Dose-response Sensitivity Research Articles

Threshold for increased liver weight is protective of other effects in Peromyscus exposed to PFNA.

Perfluorononanoic acid (PFNA) is a commercially relevant, long-chain (8 fully fluorinated carbon) perfluorinated carboxylic acid. PFNA has limited terrestrial ecotoxicity data and is detected in humans, animals, and the environment. This study is the fourth in a series with the objective of investigating the toxicity of a suite of per- and polyfluoroalkyl substances (PFAS) detected on military installations in a mammal indigenous to North America. Peromyscus leucopus (white-footed mice, ∼25/sex/dose) were exposed via oral gavage to either 0, 0.03, 0.14, 1, or 3 mg PFNA/kg-d for 112 consecutive days (4 wk premating exposure followed by an additional 12 wk of exposure after onset of mating). Parental generation animals were assessed for potential reproductive and developmental effects, organ weight changes, thyroid modulation, and immunotoxicity. Pup weight and survival were assessed at postnatal days 0, 1, 4, 7, and 10. Change in liver weight was determined to yield the most sensitive dose response according to benchmark dose analysis, and serves as the most protective point of departure (BMDL = 0.37 mg/kg-d PFNA). Other effects of PFNA exposure included reduced formation of plaque-forming cells, which are indicative of functional immune deficits (BMDL = 2.31 mg/kg-d); decreased serum thyroxine (BMDL = 0.93 mg/kg-d) without changes in some other hormones; and increased stillbirths (BMDL = 0.61 mg/kg-d PFNA). Pup weight and survival were not affected by PFNA exposure. Combined with data from previous studies, data from Peromyscus provide a One Health perspective on health effects of PFAS.

Improved sensitivity and ambient light stability of radiochromic plastic dosimeters through composite azo compounds

The aim of this study is to evaluate and compare the dose sensitivity and ambient light resistance of radiochromic plastic dosimeters (RPDs) incorporating mixed azo compound with those incorporating individual azo compounds.RPDs were fabricated using a mixture of polyurethane, leuco dye, initiator, and solvent.In this study, three azo compounds (tartrazine, sunset yellow, and allura red) were incorporated into RPDs either individually or in combination. Thus, we produced five dosimeter types: one original RPD (A) without azo compounds, three RPDs (B, C, D) with individual azo compounds, and one RPD (E) with mixed azo compounds. Initially, to compare dose response and sensitivity, one group of each sample was delivered to doses ranging from 0.2 Gy to 3 Gy with 6 MV photon beams at 600 cGy/min. To assess ambient light resistance, another group was exposed to light for varying durations. Following irradiation and light exposure, optical density (OD) was obtained using a cone-beam optical CT scanner for each group. Wavelength spectra for each sample were acquired using a spectrometer. This study encompassed analysis and comparison of dose response curves, sensitivity, and netOD-time graphs among samples. Additionally, the absorption wavelength spectra of the samples were compared with the light spectrum emitted by a light bulb.The dose response curves were represented by linear functions, with the slope indicating the sensitivity of each sample. The sensitivity for samples A-E were 0.0759, 0.0988, 0.0902, 0.0809, and 0.1013 ΔOD/Gy, respectively. Samples B-E demonstrated increases in sensitivity of 30.1%, 18.8%, 6.5%, and 33.4%, respectively, compared to sample A. Sample E, which incorporated mixed azo compounds, demonstrated the highest sensitivity and remarkable resistance to ambient light. The results suggested that all azo compounds influenced the sensitivity of the RPDs, and that mixed azo compounds does not reduce the sensitivity of the RPDs. The ambient light resistance was dictated by the overlap between the light bulb's wavelength and the azo dyes' absorption range, which for mixed azo compounds spanned widely from 300 nm to 600 nm. The mixed azo compounds, as opposed to a single azo compound, allowed for the absorption of a wider range of light wavelengths, leading to an increased resistance to ambient light.Our study demonstrated that the inclusion of azo compounds enhances the sensitivity of RPDs. Specifically, the use of mixed azo compounds provided the highest sensitivity and exhibited superior resistance to ambient light. This improved performance can be attributed to the broader absorption wavelength spectrum achievable with mixed azo compounds, enabling absorption across a wider range of light wavelengths. These findings highlight the potential utility of mixed azo compounds in the fabrication of RPDs, enhancing their function as highly sensitive and resistant dosimeters to ambient light.

