Variable Dose Research Articles

A mathematical framework for comparison of intermittent versus continuous adaptive chemotherapy dosing in cancer

Chemotherapy resistance in cancer remains a barrier to curative therapy in advanced disease. Dosing of chemotherapy is often chosen based on the maximum tolerated dosing principle; drugs that are more toxic to normal tissue are typically given in on-off cycles, whereas those with little toxicity are dosed daily. When intratumoral cell-cell competition between sensitive and resistant cells drives chemotherapy resistance development, it has been proposed that adaptive chemotherapy dosing regimens, whereby a drug is given intermittently at a fixed-dose or continuously at a variable dose based on tumor size, may lengthen progression-free survival over traditional dosing. Indeed, in mathematical models using modified Lotka-Volterra systems to study dose timing, rapid competitive release of the resistant population and tumor outgrowth is apparent when cytotoxic chemotherapy is maximally dosed. This effect is ameliorated with continuous (dose modulation) or intermittent (dose skipping) adaptive therapy in mathematical models and experimentally, however, direct comparison between these two modalities has been limited. Here, we develop a mathematical framework to formally analyze intermittent adaptive therapy in the context of bang-bang control theory. We prove that continuous adaptive therapy is superior to intermittent adaptive therapy in its robustness to uncertainty in initial conditions, time to disease progression, and cumulative toxicity. We additionally show that under certain conditions, resistant population extinction is possible under adaptive therapy or fixed-dose continuous therapy. Here, continuous fixed-dose therapy is more robust to uncertainty in initial conditions than adaptive therapy, suggesting an advantage of traditional dosing paradigms.

Variable-RBE-induced NTCP predictions for various side-effects following proton therapy for brain tumors – Identification of high-risk patients and risk mitigation

Background and purposeDisregarding the increase of relative biological effectiveness (RBE) may raise the risk of acute and late adverse events after proton beam therapy (PBT). This study aims to explore the relationship between variable RBE (above 1.1)-induced normal tissue complication probabilities (NTCP) and patient-specific factors, identify patients at high risk of RBE-induced NTCP increase, and assess risk mitigation by incorporating RBE variability into treatment planning. Materials and methodsWe retrospectively analyzed 105 primary brain tumor patients treated with PBT (RBE = 1.1). We calculated differences in estimated NTCP (ΔNTCP) using a variable RBE-weighted dose (DRBE, Wedenberg model) and a constant RBE-weighted dose (DRBE=1.1), across 16 NTCP models. These differences were correlated with patient-specific characteristics. Based on ΔNTCP, patients were classified as high risk (32 %) or low risk (68 %) for adverse events due to RBE-induced NTCP. This classification was compared with alternative classifications based on (a) relevant patient-specific characteristics, (b) DRBE=1.1, and (c) the difference between DRBE and DRBE=1.1 (ΔD), assessing the balanced accuracy. The potential to reduce RBE-induced NTCP through track-end and linear energy transfer (LET) optimization was evaluated in six example patients. ResultsUsing a variable RBE instead of a constant one resulted in NTCP increases (up to 32 percentage points). Variable-RBE-induced NTCP increases were strongly negatively correlated with the distance between the clinical target volume (CTV) and the organ at risk (OAR) for most side-effects, and positively correlated with CTV volume for certain side-effects. High increases were associated with (a) specific patient factors, particularly the proximity of the CTV to OARs, (b) DRBE=1.1, and (c) ΔD, with a balanced accuracy of 0.88, 0.94, and 0.86, respectively. Optimization of track-ends and LET considerably reduced NTCP values, achieving a mean reduction of 31 % for optimized OARs. ConclusionThe risk of variable-RBE-induced NTCP strongly depends on patient-specific factors and the considered side-effect. A small distance between the tumor and OARs notably increases the risk. Integrating biologically-guided objectives into treatment planning can effectively mitigate the risk.

On-farm experimentation of precision agriculture for differential seed and fertilizer management in semi-arid rainfed zones

