Search Results (2,088)

Background/Objectives: Multi-scenario calculational methods have been used to evaluate proton teletherapy plan robustness but few studies have been performed to determine the accuracy of these calculational methods. This study evaluates a multi-scenario method by comparing calculations to measurements made in phantoms that simulate the effects of possible uncertainties. Methods: Plans were made using four phantoms in which the delivered dose was highly sensitive to positional and penetration uncertainties. The effects of alignment and penetration uncertainties on the dose distributions of each of those phantoms were simulated by performing calculations using nine different uncertainty scenarios and comparing the calculations to measurements with induced physical alignment displacements. Measured dose distributions were obtained by exposing films placed inside the phantoms and extracting multiple linear profiles. The maximum and minimum doses obtained for each of the calculational scenarios were compared with the measured dose profiles. In addition, comparisons of DVHs for nominal and uncertainty scenarios were performed. Results: The results showed that, under the influence of uncertainties, the minimum dose for the four phantoms decreased by more than 20 Gy, the V_95% coverage fluctuated by more than 10%, but the maximum dose parameter changed by less than 5 Gy. This was expected, as no margins for uncertainties were applied around the targets. The envelope bounded by the maximum and minimum possible calculated doses contained most of the measurements, although the shapes of the dose profiles displayed some mismatches for wedge and head phantoms. There were a few points where the measured maximum dose for bone and lung slab phantom cases was slightly higher than the maximum dose calculated from the nine scenarios. Conclusions: This study demonstrates that a nine-scenario method can adequately evaluate the robustness of simple mono-directional plans containing heterogeneities. Full article

Background: Novel therapies are needed for children, adolescents, and young adults with relapse/refractory leukemia or solid tumors. The proteasome inhibitor carfilzomib has demonstrated pre-clinical activity against several pediatric malignancies when used alone or in combination. Therefore, a multicenter dose-escalation phase 1 study of carfilzomib administered in combination with cyclophosphamide and etoposide was conducted. Methods: Study eligibility included an age of 6 months to <30 years with relapsed/refractory leukemia (stratum A) or a relapsed/refractory non-CNS solid tumor (stratum B), Karnofsky/Lansky score ≥ 50, and adequate organ function. A 5-day regimen of cyclophosphamide 440 mg/m²/day, etoposide 100 mg/m²/day, and carfilzomib was administered every 28 days with growth factor support. The carfilzomib starting dose was 11 mg/m²/day, and dose escalation followed a rolling-six design, managed independently for each stratum. Dose-limiting toxicity (DLT) was assessed during the first cycle, and disease response was assessed after one cycle (stratum A) or two cycles (stratum B). Results: Thirty-eight patients were treated (14 in stratum A; 24 in stratum B). For stratum A, the maximum tolerated dose (MTD) for carfilzomib was 11 mg/m²/day. Three DLTs were observed: thrombocytopenia, pericarditis, and posterior reversible encephalopathy syndrome (PRES). Most patients received one cycle. For stratum B, an MTD was not reached. The highest dose level administered and recommended in phase 2 was 20 mg/m²/days 1–2 and 36 mg/m²/days 3–5 for cycle 1, then 36 mg/m² for days 1–5 of all subsequent cycles. There was a single DLT of PRES. A dose expansion for additional toxicity data was conducted. Overall, twenty patients received ≥ 2 cycles (range, 2–14). Conclusions: A 5-day schedule of carfilzomib/cyclophosphamide/etoposide was well-tolerated in patients with solid tumors. Patients with sarcomas benefited most, warranting further evaluation. Full article

