Dose-Response Calculator for ArcGIS

USGS Publications Warehouse

Hanser, Steven E.; Aldridge, Cameron L.; Leu, Matthias; Nielsen, Scott E.

2011-01-01

The Dose-Response Calculator for ArcGIS is a tool that extends the Environmental Systems Research Institute (ESRI) ArcGIS 10 Desktop application to aid with the visualization of relationships between two raster GIS datasets. A dose-response curve is a line graph commonly used in medical research to examine the effects of different dosage rates of a drug or chemical (for example, carcinogen) on an outcome of interest (for example, cell mutations) (Russell and others, 1982). Dose-response curves have recently been used in ecological studies to examine the influence of an explanatory dose variable (for example, percentage of habitat cover, distance to disturbance) on a predicted response (for example, survival, probability of occurrence, abundance) (Aldridge and others, 2008). These dose curves have been created by calculating the predicted response value from a statistical model at different levels of the explanatory dose variable while holding values of other explanatory variables constant. Curves (plots) developed using the Dose-Response Calculator overcome the need to hold variables constant by using values extracted from the predicted response surface of a spatially explicit statistical model fit in a GIS, which include the variation of all explanatory variables, to visualize the univariate response to the dose variable. Application of the Dose-Response Calculator can be extended beyond the assessment of statistical model predictions and may be used to visualize the relationship between any two raster GIS datasets (see example in tool instructions). This tool generates tabular data for use in further exploration of dose-response relationships and a graph of the dose-response curve.

The frequency of U-shaped dose responses in the toxicological literature.

PubMed

Calabrese, E J; Baldwin, L A

2001-08-01

Hormesis has been defined as a dose-response relationship in which there is a stimulatory response at low doses, but an inhibitory response at high doses, resulting in a U- or inverted U-shaped dose response. To assess the proportion of studies satisfying criteria for evidence of hormesis, a database was created from published toxicological literature using rigorous a priori entry and evaluative criteria. One percent (195 out of 20,285) of the published articles contained 668 dose-response relationships that met the entry criteria. Subsequent application of evaluative criteria revealed that 245 (37% of 668) dose-response relationships from 86 articles (0.4% of 20,285) satisfied requirements for evidence of hormesis. Quantitative evaluation of false-positive and false-negative responses indicated that the data were not very susceptible to such influences. A complementary analysis of all dose responses assessed by hypothesis testing or distributional analyses, where the units of comparison were treatment doses below the NOAEL, revealed that of 1089 doses below the NOAEL, 213 (19.5%) satisfied statistical significance or distributional data evaluative criteria for hormesis, 869 (80%) did not differ from the control, and 7 (0.6%) displayed evidence of false-positive values. The 32.5-fold (19.5% vs 0.6%) greater occurrence of hormetic responses than a response of similar magnitude in the opposite (negative) direction strongly supports the nonrandom nature of hormetic responses. This study, which provides the first documentation of a data-derived frequency of hormetic responses in the toxicologically oriented literature, indicates that when the study design satisfies a priori criteria (i.e., a well-defined NOAEL, > or = 2 doses below the NOAEL, and the end point measured has the capacity to display either stimulatory or inhibitory responses), hormesis is frequently encountered and is broadly represented according to agent, model, and end point. These findings have broad-based implications for study design, risk assessment methods, and the establishment of optimal drug doses and suggest important evolutionarily adaptive strategies for dose-response relationships.

The Model Averaging for Dichotomous Response Benchmark Dose (MADr-BMD) Tool

EPA Pesticide Factsheets

Providing quantal response models, which are also used in the U.S. EPA benchmark dose software suite, and generates a model-averaged dose response model to generate benchmark dose and benchmark dose lower bound estimates.

Modeling Rabbit Responses to Single and Multiple Aerosol ...

EPA Pesticide Factsheets

Journal Article Survival models are developed here to predict response and time-to-response for mortality in rabbits following exposures to single or multiple aerosol doses of Bacillus anthracis spores. Hazard function models were developed for a multiple dose dataset to predict the probability of death through specifying dose-response functions and the time between exposure and the time-to-death (TTD). Among the models developed, the best-fitting survival model (baseline model) has an exponential dose-response model with a Weibull TTD distribution. Alternative models assessed employ different underlying dose-response functions and use the assumption that, in a multiple dose scenario, earlier doses affect the hazard functions of each subsequent dose. In addition, published mechanistic models are analyzed and compared with models developed in this paper. None of the alternative models that were assessed provided a statistically significant improvement in fit over the baseline model. The general approach utilizes simple empirical data analysis to develop parsimonious models with limited reliance on mechanistic assumptions. The baseline model predicts TTDs consistent with reported results from three independent high-dose rabbit datasets. More accurate survival models depend upon future development of dose-response datasets specifically designed to assess potential multiple dose effects on response and time-to-response. The process used in this paper to dev

Comparison of two dosing schedules for subcutaneous injections of low-dose anti-CD20 veltuzumab in relapsed immune thrombocytopenia

PubMed Central

Liebman, Howard A.; Saleh, Mansoor N.; Bussel, James B.; Negrea, O. George; Horne, Heather; Wegener, William A.; Goldenberg, David M.

2016-01-01

We compared two dosing schedules for subcutaneous injections of a low-dose humanized anti-CD20 antibody, veltuzumab, in immune thrombocytopenia. Fifty adults with primary immune thrombocytopenia, in whom one or more lines of standard therapy had failed and who had a platelet count <30×109/L but no major bleeding, initially received escalating 80, 160, or 320 mg doses of subcutaneous veltuzumab administered twice, 2 weeks apart; the last group received once-weekly doses of 320 mg for 4 weeks. In all dose groups, injection reactions were transient and mild to moderate; there were no other safety issues. Forty-seven response-evaluable patients had 23 (49%) objective responses (platelet counts ≥30×109/L and ≥2 × baseline) including 15 (32%) complete responses (platelets ≥100×109/L). Responses (including complete responses) and bleeding reduction occurred in all dose groups and were not dose-dependent. In contrast, response duration increased progressively with total dose, reaching a median of 2.7 years with the four once-weekly 320-mg doses. Among nine responders retreated at relapse, three at higher dose levels responded again, including one patient who was retreated four times. In all dose groups, B-cell depletion occurred after the first dose until recovery starting 12 to 16 weeks after treatment. Veltuzumab serum levels increased with dose group according to total dose administered, but terminal half-life and clearance were comparable. Human anti-veltuzumab antibody titers developed without apparent dose dependence in nine patients, of whom six responded including five who had complete responses. Subcutaneous veltuzumab was convenient, well-tolerated, and active, without causing significant safety concerns. Platelet responses and bleeding reduction occurred in all dose groups, and response durability appeared to improve with higher doses. Clinicaltrials.gov identifier: NCT00547066 PMID:27515248

Probabilistic assessment method of the non-monotonic dose-responses-Part I: Methodological approach.

PubMed

Chevillotte, Grégoire; Bernard, Audrey; Varret, Clémence; Ballet, Pascal; Bodin, Laurent; Roudot, Alain-Claude

2017-08-01

More and more studies aim to characterize non-monotonic dose response curves (NMDRCs). The greatest difficulty is to assess the statistical plausibility of NMDRCs from previously conducted dose response studies. This difficulty is linked to the fact that these studies present (i) few doses tested, (ii) a low sample size per dose, and (iii) the absence of any raw data. In this study, we propose a new methodological approach to probabilistically characterize NMDRCs. The methodology is composed of three main steps: (i) sampling from summary data to cover all the possibilities that may be presented by the responses measured by dose and to obtain a new raw database, (ii) statistical analysis of each sampled dose-response curve to characterize the slopes and their signs, and (iii) characterization of these dose-response curves according to the variation of the sign in the slope. This method allows characterizing all types of dose-response curves and can be applied both to continuous data and to discrete data. The aim of this study is to present the general principle of this probabilistic method which allows to assess the non-monotonic dose responses curves, and to present some results. Copyright © 2017 Elsevier Ltd. All rights reserved.

Nonmonotonic Dose-Response Curves and Endocrine-Disrupting Chemicals: Fact or Falderal?**

EPA Science Inventory

Nonmonotonic Dose-Response Curves and Endocrine-Disrupting Chemicals: Fact or Falderal? The shape of the dose response curve in the low dose region has been debated since the 1940s, originally focusing on linear no threshold (LNT) versus threshold responses for cancer and noncanc...

A MULTIMODEL APPROACH FOR CALCULATING BENCHMARK DOSE

EPA Science Inventory

A Multimodel Approach for Calculating Benchmark Dose
Ramon I. Garcia and R. Woodrow Setzer

In the assessment of dose response, a number of plausible dose- response models may give fits that are consistent with the data. If no dose response formulation had been speci...

The use of mode of action information in risk assessment: quantitative key events/dose-response framework for modeling the dose-response for key events.

PubMed

Simon, Ted W; Simons, S Stoney; Preston, R Julian; Boobis, Alan R; Cohen, Samuel M; Doerrer, Nancy G; Fenner-Crisp, Penelope A; McMullin, Tami S; McQueen, Charlene A; Rowlands, J Craig

2014-08-01

The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Action/Human Relevance Framework and Key Events/Dose Response Framework (KEDRF) to make the best use of quantitative dose-response and timing information for Key Events (KEs). The resulting Quantitative Key Events/Dose-Response Framework (Q-KEDRF) provides a structured quantitative approach for systematic examination of the dose-response and timing of KEs resulting from a dose of a bioactive agent that causes a potential adverse outcome. Two concepts are described as aids to increasing the understanding of mode of action-Associative Events and Modulating Factors. These concepts are illustrated in two case studies; 1) cholinesterase inhibition by the pesticide chlorpyrifos, which illustrates the necessity of considering quantitative dose-response information when assessing the effect of a Modulating Factor, that is, enzyme polymorphisms in humans, and 2) estrogen-induced uterotrophic responses in rodents, which demonstrate how quantitative dose-response modeling for KE, the understanding of temporal relationships between KEs and a counterfactual examination of hypothesized KEs can determine whether they are Associative Events or true KEs.

Radiation Dose-Response Model for Locally Advanced Rectal Cancer After Preoperative Chemoradiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Appelt, Ane L., E-mail: ane.lindegaard.appelt@slb.regionsyddanmark.dk; University of Southern Denmark, Odense; Ploen, John

2013-01-01

Purpose: Preoperative chemoradiation therapy (CRT) is part of the standard treatment of locally advanced rectal cancers. Tumor regression at the time of operation is desirable, but not much is known about the relationship between radiation dose and tumor regression. In the present study we estimated radiation dose-response curves for various grades of tumor regression after preoperative CRT. Methods and Materials: A total of 222 patients, treated with consistent chemotherapy and radiation therapy techniques, were considered for the analysis. Radiation therapy consisted of a combination of external-beam radiation therapy and brachytherapy. Response at the time of operation was evaluated from themore » histopathologic specimen and graded on a 5-point scale (TRG1-5). The probability of achieving complete, major, and partial response was analyzed by ordinal logistic regression, and the effect of including clinical parameters in the model was examined. The radiation dose-response relationship for a specific grade of histopathologic tumor regression was parameterized in terms of the dose required for 50% response, D{sub 50,i}, and the normalized dose-response gradient, {gamma}{sub 50,i}. Results: A highly significant dose-response relationship was found (P=.002). For complete response (TRG1), the dose-response parameters were D{sub 50,TRG1} = 92.0 Gy (95% confidence interval [CI] 79.3-144.9 Gy), {gamma}{sub 50,TRG1} = 0.982 (CI 0.533-1.429), and for major response (TRG1-2) D{sub 50,TRG1} and {sub 2} = 72.1 Gy (CI 65.3-94.0 Gy), {gamma}{sub 50,TRG1} and {sub 2} = 0.770 (CI 0.338-1.201). Tumor size and N category both had a significant effect on the dose-response relationships. Conclusions: This study demonstrated a significant dose-response relationship for tumor regression after preoperative CRT for locally advanced rectal cancer for tumor dose levels in the range of 50.4-70 Gy, which is higher than the dose range usually considered.« less

A study on comparison of Gafchromic EBT2 film response under single and cumulative exposure conditions

PubMed Central

Ganapathy, K.; Kurup, P.G.G.; Murali, V.; Muthukumaran, M.; Velmurugan, J.

2013-01-01

Gafchromic films are used as dosimeter for in vivo and in phantom dose measurements. The dose response of Gafchromic EBT2 film under single and repeated exposure conditions is compared in this study to analyze the usability of Gafchromic EBT2 films in cumulative dose measurements. The post-irradiation change in response of the film is studied for up to 4 days after irradiation. The effect of repeated exposure to scanner light on the response of the film is also studied. To check usability of Gafchromic EBT2 films in cumulative dose measurements, three EBT2 films were exposed to a daily fraction dose of 100 cGy, 150 cGy and 200 cGy, respectively, for 4 days. The dose response of the films exposed to cumulative irradiation was compared with the dose measured from films exposed to the same dose but in a single exposure. It is observed that the post-irradiation darkening of the film does not saturate and continue to take place even 4 days after irradiation. The dose measured from the EBT2 films after 4 days from irradiation was around 2% higher than the dose measured from the same films at 24 hours post-irradiation. It was also observed that the repeated exposure to scanner light does not produce any significant change in the film response. The dose response of films exposed to cumulative irradiation agrees with the dose response of films exposed to the same dose in a single irradiation with less than 3% difference. Gafchromic EBT2 films can be used to measure the cumulative dose delivered over multiple fractions, when the delivered dose is uniform across the film. PMID:24672151

The hormesis database: the occurrence of hormetic dose responses in the toxicological literature.

PubMed

Calabrese, Edward J; Blain, Robyn B

2011-10-01

In 2005 we published an assessment of dose responses that satisfied a priori evaluative criteria for inclusion within the relational retrieval hormesis database (Calabrese and Blain, 2005). The database included information on study characteristics (e.g., biological model, gender, age and other relevant aspects, number of doses, dose distribution/range, quantitative features of the dose response, temporal features/repeat measures, and physical/chemical properties of the agents). The 2005 article covered information for about 5000 dose responses; the present article has been expanded to cover approximately 9000 dose responses. This assessment extends and strengthens the conclusion of the 2005 paper that the hormesis concept is broadly generalizable, being independent of biological model, endpoint measured and chemical class/physical agent. It also confirmed the definable quantitative features of hormetic dose responses in which the strong majority of dose responses display maximum stimulation less than twice that of the control group and a stimulatory width that is within approximately 10-20-fold of the estimated toxicological or pharmacological threshold. The remarkable consistency of the quantitative features of the hormetic dose response suggests that hormesis may provide an estimate of biological plasticity that is broadly generalized across plant, microbial and animal (invertebrate and vertebrate) models. Copyright © 2011 Elsevier Inc. All rights reserved.

DOSE-RESPONSE BEHAVIOR OF ANDROGENIC AND ANTIANDROGENIC CHEMICALS: IMPLICATIONS FOR LOW-DOSE EXTRAPOLATION AND CUMULATIVE TOXICITY

EPA Science Inventory

DOSE-RESPONSE BEHAVIOR OF ANDROGENIC AND ANTIANDROGENIC CHEMICALS: IMPLICATIONS FOR LOW-DOSE EXTRAPOLATION AND CUMULATIVE TOXICITY. LE Gray Jr, C Wolf, J Furr, M Price, C Lambright, VS Wilson and J Ostby. USEPA, ORD, NHEERL, EB, RTD, RTP, NC, USA.
Dose-response behavior of a...

Investigation of dose characteristics in three-dimensional MAGAT-type polymer gel dosimetry with MSE MR imaging

NASA Astrophysics Data System (ADS)

Lee, Jason J. S.; Tsai, Chia-Jung; Lo, Man-Kuok; Huang, Yung-Hui; Chen, Chien-Chuan; Wu, Jay; Tyan, Yeu-Sheng; Wu, Tung-Hsin

2008-05-01

A new type of normoxic polymer gel dosimeter, named MAGAT responses well to absorbed dose even when manufacturing in the presence of normal levels of oxygen. The aim of this study was to evaluate dose response, diffusion effect and cumulated dose response under multiple fractional irradiations of the MAGAT gel dosimeter using Multiple Spin-Echo (MSE) Magnetic Resonance (MR) sequence. Dose response was performed by irradiating MAGAT-gel-filled testing vials with a 6 MV linear accelerator and a linear relationship was present with doses from 0 to 6 Gy, but gradually, a bi-exponential function result was obtained with given doses up to 20 Gy. No significant difference in dose response was present between single and cumulated doses (p > 0.05). For study of diffusion effect, edge sharpness of the R2 map imaging between two split doses was smaller than 1 cm of dose profile penumbra between 20% and 80%. In conclusion, the MAGAT polymer gel dosimeter with MSE MR imaging is a promising method for dose verification in clinical radiation therapy practice.

THE DEPRESSANT EFFECT OF CONTINUOUS COBALT-60 RADIATION ON THE SECONDARY TETANUS ANTITOXIN RESPONSE IN MICE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stoner, R.D.; Hale, W.M.