Intramammary Infusion of Micronised Purified Flavonoid Fraction (MPFF) in Mastitis-Diagnosed Dairy Cows Naturally Infected by Staphylococcus spp. in the Late Lactation.

Infectious mastitis is the most prevalent health problem in dairy cattle that can result in permanent economic losses on dairy farms. The micronised purified flavonoid fraction (MPFF) is a biocompatible active polyphenolic compound derived from flavonoid glycosides which exhibits several antimicrobial, anti-inflammatory, and phlebotonic properties. The goal was to assess the effects of an alternative therapy for mastitis based on MPFF intramammary infusions in late lactation in dairy cows naturally infected by Staphylococcus spp. The California Mastitis Test (CMT scores) was performed to detect mastitis-positive quarters in twelve dairy farms. All cows were screened for immune response by measuring somatic cell counts (SCCs; cells/mL) in milk samples from each quarter. In addition, bacteriological identification, pathogenic bacterial isolates, and total bacterial counts (TBCs; CFU/mL) were assessed before (day 0, last milking day) and after (day 3 post-calving) MPFF application. Antimicrobial sensitivity patterns of the pathogenic isolated bacteria were evaluated. Finally, cure rates (%) were determined for each MPFF treatment. Around 15 mastitis-related genera were isolated. Staphylococcus aureus (25.2%) and coagulase-negative Staphylococci (CNS; 22.4%) were the most prevalent pathogens. No statistical differences were observed in SCCs and TBCs after low, medium, and high MPFF dose administration in S. aureus-positive mastitis cases (p > 0.05). However, differences were observed in SCCs and TBCs after medium and high MPFF dose administration in CNS-positive quarters (p < 0.05). The pathogenic bacteria isolate reduction after MPFF applications showed a dose-response fashion (p < 0.01) while isolates obtained from controls and low MPFF-treated quarters remained similar, irrespective of the pathogen (p > 0.05). Sensitivity patterns were variable, although S. aureus remained resistant, irrespective of the MPFF dose. However, CNS showed a dose-response sensitivity pattern. Finally, the cure rate (%) on day 3 post-partum improved significantly using medium and higher MPFF doses in CNS-positive quarters (p < 0.05). In conclusion, MPFF treatment was found to be more effective for CNS-positive cases in the late lactation due to noticeable dose-specific responses regarding somatic cells, bacterial counts, sensitivity patterns, and cure rates in dairy cattle.

The variability of single grain quartz luminescence properties investigated using EMCCD imaging

Optically stimulated luminescence (OSL) signals from individual quartz grains are frequently used for equivalent dose and age determination in luminescence dating. Typically, signals from individual grains are stimulated with a focussed solid-state laser and detected via a photomultiplier tube. In contrast to the light-emitting diodes (LEDs) usually used when stimulating multiple-grain aliquots, the laser has a much higher stimulation power density. An absolute value for the effective stimulation power cannot easily be quantified, and the power delivered to each grain cannot be considered consistent throughout a measurement sequence. Both intra- and inter-sample variability in single grain luminescence signals parameters such as dose response form, decay rate, and sensitivity have long been recognised, however there remains uncertainty over how much of this variability is intrinsic to quartz grains or whether some should be attributed to variation in the effective stimulation power associated with the laser system. To better characterise intrinsic variability of single quartz OSL signals, an electron multiplier charge coupled device (EMCCD) attachment for the Risø reader was used for detecting and imaging luminescence signals. Whilst the EMCCD system currently offers a lower detection sensitivity when compared to the laser system, the ability to use LEDs for stimulation of the OSL signal circumvents the power variability associated with the laser system and allows an investigation of intrinsic variability to be made. In this paper, signal intensity and the composition of components in single grain luminescence signals are considered, and curve deconvolution is undertaken to calculate photo ionisation cross-sections for single grain quartz signals. For the samples considered, intra-sample variability in these characteristics is observed in single grain quartz luminescence signals imaged using an EMCCD.