IntroductionThis study explores the integration of precision agriculture technologies (PATs) in rainfed cereal production within semi-arid regions.Methodsutilizing the Veris 3100 sensor for apparent soil electrical conductivity (ECa) mapping, differentiated management zones (MZs) were established in experimental plots in Valsalada, NE Spain. Site-specific variable dose technology was applied for seed and fertilizer applications, tailoring inputs to distinct fertility levels within each MZ. Emphasizing nitrogen (N) management, the study evaluated the impact of variable-rate applications on crop growth, yield, nitrogen use efficiency (NUE), and economic returns. For the 2021/2022 and 2022/2023 seasons, seeding rates ranged from 350 to 450 grains/m2, and basal fertilizer dosages varied between high and low levels. Additionally, the total nitrogen units were distributed differently between the two seasons, while maintaining a uniform topdressing fertilizer dose across all treatments.ResultsResults revealed a significant increase in yield in MZ 2 (higher fertility) compared to MZ 1 (lower fertility). NUE demonstrated notable improvement in MZ 2, emphasizing the effectiveness of variable-rate N applications. Economic returns, calculated as partial net income, showed a considerable advantage in MZ 2 over MZ 1, resulting in negative outcomes for low-fertility areas in several of the analyzed scenarios, and highlighting the financial benefits of tailored input management.ConclusionThis research provides quantitative evidence supporting the viability and advantages of adopting PATs in rainfed cereal production. The study contributes valuable insights into optimizing input strategies, enhancing N management, and improving economic returns in semi-arid regions.

Consequences of acute and long-term excessive iodine intake: A literature review focusing on seaweed as a potential dietary iodine source.

Macroalgae, also called seaweed, are becoming more widespread as food in Western diets. Seaweed can accumulate iodine, an essential nutrient for humans. However, some species of seaweed may contain very high amounts of iodine, and therefore, iodine has been identified as one of the major hazards in the seaweed food chain. Macroalgae may be consumed regularly, though many consumers report eating macroalgae only occasionally. The aim of this paper is to explore possible health consequences of excessive iodine intake according to long-term (chronic) or occasional (acute) excessive exposure to iodine, relating to a regular (chronic) or occasional (acute) seaweed intake, respectively. Furthermore, through a modeling exercise, we add different amounts of seaweed to the diet in a population group to explore the possible safe amounts that can be added without exceeding excessive iodine intakes and risking detrimental health effects. Chronic excessive iodine intakes were associated with several negative health outcomes at variable doses in various studies. For acute excessive iodine exposure, negative health effects seemed to be associated with higher iodine exposures. However, the research on this topic was limited. The chronic and acute iodine exposures needed to result in negative health outcomes may easily be ingested by macroalgae consumption. Adding seaweed to the diet must be done thoughtfully to avoid the risk of exceeding thresholds for excessive iodine intake.

5158 Estrogen for Feminizing Gender Affirming Hormone Therapy: Understanding the Influence of Route of Administration and Dose on Serum Estradiol and Testosterone Levels

Abstract Disclosure: D.J. Slack: None. A. Di Via Ioschpe: None. M. Saturno: None. S. Kihuwa-Mani: None. U. Amakiri: None. S. Karim: None. D. Guerra: None. J.D. Safer: None. For feminizing gender affirming hormone therapy (GAHT), the Endocrine Society and WPATH SOC 8 suggest targeting testosterone (T) levels below 50 ng/dL and estradiol (E2) levels in the range of 100-200 pg/mL. Exogenous estrogen may be given via several routes of administration (ROA) and at a variety of doses, but little is known about how ROA and dose influence T and E2 levels. We sought to investigate the relationship between estrogen dosage, ROA, and hormonal profiles in trans feminine individuals. We conducted a chart review of patients in the Mount Sinai Health System and included all patients who had active prescriptions for feminizing GAHT with both T and E2 levels recorded (n = 585), excluding those with a history of orchiectomy. For oral (PO) estrogen, there was a negative correlation between dose and serum T (p < .01), LH (p < .05), and FSH (p < .05), but no correlation with E2. For transdermal (TD) estrogen, dose did not correlate with serum T, E2, LH, or FSH. For intramuscular (IM) estrogen, there was a positive correlation with serum E2 (p < .05), LH (p < .05), and FSH (p < .01), but no correlation with T. Individuals were then stratified into groups of T and E2 ranges that were determined via bell-curve frequency distributions. Within each group, the relative proportion of users of a given ROA, their mean dose of estrogen given via that ROA, and their resulting mean T and E2 levels were calculated. For users of IM estrogen, a significantly higher proportion of individuals had T < 50 ng/dL as opposed to T >= 50 ng/dL. IM users also much more frequently exhibited E2 >= 200 pg/mL than E2 < 200 pg/mL. For users of PO estrogen, a higher proportion of individuals had T >= 100 ng/dL compared to T < 50 ng/dL, with the proportion of those with T 50-99 ng/dL not differing from either group. A higher proportion of users of PO estrogen had E2 50 - 199 pg/mL compared to E2 < 25 ng/dL and E2 > 200 pg/mL, with the proportion of those with E2 25-49 pg/mL not differing significantly from either. For users of TD estrogen, there was a higher proportion of those with T 50 - 99 ng/dL compared to < 50 ng/dL and >= 200 ng/dL, with the proportion of those with T 100 - 199 ng/dL not differing from either group. A higher proportion of users of TD estrogen had E2 25 - 49 pg/mL compared to E2 100 - 199 pg/mL and E2 > 300 pg/mL, while the frequency of those with E2 < 25 pg/mL, 50 - 99 pg/mL, or 200 - 299 pg/mL did not differ significantly. Our results indicate a propensity for users of IM estrogen to achieve T suppression and to overshoot E2 targets, while users of PO estrogen were most likely to have E2 levels at-target but less likely to achieve T suppression. Users of TD estrogen appear least likely to achieve either target. While further research is needed to confirm and expand upon our findings, our data are an important step forward in providing clinicians with some predictive capability as to the serum E2 and T levels they might expect with the use of exogenous estrogen at a given dose and ROA. Presentation: 6/2/2024