1958-05-01

The radiosensitivity of the secondary tetanus antitoxin response in mice was demonstrated after rather low doses of continuous gamma -radiation given at a dose rate of 4 rep/hr. Accumulated doses of 48 to 288 rep depressed antitoxin formation. Comparable doses of acute gamma radiation did not depress antitoxin production. Acute doses of 350 to 650 rep sharply depressed the secondary antibody response, however. Extended periods of continuous gamma -radiation from 10 to 28 days to accumulated doses of 960 to 2688 rep markedly depressed the secondary antibody response. An accumulated dose of 2688 rep was needed to depress antitoxin formationmore » to the level observed after an acute dose of 650 rep. When the secondary stimulus of fluid tetanus toxoid was given prior to 10 days of continuous exposure to an accumulated dose of 860 rep, the secondary antibody respense was not depressed. Irradiated mice recovered the ability to produce a normal secondary antitoxin response during the second week after an accumulated dose of 1248 rep. The secondary antitoxin response was depressed in mice given long-continued gamma -radiation at a dose rate of 1 rep/hr. (auth)« less

Investigation of vacuum pumping on the dose response of the MAGAS normoxic polymer gel dosimeter.

PubMed

Venning, A J; Mather, M L; Baldock, C

2005-06-01

The effect of vacuum pumping on the dose response of the MAGAS polymer gel dosimeter has been investigated. A delay of several days post-manufacture before irradiation was previously necessary due to the slow oxygen scavenging of ascorbic acid. The MAGAS polymer gel dosimeter was vacuum pumped before gelation to remove dissolved oxygen. The MAGAS polymer gel dosimeter was poured into glass screw-top vials, which were irradiated at various times, post-manufacture to a range of doses. Magnetic resonance imaging techniques were used to determine the R2-dose response and R2-dose sensitivity of the MAGAS polymer gel. The results were compared with a control batch of MAGAS polymer gel that was not vacuum pumped. It was shown that vacuum pumping on the MAGAS polymer gel solution immediately prior to sealing in glass screw-top vials initially increases the R2-dose response and R2-dose sensitivity of the dosimeter. An increase in the R2-dose response and R2-dose sensitivity was observed with increasing time between manufacture and irradiation. Over the range of post-manufacture irradiation times investigated, the greatest R2-dose response and R2-dose sensitivity occurred at 96 hours.

Dose-response relationships for carcinogens: a review.

PubMed Central

Zeise, L; Wilson, R; Crouch, E A

1987-01-01

We review the experimental evidence for various shapes of dose-response relationships for carcinogens and summarize those experiments that give the most information on relatively low doses. A brief review of some models is given to illustrate the shapes of dose-response curve expected from them. Our major interest is in the use of dose-response relationships to estimate risks to humans at low doses, and so we pay special attention to experimentally observed and theoretically expected nonlinearities. There are few experimental examples of nonlinear dose-response relations in humans, but this may simply be due to the limitations in the data. The several examples in rodents, even though for high dose data, suggest that nonlinearity is common. In some cases such nonlinearities may be rationalized on the basis of the pharmacokinetics of the test compound or its metabolites. PMID:3311725

A swinging seesaw as a novel model mechanism for time-dependent hormesis under dose-dependent stimulatory and inhibitory effects: A case study on the toxicity of antibacterial chemicals to Aliivibrio fischeri.

PubMed

Sun, Haoyu; Calabrese, Edward J; Zheng, Min; Wang, Dali; Pan, Yongzheng; Lin, Zhifen; Liu, Ying

2018-08-01

Hormesis occurs frequently in broadly ranging biological areas (e.g. plant biology, microbiology, biogerontology), toxicology, pharmacology and medicine. While numerous mechanisms (e.g. receptor and pathway mediated pathway responses) account for stimulatory and inhibitory features of hormetic dose responses, the vast majority emphasizes the inclusion of many doses but only one timepoint or use of a single optimized dose that is assessed over a broad range of timepoints. In this paper, a toxicity study was designed using a large number of properly spaced doses with responses determined over a large number of timepoints, which could help us reveal the underlying mechanism of hormesis. We present the results of a dose-time-response study on hormesis using five antibacterial chemicals on the bioluminescence of Aliivibrio fischeri, measuring expression of protein mRNA based on quorum sensing, simulating bioluminescent reaction and analyzing toxic actions of test chemicals. The findings show dose-time-dependent responses conforming to the hormetic dose-response model, while revealing unique response dynamics between agent induced stimulatory and inhibitory effects within bacterial growth phase dynamics. These dynamic dose-time features reveal a type of biological seesaw model that integrates stimulatory and inhibitory responses within unique growth phase, dose and time features, which has faultlessly explained the time-dependent hormetic phenomenon induced by five antibacterial chemicals (characterized by low-dose stimulation and high-dose inhibition). This study offers advances in understanding cellular dynamics, the biological integration of diverse and opposing responses and their role in evolutionary adaptive strategies to chemicals, which can provide new insight into the mechanistic investigation of hormesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Biphasic dose responses in biology, toxicology and medicine: accounting for their generalizability and quantitative features.

PubMed

Calabrese, Edward J

2013-11-01

The most common quantitative feature of the hormetic-biphasic dose response is its modest stimulatory response which at maximum is only 30-60% greater than control values, an observation that is consistently independent of biological model, level of organization (i.e., cell, organ or individual), endpoint measured, chemical/physical agent studied, or mechanism. This quantitative feature suggests an underlying "upstream" mechanism common across biological systems, therefore basic and general. Hormetic dose response relationships represent an estimate of the peak performance of integrative biological processes that are allometrically based. Hormetic responses reflect both direct stimulatory or overcompensation responses to damage induced by relatively low doses of chemical or physical agents. The integration of the hormetic dose response within an allometric framework provides, for the first time, an explanation for both the generality and the quantitative features of the hormetic dose response. Copyright © 2013 Elsevier Ltd. All rights reserved.

SU-E-T-137: The Response of TLD-100 in Mixed Fields of Photons and Electrons.

PubMed

Lawless, M; Junell, S; Hammer, C; DeWerd, L

2012-06-01

Thermoluminescent dosimeters are used routinely for dosimetric measurements of photon and electron fields. However, no work has been published characterizing TLDs for use in combined photon and electron fields. This work investigates the response of TLD-100 (LiF:Mg,Ti) in mixed fields of photon and electron beam qualities. TLDs were irradiated in a 6 MV photon beam, 6 MeV electron beam, and a NIST traceable cobalt-60 beam. TLDs were also irradiated in a mixed field of the electron and photon beams. All irradiations were normalized to absorbed dose to water as defined in the AAPM TG-51 report. The average response per dose (nC/Gy) for each linac beam quality was normalized to the average response per dose of the TLDs irradiated by the cobalt-60 standard.Irradiations were performed in a water tank and a Virtual Water™ phantom. Two TLD dose calibration curves for determining absorbed dose to water were generated using photon and electron field TLD response data. These individual beam quality dose calibration curves were applied to the TLDs irradiated in the mixed field. The TLD response in the mixed field was less sensitive than the response in the photon field and more sensitive than the response in the electron field. TLD determination of dose in the mixed field using the dose calibration curve generated by TLDs irradiated by photons resulted in an underestimation of the delivered dose, while the use of a dose calibration curve generated using electrons resulted in an overestimation of the delivered dose. The relative response of TLD-100 in mixed fields fell consistently between the photon nd electron relative responses. When using TLD-100 in mixed fields, the user must account for this intermediate response to avoid an over- or underestimation of the dose due to calibration in a single photon or electron field. © 2012 American Association of Physicists in Medicine.

Evaluation and comparison of absorbed dose for electron beams by LiF and diamond dosimeters

NASA Astrophysics Data System (ADS)

Mosia, G. J.; Chamberlain, A. C.

2007-09-01

The absorbed dose response of LiF and diamond thermoluminescent dosimeters (TLDs), calibrated in 60Co γ-rays, has been determined using the MCNP4B Monte Carlo code system in mono-energetic megavoltage electron beams from 5 to 20 MeV. Evaluation of the dose responses was done against the dose responses of published works by other investigators. Dose responses of both dosimeters were compared to establish if any relation exists between them. The dosimeters were irradiated in a water phantom with the centre of their top surfaces (0.32×0.32 cm 2), placed at dmax perpendicular to the radiation beam on the central axis. For LiF TLD, dose responses ranged from 0.945±0.017 to 0.997±0.011. For the diamond TLD, the dose response ranged from 0.940±0.017 to 1.018±0.011. To correct for dose responses by both dosimeters, energy correction factors were generated from dose response results of both TLDs. For LiF TLD, these correction factors ranged from 1.003 up to 1.058 and for diamond TLD the factors ranged from 0.982 up to 1.064. The results show that diamond TLDs can be used in the place of the well-established LiF TLDs and that Monte Carlo code systems can be used in dose determinations for radiotherapy treatment planning.

Biphasic and triphasic dose responses in zebrafish embryos to low-dose 150 kV X-rays with different levels of hardness.

PubMed

Kong, Eva Yi; Cheng, Shuk Han; Yu, Kwan Ngok

2016-07-01

The in vivo low-dose responses of zebrafish (Danio rerio) embryos to 150 kV X-rays with different levels of hardness were examined through the number of apoptotic events revealed at 24 h post fertilization by vital dye acridine orange staining. Our results suggested that a triphasic dose response was likely a common phenomenon in living organisms irradiated by X-rays, which comprised an ultra-low-dose inhibition, low-dose stimulation and high-dose inhibition. Our results also suggested that the hormetic zone (or the stimulation zone) was shifted towards lower doses with application of filters. The non-detection of a triphasic dose response in previous experiments could likely be attributed to the use of hard X-rays, which shifted the hormetic zone into an unmonitored ultra-low-dose region. In such cases where the subhormetic zone was missed, a biphasic dose response would be reported instead. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Dose Response Data for Hormonally Active Chemicals ...

EPA Pesticide Factsheets

The shape of the dose response curve in the low dose region has been debated since the late 1940s. The debate originally focused on linear no threshold (LNT) vs threshold responses in the low dose range for cancer and noncancer related effects. For noncancer effects the default assumption is that noncancer effects generally display threshold rather than LNT responses. More recently, claims have arisen that the chemicals, like endocrine disrupters (EDS), which act via high affinity, low capacity nuclear receptors, may display LNT or nonmonotonic low dose responses: responses that could be missed in multigenerational guideline toxicity testing. This presentation will discuss LNT, threshold and nonmonotonic dose response relationships from case studies of chemicals that disrupt reproductive development and function via the ER, AR and AhR pathways and will include in vitro and in vivo multigenerational data. The in vivo studies in this discussion include only robust, well designed, comprehensive studies that administered the chemical via a relevant route(s) of exposure over a broad dose response range, including low dose(s) in the microgram/kg/d range. The chemicals include ethinyl estradiol, estradiol, genistein, bisphenol a, trenbolone, finasteride, flutamide, phthalate esters and 2,3,7,8 TCDD. The objective is to critically evaluate the data from well done studies in this field to address concerns that current multigenerational reproductive test gui

Threshold-type dose response for induction of neoplastic transformation by 1 GeV/nucleon iron ions.

PubMed

Elmore, E; Lao, X-Y; Kapadia, R; Redpath, J L

2009-06-01

Neoplastic transformation of HeLa x skin fibroblast human hybrid cells by doses of 1 GeV/nucleon iron ions in the range 1 cGy to 1 Gy to exposed cultures has been examined. The data indicate a threshold-type dose-response curve with no increase in transformation frequency until doses above 20 cGy. At doses <10 cGy, not all exposed cells receive a direct traversal of an iron-ion track core, but all exposed cells receive up to several mGy of low-LET radiation associated with the delta-ray penumbra. It is proposed that the threshold-type response seen is a consequence of an adaptive response associated with the delta-ray exposure. For comparison purposes, the dose response for (137)Cs gamma rays over the same dose range was examined using the same experimental procedure. As we have shown previously, the dose response for (137)Cs gamma radiation was J-shaped. The iron ions were 1.5 to 1.7 times more biologically effective than the gamma radiation over the dose range examined.

The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview

DOE Office of Scientific and Technical Information (OSTI.GOV)

Calabrese, Edward J.; Blain, Robyn

A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying amore » broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings.« less

The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview.

PubMed

Calabrese, Edward J; Blain, Robyn

2005-02-01

A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying a broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings.

Orexinergic Neurotransmission in Temperature Responses to Methamphetamine and Stress: Mathematical Modeling as a Data Assimilation Approach

PubMed Central

Behrouzvaziri, Abolhassan; Fu, Daniel; Tan, Patrick; Yoo, Yeonjoo; Zaretskaia, Maria V.; Rusyniak, Daniel E.; Molkov, Yaroslav I.; Zaretsky, Dmitry V.

2015-01-01

Experimental Data Orexinergic neurotransmission is involved in mediating temperature responses to methamphetamine (Meth). In experiments in rats, SB-334867 (SB), an antagonist of orexin receptors (OX1R), at a dose of 10 mg/kg decreases late temperature responses (t>60 min) to an intermediate dose of Meth (5 mg/kg). A higher dose of SB (30 mg/kg) attenuates temperature responses to low dose (1 mg/kg) of Meth and to stress. In contrast, it significantly exaggerates early responses (t<60 min) to intermediate and high doses (5 and 10 mg/kg) of Meth. As pretreatment with SB also inhibits temperature response to the stress of injection, traditional statistical analysis of temperature responses is difficult. Mathematical Modeling We have developed a mathematical model that explains the complexity of temperature responses to Meth as the interplay between excitatory and inhibitory nodes. We have extended the developed model to include the stress of manipulations and the effects of SB. Stress is synergistic with Meth on the action on excitatory node. Orexin receptors mediate an activation of on both excitatory and inhibitory nodes by low doses of Meth, but not on the node activated by high doses (HD). Exaggeration of early responses to high doses of Meth involves disinhibition: low dose of SB decreases tonic inhibition of HD and lowers the activation threshold, while the higher dose suppresses the inhibitory component. Using a modeling approach to data assimilation appears efficient in separating individual components of complex response with statistical analysis unachievable by traditional data processing methods. PMID:25993564

Statistical strategies for averaging EC50 from multiple dose-response experiments.

PubMed

Jiang, Xiaoqi; Kopp-Schneider, Annette

2015-11-01

In most dose-response studies, repeated experiments are conducted to determine the EC50 value for a chemical, requiring averaging EC50 estimates from a series of experiments. Two statistical strategies, the mixed-effect modeling and the meta-analysis approach, can be applied to estimate average behavior of EC50 values over all experiments by considering the variabilities within and among experiments. We investigated these two strategies in two common cases of multiple dose-response experiments in (a) complete and explicit dose-response relationships are observed in all experiments and in (b) only in a subset of experiments. In case (a), the meta-analysis strategy is a simple and robust method to average EC50 estimates. In case (b), all experimental data sets can be first screened using the dose-response screening plot, which allows visualization and comparison of multiple dose-response experimental results. As long as more than three experiments provide information about complete dose-response relationships, the experiments that cover incomplete relationships can be excluded from the meta-analysis strategy of averaging EC50 estimates. If there are only two experiments containing complete dose-response information, the mixed-effects model approach is suggested. We subsequently provided a web application for non-statisticians to implement the proposed meta-analysis strategy of averaging EC50 estimates from multiple dose-response experiments.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hobbs, R; Le, Y; Armour, E

Purpose: Dose-response studies in radiation therapy are typically using single response values for tumors across ensembles of tumors. Using the high dose rate (HDR) treatment plan dose grid and pre- and post-therapy FDG-PET images, we look for correlations between voxelized dose and FDG uptake response in individual tumors. Methods: Fifteen patients were treated for localized rectal cancer using 192Ir HDR brachytherapy in conjunction with surgery. FDG-PET images were acquired before HDR therapy and 6–8 weeks after treatment (prior to surgery). Treatment planning was done on a commercial workstation and the dose grid was calculated. The two PETs and the treatmentmore » dose grid were registered to each other using non-rigid registration. The difference in PET SUV values before and after HDR was plotted versus absorbed radiation dose for each voxel. The voxels were then separated into bins for every 400 cGy of absorbed dose and the bin average values plotted similarly. Results: Individual voxel doses did not correlate with PET response; however, when group into tumor subregions corresponding to dose bins, eighty percent of the patients showed a significant positive correlation (R2 > 0) between PET uptake difference in the targeted region and the absorbed dose. Conclusion: By considering larger ensembles of voxels, such as organ average absorbed dose or the dose bins considered here, valuable information may be obtained. The dose-response correlations as measured by FDG-PET difference potentially underlines the importance of FDG-PET as a measure of response, as well as the value of voxelized information.« less

SU-G-BRB-14: Uncertainty of Radiochromic Film Based Relative Dose Measurements

DOE Office of Scientific and Technical Information (OSTI.GOV)