Methyl thymol blue solution and film dosimeter for high dose measurements

A novel radio-chromic solutions and polyvinyl alcohol (PVA) films with different concentrations of methyl thymol blue (MTB) dye have been investigated and studied for high dose applications. The MTB dosimeters were exposed to irradiation using gamma ray 60Co source from 2.5 to 50 kGy for film, and from 0.10 to 2.5 kGy for solutions. The radio-chromic dosimeters were investigated using ultraviolet visible (UV–Vis) spectrophotometry. The effect of MTB dye concentration, relative humidity, and stability of the dosimeters were investigated. The results show that the dose response sensitivity of the dosimeters improved significantly with increasing the absorbed dose and MTB dye concentrations. The un-irradiated and irradiated dosimeters show a perfect stability for one week. Hence, these films can be used as dosimeters in industrial radiation processing. The study shows that the useful dose range is in the range of 2.5–20 kGy and 0.1–1.2 kGy, for film and solution dosimeters, respectively.

Serum trace metal association with response to erythropoiesis stimulating agents in incident and prevalent hemodialysis patients

Alterations in hemodialysis patients’ serum trace metals have been documented. Early studies addressing associations levels of serum trace metals with erythropoietic responses and/or hematocrit generated mixed results. These studies were conducted prior to current approaches for erythropoiesis stimulating agent (ESA) drug dosing guidelines or without consideration of inflammation markers (e.g. hepcidin) important for regulation of iron availability. This study sought to determine if the serum trace metal concentrations of incident or chronic hemodialysis patients associated with the observed ESA response variability and with consideration to ESA dose response, hepcidin, and high sensitivity C-reactive protein levels. Inductively-coupled plasma-mass spectrometry was used to measure 14 serum trace metals in 29 incident and 79 prevalent dialysis patients recruited prospectively. We compared these data to three measures of ESA dose response, sex, and dialysis incidence versus dialysis prevalence. Hemoglobin was negatively associated with ESA dose and cadmium while positively associated with antimony, arsenic and lead. ESA dose was negatively associated with achieved hemoglobin and vanadium while positively associated with arsenic. ESA response was positively associated with arsenic. Vanadium, nickel, cadmium, and tin were increased in prevalent patients. Manganese was increased in incident patients. Vanadium, nickel, and arsenic increased with time on dialysis while manganese decreased. Changes in vanadium and manganese were largest and appeared to have some effect on anemia. Incident and prevalent patients’ chromium and antimony levels exceeded established accepted upper limits of normal.

Evaluation of ferrous benzoic methylthymol-blue gel as a dosimeter via magnetic resonance imaging.

In previous studies, methylthymol-blue and benzoic acid have been introduced as a diffuser limiter and sensitivity enhancer in the gel dosimeter composition, respectively. This work focused on analyzing a formulation of the Fricke gel dosimeter consisting of methylthymol-blue and benzoic acid through magnetic resonance imaging. The gel dosimeter samples were irradiated using 6, 10, and 15 MV photons with different levels of doses and read using a 1.5T scanner in order to evaluate the dose-response sensitivity and to study the effect of benzoic acid concentration, diffusion coefficient and temperature and to determine the temporal stability of the gel dosimeter. Inspection of radiological properties revealed that this gel dosimeter can be considered as a tissue equivalent medium. Within the dose range 0 to 1000cGy, the R1 sensitivity and R2 sensitivity of the gel dosimeter equaled 0.058±0.003 and 0.092±0.004s-1Gy-1, respectively. The diffusion coefficient was less than 0.85±0.02mm2h-1 for doses higher than 200cGy. In addition, by changing the temperature from 15C to 25, the R1 sensitivity and R2 sensitivity decreased about 5 and 11%, respectively. Further, no significant energy and dose rate dependence were observed over photon energies of 6, 10, and 15 MV and over the range 65 to 525cGymin-1. Based on our observation, the ferrous benzoic acid methylthymol-blue gel dosimeter can be suggested to measure the dose distribution. Further analysis is required to clarify its performance in clinical situations.

Temperature dependence and temporal stability of stacked radiochromic sheets for three-dimensional dose verification.