Background: Slow transit constipation (STC) represents a refractory gastrointestinal disorder with limited therapeutic options. Deglycosylated azithromycin (Deg-AZM) is a small molecule Transgelin agonist effective against STC, which has been approved for 2024 clinical trials. Objectives: This study comprehensively evaluated the cardiac safety (hERG inhibition), acute cardiovascular–respiratory effects, and single/repeated-dose toxicity of Deg-AZM in Beagle dogs to de-risk clinical translation. Methods: Using automated patch-clamp (hERG-HEK293 cells; 0.1–1000 μM), telemetric monitoring in Beagles (3/8/24 mg/kg; Latin square design), and GLP-compliant toxicity studies (single-dose: 150–300 mg/kg; 28-day: 5–50 mg/kg/day), we assessed functional, biochemical, histopathological, and toxicokinetic parameters. Results: Deg-AZM showed negligible hERG inhibition (maximum 21.3% at 1000 μM). Transient PR prolongation (24 mg/kg; resolved by 4 h) and respiratory rate reduction (8–24 mg/kg; resolved by 2 h) occurred at supratherapeutic doses. Single-dose toxicity revealed one mortality at 300 mg/kg (acute cardiac ischemia), while 28-day studies identified fully reversible myocardial vacuolation at 50 mg/kg. Toxicokinetics demonstrated dose-proportional exposure (AUC and C_max) and low accumulation (accumulation factors ≤ 1.5). No hematological, coagulation, or hepatic toxicity was observed. Conclusions: With absent hERG liability and manageable transient physiological effects, Deg-AZM exhibited a favorable preclinical safety profile supporting its clinical development for STC. Full article

Long COVID, characterized by persistent symptoms following acute SARS-CoV-2 infection, has emerged as a significant public health challenge with wide-ranging clinical and socioeconomic implications. Developing an effective risk assessment strategy is essential for the early identification and management of individuals susceptible to prolonged symptoms. This study uses a quantitative approach to characterize the dose–response relationships between spike protein concentrations and effects, including Long COVID symptom numbers and the release of proinflammatory mediators. A mathematical model is also developed to describe the time-dependent change in spike protein concentrations post diagnosis in twelve Long COVID patients with a cluster analysis. Based on the spike protein concentration–Long COVID symptom numbers relationship, we estimated a maximum symptom number (~20) that can be used to reflect a persistent predictor. We found that among the crucial biomarkers associated with Long COVID proinflammatory mediator, CXCL8 has the lowest 50% effective dose (0.01 μg mL⁻¹), followed by IL-6 (0.39), IL-1β (0.46), and TNF-α (0.56). This work provides a comprehensive risk assessment strategy with dose–response tools and mathematical modeling developed to estimate potential spike protein concentration. Our study suggests persistent Long COVID guidelines for personalized care strategies and could inform public health policies to support early interventions that reduce long-term disability and healthcare burdens with possible other post-infection syndromes. Full article

To explore a more personalized approach to radiation therapy for adjuvant whole-breast irradiation in triple-negative breast cancer (TNBC), we analyzed the cell lines BT549 and MDA-MB-231 as in vitro models for radiobiological characterization. The local disease-free survival (LSR) values were determined for both cell lines’ median, maximum, and minimum α and β parameters to achieve an LSR probability of close to 100% in a five-fraction schedule. Based on these findings, fifteen treatment plans were created for BC to simulate the proposed dose schedule. For the MDA-MB-231 cell line, the α/β ratios were 3.79 Gy (minimum), 15 Gy (maximum), and 7 Gy (median). For the BT-549 cell line, the α/β ratios were 5.95 Gy (minimum), 22.93 Gy (maximum), and 16.51 Gy (median). To achieve an LSR probability of close to 100%, the required doses per fraction were 5.2 Gy, 5.3 Gy, and 7.3 Gy for MDA-MB-231 and 8 Gy, 9.1 Gy, and 9.9 Gy for BT-549. We selected the highest dose per fraction, 9.9 Gy × 5, to simulate the worst-case scenario. To achieve 100% cell death effectiveness in TNBC, it is likely that higher radiation doses are required—doses that are not feasible within the setting of adjuvant whole-breast irradiation. Our model, which relies on the intrinsic biological features of the tumor, paves the way to reach more tailored RT plans and to improve the classic LQ model. Full article