5158 Estrogen for Feminizing Gender Affirming Hormone Therapy: Understanding the Influence of Route of Administration and Dose on Serum Estradiol and Testosterone Levels

Abstract Disclosure: D.J. Slack: None. A. Di Via Ioschpe: None. M. Saturno: None. S. Kihuwa-Mani: None. U. Amakiri: None. S. Karim: None. D. Guerra: None. J.D. Safer: None. For feminizing gender affirming hormone therapy (GAHT), the Endocrine Society and WPATH SOC 8 suggest targeting testosterone (T) levels below 50 ng/dL and estradiol (E2) levels in the range of 100-200 pg/mL. Exogenous estrogen may be given via several routes of administration (ROA) and at a variety of doses, but little is known about how ROA and dose influence T and E2 levels. We sought to investigate the relationship between estrogen dosage, ROA, and hormonal profiles in trans feminine individuals. We conducted a chart review of patients in the Mount Sinai Health System and included all patients who had active prescriptions for feminizing GAHT with both T and E2 levels recorded (n = 585), excluding those with a history of orchiectomy. For oral (PO) estrogen, there was a negative correlation between dose and serum T (p < .01), LH (p < .05), and FSH (p < .05), but no correlation with E2. For transdermal (TD) estrogen, dose did not correlate with serum T, E2, LH, or FSH. For intramuscular (IM) estrogen, there was a positive correlation with serum E2 (p < .05), LH (p < .05), and FSH (p < .01), but no correlation with T. Individuals were then stratified into groups of T and E2 ranges that were determined via bell-curve frequency distributions. Within each group, the relative proportion of users of a given ROA, their mean dose of estrogen given via that ROA, and their resulting mean T and E2 levels were calculated. For users of IM estrogen, a significantly higher proportion of individuals had T < 50 ng/dL as opposed to T >= 50 ng/dL. IM users also much more frequently exhibited E2 >= 200 pg/mL than E2 < 200 pg/mL. For users of PO estrogen, a higher proportion of individuals had T >= 100 ng/dL compared to T < 50 ng/dL, with the proportion of those with T 50-99 ng/dL not differing from either group. A higher proportion of users of PO estrogen had E2 50 - 199 pg/mL compared to E2 < 25 ng/dL and E2 > 200 pg/mL, with the proportion of those with E2 25-49 pg/mL not differing significantly from either. For users of TD estrogen, there was a higher proportion of those with T 50 - 99 ng/dL compared to < 50 ng/dL and >= 200 ng/dL, with the proportion of those with T 100 - 199 ng/dL not differing from either group. A higher proportion of users of TD estrogen had E2 25 - 49 pg/mL compared to E2 100 - 199 pg/mL and E2 > 300 pg/mL, while the frequency of those with E2 < 25 pg/mL, 50 - 99 pg/mL, or 200 - 299 pg/mL did not differ significantly. Our results indicate a propensity for users of IM estrogen to achieve T suppression and to overshoot E2 targets, while users of PO estrogen were most likely to have E2 levels at-target but less likely to achieve T suppression. Users of TD estrogen appear least likely to achieve either target. While further research is needed to confirm and expand upon our findings, our data are an important step forward in providing clinicians with some predictive capability as to the serum E2 and T levels they might expect with the use of exogenous estrogen at a given dose and ROA. Presentation: 6/2/2024

Effects of plant hormones and genotypes on anther culture response of safflower (Carthamus tinctorius L.)