Recently a novel radiochromic sheet dosimeter, termed as PRESAGE sheets, consisting of leuco crystal violet dye and radical initiator had been developed and characterized. This study examines the dosimeter's temporal stability and storage temperature dependence postirradiation, and its applicability for dose verification in three dimensions (3D) as a stack dosimeter. PRESAGE sheets were irradiated using 6MV photons at a dose range of 0-20Gy with the change in optical density measured using a flatbed scanner. Following their irradiation, PRESAGE sheets were stored in different temperature environments (-18 °C, 4 °C, and 22 °C) and scanned at different time points, ranging from 1 to 168h postirradiation, to track changes in measured signal and linearity of dose response. Multiple PRESAGE sheets were bound together to create a 12×13×8.7cm3 film stack, with EBT3 film inserted between the sheets in the central region of the stack, that was treated using a clinical VMAT plan. Based on the results from the time and storage temperature study, two-dimensional (2D) relative dose distribution measurements in PRESAGE were acquired promptly following irradiation at selected planes in the coronal, sagittal, and axial orientation of the film stack and compared to the treatment planning system calculations in their respective axes. Dose distribution measurements on the coronal axis of the stack dosimeter were also independently verified using EBT3 film. The dose response was observed to be linear (R2 >0.995) with sheets stored in colder temperatures retaining their signal and dose response sensitivity for extended periods postirradiation. Sheets stored in 22 °C environment should be measured within an hour postirradiation. Sheets stored in a 4 °C and -18 °C environment can be scanned up to 20- and 72 h postirradiation, respectively, while preserving the integrity of their dose response sensitivity and linearity of dose response within a mean absolute percent error of 2.0%. For instance, at 20 h postirradiation the dose response sensitivity for sheets stored in a -18 °C, 4 °C, and 22 °C temperature environment was measured to be 97%, 91%, and 77% of their original values measured within an hour postirradiation, respectively. The 2D gamma pass rate for central slices exceed 95% for PRESAGE film stack compared with treatment planning system on selected planes in the axial, coronal, and sagittal orientation and EBT3 film in the coronal orientation using a 2D gamma index of 2%/2mm. The gamma pass rate in comparing the calculated dose distribution with the measured dose distribution from PRESAGE-LCV was observed to decrease in sheets scanned at later elapsed times postirradiation. In one example, the gamma pass rate for 2%/2mm criteria in the coronal plane was observed to decrease from 97.7% pass rate when scanned within an hour postirradiation to 92.1% pass rate when scanned at 20 h postirradiation under room temperature conditions. This is the first study to demonstrate that the temporal stability of PRESAGE sheets can be enhanced through its storage in colder temperature environments postirradiation and that sheets as a film stack dosimeter hold promise for precise relative dose distribution measurements in 3D where advanced optical CT is unavailable.

Abstract 6149: An innovative integrated cloud-based data portal for orthotopic patient-derived xenografts (O-PDX) available through the Childhood Solid Tumor Network (CSTN)

Abstract Despite making significant advances over the past 25 years in our understanding of the most common adult solid tumors, much less is known about childhood solid tumors. We have previously described a protocol to produce orthotopic patient-derived xenografts (O-PDX) at diagnosis, recurrence and autopsy. These O-PDX models provide both in vivo and in vitro systems to study mechanisms of disease origin, tumor progression and preclinical testing. Here, we present an innovative cloud-based all-in-one data portal to explore various biological features of these pediatric O-PDX models. The vast diversity of the collected childhood solid tumors is represented in 166 O-PDX models, consisting of 21 diagnoses including Neuroblastoma, Osteosarcoma, Rhabdomyosarcoma, and a large number of rare solid tumors including Ewing Sarcoma, Desmoplastic Small Cell Round Tumor, Fibrosarcoma, High Grade Sarcoma, Liposarcoma, Retinoblastoma, Rhabdoid Tumor and Synovial Sarcoma. The O-PDX models have been characterized and compared to the original patient tumor using various methods and assays including histology, electron microscopy, short tandem repeat DNA profiling, chemical compound screening as well as genomic sequencing (whole genome sequencing, whole exome sequencing, and RNA Sequencing) and clonal analysis to determine the clonal population in the O-PDX. Somatic genetic mutations as well as clonal architecture is retained in the majority of O-PDX tumors. The data on O-PDX models can now be visualized and compared in our web-based CSTN data portal on St Jude Cloud (www.stjude.cloud). The user-friendly interface allows both gene and sample level search and visualization. For genomics variations, the presence or absence of a particular variant can be observed through interactive heatmaps. In addition to genomic and transcriptomic profiles, some of these models have extensive epigenomic and proteomic profiling which are integrated into the portal. We have also included chemical sensitivity heatmaps and dose response curves for common oncology drugs using primary cultures of the O-PDXs and cell lines. Importantly, the raw genomics sequencing data is also available from St Jude Cloud, following a straightforward application and approval process for access. In summary, the integration of data from multi-omics and beyond at the CSTN data portal provides a rich resource for both academic and industrial research community to find the appropriate models to advance the knowledge and therapeutic solutions to the catastrophic childhood solid tumors. *co-first #co-corresponding Citation Format: Asa Karlstrom, Ti-Cheng Chang, Darrell Gentry, Xin Zhou, Elizabeth Stewart, Brittney Gordon, Sara M. Federico, Rachel Brennan, Michael R. Clay, Sharon Frase, Armita Bahrami, Xiang Chen, Anang A. Shelat, Nathaniel R. Twarog, Daniel Alford, Anthony Woodard, Edgar Sioson, Irina McGuire, Cynthia Williams, Nedra Robison, Brandon McMahan, Ashok K. Boddu, Swapnali Mohite, Kirby Birch, Clay McLeod, Michael Rusch, Alberto Pappo, Keith Perry, Gang Wu, Ed Suh, Michael A. Dyer. An innovative integrated cloud-based data portal for orthotopic patient-derived xenografts (O-PDX) available through the Childhood Solid Tumor Network (CSTN) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6149.

