware or software, or vendor-assisted modifications to broaden accessibility for FLASH studies. Methods: A LINAC was converted to eFLASH with pulse control and monitoring. Automatic frequency control (AFC) was optimized to stabilize dose per pulse (DPP). Beam data were measured with EBT-XD films, and a Monte Carlo (MC) model was commissioned for in vivo dose calculation. We demonstrated in vivo dosimetry in planning studies of mouse whole-brain and rat spinal cord (C1–T2) irradiation. We further assessed the impact of AFC optimization on the FLASH spinal cord study. Results: AFC optimization stabilized DPP at ~0.6 Gy/pulse, reducing large fluctuations under the default setting. MC agreed with measurements within 2% for PDDs and profiles. MC planning showed uniform whole-brain irradiation with 6 MeV FLASH, while the spinal cord study exhibited up to 10% dose fall-off within 1 cm along the cord, suggesting potential dose-volume effects confounding FLASH sparing. Following AFC optimization, 50% of the C1–T2 cord reached >133 Gy/s, a 23% increase versus default. Conclusions: We demonstrated a cost-effective eFLASH platform and verified its accuracy for preclinical studies, expanding the accessibility of FLASH research. Full article