Devic, S; Tomic, N; DeBlois, F

2016-06-15

Purpose: Due to inherently non-linear dose response, measurement of relative dose distribution with radiochromic film requires measurement of absolute dose using a calibration curve following previously established reference dosimetry protocol. On the other hand, a functional form that converts the inherently non-linear dose response curve of the radiochromic film dosimetry system into linear one has been proposed recently [Devic et al, Med. Phys. 39 4850–4857 (2012)]. However, there is a question what would be the uncertainty of such measured relative dose. Methods: If the relative dose distribution is determined going through the reference dosimetry system (conversion of the response bymore » using calibration curve into absolute dose) the total uncertainty of such determined relative dose will be calculated by summing in quadrature total uncertainties of doses measured at a given and at the reference point. On the other hand, if the relative dose is determined using linearization method, the new response variable is calculated as ζ=a(netOD)n/ln(netOD). In this case, the total uncertainty in relative dose will be calculated by summing in quadrature uncertainties for a new response function (σζ) for a given and the reference point. Results: Except at very low doses, where the measurement uncertainty dominates, the total relative dose uncertainty is less than 1% for the linear response method as compared to almost 2% uncertainty level for the reference dosimetry method. The result is not surprising having in mind that the total uncertainty of the reference dose method is dominated by the fitting uncertainty, which is mitigated in the case of linearization method. Conclusion: Linearization of the radiochromic film dose response provides a convenient and a more precise method for relative dose measurements as it does not require reference dosimetry and creation of calibration curve. However, the linearity of the newly introduced function must be verified. Dave Lewis is inventor and runs a consulting company for radiochromic films.« less

Poster — Thur Eve — 27: Flattening Filter Free VMAT Quality Assurance: Dose Rate Considerations for Detector Response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Viel, Francis; Duzenli, Cheryl; British Columbia Cancer Agency, Department of Medical Physics, Vancouver Centre

2014-08-15

Introduction: Radiation detector responses can be affected by dose rate. Due to higher dose per pulse and wider range of mu rates in FFF beams, detector responses should be characterized prior to implementation of QA protocols for FFF beams. During VMAT delivery, the MU rate may also vary dramatically within a treatment fraction. This study looks at the dose per pulse variation throughout a 3D volume for typical VMAT plans and the response characteristics for a variety of detectors, and makes recommendations on the design of QA protocols for FFF VMAT QA. Materials and Methods: Linac log file data andmore » a simplified dose calculation algorithm are used to calculate dose per pulse for a variety of clinical VMAT plans, on a voxel by voxel basis, as a function of time in a cylindrical phantom. Diode and ion chamber array responses are characterized over the relevant range of dose per pulse and dose rate. Results: Dose per pulse ranges from <0.1 mGy/pulse to 1.5 mGy/pulse in a typical VMAT treatment delivery using the 10XFFF beam. Diode detector arrays demonstrate increased sensitivity to dose (+./− 3%) with increasing dose per pulse over this range. Ion chamber arrays demonstrate decreased sensitivity to dose (+/− 1%) with increasing dose rate over this range. Conclusions: QA protocols should be designed taking into consideration inherent changes in detector sensitivity with dose rate. Neglecting to account for changes in detector response with dose per pulse can lead to skewed QA results.« less

The Role of High Dose Interleukin-2 in the Era of Targeted Therapy.

PubMed

Gills, Jessie; Parker, William P; Pate, Scott; Niu, Sida; Van Veldhuizen, Peter; Mirza, Moben; Holzbeierlein, Jeffery M; Lee, Eugene K

2017-09-01

We assessed survival outcomes following high dose interleukin-2 in a contemporary cohort of patients during the era of targeted agents. We retrospectively reviewed the records of patients with metastatic renal cell carcinoma treated with high dose interleukin-2 between July 2007 and September 2014. Clinicopathological data were abstracted and patient response to therapy was based on RECIST (Response Evaluation Criteria In Solid Tumors), version 1.1 criteria. The Kaplan-Meier method was used to estimate progression-free and overall survival in the entire cohort, the response to high dose interleukin-2 in regard to previous targeted agent therapy and the response to the targeted agent in relation to the response to high dose interleukin-2. We identified 92 patients, of whom 87 had documentation of a response to high dose interleukin-2. Median overall survival was 34.4 months from the initiation of high dose interleukin-2 therapy in the entire cohort. Patients who received targeted therapy before high dose interleukin-2 had overall survival (median 34.4 and 30.0 months, p = 0.88) and progression-free survival (median 1.5 and 1.7 months, p = 0.8) similar to those in patients who received no prior therapy, respectively. Additionally, patients with a complete or partial response to high dose interleukin-2 had similar outcomes for subsequent targeted agents compared to patients whose best response was stable or progressive disease (median overall survival 30.1 vs 25.4 months, p = 0.4). Our data demonstrate that patient responses to high dose interleukin-2 and to targeted agents before and after receiving high dose interleukin-2 are independent. As such, carefully selected patients should be offered high dose interleukin-2 for the possibility of a complete and durable response without the fear of limiting the treatment benefit of targeted agents. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Dose Response Data for Hormonally Active Chemicals: Estrogens, Antiandrogens and Androgens

EPA Science Inventory

The shape of the dose response curve in the low dose region has been debated since the late 1940s. The debate originally focused on linear no threshold (LNT) vs threshold responses in the low dose range for cancer and noncancer related effects. For noncancer effects the defaul...

Nonparametric estimation of benchmark doses in environmental risk assessment

PubMed Central

Piegorsch, Walter W.; Xiong, Hui; Bhattacharya, Rabi N.; Lin, Lizhen

2013-01-01

Summary An important statistical objective in environmental risk analysis is estimation of minimum exposure levels, called benchmark doses (BMDs), that induce a pre-specified benchmark response in a dose-response experiment. In such settings, representations of the risk are traditionally based on a parametric dose-response model. It is a well-known concern, however, that if the chosen parametric form is misspecified, inaccurate and possibly unsafe low-dose inferences can result. We apply a nonparametric approach for calculating benchmark doses, based on an isotonic regression method for dose-response estimation with quantal-response data (Bhattacharya and Kong, 2007). We determine the large-sample properties of the estimator, develop bootstrap-based confidence limits on the BMDs, and explore the confidence limits’ small-sample properties via a short simulation study. An example from cancer risk assessment illustrates the calculations. PMID:23914133

The dose-response of salvage radiotherapy following radical prostatectomy: A systematic review and meta-analysis.

PubMed

King, Christopher R

2016-11-01

To date neither the optimal radiotherapy dose nor the existence of a dose-response has been established for salvage RT (SRT). A systematic review from 1996 to 2015 and meta-analysis was performed to identify the pathologic, clinical and treatment factors associated with relapse-free survival (RFS) after SRT (uniformly defined as a PSA>0.2ng/mL or rising above post-SRT nadir). A sigmoidal dose-response curve was objectively fitted and a non-parametric statistical test used to determine significance. 71 studies (10,034 patients) satisfied the meta-analysis criteria. SRT dose (p=0.0001), PSA prior to SRT (p=0.0009), ECE+ (p=0.039) and SV+ (p=0.046) had significant associations with RFS. Statistical analyses confirmed the independence of SRT dose-response. Omission of series with ADT did not alter results. Dose-response is well fit by a sigmoidal curve (p=0.0001) with a TCD 50 of 65.8Gy, with a dose of 70Gy achieving 58.4% RFS vs. 38.5% for 60Gy. A 2.0% [95% CI 1.1-3.2] improvement in RFS is achieved for each Gy. The SRT dose-response remarkably parallels that for definitive RT of localized disease. This study provides level 2a evidence for dose-escalated SRT>70Gy. The presence of an SRT dose-response for microscopic disease supports the hypothesis that prostate cancer is inherently radio-resistant. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Fewer Doses of HPV Vaccine Result in Immune Response Similar to Three-Dose Regimen

MedlinePlus

... Releases NCI News Note Fewer doses of HPV vaccine result in immune response similar to three-dose ... that two doses of a human papillomavirus (HPV) vaccine, trademarked as Cervarix, resulted in similar serum antibody ...

Continuous Toxicological Dose-Response Relationships Are Pretty Homogeneous (Society for Risk Analysis Annual Meeting)

EPA Science Inventory

Dose-response relationships for a wide range of in vivo and in vitro continuous datasets are well-described by a four-parameter exponential or Hill model, based on a recent analysis of multiple historical dose-response datasets, mostly with more than five dose groups (Slob and Se...

Nonmonotonic dose response curves (NMDRCs) are common after Estrogen or Androgen signaling pathway disruption. Fact or Falderal?##

EPA Science Inventory

Nonmonotonic dose response curves (NMDRCs) are common after Estrogen or Androgen signaling pathway disruption. Fact or Falderal? Leon Earl Gray Jr, USEPA, ORD, NHEERL, TAD, RTB. RTP, NC, USA The shape of the dose response curve in the low dose region has been debated since th...

Dose-Response for Multiple Biomarkers of Exposure and Genotoxic Effect Following Repeated Treatment of Rats with the Alkylating Agents, MMS and MNU.

PubMed

Ji, Zhiying; LeBaron, Matthew J; Schisler, Melissa R; Zhang, Fagen; Bartels, Michael J; Gollapudi, B Bhaskar; Pottenger, Lynn H

2016-05-01

The nature of the dose-response relationship for various in vivo endpoints of exposure and effect were investigated using the alkylating agents, methyl methanesulfonate (MMS) and methylnitrosourea (MNU). Six male F344 rats/group were dosed orally with 0, 0.5, 1, 5, 25 or 50mg/kg bw/day (mkd) of MMS, or 0, 0.01, 0.1, 1, 5, 10, 25 or 50 mkd of MNU, for 4 consecutive days and sacrificed 24h after the last dose. The dose-responses for multiple biomarkers of exposure and genotoxic effect were investigated. In MMS-treated rats, the hemoglobin adduct level, a systemic exposure biomarker, increased linearly with dose (r (2) = 0.9990, P < 0.05), indicating the systemic availability of MMS; however, the N7MeG DNA adduct, a target exposure biomarker, exhibited a non-linear dose-response in blood and liver tissues. Blood reticulocyte micronuclei (MN), a genotoxic effect biomarker, exhibited a clear no-observed-genotoxic-effect-level (NOGEL) of 5 mkd as a point of departure (PoD) for MMS. Two separate dose-response models, the Lutz and Lutz model and the stepwise approach using PROC REG both supported a bilinear/threshold dose-response for MN induction. Liver gene expression, a mechanistic endpoint, also exhibited a bilinear dose-response. Similarly, in MNU-treated rats, hepatic DNA adducts, gene expression changes and MN all exhibited clear PoDs, with a NOGEL of 1 mkd for MN induction, although dose-response modeling of the MNU-induced MN data showed a better statistical fit for a linear dose-response. In summary, these results provide in vivo data that support the existence of clear non-linear dose-responses for a number of biologically significant events along the pathway for genotoxicity induced by DNA-reactive agents. © The Author 2015. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Effect of aerosol fenoterol on the severity of bronchial hyperreactivity in patients with asthma.

PubMed Central

Salome, C M; Schoeffel, R E; Yan, K; Woolcock, A J

1983-01-01

Beta adrenergic agents given by aerosol decrease the responsiveness of the airways to histamine and methacholine in subjects with asthma, causing a shift of the dose response curve to the right. To find out whether the shift is related to the dose of beta adrenergic agent given and to determine the duration of the reduced responsiveness, eight subjects with asthma were given histamine inhalation tests after inhaled saline and after increasing doses of inhaled fenoterol on different days. The histamine inhalation tests were repeated at hourly intervals for five hours after a selected dose of fenoterol. Fenoterol caused a dose related shift to the right of the histamine dose response curve in each subject and in some the dose response relationship reached the "non-symptomatic range." The shift in the dose response curve was short lived and had returned towards the control position within three hours in all subjects. There was no change in shape of the curves at the time of maximal shift. The results show that inhaled fenoterol greatly reduces the airway responsiveness to histamine, but up to 400 micrograms of fenoterol every four to five hours may be needed to keep the responsiveness of the airways in the non-symptomatic range. PMID:6648868

Response of TLD-100 in mixed fields of photons and electrons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lawless, Michael J.; Junell, Stephanie; Hammer, Cliff

Purpose: Thermoluminescent dosimeters (TLDs) are routinely used for dosimetric measurements of high energy photon and electron fields. However, TLD response in combined fields of photon and electron beam qualities has not been characterized. This work investigates the response of TLD-100 (LiF:Mg,Ti) to sequential irradiation by high-energy photon and electron beam qualities. Methods: TLDs were irradiated to a known dose by a linear accelerator with a 6 MV photon beam, a 6 MeV electron beam, and a NIST-traceable {sup 60}Co beam. TLDs were also irradiated in a mixed field of the 6 MeV electron beam and the 6 MV photon beam.more » The average TLD response per unit dose of the TLDs for each linac beam quality was normalized to the average response per unit dose of the TLDs irradiated by the {sup 60}Co beam. Irradiations were performed in water and in a Virtual Water Trade-Mark-Sign phantom. The 6 MV photon beam and 6 MeV electron beam were used to create dose calibration curves relating TLD response to absorbed dose to water, which were applied to the TLDs irradiated in the mixed field. Results: TLD relative response per unit dose in the mixed field was less sensitive than the relative response in the photon field and more sensitive than the relative response in the electron field. Application of the photon dose calibration curve to the TLDs irradiated in a mixed field resulted in an underestimation of the delivered dose, while application of the electron dose calibration curve resulted in an overestimation of the dose. Conclusions: The relative response of TLD-100 in mixed fields fell between the relative response in the photon-only and electron-only fields. TLD-100 dosimetry of mixed fields must account for this intermediate response to minimize the estimation errors associated with calibration factors obtained from a single beam quality.« less

Response of TLD-100 in mixed fields of photons and electrons.

PubMed

Lawless, Michael J; Junell, Stephanie; Hammer, Cliff; DeWerd, Larry A

2013-01-01

Thermoluminescent dosimeters (TLDs) are routinely used for dosimetric measurements of high energy photon and electron fields. However, TLD response in combined fields of photon and electron beam qualities has not been characterized. This work investigates the response of TLD-100 (LiF:Mg,Ti) to sequential irradiation by high-energy photon and electron beam qualities. TLDs were irradiated to a known dose by a linear accelerator with a 6 MV photon beam, a 6 MeV electron beam, and a NIST-traceable (60)Co beam. TLDs were also irradiated in a mixed field of the 6 MeV electron beam and the 6 MV photon beam. The average TLD response per unit dose of the TLDs for each linac beam quality was normalized to the average response per unit dose of the TLDs irradiated by the (60)Co beam. Irradiations were performed in water and in a Virtual Water™ phantom. The 6 MV photon beam and 6 MeV electron beam were used to create dose calibration curves relating TLD response to absorbed dose to water, which were applied to the TLDs irradiated in the mixed field. TLD relative response per unit dose in the mixed field was less sensitive than the relative response in the photon field and more sensitive than the relative response in the electron field. Application of the photon dose calibration curve to the TLDs irradiated in a mixed field resulted in an underestimation of the delivered dose, while application of the electron dose calibration curve resulted in an overestimation of the dose. The relative response of TLD-100 in mixed fields fell between the relative response in the photon-only and electron-only fields. TLD-100 dosimetry of mixed fields must account for this intermediate response to minimize the estimation errors associated with calibration factors obtained from a single beam quality.

Shape and Steepness of Toxicological Dose-Response Relationships of Continuous Endpoints

EPA Science Inventory

A re-analysis of a large number of historical dose-response data for continuous endpoints indicates that an exponential or a Hill model with four parameters both adequately describe toxicological dose-responses. The four parameters relate to the background response, the potency o...

Individualized Radiation Dose Escalation Based on the Decrease in Tumor FDG Uptake and Normal Tissue Constraints Improve Survival in Patients With Esophageal Carcinoma.

PubMed

Ma, Jinbo; Wang, Zhaoyang; Wang, Chengde; Chen, Ercheng; Dong, Yaozong; Song, Yipeng; Wang, Wei; You, Dong; Jiang, Wei; Zang, Rukun

2017-02-01

To determine whether individualized radiation dose escalation after planned chemoradiation based on the decrease in tumor and normal tissue constraints can improve survival in patients with esophageal carcinoma. From August 2005 to December 2010, 112 patients with squamous esophageal carcinoma were treated with radical concurrent chemoradiation. Patients received positron emission tomography-computer tomography scan twice, before radiation and after radiation dose of 50.4 Gy. All patients were noncomplete metabolic response groups according to the Response Evaluation Criteria in solid tumors. Only 52 patients with noncomplete metabolic response received individualized dose escalation based on tumor and normal tissue constraints. Survival and treatment failure were observed and analyzed using SPSS (13.0). The rate of complete metabolic response for patients with noncomplete metabolic response after dose escalation reached 17.3% (9 of 52). The 2-year overall survival rates for patients with noncomplete metabolic response in the conventional and dose-escalation groups were 20.5% and 42.8%, respectively( P = .001). The 2-year local control rates for patients were 35.7% and 76.2%, respectively ( P = .002). When patients were classified into partial metabolic response and no metabolic response, 2-year overall survival rates for patients with partial metabolic response were significantly different in conventional and dose-escalation groups (33.8% vs 78.4%; P = .000). The 2-year overall survival rates for patients with no metabolic response in two groups (8.6% vs 15.1%) did not significantly differ ( P = .917). Individualized radiation dose escalation has the potential to improve survival in patients with esophageal carcinoma according to increased rate of complete metabolic response. However, further trials are needed to confirm this and to identify patients who may benefit from dose escalation.

Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses

PubMed Central

Colborn, Theo; Hayes, Tyrone B.; Heindel, Jerrold J.; Jacobs, David R.; Lee, Duk-Hee; Shioda, Toshi; Soto, Ana M.; vom Saal, Frederick S.; Welshons, Wade V.; Zoeller, R. Thomas

2012-01-01

For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from the cell culture, animal, and epidemiology literature. We illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health. PMID:22419778

Statistical analysis of nonmonotonic dose-response relationships: research design and analysis of nasal cell proliferation in rats exposed to formaldehyde.

PubMed

Gaylor, David W; Lutz, Werner K; Conolly, Rory B

2004-01-01

Statistical analyses of nonmonotonic dose-response curves are proposed, experimental designs to detect low-dose effects of J-shaped curves are suggested, and sample sizes are provided. For quantal data such as cancer incidence rates, much larger numbers of animals are required than for continuous data such as biomarker measurements. For example, 155 animals per dose group are required to have at least an 80% chance of detecting a decrease from a 20% incidence in controls to an incidence of 10% at a low dose. For a continuous measurement, only 14 animals per group are required to have at least an 80% chance of detecting a change of the mean by one standard deviation of the control group. Experimental designs based on three dose groups plus controls are discussed to detect nonmonotonicity or to estimate the zero equivalent dose (ZED), i.e., the dose that produces a response equal to the average response in the controls. Cell proliferation data in the nasal respiratory epithelium of rats exposed to formaldehyde by inhalation are used to illustrate the statistical procedures. Statistically significant departures from a monotonic dose response were obtained for time-weighted average labeling indices with an estimated ZED at a formaldehyde dose of 5.4 ppm, with a lower 95% confidence limit of 2.7 ppm. It is concluded that demonstration of a statistically significant bi-phasic dose-response curve, together with estimation of the resulting ZED, could serve as a point-of departure in establishing a reference dose for low-dose risk assessment.

Nonmonotonic dose response curves (NMDRCs) are common after Estrogen or Androgen signaling pathway disruption. Fact or Falderal? ###SETAC

EPA Science Inventory

The shape of the dose response curve in the low dose region has been debated since the late 1940s. The debate originally focused on linear no threshold (LNT) vs threshold responses in the low dose range for cancer and noncancer related effects. Recently, claims have arisen tha...

Animal and human dose-response models for Brucella species.

PubMed

Teske, Sondra S; Huang, Yin; Tamrakar, Sushil B; Bartrand, Timothy A; Weir, Mark H; Haas, Charles N

2011-10-01

Human Brucellosis is one of the most common zoonotic diseases worldwide. Disease transmission often occurs through the handling of domestic livestock, as well as ingestion of unpasteurized milk and cheese, but can have enhanced infectivity if aerosolized. Because there is no human vaccine available, rising concerns about the threat of Brucellosis to human health and its inclusion in the Center for Disease Control's Category B Bioterrorism/Select Agent List make a better understanding of the dose-response relationship of this microbe necessary. Through an extensive peer-reviewed literature search, candidate dose-response data were appraised so as to surpass certain standards for quality. The statistical programming language, "R," was used to compute the maximum likelihood estimation to fit two models, the exponential and the approximate beta-Poisson (widely used for quantitative risk assessment) to dose-response data. Dose-response models were generated for prevalent species of Brucella: Br. suis, Br. melitensis, and Br. abortus. Dose-response models were created for aerosolized Br. suis exposure to guinea pigs from pooled studies. A parallel model for guinea pigs inoculated through both aerosol and subcutaneous routes with Br. melitensis showed that the median infectious dose corresponded to a 30 colony-forming units (CFU) dose of Br. suis, much less than the N(50) dose of about 94 CFU for Br. melitensis organisms. When Br. melitensis was tested subcutaneously on mice, the N(50) dose was higher, 1,840 CFU. A dose-response model was constructed from pooled data for mice, rhesus macaques, and humans inoculated through three routes (subcutaneously/aerosol/intradermally) with Br. melitensis. © 2011 Society for Risk Analysis.

Comparative transcriptome analysis of rice seedlings induced by different doses of heavy ion radiation

NASA Astrophysics Data System (ADS)

Zhao, Qian; Sun, Yeqing; Wang, Wei

2016-07-01

Highly ionizing radiation (HZE) in space is considered as a main factor causing biological effects on plant seeds. To investigate the different effects on genome-wide gene expression of low-dose and high-dose ion radiation, we carried out ground-base carbon particle HZE experiments with different cumulative doses (0Gy, 0.2Gy, 2Gy) to rice seeds and then performed comparative transcriptome analysis of the rice seedlings. We identified a total of 2551 and 1464 differentially expressed genes (DEGs) in low-dose and high-dose radiation groups, respectively. Gene ontology analyses indicated that low-dose and high-dose ion radiation both led to multiple physiological and biochemical activities changes in rice. By Gene Ontology analyses, the results showed that only one process-oxidation reduction process was enriched in the biological process category after high-dose ion radiation, while more processes such as response to biotic stimulus, heme binding, tetrapyrrole binding, oxidoreductase activity, catalytic activity and oxidoreductase activity were significantly enriched after low-dose ion radiation. The results indicated that the rice plants only focused on the process of oxidation reduction to response to high-dose ion radiation, whereas it was a coordination of multiple biological processes to response to low-dose ion radiation. To elucidate the transcriptional regulation of radiation stress-responsive genes, we identified several DEGs-encoding TFs. AP2/EREBP, bHLH, C2H2, MYB and WRKY TF families were altered significantly in response to ion radiation. Mapman analysis speculated that the biological effects on rice seedlings caused by the radiation stress might share similar mechanisms with the biotic stress. Our findings highlight important alterations in the expression of radiation response genes, metabolic pathways, and TF-encoding genes in rice seedlings exposed to low-dose and high-dose ion radiation.

Dose-response relationships and extrapolation in toxicology - Mechanistic and statistical considerations

EPA Science Inventory

Controversy on toxicological dose-response relationships and low-dose extrapolation of respective risks is often the consequence of misleading data presentation, lack of differentiation between types of response variables, and diverging mechanistic interpretation. In this chapter...

WE-D-BRE-06: Quantification of Dose-Response for High Grade Esophagtis Patients Using a Novel Voxel-To-Voxel Method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Niedzielski, J; Martel, M; Tucker, S

2014-06-15

Purpose: Radiation induces an inflammatory response in the esophagus, discernible on CT studies. This work objectively quantifies the voxel esophageal radiation-response for patients with acute esophagitis. This knowledge is an important first-step towards predicting the effect of complex dose distributions on patient esophagitis symptoms. Methods: A previously validated voxel-based methodology of quantifying radiation esophagitis severity was used to identify the voxel dose-response for 18 NSCLC patients with severe esophagitis (CTCAE grading criteria, grade2 or higher). The response is quantified as percent voxel volume change for a given dose. During treatment (6–8 weeks), patients had weekly 4DCT studies and esophagitis scoring.more » Planning CT esophageal contours were deformed to each weekly CT using a demons DIR algorithm. An algorithm using the Jacobian Map from the DIR of the planning CT to all weekly CTs was used to quantify voxel-volume change, along with corresponding delivered voxel dose, to the planning voxel. Dose for each voxel for each time-point was calculated on each previous weekly CT image, and accumulated using DIR. Thus, for each voxel, the volume-change and delivered dose was calculated for each time-point. The data was binned according to when the volume-change first increased by a threshold volume (10%–100%, in 10% increments), and the average delivered dose calculated for each bin. Results: The average dose resulting in a voxel volume increase of 10–100% was 21.6 to 45.9Gy, respectively. The mean population dose to give a 50% volume increase was 36.3±4.4Gy, (range:29.8 to 43.5Gy). The average week of 50% response was 4.1 (range:4.9 to 2.8 weeks). All 18 patients showed similar dose to first response curves, showing a common trend in the initial inflammatoryresponse. Conclusion: We extracted the dose-response curve of the esophagus on a voxel-to-voxel level. This may be useful for estimating the esophagus response (and patient symptoms) to complicated dose distributions.« less

PREDICTING THE RISKS OF NEUROTOXIC VOLATILE ORGANIC COMPOUNDS BASED ON TARGET TISSUE DOSE.

EPA Science Inventory

Quantitative exposure-dose-response models relate the external exposure of a substance to the dose in the target tissue, and then relate the target tissue dose to production of adverse outcomes. We developed exposure-dose-response models to describe the affects of acute exposure...

Polymer gel dosimeters with reduced toxicity: a preliminary investigation of the NMR and optical dose response using different monomers

NASA Astrophysics Data System (ADS)

Senden, R. J.; DeJean, P.; McAuley, K. B.; Schreiner, L. J.

2006-07-01

In this work, three new polymer gel dosimeter recipes were investigated that may be more suitable for widespread applications than polyacrylamide gel dosimeters, since the extremely toxic acrylamide has been replaced with the less harmful monomers N-isopropylacrylamide (NIPAM), diacetone acrylamide and N-vinylformamide. The new gel dosimeters studied contained gelatin (5 wt%), monomer (3 wt%), N,N'-methylene-bis-acrylamide crosslinker (3 wt%) and tetrakis (hydroxymethyl) phosphonium chloride antioxidant (10 mM). The NMR response (R2) of the dosimeters was analysed for conditions of varying dose, dose rate, time post-irradiation, and temperature during irradiation and scanning. It was shown that the dose-response behaviour of the NIPAM/Bis gel dosimeter is comparable to that of normoxic polyacrylamide gel (PAGAT) in terms of high dose-sensitivity and low dependence on dose rate and irradiation temperature, within the ranges considered. The dose-response (R2) of NIPAM/Bis appears to be linear over a greater dose range than the PAGAT gel dosimeter. The effects of time post-irradiation (temporal instability) and temperature during NMR scanning on the R2 response were more significant for NIPAM/Bis dosimeters. Diacetone acrylamide and N-vinylformamide gel dosimeters possessed considerably lower dose-sensitivities. The optical dose-response, measured in terms of the attenuation coefficient for each polymer gel dosimeter, showed potential for the use of optical imaging techniques in future studies.

Design considerations and analysis planning of a phase 2a proof of concept study in rheumatoid arthritis in the presence of possible non-monotonicity.

PubMed

Liu, Feng; Walters, Stephen J; Julious, Steven A

2017-10-02

It is important to quantify the dose response for a drug in phase 2a clinical trials so the optimal doses can then be selected for subsequent late phase trials. In a phase 2a clinical trial of new lead drug being developed for the treatment of rheumatoid arthritis (RA), a U-shaped dose response curve was observed. In the light of this result further research was undertaken to design an efficient phase 2a proof of concept (PoC) trial for a follow-on compound using the lessons learnt from the lead compound. The planned analysis for the Phase 2a trial for GSK123456 was a Bayesian Emax model which assumes the dose-response relationship follows a monotonic sigmoid "S" shaped curve. This model was found to be suboptimal to model the U-shaped dose response observed in the data from this trial and alternatives approaches were needed to be considered for the next compound for which a Normal dynamic linear model (NDLM) is proposed. This paper compares the statistical properties of the Bayesian Emax model and NDLM model and both models are evaluated using simulation in the context of adaptive Phase 2a PoC design under a variety of assumed dose response curves: linear, Emax model, U-shaped model, and flat response. It is shown that the NDLM method is flexible and can handle a wide variety of dose-responses, including monotonic and non-monotonic relationships. In comparison to the NDLM model the Emax model excelled with higher probability of selecting ED90 and smaller average sample size, when the true dose response followed Emax like curve. In addition, the type I error, probability of incorrectly concluding a drug may work when it does not, is inflated with the Bayesian NDLM model in all scenarios which would represent a development risk to pharmaceutical company. The bias, which is the difference between the estimated effect from the Emax and NDLM models and the simulated value, is comparable if the true dose response follows a placebo like curve, an Emax like curve, or log linear shape curve under fixed dose allocation, no adaptive allocation, half adaptive and adaptive scenarios. The bias though is significantly increased for the Emax model if the true dose response follows a U-shaped curve. In most cases the Bayesian Emax model works effectively and efficiently, with low bias and good probability of success in case of monotonic dose response. However, if there is a belief that the dose response could be non-monotonic then the NDLM is the superior model to assess the dose response.

European Academy of Allergy and Clinical Immunology task force report on 'dose-response relationship in allergen-specific immunotherapy'.

PubMed

Calderón, M A; Larenas, D; Kleine-Tebbe, J; Jacobsen, L; Passalacqua, G; Eng, P A; Varga, E M; Valovirta, E; Moreno, C; Malling, H J; Alvarez-Cuesta, E; Durham, S; Demoly, P

2011-10-01

For a century, allergen-specific immunotherapy (SIT) has proven to be an effective treatment for allergic rhinitis, asthma, and insect sting allergy. However, as allergen doses are frequently adapted to the individual patient, there are few data on dose-response relationship in SIT. Allergen products for SIT are being increasingly required to conform to regulatory requirements for human medicines, which include the need to demonstrate dose-dependent effects. This report, produced by a Task Force of the EAACI Immunotherapy Interest Group, evaluates the currently available data on dose-response relationships in SIT and aims to provide recommendations for the design of future studies. Fifteen dose-ranging studies fulfilled the inclusion criteria and twelve reported a dose-response relationship for clinical efficacy. Several studies also reported a dose-response relationship for immunological and safety endpoints. Due to the use of different reference materials and methodologies for the determination of allergen content, variations in study design, and choice of endpoints, no comparisons could be made between studies and, as a consequence, no general dosing recommendations can be made. Despite recently introduced guidelines on the standardization of allergen preparations and study design, the Task Force identified a need for universally accepted standards for the measurement of allergen content in SIT preparations, dosing protocols, and selection of clinical endpoints to enable dose-response effects to be compared across studies. © 2011 John Wiley & Sons A/S.

A single dose of inactivated hepatitis A vaccine promotes HAV-specific memory cellular response similar to that induced by a natural infection.

PubMed

Melgaço, Juliana Gil; Morgado, Lucas Nóbrega; Santiago, Marta Almeida; Oliveira, Jaqueline Mendes de; Lewis-Ximenez, Lia Laura; Hasselmann, Bárbara; Cruz, Oswaldo Gonçalves; Pinto, Marcelo Alves; Vitral, Claudia Lamarca

2015-07-31

Based on current studies on the effects of single dose vaccines on antibody production, Latin American countries have adopted a single dose vaccine program. However, no data are available on the activation of cellular response to a single dose of hepatitis A. Our study investigated the functional reactivity of the memory cell phenotype after hepatitis A virus (HAV) stimulation through administration of the first or second dose of HAV vaccine and compared the response to that of a baseline group to an initial natural infection. Proliferation assays showed that the first vaccine dose induced HAV-specific cellular response; this response was similar to that induced by a second dose or an initial natural infection. Thus, from the first dose to the second dose, increase in the frequencies of classical memory B cells, TCD8 cells, and central memory TCD4 and TCD8 cells were observed. Regarding cytokine production, increased IL-6, IL-10, TNF, and IFNγ levels were observed after vaccination. Our findings suggest that a single dose of HAV vaccine promotes HAV-specific memory cell response similar to that induced by a natural infection. The HAV-specific T cell immunity induced by primary vaccination persisted independently of the protective plasma antibody level. In addition, our results suggest that a single dose immunization system could serve as an alternative strategy for the prevention of hepatitis A in developing countries. Copyright © 2015 Elsevier Ltd. All rights reserved.

A review: Development of a microdose model for analysis of adaptive response and bystander dose response behavior.