Particles size increase assisted enhancement of thermoluminescence emission in gadolinium and dysprosium oxide doped phosphate glasses

This paper presents results of research on the influence of particles size of Gd2O3 and Dy2O3 doped phosphate glasses on the intensity of thermoluminescence (TL) signals. The obtained glasses were investigated towards potential application in high dose radiation measurements. Simultaneously, next to the glass powders, the glass/polytetrafluoroethylene composite detectors were prepared and used to study dosimetric signal dependencies and influence of glass particles size on their TL behavior. The thermoluminescence dosimetry (TLD) technique was used as the main investigation tool to study detectors dose response. Next to the sole effect of the glass particles size, the results present also an influence of the rare earth dopants on intensity of TL signal. The obtained data present the dosimetric properties of raw and doped phosphate glass (effect of particles size, dose response and radiation sensitivity). It has been found that incorporation of rare earth oxides into glass matrix changes substantially the thermoluminescent behavior of a pure phosphate glass. The highest luminescence yield was found for the samples with the largest glass particles (up to 1000 μm). The incorporation of dysprosium or gadolinium ions into the glass matrix influences both the structure of the electron traps in the glass matrix and TL emission intensity vs. particles size. The dependence of the thermoluminescence signals intensity vs. particles size for all samples can be considered as a saturation type curve. The investigated phosphate glasses exhibit good thermoluminescence properties for the high energy beta radiation dose measurement applications.

Scintillation and dosimetric properties of Ce-doped MgAl2O4 single crystals

The undoped and Ce-doped MgAl2O4 single crystals were synthesized by the floating zone method equipped with four xenon arc lamps, and the photoluminescence (PL), scintillation, and dosimetric properties were investigated. The Ce-doped crystals showed PL emission peaks at around 420 and 720 nm. The former was ascribed to the 5 d-4f transition of Ce3+ ion, and the latter was ascribed Mg deficiency. The PL decay time profiles of the Ce-doped crystals exhibited the fast decay, and the decay time constants were the typical value of others Ce-doped materials. Thus, the decay time constants were attributed to the 5 d-4f transitions of Ce3+ ion. In addition, optically-stimulated luminescence (OSL) signals could be detected in all the crystals when the stimulation wavelength was 470 nm. The OSL dose response functions showed linearly proportional relationship from 10 to 1000 mGy in all the Ce-doped crystals. The thermally-stimulated luminescence (TSL) glow curves exhibit three peaks due to antisite of Al3+ ion, V center and antisite of Mg2+ ion. All the Ce-doped crystals showed improved TSL intensity and dose response sensitivity compared the undoped crystal. The 0.2 and 1% Ce-doped crystals showed linearly response at the dose range of the 0.1–1000 mGy.