The lotus (Nelumbo nucifera Gaertn.) is an ornamental aquatic plant, highly valued in Asian cultures for its religious symbolism, culinary uses, and medicinal properties. However, the lotus exhibits low genetic diversity in nature, which limits the genetic resources available for breeding programs. Gamma irradiation is an effective method for inducing genetic variation in lotus breeding. The present study examines the gamma sensitivity of lotus seedlings, along with the morphological and anatomical changes induced by various gamma dosages. The results showed that high-dose gamma irradiation (≥100 Gy) significantly inhibited seedling growth and altered most anatomical parameters, each exhibiting distinct dose–response patterns except for midrib diameter. The 100 Gy treatment resulted in the maximum stem diameter, while root diameter peaked at 500 Gy, and the highest dose (600 Gy) produced the largest petioles. Gamma irradiation also triggered tannin accumulation and reduced aerenchyma formation in the leaves. The obtained results demonstrate organ-specific responses to gamma irradiation in the lotus, with leaves being the most sensitive, while petioles, stems, and roots exhibited more variable dose-dependent effects. Full article

Background/Objectives: MB09 is a denosumab biosimilar to the reference products (RPs) Xgeva and Prolia. A population pharmacokinetic (popPK) meta-analysis was conducted to characterize the denosumab PK profile and to support MB09 biosimilarity. Methods: Pooled denosumab PK data from one phase I study [255 healthy adult men receiving a single 35 mg subcutaneous (SC) dose] and one phase III study (555 postmenopausal women with osteoporosis receiving two 60 mg SC doses, one every six months) were used. A one-compartment model with first-order absorption and elimination and parallel non-linear saturable clearance was used. Body weight was included on clearance as a structural covariate and treatment was tested as a covariate on all PK parameters. PK biosimilarity was assessed at 35 mg dose. Results: For a 70 kg subject, the apparent clearance and central volume of distribution for denosumab were 0.123 L/day [95% confidence interval (CI): 0.114, 0.132] and 9.33 L (95% CI: 9.11, 9.55), respectively. The Michaelis constant was 0.124 ng/mL and the maximum rate for the non-linear clearance was 0.139 ng/day. Model-based bioequivalence criteria were met for RP Xgeva, European and US-sourced, versus MB09 for a dose of 60 mg SC. The mean area under the plasma concentration curve (AUC) resultant from the simulation of MB09 120 mg SC was similar to the published mean AUC observed for Xgeva 120 mg SC every four weeks. Conclusions: This analysis provides a valuable assessment of denosumab PK characteristics and elucidates in more detail how the MB09 PK profile compares to the denosumab RPs, supporting the totality of evidence on MB09 biosimilarity. Full article

Western Pará, northern Brazil, is a significant region for mineral exploration, leading to the deposition of potentially toxic elements in soils and water basins. This study evaluated concentrations of mercury (Hg), lead (Pb), cadmium (Cd), and arsenic (As) in cattle muscle tissue from three municipalities: Oriximiná, Itaituba, and Monte Alegre. Metal concentrations were determined using inductively coupled plasma mass spectrometry (ICP-MS). The estimated daily intake (EDI) of toxic metals via beef consumption (71 g/person/day) was below oral reference doses values (RfDo). Target hazard quotient (THQ) and total THQ (TTHQ) values for all metals were below 1, indicating no significant non-carcinogenic health risk. Monte Alegre exhibited the highest THQ for As and Pb, Oriximiná for Cd, and Itaituba for Hg. Although the overall assessment suggests low risk, elevated Hg concentrations were detected in 10% of the samples, with at least one animal from each municipality exceeding the European Union maximum residue limit (0.01 mg/kg). These findings indicate localized contamination and potential mercury bioaccumulation. Given the rising anthropogenic activities (such as mining and deforestation), continued monitoring of heavy metal levels in animal tissues is recommended to ensure long-term food safety and public health. Full article