Safflower (Carthamus tinctorius L.) belongs to the composite family with various uses, from the stem to the seeds. In vitro flowering and embryo rescue are common techniques for improving safflower hybrid fertility by overcoming breeding constraints. However, anther culture expedites the production of superior types. The aim of the study was to evaluate the effect of plant hormones and genotypes on anther culture responses and to develop a suitable protocol. In both safflower genotypes, callus, shoot, and root formation were investigated using ten factorial hormone treatments. To promote callus induction and shoot regeneration, variable doses of Thidiazuron (TDZ) at 1 mg/l indole butyric acid (IBA) and variable benzylaminopurine (BAP) at 0.5 mg/l NAA were added to the MS medium, respectively. ½ MS media with varying IBA concentrations at a fixed 0.5 mg/l NAA were used for root regeneration. Results showed that Turkan was superior in all aspects of callus induction, and the highest degree of callus formation (46 %) was observed at 0.5 mg/l TDZ. On the other hand, the local safflower performed better for shoot and root regeneration. The highest shoot regeneration capacity (20 %) was shown at 2.0 mg/l BAP, while shoot rooting was reached (21 %) at 1.0 mg/l IBA of culture media. Despite successful in vitro regeneration, acclimated plantlets did not survive in the glasshouse. In this study, we demonstrated the higher capability for both shoot and root regeneration of calli produced from local safflower anthers. More effort is required to improve shoot and root development for both genotypes.

Utilization of Diversified Cover Crops as Green Manure-Enhanced Soil Organic Carbon, Nutrient Transformation, Microbial Activity, and Maize Growth

Studying green manure in several returning methods to enhance soil fertility and crop benefits is a strong foundation for cropland nutrient management. However, how different types of green manures and their variable doses affect the efficacy of applied manures, either buried or mulched, remain overlooked. The objective of this study was to optimize green manure management to enhance soil fertility and maize biomass using five types of green manures (white mustard, forest rye, fiddleneck, sufflower, and pea) in two different doses (low, 5 g per pot, and high, 10 g per pot), which were either buried or mulched before and after maize sowing. Results revealed that total carbon content increased due to green manure treatments, representing a 10% increase over control, particularly through buried w. mustard (10% increase before maize cultivation) and mulched safflower and pea (12% and 11% increase after maize cultivation over control). Dry maize aboveground biomass yields also improved across all variants, with buried mustard yielding 18.4 g·plant−1 (compared to 8.6 g·plant−1 in the control), mulched mustard yielding 16.4 g·plant−1, and buried pea yielding 17.8 g·plant−1. Green mulching generally acidified the soil (pH 5.71 compared to 6.21 in the control), except for buried fiddleneck (pH 6.39 after maize cultivation) at a high dose of manures. Carbon-mineralizing enzyme activities (dehydrogenase and β-glucosidase) were significantly increased by green manures, with buried fiddleneck showing a 22.6% and 20.6% increase over the control, and mulched fiddleneck showing a 24.5% and 22.4% increase under high doses. The study suggests that partially decomposed and mineralized mulched biomass may induce a negative priming effect on carbon-mineralizing enzymes due to a decrease in the C/N ratio of the soil. It emphasizes that the nutrient content and stoichiometry of green manures, alongside soil characteristics such as the C/N ratio, are critical factors for sustainable soil management and carbon sequestration. These findings underscore the need for careful selection and management of green manures to optimize soil health and carbon-storage outcomes.

2190: NTCP modeling for rectal complication based on variable RBE-weighted proton dose for prostate cancer

2190: NTCP modeling for rectal complication based on variable RBE-weighted proton dose for prostate cancer

Drivers of Pharmaceutical Compounding: Regional Experience Analysis Using Irkutsk Pharmacy Organisations as a Case Study