Diminishing Returns From Ultrahypofractionated Radiation Therapy for Prostate Cancer

More than a decade of randomized controlled trials in prostate cancer has established a positive radiation dose response at moderate doses and a consistently low α/β ratio in the linear quadratic model for moderate hypofractionation. The recently published large randomized trial of ultrahypofractionated prostate cancer radiation therapy adds substantially to our current knowledge of dose response and fractionation sensitivity. Randomized trials of dose escalation and hypofractionation of radiation therapy were meta-analyzed to yield the overall best estimate of the α/β ratio. Additionally, a putative saturation of dose effect previously reported at approximately 80 Gy EQD2 was investigated by mapping the relative effectiveness assessed at 5 years onto a single reference dose-response curve. Meta-analysis of 14 randomized trials including 13,384 patients yielded a best estimate of α/β = 1.6 Gy (95% confidence interval, 1.3-2.0 Gy) but with highly significant heterogeneity (I2 = 70%, P = .0005). Further analysis indicated an association between increasing dose per fraction in the experimental arm and increasing α/β ratio (slope, 0.6 Gy increase in α/β per Gy increase in fraction size; P = .017). This deviation from the linear quadratic model could, however, also be explained by biochemical control maxing out at doses above approximately 80 Gy. Biochemical control data from randomized controlled trials of dose-per-fraction escalation in prostate cancer radiation therapy are inconsistent with the presence of a constant fractionation sensitivity in the linear-quadratic model and/or a monotonic dose response for biochemical control beyond 80 Gy equivalent dose. These observations have a potential effect on the optimal doses in future trials and the interpretation of ongoing trials of ultrahypofractionation.

Ultrahypofractionation Should be a Standard of Care Option for Intermediate-Risk Prostate Cancer

Ultrahypofractionation Should be a Standard of Care Option for Intermediate-Risk Prostate Cancer

Verification of lithium formate monohydrate in 3D-printed container for electron paramagnetic resonance dosimetry in radiotherapy

The nondestructive dosimetry achieved with electron paramagnetic resonance (EPR) dosimetry facilitates repetitive recording by the same dosimeter to increase the reliability of data. In precedent studies, solid paraffin was needed as a binder material to make the lithium formate monohydrate (LFM) EPR dosimeter stable and nonfragile; however, its use complicates dosimetry. This study proposes a newly designed pure LFM EPR dosimeter created by inserting LFM into a 3D-printed container. Dosimetric characteristics of the LFM EPR dosimeter and container, such as reproducibility, linearity, energy dependence, and angular dependence, were evaluated and verified through a radiation therapy planning system (RTPS). The LFM EPR dosimeters were irradiated using a clinical linear accelerator. The EPR spectra of the dosimeters were acquired using a Bruker EMX EPR spectrometer. Through this study, it was confirmed that there is no tendency in the EPR response of the container based on irradiation dose or radiation energy. The results show that the LFM EPR dosimeters have a highly sensitive dose response with good linearity. The energy dependence across each photon and electron energy range seems to be negligible. Based on these results, LFM powder in a 3D-printed container is a suitable option for dosimetry of radiotherapy. Furthermore, the LFM EPR dosimeter has considerable potential for in vivo dosimetry and small-field dosimetry via additional experiments, owing to its small effective volume and highly sensitive dose response compared with a conventional dosimeter.

Optimization for stability of the deformable FlexyDos3D radiation dosimeter and curing effects

Previous formulations of the FlexyDos3D dosimeter have shown significant changes in the dose-response over time. In this study, various formulations of the dosimeter were created and tested to see if this stability could be improved. A dosimeter that was stable over a three-day period was found. Rapid manufacture of this dosimeter for patient-specific validation of radiotherapy treatments is desirable. The use of 3D printing manufacturing techniques for thermosetting polymers require high temperatures to cure the polymer within a reasonable time. The effect of different curing temperatures and times were investigated for the FlexyDos3D radiation dosimeter for its effect on stability. No significant difference in the dose-response was found for dosimeters cured for different curing times beyond an hour. A significant dose-response offset was found between dosimeters cured at different temperatures, but the dose-response sensitivity was the same.