PubMed

Leonard, Bobby E

2008-02-27

Prior work has provided incremental phases to a microdosimetry modeling program to describe the dose response behavior of the radio-protective adaptive response effect. We have here consolidated these prior works (Leonard 2000, 2005, 2007a, 2007b, 2007c) to provide a composite, comprehensive Microdose Model that is also herein modified to include the bystander effect. The nomenclature for the model is also standardized for the benefit of the experimental cellular radio-biologist. It extends the prior work to explicitly encompass separately the analysis of experimental data that is 1.) only dose dependent and reflecting only adaptive response radio-protection, 2.) both dose and dose-rate dependent data and reflecting only adaptive response radio-protection for spontaneous and challenge dose damage, 3.) only dose dependent data and reflecting both bystander deleterious damage and adaptive response radio-protection (AR-BE model). The Appendix cites the various applications of the model. Here we have used the Microdose Model to analyze the, much more human risk significant, Elmore et al (2006) data for the dose and dose rate influence on the adaptive response radio-protective behavior of HeLa x Skin cells for naturally occurring, spontaneous chromosome damage from a Brachytherapy type (125)I photon radiation source. We have also applied the AR-BE Microdose Model to the Chromosome inversion data of Hooker et al (2004) reflecting both low LET bystander and adaptive response effects. The micro-beam facility data of Miller et al (1999), Nagasawa and Little (1999) and Zhou et al (2003) is also examined. For the Zhou et al (2003) data, we use the AR-BE model to estimate the threshold for adaptive response reduction of the bystander effect. The mammogram and diagnostic X-ray induction of AR and protective BE are observed. We show that bystander damage is reduced in the similar manner as spontaneous and challenge dose damage as shown by the Azzam et al (1996) data. We cite primary unresolved questions regarding adaptive response behavior and bystander behavior. The five features of major significance provided by the Microdose Model so far are 1. Single Specific Energy Hits initiate Adaptive Response. 2. Mammogram and diagnostic X-rays induce a protective Bystander Effect as well as Adaptive Response radio-protection. 3. For mammogram X-rays the Adaptive Response protection is retained at high primer dose levels. 4. The dose range of the AR protection depends on the value of the Specific Energy per Hit, 1 >. 5. Alpha particle induced deleterious Bystander damage is modulated by low LET radiation.

Dose-response characteristics of an amorphous silicon EPID.

PubMed

Winkler, Peter; Hefner, Alfred; Georg, Dietmar

2005-10-01

Electronic portal imaging devices (EPIDs) were originally developed for the purpose of patient setup verification. Nowadays, they are increasingly used as dosimeters (e.g., for IMRT verification and linac-specific QA). A prerequisite for any clinical dosimetric application is a detailed understanding of the detector's dose-response behavior. The aim of this study is to investigate the dosimetric properties of an amorphous silicon EPID (Elekta IVIEWGT) with respect to three photon beam qualities: 6, 10, and 25 MV. The EPID showed an excellent temporal stability on short term as well as on long term scales. The stability throughout the day was strongly influenced by warming up, which took several hours and affected EPID response by 2.5%. Ghosting effects increased the sensitivity of the EPID. They became more pronounced with decreasing time intervals between two exposures as well as with increasing dose. Due to ghosting, changes in pixel sensitivity amounted up to 16% (locally) for the 25 MV photon beam. It was observed that the response characteristics of our EPID depended on dose as well as on dose rate. Doubling the dose rate increased the EPID sensitivity by 1.5%. This behavior was successfully attributed to a dose per frame effect, i.e., a nonlinear relationship between the EPID signal and the dose which was delivered to the panel between two successive readouts. The sensitivity was found to vary up to 10% in the range of 1 to 1000 monitor units. This variation was governed by two independent effects. For low doses, the EPID signal was reduced due to the linac's changing dose rate during startup. Furthermore, the detector reading was influenced by intrabeam variations of EPID sensitivity, namely, an increase of detector response during uniform exposure. For the beam qualities which were used, the response characteristics of the EPID did not depend on energy. Differences in relative dose-response curves resulted from energy dependent temporal output characteristics of the accelerator. If ghosting is prevented from affecting the results and all dose-response effects are properly corrected for, the EPID signal becomes independent of dose rate, dose, and exposure time.

Dose-response-a challenge for allelopathy?

PubMed

Belz, Regina G; Hurle, Karl; Duke, Stephen O

2005-04-01

The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2H-1,4-benzoxaxin-3(4H)-one); BOA (benzoxazolin-2(3H)-one); MBOA (6-methoxy-benzoxazolin-2(3H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants (Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions.

The Effects of Low Dose Irradiation on Inflammatory Response Proteins in a 3D Reconstituted Human Skin Tissue Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Varnum, Susan M.; Springer, David L.; Chaffee, Mary E.

Skin responses to moderate and high doses of ionizing radiation include the induction of DNA repair, apoptosis, and stress response pathways. Additionally, numerous studies indicate that radiation exposure leads to inflammatory responses in skin cells and tissue. However, the inflammatory response of skin tissue to low dose radiation (<10 cGy) is poorly understood. In order to address this, we have utilized a reconstituted human skin tissue model (MatTek EpiDerm FT) and assessed changes in 23 cytokines twenty-four and forty eight hours following treatment of skin with either 3 or 10 cGy low-dose of radiation. Three cytokines, IFN-γ, IL-2, MIP-1α, weremore » significantly altered in response to low dose radiation. In contrast, seven cytokines were significantly altered in response to a high radiation dose of 200 cGy (IL-2, IL-10, IL-13, IFN-γ, MIP-1α, TNF α, and VEGF) or the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (G-CSF, GM-CSF, IL-1α, IL-8, MIP-1α, MIP-1β, RANTES). Additionally, radiation induced inflammation appears to have a distinct cytokine response relative to the non-radiation induced stressor, TPA. Overall, these results indicate that there are subtle changes in the inflammatory protein levels following exposure to low dose radiation and this response is a sub-set of what is seen following a high dose in a human skin tissue model.« less

PHYSIOLOCIGALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT

EPA Science Inventory

PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT. Barton HA. Experimental Toxicology Division, National Health and Environmental Effects Laboratory, ORD, U.S. EPA
Dose-response analysis requires quantitatively linking infor...

A distributed lag approach to fitting non-linear dose-response models in particulate matter air pollution time series investigations.

PubMed

Roberts, Steven; Martin, Michael A

2007-06-01

The majority of studies that have investigated the relationship between particulate matter (PM) air pollution and mortality have assumed a linear dose-response relationship and have used either a single-day's PM or a 2- or 3-day moving average of PM as the measure of PM exposure. Both of these modeling choices have come under scrutiny in the literature, the linear assumption because it does not allow for non-linearities in the dose-response relationship, and the use of the single- or multi-day moving average PM measure because it does not allow for differential PM-mortality effects spread over time. These two problems have been dealt with on a piecemeal basis with non-linear dose-response models used in some studies and distributed lag models (DLMs) used in others. In this paper, we propose a method for investigating the shape of the PM-mortality dose-response relationship that combines a non-linear dose-response model with a DLM. This combined model will be shown to produce satisfactory estimates of the PM-mortality dose-response relationship in situations where non-linear dose response models and DLMs alone do not; that is, the combined model did not systemically underestimate or overestimate the effect of PM on mortality. The combined model is applied to ten cities in the US and a pooled dose-response model formed. When fitted with a change-point value of 60 microg/m(3), the pooled model provides evidence for a positive association between PM and mortality. The combined model produced larger estimates for the effect of PM on mortality than when using a non-linear dose-response model or a DLM in isolation. For the combined model, the estimated percentage increase in mortality for PM concentrations of 25 and 75 microg/m(3) were 3.3% and 5.4%, respectively. In contrast, the corresponding values from a DLM used in isolation were 1.2% and 3.5%, respectively.

The effects of a selective 5-HT2 receptor antagonist (ICI 170,809) on platelet aggregation and pupillary responses in healthy volunteers.

PubMed Central

Millson, D S; Jessup, C L; Swaisland, A; Haworth, S; Rushton, A; Harry, J D

1992-01-01

1. ICI 170,809 (2-(2-dimethylamino-2-methylpropylthio)-3-phenylquinoline hydrochloride) is a potent 5-hydroxytryptamine (5-HT) type 2 postsynaptic receptor antagonist. 2. Effects of ICI 170,809 as single oral doses (3, 7, 15 and 30 mg) or placebo were studied on the duration of antagonism for the ex vivo platelet aggregatory response to 5-HT and to the pupillary light constrictor response in eight healthy male volunteers. 3. Pupillary dark adapted responses to a 0.5 s light stimulus were measured using a portable infrared pupillometer, for up to 24 h after dosing. 4. The in vitro platelet 5-HT aggregation response was reduced by ICI 170,809, with depression of the dose-response curve to 5-HT at all concentrations of 5-HT and with no evidence for a parallel shift. 5. The ex vivo platelet 5-HT response demonstrated a dose related significant (P less than 0.02) decrease in aggregation reaching a maximum at 2 h after dosing with the effect persisting for at least 8 h after dosing with the 7 and 15 mg doses. 6. Resting pupil diameter (RPD), and light induced pupillary responses in the dark adapted pupil, showed a significant (P less than 0.01) dose related reduction with significant (P less than 0.05) effects still present with the 15 and 30 mg doses at 8 h after dosing. 7. We conclude that, changes in both ex vivo platelet aggregation to 5-HT and dark adapted pupil size, are significantly correlated (P less than 0.0001) with log plasma concentrations (ng ml-1) of ICI 170,809, enabling the assessment of 5-HT2-receptor antagonism in man. PMID:1576048

Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework.

PubMed

Calabrese, Edward J; Bachmann, Kenneth A; Bailer, A John; Bolger, P Michael; Borak, Jonathan; Cai, Lu; Cedergreen, Nina; Cherian, M George; Chiueh, Chuang C; Clarkson, Thomas W; Cook, Ralph R; Diamond, David M; Doolittle, David J; Dorato, Michael A; Duke, Stephen O; Feinendegen, Ludwig; Gardner, Donald E; Hart, Ronald W; Hastings, Kenneth L; Hayes, A Wallace; Hoffmann, George R; Ives, John A; Jaworowski, Zbigniew; Johnson, Thomas E; Jonas, Wayne B; Kaminski, Norbert E; Keller, John G; Klaunig, James E; Knudsen, Thomas B; Kozumbo, Walter J; Lettieri, Teresa; Liu, Shu-Zheng; Maisseu, Andre; Maynard, Kenneth I; Masoro, Edward J; McClellan, Roger O; Mehendale, Harihara M; Mothersill, Carmel; Newlin, David B; Nigg, Herbert N; Oehme, Frederick W; Phalen, Robert F; Philbert, Martin A; Rattan, Suresh I S; Riviere, Jim E; Rodricks, Joseph; Sapolsky, Robert M; Scott, Bobby R; Seymour, Colin; Sinclair, David A; Smith-Sonneborn, Joan; Snow, Elizabeth T; Spear, Linda; Stevenson, Donald E; Thomas, Yolene; Tubiana, Maurice; Williams, Gary M; Mattson, Mark P

2007-07-01

Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.

Thermoluminescent dosimetry in electron beams: energy dependence.

PubMed

Robar, V; Zankowski, C; Olivares Pla, M; Podgorsak, E B

1996-05-01

The response of thermoluminescent dosimeters to electron irradiations depends on the radiation dose, mean electron energy at the position of the dosimeter in phantom, and the size of the dosimeter. In this paper the semi-empirical expression proposed by Holt et al. [Phys. Med. Biol. 20, 559-570 (1975)] is combined with the calculated electron dose fraction to determine the thermoluminescent dosimetry (TLD) response as a function of the mean electron energy and the dosimeter size. The electron and photon dose fractions, defined as the relative contributions of electrons and bremsstrahlung photons to the total dose for a clinical electron beam, are calculated with Monte Carlo techniques using EGS4. Agreement between the calculated and measured TLD response is very good. We show that the considerable reduction in TLD response per unit dose at low electron energies, i.e., at large depths in phantom, is offset by an ever-increasing relative contribution of bremsstrahlung photons to the total dose of clinical electron beams. This renders the TLD sufficiently reliable for dose measurements over the entire electron depth dose distribution despite the dependence of the TLD response on electron beam energy.

Dose-responses for mortality from cerebrovascular and heart diseases in atomic bomb survivors: 1950-2003.

PubMed

Schöllnberger, Helmut; Eidemüller, Markus; Cullings, Harry M; Simonetto, Cristoforo; Neff, Frauke; Kaiser, Jan Christian

2018-03-01

The scientific community faces important discussions on the validity of the linear no-threshold (LNT) model for radiation-associated cardiovascular diseases at low and moderate doses. In the present study, mortalities from cerebrovascular diseases (CeVD) and heart diseases from the latest data on atomic bomb survivors were analyzed. The analysis was performed with several radio-biologically motivated linear and nonlinear dose-response models. For each detrimental health outcome one set of models was identified that all fitted the data about equally well. This set was used for multi-model inference (MMI), a statistical method of superposing different models to allow risk estimates to be based on several plausible dose-response models rather than just relying on a single model of choice. MMI provides a more accurate determination of the dose response and a more comprehensive characterization of uncertainties. It was found that for CeVD, the dose-response curve from MMI is located below the linear no-threshold model at low and medium doses (0-1.4 Gy). At higher doses MMI predicts a higher risk compared to the LNT model. A sublinear dose-response was also found for heart diseases (0-3 Gy). The analyses provide no conclusive answer to the question whether there is a radiation risk below 0.75 Gy for CeVD and 2.6 Gy for heart diseases. MMI suggests that the dose-response curves for CeVD and heart diseases in the Lifespan Study are sublinear at low and moderate doses. This has relevance for radiotherapy treatment planning and for international radiation protection practices in general.

SU-E-J-274: Responses of Medulloblastoma Cells to Radiation Dosimetric Parameters in Intensity-Modulated Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, J; Molecular Imaging Program at Stanford, Stanford, CA; Bio-X Program, Stanford, CA

2015-06-15

Purpose: To evaluate radiation responses of the medulloblastoma cell line Daoy in intensity-modulated radiation therapy (IMRT), quantitative variations to variable radiation dosimetic parameters were tracked by bioluminescent images (BLIs). Methods: The luciferase and green fluorescent protein positive Daoy cells were cultured on dishes. The medulloblastoma cells irradiated to different dose rate, interval of fractionated doses, field margin and misalignment, and dose uniformity in IMRT were monitored using bioluminescent images. The cultured cells were placed into a dedicated acrylic phantom to deliver intensity-modulated fluences and calculate accurate predicted dose distribution. The radiation with dose rate from 0.5 Gy/min to 15 Gy/minmore » was irradiated by adjusting monitor unit per minute and source-to-surface distances. The intervals of fractionated dose delivery were changed considering the repair time of double strand breaks (DSB) revealed by straining of gamma-H2AX.The effect of non-uniform doses on the cells were visualized by registering dose distributions and BLIs. The viability according to dosimetric parameters was correlated with bioluminescent intensities for cross-check of radiation responses. Results: The DSB and cell responses due to the first fractionated dose delivery significantly affected final tumor control rather than other parameters. The missing tumor volumes due to the smaller field margin than the tumor periphery or field misalignment caused relapse of cell responses on BLIs. The dose rate and gradient had effect on initial responses but could not bring out the distinguishable killing effect on cancer cells. Conclusion: Visualized and quantified bioluminescent images were useful to correlate the dose distributions with spatial radiation effects on cells. This would derive the effective combination of dose delivery parameters and fractionation. Radiation responses in particular IMRT configuration could be reflected to image based-dose re-optimization.« less

Comparison of dose response functions for EBT3 model GafChromic™ film dosimetry system.

PubMed

Aldelaijan, Saad; Devic, Slobodan

2018-05-01

Different dose response functions of EBT3 model GafChromic™ film dosimetry system have been compared in terms of sensitivity as well as uncertainty vs. error analysis. We also made an assessment of the necessity of scanning film pieces before and after irradiation. Pieces of EBT3 film model were irradiated to different dose values in Solid Water (SW) phantom. Based on images scanned in both reflection and transmission mode before and after irradiation, twelve different response functions were calculated. For every response function, a reference radiochromic film dosimetry system was established by generating calibration curve and by performing the error vs. uncertainty analysis. Response functions using pixel values from the green channel demonstrated the highest sensitivity in both transmission and reflection mode. All functions were successfully fitted with rational functional form, and provided an overall one-sigma uncertainty of better than 2% for doses above 2 Gy. Use of pre-scanned images to calculate response functions resulted in negligible improvement in dose measurement accuracy. Although reflection scanning mode provides higher sensitivity and could lead to a more widespread use of radiochromic film dosimetry, it has fairly limited dose range and slightly increased uncertainty when compared to transmission scan based response functions. Double-scanning technique, either in transmission or reflection mode, shows negligible improvement in dose accuracy as well as a negligible increase in dose uncertainty. Normalized pixel value of the images scanned in transmission mode shows linear response in a dose range of up to 11 Gy. Copyright © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

A Unified Probabilistic Framework for Dose-Response Assessment of Human Health Effects.

PubMed

Chiu, Weihsueh A; Slob, Wout

2015-12-01

When chemical health hazards have been identified, probabilistic dose-response assessment ("hazard characterization") quantifies uncertainty and/or variability in toxicity as a function of human exposure. Existing probabilistic approaches differ for different types of endpoints or modes-of-action, lacking a unifying framework. We developed a unified framework for probabilistic dose-response assessment. We established a framework based on four principles: a) individual and population dose responses are distinct; b) dose-response relationships for all (including quantal) endpoints can be recast as relating to an underlying continuous measure of response at the individual level; c) for effects relevant to humans, "effect metrics" can be specified to define "toxicologically equivalent" sizes for this underlying individual response; and d) dose-response assessment requires making adjustments and accounting for uncertainty and variability. We then derived a step-by-step probabilistic approach for dose-response assessment of animal toxicology data similar to how nonprobabilistic reference doses are derived, illustrating the approach with example non-cancer and cancer datasets. Probabilistically derived exposure limits are based on estimating a "target human dose" (HDMI), which requires risk management-informed choices for the magnitude (M) of individual effect being protected against, the remaining incidence (I) of individuals with effects ≥ M in the population, and the percent confidence. In the example datasets, probabilistically derived 90% confidence intervals for HDMI values span a 40- to 60-fold range, where I = 1% of the population experiences ≥ M = 1%-10% effect sizes. Although some implementation challenges remain, this unified probabilistic framework can provide substantially more complete and transparent characterization of chemical hazards and support better-informed risk management decisions.