The neuropeptide’s multifaceted involvement in various components of neural homeostasis impacts pain and behavioral regulation. One of the highly potent neuropeptides is dermorphin, extracted from the skin of the Amazon frog (Phyllomedusa sauvagei). The unique feature of dermorphin is the D-Ala residue in its sequence, which has inspired researchers to search for dermorphin analogs for use as pharmaceuticals. The primary objective of this study is to synthesize several new linear and cyclic dermorphin analogs and evaluate them as potential non-invasive analgesics. By exploring our method for converting linear peptides into 2,5-diketopiperazine(2,5-DKP) derivatives, which stabilize peptide structures, we synthesize several new dermorphin linear peptides and chimeric cyclopeptidomimetics. These compounds were tested in vitro and in vivo to determine their biological activities and potential applicability as pharmaceuticals. For the evaluation of in vitro opioid activity, the “Guinea Pig Ileum” (GPI) test was used. D2 showed the highest activity, and cyclopeptides D3 and D4 showed high activity. We can assume that dermorphin analogues D2, D3, and D4 are potent agonists of µ-type opioid receptors and have high opioid activity. However, this needs to be verified using molecular modeling methods in further research. The analgesic effects of dermorphins have been evaluated in the “Hot-Plate” and “Tail-Flick” tests. In rats, D2 dermorphin analogues demonstrated dose-dependent analgesic effect in the “Water Tail-Flick” test after intranasal administration. A smaller dose of 0.5 µg/kg resulted in 40% analgesia and a short-term state of stupor. The maximum long-lasting analgesia was observed at a dose of 1.0 µg/kg, which induced complete stupor. The analgesic effect of peptide D2 after intraperitoneal administration at a 5.0 mg/kg dose was over 50%. The “Open-Field” test demonstrated a dose-dependent (15, 50, 150 μg/kg) peptide D2 suppression effect on behavioural reactions in rats following intranasal administration. A new modification of linear peptides, combined with a 2,5-DKP scaffold (D3 and D4), proved promising for oral use based on the results of analgesic effect evaluation in mice following intragastric administration. Full article

Background: Medically unexplained oral symptoms/syndromes (MUOS), such as Burning Mouth Syndrome and Persistent Idiopathic Facial Pain, present significant management challenges due to the lack of standardized treatments and high-level evidence. While pharmacotherapy is often employed, real-world data on treatment adherence—a pragmatic proxy for effectiveness and tolerability—remain sparse, especially in Japan. This study aimed to describe the real-world prescribing patterns of antidepressants and dopamine receptor partial agonists (DPAs) for MUOS and retrospectively investigate their association with treatment continuation. Methods: This retrospective observational study analyzed data from patients initiating pharmacotherapy for MUOS at a specialized clinic in Japan (April 2021–March 2023). We used Cox proportional hazards models to evaluate treatment continuation for amitriptyline monotherapy and antidepressant–aripiprazole adjunctive therapy. The primary outcome was the time to discontinuation. Dosage effects were modeled using B-splines to capture nonlinearity. Results: Among 702 MUOS patients who started pharmacotherapy, 493 received amitriptyline as the first prescription, and 108 received aripiprazole as an adjunctive therapy. For amitriptyline monotherapy, a nonlinear relationship was observed between dosage and discontinuation risk, with a relatively lower hazard around 25 mg/day across age groups. In the antidepressant–aripiprazole adjunctive group, the overall hazard ratio for discontinuation was higher (HR = 4.75, p < 0.0005) compared to non-adjunctive therapy, likely due to indication bias reflecting more treatment-resistant cases. However, within the aripiprazole adjunctive group, a U-shaped relationship was identified between maximum aripiprazole dosage and discontinuation risk, with the lowest hazard (HR ≈ 0.30) observed at approximately 1.7–1.8 mg/day. Mild side effects such as drowsiness, dry mouth, constipation, tremor, insomnia, and weight gain were noted, but no severe adverse events occurred. Conclusions: This real-world data analysis suggests specific dosage ranges (amitriptyline ≈ 25 mg/day; aripiprazole augmentation ≈ 1.7–1.8 mg/day) are associated with longer treatment continuation in MUOS patients. Treatment continuation reflects a crucial balance between symptom relief and tolerability, essential for managing these chronic conditions. It is critical to emphasize that these findings are descriptive and observational, derived from a specialized setting, and do not constitute prescriptive recommendations. They highlight the importance of individualized dosing. Definitive evidence-based strategies require validation through prospective randomized controlled trials. Full article