Preliminary study of normoxic PAGAT polymer gel dosimeter by adding formaldehyde

The performance of normoxic PAG (nPAG) gel dosimeter with respect to spatial integrity, temperature sensitivity and dose-rate dependency makes it more reliable than PAG gel dosimeter. As a 3D dose distribution measurement in dosimetry, nPAG gel dosimeter with THPC as anti-oxidant, named PAGAT was studied. 2.9% mass concentration of the formaldehyde solution was added into PAGAT to solidify the gel, named PAGAT-f. The melting point of PAGAT-f polymer gel was increased by adding formaldehyde and can be stored at room temperature after gel preparation without refrigeration. After irradiation with a 9 MV LINAC, magnetic resonance imaging (MRI) is employed as readout modality. It’s found that by adding formaldehyde, R2-dose response of PAGAT-f is similar to PAGAT but the dose response sensitivity of PAGAT-f is better than that of PAGAT at low doses. The results prove the feasibility and good temporal stability of PAGAT-f for dose distribution measurement.

High dose sensitivity of N-(isobutoxymethyl)acrylamide polymer gel dosimeters with improved monomer solubility using acetone co-solvent

Normoxic N-(isobutoxymethyl)acrylamide polymer gel (NIBMAGAT) dosimeters have been prepared in deionized water with acetone as a co-solvent for radiotherapy with very low levels of turbidity. The polymer gel dosimeters were irradiated in a cubic water phantom using a 6 MV X-ray radiation beam of a medical linear accelerator for doses from 1 to 20 Gy. A 0.5 Tesla nuclear magnetic resonance spectroscopy was used to measure the transverse relaxation rate (R2) of un-irradiated and irradiated gel samples. The polymer dosimeter presents a linear dose response for doses up to 10 Gy with significant R2 sensitivity of 0.4776 s−1 Gy−1. A higher NIBMA monomer concentration results from higher NIBMA solubility in water and acetone enhances significantly (i.e. more than six times) the performance of NIBMAGAT polymer gel dosimeters for radiotherapy dosimetry. The key parameters such as dose rate, radiation beam energy and post irradiation stability up to 10 days were investigated. We found these parameters had no significant effect on the dose response and dose sensitivity of NIBMAGAT gel dosimeters.

A Zebrafish Behavior Assay for Assessing Anti-Epileptic Drug Efficacy

The availability of zebrafish larvae model of epileptic seizure provides opportunities to identify novel anticonvulsants for treatment of people with epilepsy. However, the major parameters of Zebrafishbehavior assay for assessing anti-epileptic drug efficacy existed disparity. In this study, we chose the high, medium, slow-speed moved distances and the total distances moved for seizure-like activity quantification in individual wells of a 48-well plate in the dark phase. Results also showed that the high-speed moved distances were given a more reasonable and sensitive dose-response curve than the total distances in zebrafish larvae model exposed to 10 mMpentylenetetrazole (PTZ). Moreover, this seizure-like swimming pattern was alleviated by the addition of either phenytoin (PHT) or valproate sodium (VPA), two commonly prescribed anti-epileptic drugs (AEDs). They exhibited concentration-dependent inhibition of both locomotor activity and PTZ-induced c-fostranscription, confirming their anticonvulsant characteristics. Whereas carbamazepine (CBZ) promoted zebrafish larvae movement by 26% at 30 μM and 116.7% at 100 μM, and sharply suppressed zebrafish larvae motility about 94.8% at 300 μM.C-fos expression significantly decreased at 30 μM and 300 μM CBZ, which was found to oppose various aspects of the PTZ-induced changes in activity. These results indicated that this zebrafish larvae model could be useful for studying drug efficacy, predicting drug targets and aiding our understanding of disease etiology.

Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory or High-Risk Leukemias: A Report from the LEAP Consortium