SU-F-T-329: Characteristic Study of a Rado-Photoluminescenct Glass Dosimeter with Accumulated Dose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, D; Chung, W; Chung, M

Purpose: This study investigated the effect of accumulated dose on radiophotoluminescent glass dosimeter in megavoltage photon. Methods: 45 commercially-available radio-photoluminescence glass dosimeters (RPLGD; GD-302M, Asahi Techno Glass Co., Shizuoka, JAPAN) were irradiated to 10 × 10 cm{sup 2} open-field with 6, 10 and 15 MV photon beams at 100 cm of source to surface distance and dose maximum depths. Each energy has consists of five groups which is consists of three detectors. A group #1 and #2 was irradiated about 1 Gy to 100 Gy, and estimated the integral dose response with and without annealing procedure. A group #3 wasmore » read the dose after irradiated 10 Gy of dose by 10 times repeatedly to estimate the fading effect of RPLGD. A group #4 and #5 was produced same ways with different irradiation dose such as 50 Gy for group #4 and 100 Gy for group #5. Results: From the results of group #1 and #2, an annealed detector shows linear response to integral dose but other detectors without the annealing process, has supra linearity for integral dose especially close to 100 Gy dose. For group #3, #4 and #5, the dose response of repeated irradiation, the dose response was decreased about 15%, 12% and 7% for 6 MV, 10 MV and 15MV. Conclusion: It was found that RPLGD response to accumulated dose was supra linear and this respond was altered with amount of accumulated dose to the RPLGD. In addition, the fading effect need to be concern with RPLGD.« less

Dose response and repair kinetics of gamma-H2AX foci induced by in vitro irradiation of whole blood and T-lymphocytes with X- and gamma-radiation.

PubMed

Beels, Laurence; Werbrouck, Joke; Thierens, Hubert

2010-09-01

Dose response and repair kinetics of phosphorylated histone H2A isoform X (gamma-H2AX) foci in T-lymphocytes were investigated in the low-dose range after in vitro irradiation of whole blood and T-lymphocytes with 100 kVp X-rays and (60)Co gamma-rays. Whole blood or isolated T-lymphocytes were irradiated in vitro and gamma-H2AX foci were scored. Dose response was determined in the 0-500 mGy dose range. Foci kinetics were studied at doses of 5 and 200 mGy up to 24 h post-irradiation. After X-irradiation, the dose response for whole blood shows a biphasic behaviour with a low-dose hypersensitivity, which is less pronounced for isolated T-lymphocytes. In contrast, gamma-radiation shows a linear dose response for both irradiation conditions. Concerning repair kinetics, delayed repair was found after X-ray whole blood irradiation (5 and 200 mGy) with 40% of the foci persisting 24 h post-irradiation. This number of foci is reduced to 10% after irradiation of isolated T-lymphocytes with 200 mGy X-rays. On the contrary, gamma-H2AX foci are reduced to background levels 24 h post-irradiation with 200 mGy (60)Co gamma-rays. gamma-H2AX foci response and repair kinetics depend on irradiation conditions and radiation quality, possibly linked to Bystander response.

Contrasting effects of low versus high ascorbate doses on blood pressure responses to oral nitrite in L-NAME-induced hypertension.

PubMed

Pinheiro, Lucas C; Ferreira, Graziele C; Vilalva, Kelvin H; Toledo, José C; Tanus-Santos, Jose E

2018-04-01

Nitrite reduces blood pressure (BP) in both clinical and experimental hypertension. This effect is attributable to the formation of nitric oxide (NO) and other NO-related species, which may be improved by ascorbate or other antioxidants. However, the BP responses to oral nitrite result, at least in part, of increased gastric S-nitrosothiol formation. This study tested the hypothesis that ascorbate may destroy S-nitrosothiols and therefore not all doses of ascorbate enhance the BP responses to oral nitrite. We assessed the BP responses to oral sodim nitrite (0.2 mmol/kg) in L-NAME hypertensive rats pretreated with ascorbate (0, 0.02, 0.2, or 2 mmol/kg). Plasma and gastric wall concentrations of nitrite and nitroso compounds concentrations were determined using an ozone-based reductive chemiluminescence assay. Nitrate concentrations were determined using the Griess reaction. Free thiol concentrations were determined by a colorimetric assay. The BP responses to nitrite exhibited a bell-shape profile as they were not modified by ascorbate 0.02 mmol/l, whereas the 0.2 mmol/kg dose enhanced and the 2 mmol/kg dose attenuated BP responses. In parallel with BP responses, nitrite-induced increases in plasma nitrite and RSNO species were not modified by ascorbate 0.02 mmol/l, whereas the 0.2 mmol/kg dose enhanced and the 2 mmol/kg dose attenuated them. Similar experiments were carried out with an equimolar dose of S-nitrosogluthathione. Ascorbate dose-dependently impaired the BP responses to S-nitrosogluthathione, and the corresponding increases in plasma RSNO, but not in plasma nitrite concentrations. This is the first study to show that while ascorbate dose-dependently impairs the BP responses to oral S-nitrosogluthathione, there are contrasting effects when low versus high ascorbate doses are compared with respect to its effects on the blood pressure responses to oral nitrite administration. Our findings may have special implications to patients taking ascorbate, as high doses of this vitamin may impair protective mechanisms associated with nitrite or nitrate from dietary sources. Copyright © 2018 Elsevier Inc. All rights reserved.

ENDOCRINE ACTIVE SUBSTANCES AND DOSE-RESPONSE FOR INDIVIDUALS AND POPULATIONS

EPA Science Inventory

Endocrine Active Substances and Dose-Response for Individuals and Populations
Hugh A. Barton

Abstract for IUPAC-SCOPE article

Dose-response characteristics for endocrine disruption have been major focuses in efforts to understand potential impacts on human and ec...

EVALUATING QUANTITATIVE FORMULAS FOR DOSE-RESPONSE ASSESSMENT OF CHEMICAL MIXTURES

EPA Science Inventory

Risk assessment formulas are often distinguished from dose-response models by being rough but necessary. The evaluation of these rough formulas is described here, using the example of mixture risk assessment. Two conditions make the dose-response part of mixture risk assessment d...

Analysis of Transcriptomic Dose Response Data in the ...

EPA Pesticide Factsheets

Slide presentation at the HESI-HEALTH Canada-McGill Workshop on Transcriptomic Dose Response Data in the Context of Chemical Risk Assessment Slide presentation at the HESI-HEALTH Canada-McGill Workshop on Transcriptomic Dose Response Data in the Context of Chemical Risk Assessment

Interpretation of the margin of exposure for genotoxic carcinogens - elicitation of expert knowledge about the form of the dose response curve at human relevant exposures.

PubMed

Boobis, Alan; Flari, Villie; Gosling, John Paul; Hart, Andy; Craig, Peter; Rushton, Lesley; Idahosa-Taylor, Ehi

2013-07-01

The general approach to risk assessment of genotoxic carcinogens has been to advise reduction of exposure to "as low as reasonably achievable/practicable" (ALARA/P). However, whilst this remains the preferred risk management option, it does not provide guidance on the urgency or extent of risk management actions necessary. To address this, the "Margin of Exposure" (MOE) approach has been proposed. The MOE is the ratio between the point of departure for carcinogenesis and estimated human exposure. However, interpretation of the MOE requires implicit or explicit consideration of the shape of the dose-response curve at human relevant exposures. In a structured elicitation exercise, we captured expert opinion on available scientific evidence for low dose-response relationships for genotoxic carcinogens. This allowed assessment of: available evidence for the nature of dose-response relationships at human relevant exposures; the generality of judgments about such dose-response relationships; uncertainties affecting judgments on the nature of such dose-response relationships; and whether this last should differ for different classes of genotoxic carcinogens. Elicitation results reflected the variability in experts' views on the form of the dose-response curve for low dose exposure and major sources of uncertainty affecting the assumption of a linear relationship. Copyright © 2013 Elsevier Ltd. All rights reserved.

Investigation of J-shaped dose-responses induced by exposure to the alkylating agent N-methyl-N-nitrosourea.

PubMed

Chapman, Katherine E; Hoffmann, George R; Doak, Shareen H; Jenkins, Gareth J S

2017-07-01

Hormesis is defined as a biphasic dose-response where biological effects of low doses of a stressor demonstrate the opposite effect to high-dose effects of the same stressor. Hormetic, or J-shaped, dose-response relationships are relatively rarely observed in toxicology, resulting in a limited understanding and even some skepticism of the concept. Low dose-response studies for genotoxicity endpoints have been performed at Swansea University for over a decade. However, no statistically significant decreases below control genotoxicity levels have been detected until recently. A hormetic-style dose-response following a 24h exposure to the alkylating agent N-methyl-N-nitrosourea (MNU) was observed in a previous study for HPRT mutagenesis in the human lymphoblastoid cell line AHH-1. A second recent study demonstrated a J-shaped dose-response for the induction of micronuclei by MNU in a 24h treatment in a similar test system. Following mechanistic investigations, it was hypothesized that p53 may be responsible for the observed hormetic phenomenon. As genotoxic carcinogens are a major causative factor of many cancers, consideration of hormesis in carcinogenesis could be important in safety assessment. The data examined here offer possible insights into hormesis, including its estimated prevalence, underlying mechanisms and lack of generalizability. Copyright © 2017 Elsevier B.V. All rights reserved.

Using machine learning to model dose-response relationships.

PubMed

Linden, Ariel; Yarnold, Paul R; Nallamothu, Brahmajee K

2016-12-01

Establishing the relationship between various doses of an exposure and a response variable is integral to many studies in health care. Linear parametric models, widely used for estimating dose-response relationships, have several limitations. This paper employs the optimal discriminant analysis (ODA) machine-learning algorithm to determine the degree to which exposure dose can be distinguished based on the distribution of the response variable. By framing the dose-response relationship as a classification problem, machine learning can provide the same functionality as conventional models, but can additionally make individual-level predictions, which may be helpful in practical applications like establishing responsiveness to prescribed drug regimens. Using data from a study measuring the responses of blood flow in the forearm to the intra-arterial administration of isoproterenol (separately for 9 black and 13 white men, and pooled), we compare the results estimated from a generalized estimating equations (GEE) model with those estimated using ODA. Generalized estimating equations and ODA both identified many statistically significant dose-response relationships, separately by race and for pooled data. Post hoc comparisons between doses indicated ODA (based on exact P values) was consistently more conservative than GEE (based on estimated P values). Compared with ODA, GEE produced twice as many instances of paradoxical confounding (findings from analysis of pooled data that are inconsistent with findings from analyses stratified by race). Given its unique advantages and greater analytic flexibility, maximum-accuracy machine-learning methods like ODA should be considered as the primary analytic approach in dose-response applications. © 2016 John Wiley & Sons, Ltd.

Sensitivity of the immature rat uterotrophic assay to mixtures of estrogens.

PubMed Central

Tinwell, Helen; Ashby, John

2004-01-01

We have evaluated whether mixtures of estrogens, present in the mix at doses that are individually inactive in the immature rat uterotrophic assay, can give a uterotrophic response. Seven chemicals were evaluated: nonylphenol, bisphenol A (BPA), methoxychlor, genistein (GEN), estradiol, diethylstilbestrol, and ethinyl estradiol. Dose responses in the uterotrophic assay were constructed for each chemical. The first series of experiments involved evaluating binary mixtures of BPA and GEN at dose levels that gave moderate uterotrophic responses when tested individually. The mixtures generally showed an intermediate or reduced uterotrophic effect compared with when the components of the mixture were tested alone at the dose used in the mixture. The next series of experiments used a multicomponent (complex) mixture of all seven chemicals evaluated at doses that gave either weakly positive or inactive uterotrophic responses when tested individually in the assay. Doses that were nominally equi-uterotrophic ranged over approximately six orders of magnitude for the seven chemicals. Doses of agents that gave a weak uterotrophic response when tested individually gave a marginally enhanced positive response in the assay when tested combined as a mixture. Doses of agents that gave a negative uterotrophic response when tested individually gave a positive response when tested as a mixture. These data indicate that a variety of different estrogen receptor (ER) agonists, present individually at subeffective doses, can act simultaneously to evoke an ER-regulated response. However, translating these findings into the process of environmental hazard assessment will be difficult. The simple addition of the observed, or predicted, activities for the components of a mixture is confirmed here to be inappropriate and to overestimate the actual effect induced by the mixture. Equally, isobole analysis is only suitable for two- or three-component mixtures, and concentration addition requires access to dose-response data and EC50 values (concentration giving 50% of the maximum response) for the individual components of the mixture--requirements that will rarely be fulfilled for complex environmental samples. Given these uncertainties, we conclude that it may be most expedient to select and bioassay whole environmental mixtures of potential concern. PMID:15064164

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wyrobek, A. J.; Manohar, C. F.; Nelson, D. O.

We investigated the low dose dependency of the transcriptional response of human cells to characterize the shape and biological functions associated with the dose response curve and to identify common and conserved functions of low dose expressed genes across cells and tissues. Human lymphoblastoid (HL) cells from two unrelated individuals were exposed to graded doses of radiation spanning the range of 1-10 cGy were analyzed by transcriptome profiling, qPCR and bioinformatics, in comparison to sham irradiated samples. A set of {approx}80 genes showed consistent responses in both cell lines; these genes were associated with homeostasis mechanisms (e.g., membrane signaling, moleculemore » transport), subcellular locations (e.g., Golgi, and endoplasmic reticulum), and involved diverse signal transduction pathways. The majority of radiation-modulated genes had plateau-like responses across 1-10 cGy, some with suggestive evidence that transcription was modulated at doses below 1 cGy. MYC, FOS and TP53 were the major network nodes of the low-dose response in HL cells. Comparison our low dose expression findings in HL cells with those of prior studies in mouse brain after whole body exposure, in human keratinocyte cultures, and in endothelial cells cultures, indicates that certain components of the low dose radiation response are broadly conserved across cell types and tissues, independent of proliferation status.« less

Enhancement of phototropic response to a range of light doses in Triticum aestivum coleoptiles in clinostat-simulated microgravity

NASA Technical Reports Server (NTRS)

Heathcote, D. G.; Bircher, B. W.; Brown, A. H. (Principal Investigator)

1987-01-01

The phototropic dose-response relationship has been determined for Triticum aestivum cv. Broom coleoptiles growing on a purpose-built clinostat apparatus providing gravity compensation by rotation about a horizontal axis at 2 rev min-1. These data are compared with data sets obtained with the clinostat axis vertical and stationary, as a 1 g control, and rotating vertically to examine clinostat effects other than gravity compensation. Triticum at 1 g follows the well-established pattern of other cereal coleoptiles with a first positive curvature at low doses, followed by an indifferent response region, and a second positive response at progressively increasing doses. However, these response regions lie at higher dose levels than reported for Avena. There is no significant difference between the responses observed with the clinostat axis vertical in the rotating and stationary modes, but gravity compensation by horizontal rotation increases the magnitude of first and second positive curvatures some threefold at 100 min after stimulation. The indifferent response is replaced by a significant curvature towards the light source, but remains apparent as a reduced curvature response at these dose levels.