Lanthanide-doped inorganic luminescent materials have been extensively studied and applied in X-ray detection and imaging, anti-counterfeiting, and optical information storage. However, many reported rare-earth-based luminescent materials show only single-mode optical responses, which limits their applications in complex scenarios. Here, we report a novel Na₃KMg₇(PO₄)₆:Eu phosphor synthesized by a simple high-temperature solid-state method. The multi-color luminescence of Eu²⁺ and Eu³⁺ ions in a single matrix of Na₃KMg₇(PO₄)₆:Eu, known as radio-photoluminescence, is achieved through X-ray-induced ion reduction. It demonstrated a good linear response (R² = 0.9897) and stable signal storage (storage days > 50 days) over a wide range of X-ray doses (maximum dose > 200 Gy). In addition, after X-ray irradiation, this material exhibits photochromic properties ranging from white to brown in a bright field and shows remarkable bleaching and recovery capabilities under 254 nm ultraviolet light or thermal stimulation. This dual-modal luminescent phosphor Na₃KMg₇(PO₄)₆:Eu, which combines photochromism and radio-photoluminescence, presents a dual-mode X-ray detection and imaging strategy and offers a comprehensive and novel solution for applications in anti-counterfeiting and optical information encryption. Full article

This study presents a strategy to develop crayfish shell peptides with enhanced antioxidant and angiotensin-I-converting enzyme (ACE) inhibitory properties. Crayfish shell protein hydrolysates (CSPH1–3) with different molecular weights were analyzed. CSPH2 (3–5 kDa) exhibited the strongest antioxidant activities, which could scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) and the 2,2′-azobis(3-ethylbenzothiazoline-6-sulfonic acid) sodium salt (ABTS) radical by (77.40 ± 4.54)% and (91.59 ± 0.30)%, respectively, and ACE inhibition activity of (64.74 ± 0.64)%. CSPH2 was further separated into three fractions, and CSPHF2 showed the maximum biological activity. The sequences of the purified antioxidant peptide (APAPLPPPAP) and ACE inhibitory peptide (QGPDDPLIPIM) were identified by liquid chromatography–tandem mass spectrometry (LC-MS/MS) in CSPHF2. These peptides increased the nitric oxide (NO) concentration and decreased the endothelin-1 (ET-1) content in human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner, while also inhibiting reactive oxygen species (ROS). In addition, CSPH showed protective effects in terms of oxidative damage to HepG2 cells induced by H₂O₂. These findings suggest that crayfish shell peptides have potential applications as ingredients in antihypertensive agents and antioxidants, offering significant health benefits when consumed. Full article

Ultrahigh dose rate (UHDR) radiotherapy, also known as FLASH radiotherapy (FLASH-RT), has shown potential for increasing tumor control while sparing normal tissue. In parallel, gold nanoparticles (GNPs) have been extensively explored as radiosensitizers due to their high atomic number and ability to enhance the generation of reactive oxygen species (ROS) through water radiolysis. In this study, we investigate the synergistic effects of UHDR electron beams and GNP-mediated radiosensitization using Monte Carlo (MC) simulations based on the Geant4-DNA code. A spherical water phantom with embedded GNPs of varying sizes (5–100 nm) was irradiated using pulsed electron beams (100 keV and 1 MeV) at dose rates of 60, 100, and 150 Gy/s. The chemical yield of ROS near the GNPs was quantified and compared to an equivalent water nanoparticle model, and the yield enhancement factor (YEF) was used to evaluate radiosensitization. Results demonstrated that YEF increased with smaller GNP sizes and at lower UHDR, particularly for 1 MeV electrons. A maximum YEF of 1.25 was observed at 30 nm from the GNP surface for 5 nm particles at 60 Gy/s. The elevated ROS concentration near GNPs under FLASH conditions is expected to intensify DNA damage, especially double-strand breaks, due to increased hydroxyl radical interactions within nanometric distances of critical biomolecular targets. These findings highlight the significance of nanoparticle size and beam parameters in optimizing ROS production for FLASH-RT. The results provide a computational basis for future experimental investigations into the combined use of GNPs and UHDR beams in nanoparticle-enhanced radiotherapy. Full article