INTRODUCTION. National pharmacy compounding is a priority for providing the population with medicinal products, particularly the medicinal products lacking in the Russian Federation. Investigating opportunities to improve the operation of compounding pharmacies in the Russian Federation remains essential, especially in the context of the developing personalised approach to treatment, growing practice of orphan drug development, and import substitution needs.AIM. This study aimed to identify the factors driving the development of compounding pharmacies under the current conditions.MATERIALS AND METHODS. The study focused on the Russian regulatory framework for pharmacy compounding, as well as the range of dosage forms and administration routes of the medicinal products that had been produced and packaged by the compounding pharmacies in Irkutsk in 2021–2023.RESULTS. This study showed a demand for compounded medicinal products among both healthcare providers and patients. These medicinal products covered a traditional range of compounded medicines, including custom formulae, medicines for paediatrics and geriatrics, stock preparations, and pharmacy-packaged items. In 2021–2023, the mean annual production of Irkutsk pharmacy organisations amounted to ~500,000 units of compounded medicinal products, with a variety of doses and dosage forms. The medicinal products were compounded using ~100 different active substances and over 20 approved medicinal products. This study examined the evolution of Russian pharmacy compounding legislation. The key aspects included the establishment of a pharmaceutical quality system for compounded medicinal products, the extension of shelf life for specific dosage forms, and the authorisation to use medicinal products approved in the Eurasian Economic Union in compounding. The study showed that the main factors driving the operation of compounding pharmacies were the ongoing regulatory framework transformation and the transition from standardised treatment to personalised medicine. The main impediments for compounding pharmacies included the lack of state support, the ban on compounding medicinal products produced by pharmaceutical companies, the shortage of skilled staff, the inadequate supply of equipment (first of all, production machinery), the poor availability of active substances and excipients in small packages, and the challenges associated with regulatory control and oversight over the quality of compounded medicinal products.CONCLUSIONS. Further stimulation of the active development of compounding pharmacies requires further investigation into their operation in other regions, which will help to develop legal arrangements for the federal and regional state support of compounding pharmacies, procure up-to-date materials and equipment, and train the staff for compounding pharmacies.

Gamma radiation’s influence on the tensile characteristics of waste animal fiber reinforced biocomposites

This study involves the preparation of polymer composites using untreated and treated chicken feather, leather, and cow hair fiber in combination with unsaturated polyester resin (UPR) and analyzing the effect of gamma radiation on tensile properties. These fibers were incorporated into the resin matrix at various weight percentages (2%, 5%, 7%, 10%, 12%, and 15%). Additionally, the nanoparticle ZnO was added in the composites as filler to improve the mechanical properties. The composites that utilized treated chicken feather fibers yielded superior results in comparison to those that relied on untreated fibers. Prepared composites outperformed neat composites when inorganic components were added as filler to UPR. Composite materials’ mechanical properties, particularly their tensile strength and modulus, can be improved by combining cow hair feather and chicken feather mixed fibers with ZnO filler and gamma radiation modification, according to this study. The morphological and spectroscopic analysis provides supporting evidence for the mechanical strength between the fibers and the resin. Ionizing gamma radiation modification of the fiber resulted in superior tensile characteristics. The optimized composites of animal fibers were then subjected to gamma radiation of variable dose of 0, 2.5, 5 and 7.5 kGy. The tensile properties were found to be the maximum at 5 kGy. Scanning electron microscopy was used to investigate the structural changes caused by the incorporation of animal fibers (chicken feather and cow hair) and ZnO. Composite material and UPR functional group identification were achieved by means of Fourier Transform Infrared Spectroscopy (FTIR).

Outcomes of different steroid dosing regimens in critical Covid-19 pneumonia at a Kenyan hospital: A retrospective cohort study.

Among therapeutic options for severe and critical COVID- 19 infection, dexamethasone six milligrams once daily for ten days has demonstrated mortality benefit and is guideline recommended at this dose. In practice, variable doses of steroids have been used, especially in critical care settings. Our study aimed to determine the pattern of steroid dosing and outcomes in terms of critical care mortality, occurrence of dysglycaemias, and occurrence of superadded infections in patients with critical COVID-19. A retrospective cohort study was carried out on all eligible patients admitted to the Aga Khan University Hospital, Nairobi, with critical COVID-19 between 1st March 2020 and 31st December 2021. The intervention of interest was corticosteroids quantified as the average daily dose in milligrams of dexamethasone. A steroid dose of six milligrams once a day was compared to high dose steroid dosing, which was defined as any dose greater than this. The primary outcome measure was ICU mortality and secondary outcomes included occurrence of dysglycaemias, superadded infections and duration of critical care admission. The study included 288 patients. The median age was 61.2 years (IQR: 49.7, 72.5), with 71.2% of patients being male. The most common comorbidities were diabetes mellitus (60.7%), hypertension (58%), and heart disease (12.2%). The average oxygen saturation and C-reactive protein at admission were 82% [IQR: 70.0-89.0]and 113.0 [IQR: 54.0-186.0], respectively. Fifty-eight percent of patients received a standard dose (6mg) of steroids. The mortality rate was higher in the high-dose group compared to the standard-dose group; however, the difference was not statistically significant (47.9% vs 43.7% p = 0.549). The two most common steroid associated adverse effects were uncomplicated hyperglycemia (62.2%) and superimposed bacterial pneumonia (20.1%). The high-dose group had a higher incidence of uncomplicated hyperglycemia compared to the standard-dose group (63.6% vs 61.1%). However, the incidence of diabetic ketoacidosis was lower in the high dose group (0.6% vs 6.6%). Oxygen saturation at admission was associated with survival where it was lower among non-survivor patients with critical COVID-19. The study found that high-dose steroids in the treatment of critically ill patients with COVID-19 pneumonia did not confer any mortality benefit and were associated with an increased risk of dysglycemia and superimposed infections.