Surgical Responses of Medial Rectus Muscle Recession in Thyroid Eye Disease-Related Esotropia

PubMed Central

Lyu, In Jeong; Lee, Ju-Yeun; Kong, Mingui; Park, Kyung-Ah; Oh, Sei Yeul

2016-01-01

We evaluate the surgical outcomes and surgical responses of medial rectus muscle (MR) recession patients with thyroid eye disease (TED)-related esotropia (ET). The surgical dose-response curves 1 week postoperatively and at the final visit were analyzed. Univariable and multivariable linear regression analyses were applied to investigate factors influencing surgical dose-response. A total of 43 patients with TED-related ET that underwent MR recession were included. The final success rate was 86.0% and the rate of undercorrection was 14.0%. The surgical dose-response curves of TED-related ET showed a gentle slope compared with those of standard surgical tables. In the univariable model, simultaneous vertical rectus muscle recession was the only significant factor influencing surgical dose-response of MR recession in TED-related ET (β = -0.397, P = 0.044). In a model adjusted for age, sex, type of surgery, and preoperative horizontal angle of deviation, simultaneous vertical rectus muscle recession showed marginal significance (β = -0.389, P = 0.064). The surgical dose-response curve of TED-related ET was unique. Simultaneous vertical rectus muscle recession was associated with increased surgical dose-response in TED-related ET. PMID:26796354

Phosphoprotein profiles of candidate markers for early cellular responses to low-dose γ-radiation in normal human fibroblast cells

PubMed Central

Yim, Ji-Hye; Yun, Jung Mi; Kim, Ji Young; Lee, In Kyung; Nam, Seon Young

2017-01-01

Abstract Ionizing radiation causes biological damage that leads to severe health effects. However, the effects and subsequent health implications caused by exposure to low-dose radiation are unclear. The objective of this study was to determine phosphoprotein profiles in normal human fibroblast cell lines in response to low-dose and high-dose γ-radiation. We examined the cellular response in MRC-5 cells 0.5 h after exposure to 0.05 or 2 Gy. Using 1318 antibodies by antibody array, we observed ≥1.3-fold increases in a number of identified phosphoproteins in cells subjected to low-dose (0.05 Gy) and high-dose (2 Gy) radiation, suggesting that both radiation levels stimulate distinct signaling pathways. Low-dose radiation induced nucleic acid–binding transcription factor activity, developmental processes, and multicellular organismal processes. By contrast, high-dose radiation stimulated apoptotic processes, cell adhesion and regulation, and cellular organization and biogenesis. We found that phospho-BTK (Tyr550) and phospho-Gab2 (Tyr643) protein levels at 0.5 h after treatment were higher in cells subjected to low-dose radiation than in cells treated with high-dose radiation. We also determined that the phosphorylation of BTK and Gab2 in response to ionizing radiation was regulated in a dose-dependent manner in MRC-5 and NHDF cells. Our study provides new insights into the biological responses to low-dose γ-radiation and identifies potential candidate markers for monitoring exposure to low-dose ionizing radiation. PMID:28122968

A Review: Development of a Microdose Model for Analysis of Adaptive Response and Bystander Dose Response Behavior

PubMed Central

Leonard, Bobby E.

2008-01-01

Prior work has provided incremental phases to a microdosimetry modeling program to describe the dose response behavior of the radio-protective adaptive response effect. We have here consolidated these prior works (Leonard 2000, 2005, 2007a, 2007b, 2007c) to provide a composite, comprehensive Microdose Model that is also herein modified to include the bystander effect. The nomenclature for the model is also standardized for the benefit of the experimental cellular radio-biologist. It extends the prior work to explicitly encompass separately the analysis of experimental data that is 1.) only dose dependent and reflecting only adaptive response radio-protection, 2.) both dose and dose-rate dependent data and reflecting only adaptive response radio-protection for spontaneous and challenge dose damage, 3.) only dose dependent data and reflecting both bystander deleterious damage and adaptive response radio-protection (AR-BE model). The Appendix cites the various applications of the model. Here we have used the Microdose Model to analyze the, much more human risk significant, Elmore et al (2006) data for the dose and dose rate influence on the adaptive response radio-protective behavior of HeLa x Skin cells for naturally occurring, spontaneous chromosome damage from a Brachytherapy type 125I photon radiation source. We have also applied the AR-BE Microdose Model to the Chromosome inversion data of Hooker et al (2004) reflecting both low LET bystander and adaptive response effects. The micro-beam facility data of Miller et al (1999), Nagasawa and Little (1999) and Zhou et al (2003) is also examined. For the Zhou et al (2003) data, we use the AR-BE model to estimate the threshold for adaptive response reduction of the bystander effect. The mammogram and diagnostic X-ray induction of AR and protective BE are observed. We show that bystander damage is reduced in the similar manner as spontaneous and challenge dose damage as shown by the Azzam et al (1996) data. We cite primary unresolved questions regarding adaptive response behavior and bystander behavior. The five features of major significance provided by the Microdose Model so far are 1.) Single Specific Energy Hits initiate Adaptive Response, 2.) Mammogram and diagnostic X-rays induce a protective Bystander Effect as well as Adaptive Response radio-protection. 3.) For mammogram X-rays the Adaptive Response protection is retained at high primer dose levels. 4.) The dose range of the AR protection depends on the value of the Specific Energy per Hit, . 5.) Alpha particle induced deleterious Bystander damage is modulated by low LET radiation. PMID:18648579

Regional radiation dose-response modeling of functional liver in hepatocellular carcinoma patients with longitudinal sulfur colloid SPECT/CT: a proof of concept.

PubMed

Price, Ryan G; Apisarnthanarax, Smith; Schaub, Stephanie K; Nyflot, Matthew J; Chapman, Tobias R; Matesan, Manuela; Vesselle, Hubert J; Bowen, Stephen R

2018-06-19

We report on patient-specific quantitative changes in longitudinal sulfur colloid SPECT/CT as a function of regional radiation dose distributions to normal liver in a cohort of hepatocellular carcinoma patients. Dose-response thresholds and slopes varied with baseline liver function metrics, and extreme values were found in patients with fatal hepatotoxicity. Dose-response modeling of normal liver in individual HCC patients has potential to characterize in vivo radiosensitivity, identify high risk subgroups, and personalize treatment planning dose constraints. Hepatotoxicity risk in hepatocellular carcinoma (HCC) patients is modulated by radiation dose delivered to normal liver tissue, but reported dose-response data are limited. Our prior work established baseline [ 99m Tc]sulfur colloid (SC) SPECT/CT liver function imaging biomarkers that predict clinical outcomes. We conducted a proof-of-concept investigation with longitudinal SC SPECT/CT to characterize patient-specific radiation dose-response relationships as surrogates for liver radiosensitivity. SC SPECT/CT images of 15 HCC patients with variable Child-Pugh status (8 CP-A, 7 CP-B/C) were acquired in treatment position prior to and 1 month (nominal) after SBRT (n=6) or proton therapy (n=9). Localized rigid registrations between pre/post-treatment CT to planning CT scans were performed, and transformations were applied to pre/post-treatment SC SPECT images. Radiotherapy doses were converted to EQD2 α/β=3 and Gy (RBE), and binned in 5 GyEQD2 increments within tumor-subtracted livers. Mean dose and percent change (%ΔSC) between pre- and post-treatment SPECT uptake, normalized to regions receiving < 5 GyEQD2, were calculated in each binned dose region. Dose-response data were parameterized by sigmoid functions (double exponential) consisting of maximum reduction (%ΔSC max ), dose midpoint (D mid ), and dose-response slope (α mid ) parameters. Individual patient sigmoid dose-response curves had high goodness-of-fit (median R 2 = 0.96, range 0.76-0.99). Large inter-patient variability was observed, with median (range) in %ΔSC max of 44% (20-75%), D mid of 13 Gy (4-27 GyEQD2), and α mid of 0.11 GyEQD2 -1 (0.04-0.29 GyEQD2 -1 ), respectively. Eight of 15 patients had %ΔSC max = 20-45%, while 7/15 had %ΔSC max = 60-75%, with subgroups made up of variable baseline liver function status and radiation treatment modality. Fatal hepatotoxicity occurred in patients (2/15) with low TLF (< 0.12) and low D mid (< 7 GyEQD2). Longitudinal SC SPECT/CT imaging revealed patient-specific variations in dose-response, and may identify patients with poor baseline liver function and increased sensitivity to radiation therapy. Validation of this regional liver dose-response modeling concept as a surrogate for patient-specific radiosensitivity has potential to guide HCC therapy regimen selection and planning constraints. Copyright © 2018 Elsevier Inc. All rights reserved.

BY HOW MUCH DO SHAPES OF TOXICOLOGICAL DOSE-RESPONSE RELATIONSHIPS VARY? (SOT)

EPA Science Inventory

A re-analysis of a large number of historical dose-response data for continuous endpoints showed that the shapes of the dose-response relationships were surprisingly homogenous. The datasets were selected on the sole criterion that they were expected to provide relatively good in...

NEUROTOXIC EFFECTS OF ENVIRONMENTAL AGENTS: DATA GAPS THAT CHALLENGE DOSE-RESPONSE ESTIMATION

EPA Science Inventory

Neurotoxic effects of environmental agents: Data gaps that challenge dose-response estimation
S Gutter*, P Mendola+, SG Selevan**, D Rice** (*UNC Chapel Hill; +US EPA, NHEERL; **US EPA, NCEA)

Dose-response estimation is a critical feature of risk assessment. It can be...

Estimation of dose-response models for discrete and continuous data in weed science

USDA-ARS?s Scientific Manuscript database

Dose-response analysis is widely used in biological sciences and has application to a variety of risk assessment, bioassay, and calibration problems. In weed science, dose-response methodologies have typically relied on least squares estimation under an assumption of normality. Advances in computati...

USE OF MECHANISTIC DATA TO HELP DEFINE DOSE-RESPONSE CURVES

EPA Science Inventory

Use of Mechanistic Data to Help Define Dose-Response Curves

The cancer risk assessment process described by the U.S. EPA necessitates a description of the dose-response curve for tumors in humans at low (environmental) exposures. This description can either be a default l...

Development of noise dose/visitor response relationships for the national parks overflight rule : Bryce Canyon National Park Study

DOT National Transportation Integrated Search

1998-07-01

This research was conducted in support of the National Parks Overflight Rule (National Rule). The foundation of the research program for the National Rule is the performance of noise dose/visitor response (dose-response) studies in several National P...

An Adaptive Staggered Dose Design for a Normal Endpoint.

PubMed

Wu, Joseph; Menon, Sandeep; Chang, Mark

2015-01-01

In a clinical trial where several doses are compared to a control, a multi-stage design that combines both the selection of the best dose and the confirmation of this selected dose is desirable. An example is the two-stage drop-the-losers or pick-the-winner design, where inferior doses are dropped after interim analysis. Selection of target dose(s) can be based on ranking of observed effects, hypothesis testing with adjustment for multiplicity, or other criteria at interim stages. A number of methods have been proposed and have made significant gains in trial efficiency. However, many of these designs started off with all doses with equal allocation and did not consider prioritizing the doses using existing dose-response information. We propose an adaptive staggered dose procedure that allows explicit prioritization of doses and applies error spending scheme that favors doses with assumed better responses. This design starts off with only a subset of the doses and adaptively adds new doses depending on interim results. Using simulation, we have shown that this design performs better in terms of increased statistical power than the drop-the-losers design given strong prior information of dose response.

Dynamics of Cellular Responses to Radiation

PubMed Central

Wodarz, Dominik; Sorace, Ron; Komarova, Natalia L.

2014-01-01

Understanding the consequences of exposure to low dose ionizing radiation is an important public health concern. While the risk of low dose radiation has been estimated by extrapolation from data at higher doses according to the linear non-threshold model, it has become clear that cellular responses can be very different at low compared to high radiation doses. Important phenomena in this respect include radioadaptive responses as well as low-dose hyper-radiosensitivity (HRS) and increased radioresistance (IRR). With radioadaptive responses, low dose exposure can protect against subsequent challenges, and two mechanisms have been suggested: an intracellular mechanism, inducing cellular changes as a result of the priming radiation, and induction of a protected state by inter-cellular communication. We use mathematical models to examine the effect of these mechanisms on cellular responses to low dose radiation. We find that the intracellular mechanism can account for the occurrence of radioadaptive responses. Interestingly, the same mechanism can also explain the existence of the HRS and IRR phenomena, and successfully describe experimentally observed dose-response relationships for a variety of cell types. This indicates that different, seemingly unrelated, low dose phenomena might be connected and driven by common core processes. With respect to the inter-cellular communication mechanism, we find that it can also account for the occurrence of radioadaptive responses, indicating redundancy in this respect. The model, however, also suggests that the communication mechanism can be vital for the long term survival of cell populations that are continuously exposed to relatively low levels of radiation, which cannot be achieved with the intracellular mechanism in our model. Experimental tests to address our model predictions are proposed. PMID:24722167

Study of the Genes and Mechanism Involved in the Radioadaptive Response

NASA Technical Reports Server (NTRS)

Dasgupta, Pushan R.

2009-01-01

The radioadaptive response is a phenomenon where exposure to a prior low dose of radiation reduces the level of damage induced by a subsequent high radiation dose. The molecular mechanism behind this is still not well understood. Learning more about the radioadaptive response is critical for long duration spaceflight since astronauts are exposed to low levels of cosmic radiation. The micronucleus assay was used to measure the level of damage caused by radiation. Although cells which were not washed with phosphate buffered saline (PBS) after a low priming dose of 5cGy did not show adaptation to the challenge dose, washing the cells with PBS and giving the cells fresh media after the low dose did allow radioadaptation to occur. This is consistent with the results of a previous publication by another research group. In the present study, genes involved in DNA damage signaling and the oxidative stress response were studied using RT PCR techniques in order to look at changes in expression level after the low dose with or without washing. Our preliminary results indicate that upregulation of oxidative stress response genes ANGPTL7, NCF2, TTN, and SRXN1 may be involved in the radioadaptive response. The low dose of radiation alone was found to activate the oxidative stress response genes GPR156 and MTL5, whereas, washing the cells alone caused relatively robust upregulation of the oxidative stress response genes DUSP1 and PTGS2. Washing after the priming dose showed some changes in the expression level of several DNA damage signaling genes. In addition, we studied whether washing the cells after the priming dose has an effect on the level of nitric oxide in both the media and cells, since nitric oxide levels are known to increase in the media of the cells after a high dose of radiation only if the cells were already exposed to a low priming dose. Based on this preliminary study, we propose that washing the cells after priming exposure actually eliminates some factor secreted by the cells that inhibits radioadaptation leading to the upregulation of some genes which initiates the response.

The c-Abl signaling network in the radioadaptive response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chi-Min, Yuan

2014-01-28

The radioadaptive response, or radiation hormesis, i.e. a low dose of radiation can protect cells and organisms from the effects of a subsequent higher dose, is a widely recognized phenomenon. Mechanisms underlying such radiation hormesis, however, remain largely unclear. Preliminary studies indicate an important role of c-Abl signaling in mediating the radioadaptive response. We propose to investigate how c-Abl regulates the crosstalk between p53 and NFκB in response to low doses irradiation. We found in our recent study that low dose IR induces a reciprocal p53 suppression and NFκB activation, which induces HIF-a and subsequently a metabolic reprogramming resulting inmore » a transition from oxidative phosphorylation to glycolysis. Of importance is that this glycolytic switch is essential for the radioadaptive response. This low-dose radiationinduced HIF1α activation was in sharp contrast with the high-dose IR-induced p53 activation and HIF1α inhibition. HIF1α and p53 seem to play distinct roles in mediating the radiation dose-dependent metabolic response. The induction of HIF1α-mediated glycolysis is restricted to a low dose range of radiation, which may have important implications in assessing the level of radiation exposure and its potential health risk. Our results support a dose-dependent metabolic response to IR. When IR doses are below the threshold of causing detectable DNA damage (<0.2Gy) and thus little p53 activation, HIF1α is induced resulting in induction of glycolysis and increased radiation resistance. When the radiation dose reaches levels eliciting DNA damage, p53 is activated and diminishes the activity of HIF1α and glycolysis, leading to the induction of cell death. Our work challenges the LNT model of radiation exposure risk and provides a metabolic mechanism of radioadaptive response. The study supports a need for determining the p53 and HIF1α activity as a potential reliable biological readout of radiation exposure in humans. The exquisite sensitivity of cellular metabolism to low doses of radiation could also serve as a valuable biomarker for estimating the health effects of low-level radiation exposure.« less

Induction of chromosomal aberrations at fluences of less than one HZE particle per cell nucleus.

PubMed

Hada, Megumi; Chappell, Lori J; Wang, Minli; George, Kerry A; Cucinotta, Francis A

2014-10-01

The assumption of a linear dose response used to describe the biological effects of high-LET radiation is fundamental in radiation protection methodologies. We investigated the dose response for chromosomal aberrations for exposures corresponding to less than one particle traversal per cell nucleus by high-energy charged (HZE) nuclei. Human fibroblast and lymphocyte cells were irradiated with several low doses of <0.1 Gy, and several higher doses of up to 1 Gy with oxygen (77 keV/μm), silicon (99 keV/μm) or Fe (175 keV/μm), Fe (195 keV/μm) or Fe (240 keV/μm) particles. Chromosomal aberrations at first mitosis were scored using fluorescence in situ hybridization (FISH) with chromosome specific paints for chromosomes 1, 2 and 4 and DAPI staining of background chromosomes. Nonlinear regression models were used to evaluate possible linear and nonlinear dose-response models based on these data. Dose responses for simple exchanges for human fibroblasts irradiated under confluent culture conditions were best fit by nonlinear models motivated by a nontargeted effect (NTE). The best fits for dose response data for human lymphocytes irradiated in blood tubes were a linear response model for all particles. Our results suggest that simple exchanges in normal human fibroblasts have an important NTE contribution at low-particle fluence. The current and prior experimental studies provide important evidence against the linear dose response assumption used in radiation protection for HZE particles and other high-LET radiation at the relevant range of low doses.

Time-dependent dose-response relation for absence of vaginal elasticity after gynecological radiation therapy.