The growing demand for organic products is having a transformative effect on the alcoholic beverage industry. This work investigates the possibility of producing organic ethanol only from sugarcane final molasses as a nutrient vector and Saccharomyces cerevisiae in the absence of inorganic nitrogen or phosphorus compounds. The Plackett–Bürman design included the pseudo-factors (X4–X6) due to the experimental design requirements. These factors represent the possible influence of uncontrolled variables, such as pH or nutrient interactions. Subsequently, a predictive quadratic model using Box–Behnken design with the real variables (sugar concentration, yeast dose, and incubation time) was developed and validated $(R^2=0.977)$ with internal validation; given the lack of replications and the sample size, this value should be interpreted with caution and not as generalizable predictive evidence. Further experiments with replications and cross-validation will be required to confirm its predictive capacity. Through statistical optimization, the maximum cell proliferation of $432\times {10}^6$ cells/mL was achieved under optimal conditions of 8°Brix sugar concentration, 20 g/L dry yeast, and 3 h incubation time. The optimized fermentation process produced 7.8% v/v ethanol with a theoretical fermentation efficiency of 78.52%, an alcohol-to-substrate yield of 62.15%, and a productivity of 1.86 g/L·h, representing significant improvements of 21.9%, 24.6%, 31.0%, and 10.1%, respectively, compared with non-optimized conditions. The fermentation time was reduced from 48 to 42 h while maintaining superior performance. These results demonstrate the technical feasibility of producing organic ethanol using certified organic molasses and no chemical additives. Overall, these findings should be regarded as proof of concept. All experiments were single-run without biological or technical replicates; consequently, the optimization and models are preliminary and require confirmation with replicated experiments and external validation. Full article

Overuse of chemical fertilizers can threaten the agro-ecological balance, including an excessive accumulation of certain elements, such as nitrogen and phosphorus. On the other hand, organic fertilizers and biofertilizers, which are eco-friendly and cost-effective, increase biological nitrogen fixation and enhance the availability of nutrients to plants. The aim of this research was to study the possibility of using a full (22.50 t/ha) and 50% (11.25 t/ha) treatment of sheep manure with azotobacter (100 mL/20 L) instead of inorganic fertilizers for increasing savory (Satureja hortensis L.) growth production and yield value as well as improving chemical and biological properties. The results showed that the treatment with 50% sheep manure recorded the highest total dry herb (3.18 t/ha) yield. The inorganic fertilizer resulted in the highest essential oil content (1.43% v/w) and γ-terpinene (10.38% v/v), cymol (5.90% v/v), and α-bisabolene (5.28% v/v) values. The maximum carvacrol value (42.54% v/v) was recorded in the savory herb after applying no fertilization to the plants, while the highest concentration of thymol (16.09% v/v) was obtained by applying the full sheep manure treatment. The full sheep manure + azotobacter treatment had the highest mean α-terpinene value (7.22% v/v), and the 50% sheep manure + azotobacter treatment had the highest mean α-phellandrene value (6.44% v/v). The highest DPPH activity (60.86%) and FRAP value (69.64 mg TE/g DW) were observed with the azotobacter + full sheep manure treatment, while the highest total phenolic content (96.87 mg GAE/g DW) and total flavonoid content (45.97 mg QE/g DW) in the savory herb were obtained from the combination treatment of 50% sheep manure doses + azotobacter. Principal coordinate analysis (PCA) revealed distinct clustering of treatments, with PC1 and PC2 explaining >60% of the variance, highlighting the dominant role of sheep manure doses in morphological/yield properties. Heatmap analysis grouped the treatments (right) and examined properties (bottom) as two main groups. The full sheep manure + biofertilizer and inorganic fertilizer treatments were found in the first group, depending on the treatments. Moreover, the heatmap analysis revealed that the full and 50% sheep manure (SM) treatments played critical roles in separating the examined properties, and the DPPH and carvacrol properties were grouped together compared to other properties. Thus, the results suggest that treatment with azotobacter could be employed in combination with appropriate rates of sheep manure to obtain the maximum benefits regarding herb yield, biological activity, and essential oil components. Full article