Impact of Partial Body Shielding from Very High Dose Rates on Untargeted Metabolomics in Biodosimetry.

A realistic exposure to ionizing radiation (IR) from an improvised nuclear device will likely include individuals who are partially shielded from the initial blast delivered at a very high dose rate (VHDR). As different tissues have varying levels of radiosensitivity, e.g., hematopoietic vs gastrointestinal tissues, the effects of shielding on radiation biomarkers need to be addressed. Here, we explore how biofluid (urine and serum) metabolite signatures from male and female C57BL/6 mice exposed to VHDR (5-10 Gy/s) total body irradiation (TBI, 0, 4, and 8 Gy) compare to individuals exposed to partial body irradiation (PBI) (lower body irradiated [LBI] or upper body irradiated [UBI] at an 8 Gy dose) using a data-independent acquisition untargeted metabolomics approach. Although sex differences were observed in the spatial groupings of urine signatures from TBI and PBI mice, a metabolite signature (N6,N6,N6-trimethyllysine, carnitine, propionylcarnitine, hexosamine-valine-isoleucine, taurine, and creatine) previously developed from variable dose rate experiments was able to identify individuals with high sensitivity and specificity, irrespective of radiation shielding. A panel of serum metabolites composed from previous untargeted studies on nonhuman primates had excellent performance for separating irradiated cohorts; however, a multiomic approach to complement the metabolome could increase dose estimation confidence intervals. Overall, these results support the inclusion of small-molecule markers in biodosimetry assays without substantial interference from the upper or lower body shielding.

Inhibition of autophagy as a novel treatment for neurofibromatosis type 1 tumors.

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutation of the NF1 gene that is associated with various symptoms, including the formation of benign tumors, called neurofibromas, within nerves. Drug treatments are currently limited. The mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib is used for a subset of plexiform neurofibromas (PNs) but is not always effective and can cause side effects. Therefore, there is a clear need to discover new drugs to target NF1-deficient tumor cells. Using a Drosophila cell model of NF1, we performed synthetic lethal screens to identify novel drug targets. We identified 54 gene candidates, which were validated with variable dose analysis as a secondary screen. Pathways associated with five candidates could be targeted using existing drugs. Among these, chloroquine (CQ) and bafilomycin A1, known to target the autophagy pathway, showed the greatest potential for selectively killing NF1-deficient Drosophila cells. When further investigating autophagy-related genes, we found that 14 out of 30 genes tested had a synthetic lethal interaction with NF1. These 14 genes are involved in multiple aspects of the autophagy pathway and can be targeted with additional drugs that mediate the autophagy pathway, although CQ was the most effective. The lethal effect of autophagy inhibitors was conserved in a panel of human NF1-deficient Schwann cell lines, highlighting their translational potential. The effect of CQ was also conserved in a Drosophila NF1 in vivo model and in a xenografted NF1-deficient tumor cell line grown in mice, with CQ treatment resulting in a more significant reduction in tumor growth than selumetinib treatment. Furthermore, combined treatment with CQ and selumetinib resulted in a further reduction in NF1-deficient cell viability. In conclusion, NF1-deficient cells are vulnerable to disruption of the autophagy pathway. This pathway represents a promising target for the treatment of NF1-associated tumors, and we identified CQ as a candidate drug for the treatment of NF1 tumors.

Intratumoral Chemotherapy: The Effects of Drug Concentration and Dose Apportioning on Tumor Cell Injury.

The addition of intravenous (i.v.) chemotherapy to i.v. immunotherapy for patients with lung cancer results in improved overall survival but is limited by synergistic side effects and an unknown, highly variable final cytotoxic dose within the tumor. The synergy between i.v. chemo- and immunotherapies is hypothesized to occur as a result of cell injury caused by chemotherapy, a mechanism demonstrated to drive antigen presentation within the tumor microenvironment. Intratumoral delivery of chemotherapy may thus be optimized to maximize tumor cell injury. To assess the balance between the damage versus the death of tumor cells, we developed a computational model of intratumoral dynamics within a lung cancer tumor for three different chemotherapy agents following direct injection as a function of location and number of injection sites. We based the model on the morphology of a lung tumor obtained from a thoracic CT scan. We found no meaningful difference in the extent of tumor cell damage between a centrally injected versus peripherally injected agent, but there were significant differences between a single injection versus when the total dose was apportioned between multiple injection sites. Importantly, we also found that the standard chemotherapeutic concentrations used for intravenous administration were effective at causing cell death but were too high to generate significant cell injury. This suggests that to induce maximal tumor cell injury, the optimal concentration should be several orders of magnitude lower than those typically used for intravenous therapy.