▪Despite the remarkable pace of characterizing the genomics of pediatric acute leukemias, the integration of real-time sequencing results into clinical practice has lagged. With increased availability of molecularly-targeted therapies, the promise of matching genetic lesions in patients' leukemia cells to treatment has not yet been fully realized.We established the first pediatric leukemia clinical genomics consortium in the United States, known as the Leukemia Precision-based Therapy (LEAP) Consortium, which includes 13 major pediatric cancer institutions. We hypothesized that it is feasible to identify and match, in real-time, actionable alterations with a targeted therapy for pediatric patients with relapsed, refractory or high-risk leukemias or myelodysplastic syndrome (MDS). Using a combination of a DNA-based next-generation sequencing panel and RNA-based gene fusion testing, followed by data review by our multidisciplinary molecular tumor board, we are conducting a clinical trial to test this hypothesis.To date, we have enrolled and reviewed data from 143 patients stratified by disease status: Cohort 1, patients with relapsed or refractory leukemias (n=93), and Cohort 2, patients with de novo high-risk leukemias or MDS (n=50). A matched targeted therapy (MTT) recommendation has been made for 72% (n=103) of patients, tiered based on the level of evidence linking the mutation to potential activity of targeted therapy in the context of each patient's disease (Tier 1: 11%, Tier 2: 4%, Tier 3: 41%, Tier 4: 6%, Tier 5: 10%). Of the 44 patients in Cohort 1 with clinical follow-up data, 5 (11%) had alterations in therapy made based upon sequencing results and MTT recommendation. These include the use of the MEK inhibitor trametinib for RAS mutant acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) (n=2), dasatinib for B-ALL and T-ALL with NUP214-ABL1 translocations (n=2) and ponatinib for B-ALL with an ABL1 T315I mutation (n=1). In addition, this genomic data refined diagnosis and supported additional germline assessment in a subset of patients.In parallel to the genomic sequencing, we are conducting high-throughput drug sensitivity (HTS) assays to study in vitro anti-leukemia effects of a panel of up to 120 targeted inhibitors in the context of leukemia-associated genetic alterations. Of the initial 106 accrued patients, 40 (38%) had adequate amounts of blood or bone marrow for in vitro drug testing. All samples were tested in the inhibitor panel assay, and 65% of the samples yielded interpretable results. Inhibitor screening data was compiled for all 12 patients with genetic alterations resulting in Tier 1, 2 or 3 MTT recommendations. This subset of patients had leukemias with two distinct molecular profiles: 1) oncogenic RAS signaling pathway mutations or 2) oncogenic tyrosine kinase alterations. Our molecular tumor board recommended trametinib for the first group of patients and tyrosine kinase inhibitors (TKIs), specific to the mutation, for the second group of patients. In vitro HTS data analysis demonstrated dose-response sensitivity of leukemia cells with RAS pathway mutations to trametinib, many of which had half-maximal inhibitory concentration (IC50) less than 50 nM. Similarly, leukemia cells from patients with FLT3, ABL1 or KIT mutations generally showed dose-responses to relevant TKIs with low IC50s. Overall, HTS data were concordant with MTT recommendations informed by the sequencing results.This first in the US multi-institutional prospective leukemia genomics trial brings state-of-the-art clinical genetic testing, assessment of prognostic biomarkers, selection of patients for germline testing, and targeted therapeutic treatment recommendations to children and young adults with high-risk, relapsed or refractory leukemias or MDS. Our collaboration provides a unique opportunity to perform sophisticated patient-specific in vitro drug testing assays to impact MTT discovery efforts, which we plan to validate in vivo using patient-derived xenograft models where feasible. We believe that a model like the LEAP Consortium has the potential to transform precision medicine approaches for children with high-risk leukemias and to inform future genomics-guided therapeutic trials and drug discovery efforts. DisclosuresTasian:Aleta Biopharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Incyte Corporation: Research Funding. Burke:JAZZ: Speakers Bureau; Shire: Speakers Bureau; AMGEN: Speakers Bureau. Tyner:AstraZeneca: Research Funding; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Janssen: Research Funding; Array: Research Funding; Constellation: Research Funding; Gilead: Research Funding; Aptose: Research Funding; Incyte: Research Funding; Genentech: Research Funding.

Prussian blue nanoparticles based lateral flow assay for high sensitive determination of clenbuterol

Prussian blue nanoparticles (PBNPs), one kind of metal organic frameworks with the general formula of Fe4[Fe(CN)6]3·nH2O, are increasing attractive due to their excellent properties. Here, with PBNPs as labels, a PBNP-based competitive lateral flow assay (LFA) for efficient and sensitive detection of clenbuterol was developed. With unique control structure, PBNPs are quite larger than most of the commonly used labels, meaning much fewer antibodies are needed in the probe to produce clearly visible results, which will bring a more sensitive dose-response relation between the analyte concentration and signal intensity. Under optimal conditions, the PBNP-based LFA showed a great linear relationship over the range of 0.5–5 ng mL−1 for clenbuterol. The visual limit of detection was 1.0 ng mL−1, 5-fold improvement in sensitivity compared with that of the traditional gold nanoparticles based LFA. In our perception, our work opens new possibilities to choose metal organic frameworks as labeling matrices in immunoassays.