Beta radiation-induced thermoluminescence in pure and rare earth doped ZrO2 prepared by pechini-type sol-gel

Thermoluminescence properties of ZrO2, ZrO2:Gd3+, ZrO2:Gd3+–Dy3+, ZrO2:Gd3+–Yb3+, ZrO2:Gd3+–Er3+ and ZrO2:Gd3+–Sm3+ phosphors synthesized by Pechini method were investigated. XRD measurement suggested that all the samples are monoclinic and tetragonal multiphase. Crystallite size measured using SEM is around 200 nm–250 nm. The Tmax–TSTOP, variable dose and glow curve fitting methods were applied to the phosphors and reusability, dose responses and fading characteristics were examined. The phosphors exhibit a natural TL emission which disappeared after heat treatment. The glow curves of the pure ZrO2 have thirteen individual glow peaks, which include the peaks reported for the monoclinic and tetragonal phases. Although some peaks emerge at low irradiation doses, others can only be observed at high doses. Moreover, although the dopes blanched some of the peaks of pure ZrO2, they made others more intense. These peaks can be interpreted as if they emerged caused by the rare earth doping into the matrix material. On the other hand, Gd3+, Dy3+, Yb3+, Er3+ and Sm3+ dopes did not alter the peak temperatures of the matrix material. As a result, the individual peak intensities are very sensitive to the dopes. Fundamental trapping parameters of the trap levels were calculated, and the results are in good agreement with the given values of activation energies in the literature. Fading experiments show the materials have both normal and abnormal fading characteristics in long and short-term storage.

Effect of Different Dose Rates on Dosimetric Parameters and Accuracy of the Pretreatment Quality Assurance During Intensity-modulated Radiotherapy Planning Using Anthropomorphic Phantom

Background: This study investigates the impact of varying dose rates on dosimetric parameters and pretreatment quality assurance (QA) accuracy in intensity-modulated radiotherapy (IMRT) planning using anthropomorphic phantoms. The research explores the dosimetric effects of different dose rates ranging from 100 to 600 monitor units per minute (MU/min) on parameters such as Homogeneity Index (HI), Conformity Index (CI), and dose to organs at risk (OAR). Method: Anthropomorphic phantoms, mimicking human tissues, were employed for simulation. Treatment plans were generated using the Eclipse Treatment Planning System, and dosimetric evaluations were conducted using cumulative dose-volume histograms (DVH). Furthermore, pretreatment patient-specific QA was performed using EPID portal dosimetry and Delta4 dosimetry system. Result: Treatment plans adhere to institutional protocol, ensuring the target receives ≥95% of the prescription dose while meeting OAR constraints. All plans maintain target homogeneity and conformality, keeping maximum doses within the target below 107%. Low dose plans exhibit superior target coverage, conformality, and homogeneity compared to higher doses. However, increased dose rates elevate delivered Monitor Units and maximum doses to critical structures. Gamma passing rates vary with dose rates, with the lowest at 100 MU/min and the highest at 400 MU/min for 1% 1mm criteria. Dosimetric evaluations using Delta 4 and EPID QA methods confirm plan validity across different dose rates. Conclusion: Low dose rate dosimetry is superior to higher rates for target and organ-at-risk (OAR) delivery, albeit prolonging delivery time and affecting internal organ motion. Portal dosimetry offers a faster, more convenient tool for IMRT pretreatment quality assurance (QA). Optimal results are achieved at 400 MU/min, enhancing gamma agreement between calculated and measured portal doses for complex fields. This improvement in QA enhances IMRT treatment delivery quality. However, patient-specific QA using the DELTA4 dosimetry system and ICRU 83 recommendations are insufficient for discussing dosimetric differences relevant to patient treatment.

Characterization of the First Prototype of an Angular Independent Silicon Diode Array for Quality Assurance in Stereotactic Radiosurgery

Quality assurance (QA) ensures the accurate and safe delivery of radiation treatment. However, there are several challenges for advanced radiotherapy techniques, such as stereotactic radiosurgery (SRS), where substantial doses of radiation with multi-directional beams and variable dose rates are delivered to specific areas. Current dosimeters lack high precision, exhibiting issues with dependency on the angle of measurement and the dose rate. This study investigates the characterization of a two-dimensional edgeless silicon diode array for QA in SRS. This detector underwent evaluation of its dose linearity, percentage depth dose (PDD), output factors (OFs), dose rate variability, and angular dependence with megavoltage linear accelerator beams. The edgeless array demonstrated a linear response in the direct detection of MV therapeutic X-rays with sensitivity of 6.95 × 10−3 ± 2.3 × 10−5 Gy/nC, and the percentage differences for PDD and OF measurements were found to be within 2% compared to the reference detector. A dose per pulse dependence of ±2% was demonstrated across the range of 0.12 to 0.39 mGy/pulse. The angular dependence was within 2% variation for irradiation angles greater than 80° and smaller than 120°; however, a maximum of 4% variation was observed with some diodes for angles between 80° and 120°. The improved performance of the edgeless array is likely to overcome limitations of the current dosimeters for SRS QA by operating without the need of any corrections.

Effect of pyrite on the treatment of chlorophenolic compounds with zero-valent iron-Fenton process under uncontrolled pH conditions: reaction mechanism and biodegradability

This current study explored the effect of pyrite on the treatment of chlorophenolic compounds (CP) by Fenton process with micron-sized zero-valent iron (ZVI) as the catalyst. The experiments were conducted in batch reactors with 100 mg L−1 CP, 0–0.02 M H2O2, and variable pyrite and ZVI doses (0–1 g L−1). Our findings show that while the reactor with 1 g L−1 ZVI as the only catalyst achieved only 10% CP removal efficiency due to rapid ZVI surface passivation and ZVI particle aggregation, the CP removal efficiency increased with increasing pyrite dose and reached 100% within couple of minutes in reactors with 0.8 g L−1 pyrite and 0.2 g L−1 ZVI. The CP removal was mainly driven by the oxidative treatment of CPs with some strong radicals such as hydroxyl radicals (•OH) while the adsorption onto the catalyst surface was only responsible for 10 to 25% of CP removals, depending on the type of CP studied. The positive impact of pyrite on CP removal by the ZVI/H2O2 system could be attributed to the ability of pyrite to (1) create an acidic environment for optimum Fenton process, (2) provide support material for ZVI to minimize ZVI particle agglomeration, and (3) stimulate iron redox cycling for improved surface site generation. Following oxidative Fenton treatment, the degradation intermediate products of CPs, including some aromatic compounds (benzoquinone, hydroquinone, etc.) and organic acids (e.g., acetic acid), became more biodegradable in comparison to their mother compounds. Overall, the treatment systems with a mixture of ZVI and pyrite as catalyst materials could offer a suitable cost-effective technology for the treatment of wastewater containing biologically non- or low-degradable toxic compounds such as chlorophenols.

Therapeutic Enoxaparin Dosing in Obesity.

This review aims to systematically summarize the available data on efficacy and safety of therapeutic enoxaparin in obese patients and to identify gaps to guide future research. Medline and Embase were systematically searched for eligible studies (last searched December 20, 2023). Studies were included if they reported on therapeutic dosing regimens, adverse bleeding, thrombotic outcomes, or antifactor Xa (AFXa) monitoring in obese adult patients. The systematic review management tool Covidence was used to manage the study selection and data extraction process. The reference list from eligible studies was screened to determine any additional eligible studies. Sixteen studies were included in the analysis. Studies used a variety of doses, indications, and study designs making comparison difficult. Twelve studies reported the incidence of thrombotic events (median = 1.3% [interquartile range [IQR] = 0.3%-2.3%]) and all studies reported the incidence of bleeding events (median = 5.7% [IQR = 2.4%-14.5%]). Two of the 8 studies analyzing the influence of weight/body mass index (BMI) or dose per kg on AFXa levels reported statistically significant results. One study concluded that BMI did not affect achievement of target AFXa levels. However, the second study found that dosing using actual body weight was an independent predictor of supratherapeutic AFXa levels in the obese population. This is the first comprehensive review with a focus on therapeutic dosing of enoxaparin in obesity and has been conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. Seven of the included studies were published since 2018 indicating that new evidence on this topic is emerging. There was inadequate evidence to support an optimal dosing strategy in obese patients due to the heterogeneity of the studies. The AFXa monitoring may be appropriate to guide dosing in this population. Further research is required to determine a suitable dosing regimen.