PubMed

Alevronta, Eleftheria; Åvall-Lundqvist, Elisabeth; Al-Abany, Massoud; Nyberg, Tommy; Lind, Helena; Waldenström, Ann-Charlotte; Olsson, Caroline; Dunberger, Gail; Bergmark, Karin; Steineck, Gunnar; Lind, Bengt K

2016-09-01

To investigate the dose-response relation between the dose to the vagina and the patient-reported symptom 'absence of vaginal elasticity' and how time to follow-up influences this relation. The study included 78 long-term gynecological cancer survivors treated between 1991 and 2003 with external beam radiation therapy. Of those, 24 experienced absence of vaginal elasticity. A normal tissue complication model is introduced that takes into account the influence of time to follow-up on the dose-response relation and the patient's age. The best estimates of the dose-response parameters were calculated using Probit, Probit-Relative Seriality (RS) and Probit-time models. Log likelihood (LL) values and the Akaike Information Criterion (AIC) were used to evaluate the model fit. The dose-response parameters for 'absence of vaginal elasticity' according to the Probit and Probit-time models with the 68% Confidence Intervals (CI) were: LL=-39.8, D 50 =49.7 (47.2-52.4) Gy, γ 50 =1.40 (1.12-1.70) and LL=-37.4, D 50 =46.9 (43.5-50.9) Gy, γ 50 =1.81 (1.17-2.51) respectively. The proposed model, which describes the influence of time to follow-up on the dose-response relation, fits our data best. Our data indicate that the steepness of the dose-response curve of the dose to the vagina and the symptom 'absence of vaginal elasticity' increases with time to follow-up, while D 50 decreases. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Gamma Low-Dose-Rate Ionizing Radiation Stimulates Adaptive Functional and Molecular Response in Human Aortic Endothelial Cells in a Threshold-, Dose-, and Dose Rate–Dependent Manner

PubMed Central

Vieira Dias, Juliana; Gloaguen, Celine; Kereselidze, Dimitri; Manens, Line; Tack, Karine; Ebrahimian, Teni G

2018-01-01

A central question in radiation protection research is whether low-dose and low-dose-rate (LDR) exposures to ionizing radiation play a role in progression of cardiovascular disease. The response of endothelial cells to different LDR exposures may help estimate risk of cardiovascular disease by providing the biological mechanism involved. We investigated the effect of chronic LDR radiation on functional and molecular responses of human aorta endothelial cells (HAoECs). Human aorta endothelial cells were continuously irradiated at LDR (6 mGy/h) for 15 days and analyzed at time points when the cumulative dose reached 0.05, 0.5, 1.0, and 2.0 Gy. The same doses were administered acutely at high-dose rate (HDR; 1 Gy/min). The threshold for the loss of angiogenic capacity for both LDR and HDR radiations was between 0.5 and 1.0 Gy. At 2.0 Gy, angiogenic capacity returned to normal only for HAoEC exposed to LDR radiation, associated with increased expression of antioxidant and anti-inflammatory genes. Pre-LDR, but not pre-HDR, radiation, followed by a single acute 2.0 Gy challenge dose sustained the expression of antioxidant and anti-inflammatory genes and stimulated angiogenesis. Our results suggest that dose rate is important in cellular response and that a radioadaptive response is involved for a 2.0 Gy dose at LDR. PMID:29531508

Gamma Low-Dose-Rate Ionizing Radiation Stimulates Adaptive Functional and Molecular Response in Human Aortic Endothelial Cells in a Threshold-, Dose-, and Dose Rate-Dependent Manner.

PubMed

Vieira Dias, Juliana; Gloaguen, Celine; Kereselidze, Dimitri; Manens, Line; Tack, Karine; Ebrahimian, Teni G

2018-01-01

A central question in radiation protection research is whether low-dose and low-dose-rate (LDR) exposures to ionizing radiation play a role in progression of cardiovascular disease. The response of endothelial cells to different LDR exposures may help estimate risk of cardiovascular disease by providing the biological mechanism involved. We investigated the effect of chronic LDR radiation on functional and molecular responses of human aorta endothelial cells (HAoECs). Human aorta endothelial cells were continuously irradiated at LDR (6 mGy/h) for 15 days and analyzed at time points when the cumulative dose reached 0.05, 0.5, 1.0, and 2.0 Gy. The same doses were administered acutely at high-dose rate (HDR; 1 Gy/min). The threshold for the loss of angiogenic capacity for both LDR and HDR radiations was between 0.5 and 1.0 Gy. At 2.0 Gy, angiogenic capacity returned to normal only for HAoEC exposed to LDR radiation, associated with increased expression of antioxidant and anti-inflammatory genes. Pre-LDR, but not pre-HDR, radiation, followed by a single acute 2.0 Gy challenge dose sustained the expression of antioxidant and anti-inflammatory genes and stimulated angiogenesis. Our results suggest that dose rate is important in cellular response and that a radioadaptive response is involved for a 2.0 Gy dose at LDR.

A Four-Step and Four-Criteria Approach for Evaluating Evidence of Dose Addition in Chemical Mixture Toxicity

EPA Science Inventory

Dose addition is the most frequently-used component-based approach for predicting dose response for a mixture of toxicologically-similar chemicals and for statistical evaluation of whether the mixture response is consistent with dose additivity and therefore predictable from the ...

Dose-response relationship between hand-transmitted vibration and hand-arm vibration syndrome in a tropical environment.

PubMed

Su, Anselm Ting; Maeda, Setsuo; Fukumoto, Jin; Darus, Azlan; Hoe, Victor C W; Miyai, Nobuyuki; Isahak, Marzuki; Takemura, Shigeki; Bulgiba, Awang; Yoshimasu, Kouichi; Miyashita, Kazuhisa

2013-07-01

The dose-response relationship for hand-transmitted vibration has been investigated extensively in temperate environments. Since the clinical features of hand-arm vibration syndrome (HAVS) differ between the temperate and tropical environment, we conducted this study to investigate the dose-response relationship of HAVS in a tropical environment. A total of 173 male construction, forestry and automobile manufacturing plant workers in Malaysia were recruited into this study between August 2011 and 2012. The participants were interviewed for history of vibration exposure and HAVS symptoms, followed by hand functions evaluation and vibration measurement. Three types of vibration doses-lifetime vibration dose (LVD), total operating time (TOT) and cumulative exposure index (CEI)-were calculated and its log values were regressed against the symptoms of HAVS. The correlation between each vibration exposure dose and the hand function evaluation results was obtained. The adjusted prevalence ratio for finger tingling and numbness was 3.34 (95% CI 1.27 to 8.98) for subjects with lnLVD≥20 ln m(2) s(-4) against those <16 ln m(2) s(-4). Similar dose-response pattern was found for CEI but not for TOT. No subject reported white finger. The prevalence of finger coldness did not increase with any of the vibration doses. Vibrotactile perception thresholds correlated moderately with lnLVD and lnCEI. The dose-response relationship of HAVS in a tropical environment is valid for finger tingling and numbness. The LVD and CEI are more useful than TOT when evaluating the dose-response pattern of a heterogeneous group of vibratory tools workers.

Dose-Response—A Challenge for Allelopathy?

PubMed Central

Belz, Regina G.; Hurle, Karl; Duke, Stephen O.

2005-01-01

The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2H-1,4-benzoxaxin-3(4H)-one); BOA (benzoxazolin-2(3H)-one); MBOA (6-methoxy-benzoxazolin-2(3H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants (Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions. PMID:19330161

Mechanisms and biological importance of photon-induced bystander responses: do they have an impact on low-dose radiation responses

PubMed Central

Tomita, Masanori; Maeda, Munetoshi

2015-01-01

Abstract Elucidating the biological effect of low linear energy transfer (LET), low-dose and/or low-dose-rate ionizing radiation is essential in ensuring radiation safety. Over the past two decades, non-targeted effects, which are not only a direct consequence of radiation-induced initial lesions produced in cellular DNA but also of intra- and inter-cellular communications involving both targeted and non-targeted cells, have been reported and are currently defining a new paradigm in radiation biology. These effects include radiation-induced adaptive response, low-dose hypersensitivity, genomic instability, and radiation-induced bystander response (RIBR). RIBR is generally defined as a cellular response that is induced in non-irradiated cells that receive bystander signals from directly irradiated cells. RIBR could thus play an important biological role in low-dose irradiation conditions. However, this suggestion was mainly based on findings obtained using high-LET charged-particle radiations. The human population (especially the Japanese, who are exposed to lower doses of radon than the world average) is more frequently exposed to low-LET photons (X-rays or γ-rays) than to high-LET charged-particle radiation on a daily basis. There are currently a growing number of reports describing a distinguishing feature between photon-induced bystander response and high-LET RIBR. In particular, photon-induced bystander response is strongly influenced by irradiation dose, the irradiated region of the targeted cells, and p53 status. The present review focuses on the photon-induced bystander response, and discusses its impact on the low-dose radiation effect. PMID:25361549

QMRA for Drinking Water: 2. The Effect of Pathogen Clustering in Single-Hit Dose-Response Models.

PubMed

Nilsen, Vegard; Wyller, John

2016-01-01

Spatial and/or temporal clustering of pathogens will invalidate the commonly used assumption of Poisson-distributed pathogen counts (doses) in quantitative microbial risk assessment. In this work, the theoretically predicted effect of spatial clustering in conventional "single-hit" dose-response models is investigated by employing the stuttering Poisson distribution, a very general family of count distributions that naturally models pathogen clustering and contains the Poisson and negative binomial distributions as special cases. The analysis is facilitated by formulating the dose-response models in terms of probability generating functions. It is shown formally that the theoretical single-hit risk obtained with a stuttering Poisson distribution is lower than that obtained with a Poisson distribution, assuming identical mean doses. A similar result holds for mixed Poisson distributions. Numerical examples indicate that the theoretical single-hit risk is fairly insensitive to moderate clustering, though the effect tends to be more pronounced for low mean doses. Furthermore, using Jensen's inequality, an upper bound on risk is derived that tends to better approximate the exact theoretical single-hit risk for highly overdispersed dose distributions. The bound holds with any dose distribution (characterized by its mean and zero inflation index) and any conditional dose-response model that is concave in the dose variable. Its application is exemplified with published data from Norovirus feeding trials, for which some of the administered doses were prepared from an inoculum of aggregated viruses. The potential implications of clustering for dose-response assessment as well as practical risk characterization are discussed. © 2016 Society for Risk Analysis.

Peficitinib, an Oral Janus Kinase Inhibitor, in Moderate-to-Severe Ulcerative Colitis: Results From a Randomized, Phase 2 Study.

PubMed

Sands, Bruce E; Sandborn, William J; Feagan, Brian G; Lichtenstein, Gary R; Zhang, Hongyan; Strauss, Richard; Szapary, Philippe; Johanns, Jewel; Panes, Julian; Vermeire, Severine; O'Brien, Christopher D; Yang, Zijiang; Bertelsen, Kirk; Marano, Colleen

2018-06-15

Janus kinase (JAK) inhibitors have shown efficacy in ulcerative colitis (UC). We studied the dose-response, efficacy, and safety of peficitinib, an oral JAK inhibitor, in patients with moderate-to-severe UC. In this Phase 2b, dose-ranging trial, we evaluated peficitinib at 25mg once daily (qd), 75mg qd, 150mg qd, and 75mg twice daily versus placebo for efficacy and safety in 219 patients with moderate-to-severe UC. The primary outcome was peficitinib dose-response at Week 8 with response assessed using Mayo score change from baseline. Secondary endpoints were clinical response, clinical remission, mucosal healing, change from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ), and normalization of inflammatory biomarkers at Week 8; other secondary endpoints were treatment response through Week 16 and through Week 32 for patients in clinical response at Week 8. Safety was assessed through Week 36 or 4 weeks after the last dose. A statistically significant peficitinib dose-response was not demonstrated at Week 8, although a numerically greater proportion of patients receiving peficitinib ≥75mg qd achieved clinical response, remission, and mucosal healing at Week 8, supported by IBDQ improvement and inflammatory biomarker normalization. Treatment-emergent adverse event (TEAE) rates reported through Week 8 and the final safety visit were higher in the combined peficitinib group than placebo; patients receiving doses of ≥75mg qd peficitinib reported TEAEs more frequently. While no dose-response in patients with moderate-to-severe UC was demonstrated with peficitinib, evidence of efficacy was suggested at doses ≥75mg qd. The safety profile of peficitinib was consistent with current information. ClinicalTrials.gov NCT01959282.

Antibody Secreting Cell Responses following Vaccination with Bivalent Oral Cholera Vaccine among Haitian Adults.

PubMed

Matias, Wilfredo R; Falkard, Brie; Charles, Richelle C; Mayo-Smith, Leslie M; Teng, Jessica E; Xu, Peng; Kováč, Pavol; Ryan, Edward T; Qadri, Firdausi; Franke, Molly F; Ivers, Louise C; Harris, Jason B

2016-06-01

The bivalent whole-cell (BivWC) oral cholera vaccine (Shanchol) is effective in preventing cholera. However, evaluations of immune responses following vaccination with BivWC have been limited. To determine whether BivWC induces significant mucosal immune responses, we measured V. cholerae O1 antigen-specific antibody secreting cell (ASC) responses following vaccination. We enrolled 24 Haitian adults in this study, and administered doses of oral BivWC vaccine 14 days apart (day 0 and day 14). We drew blood at baseline, and 7 days following each vaccine dose (day 7 and 21). Peripheral blood mononuclear cells (PBMCs) were isolated, and ASCs were enumerated using an ELISPOT assay. Significant increases in Ogawa (6.9 cells per million PBMCs) and Inaba (9.5 cells per million PBMCs) OSP-specific IgA ASCs were detected 7 days following the first dose (P < 0.001), but not the second dose. The magnitude of V. cholerae-specific ASC responses did not appear to be associated with recent exposure to cholera. ASC responses measured against the whole lipolysaccharide (LPS) antigen and the OSP moiety of LPS were equivalent, suggesting that all or nearly all of the LPS response targets the OSP moiety. Immunization with the BivWC oral cholera vaccine induced ASC responses among a cohort of healthy adults in Haiti after a single dose. The second dose of vaccine resulted in minimal ASC responses over baseline, suggesting that the current dosing schedule may not be optimal for boosting mucosal immune responses to V. cholerae antigens for adults in a cholera-endemic area.

NONMONOTONIC DOSE RESPONSE CURVES (NMDRCS) ARE COMMON AFTER ESTROGEN OR ANDROGEN SIGNALING PATHWAY DISRUPTION. FACT OR FALDERAL?

EPA Science Inventory

ABSTRACT BODY: The shape of the dose response curve in the low dose region has been debated since the 1940s, originally focusing on linear no threshold (LNT) versus threshold responses for cancer and noncancer effects. Recently, it has been claimed that endocrine disrupters (EDCs...

Hierarchical dose response of E. coli O157:H7 from human outbreaks incorporating heterogeneity in exposure.

PubMed

Teunis, P F M; Ogden, I D; Strachan, N J C

2008-06-01

The infectivity of pathogenic microorganisms is a key factor in the transmission of an infectious disease in a susceptible population. Microbial infectivity is generally estimated from dose-response studies in human volunteers. This can only be done with mildly pathogenic organisms. Here a hierarchical Beta-Poisson dose-response model is developed utilizing data from human outbreaks. On the lowest level each outbreak is modelled separately and these are then combined at a second level to produce a group dose-response relation. The distribution of foodborne pathogens often shows strong heterogeneity and this is incorporated by introducing an additional parameter to the dose-response model, accounting for the degree of overdispersion relative to Poisson distribution. It was found that heterogeneity considerably influences the shape of the dose-response relationship and increases uncertainty in predicted risk. This uncertainty is greater than previously reported surrogate and outbreak models using a single level of analysis. Monte Carlo parameter samples (alpha, beta of the Beta-Poisson model) can be readily incorporated in risk assessment models built using tools such as S-plus and @ Risk.

Critical target and dose and dose-rate responses for the induction of chromosomal instability by ionizing radiation

NASA Technical Reports Server (NTRS)

Limoli, C. L.; Corcoran, J. J.; Milligan, J. R.; Ward, J. F.; Morgan, W. F.

1999-01-01

To investigate the critical target, dose response and dose-rate response for the induction of chromosomal instability by ionizing radiation, bromodeoxyuridine (BrdU)-substituted and unsubstituted GM10115 cells were exposed to a range of doses (0.1-10 Gy) and different dose rates (0.092-17.45 Gy min(-1)). The status of chromosomal stability was determined by fluorescence in situ hybridization approximately 20 generations after irradiation in clonal populations derived from single progenitor cells surviving acute exposure. Overall, nearly 700 individual clones representing over 140,000 metaphases were analyzed. In cells unsubstituted with BrdU, a dose response was found, where the probability of observing delayed chromosomal instability in any given clone was 3% per gray of X rays. For cells substituted with 25-66% BrdU, however, a dose response was observed only at low doses (<1.0 Gy); at higher doses (>1.0 Gy), the incidence of chromosomal instability leveled off. There was an increase in the frequency and complexity of chromosomal instability per unit dose compared to cells unsubstituted with BrdU. The frequency of chromosomal instability appeared to saturate around approximately 30%, an effect which occurred at much lower doses in the presence of BrdU. Changing the gamma-ray dose rate by a factor of 190 (0.092 to 17.45 Gy min(-1)) produced no significant differences in the frequency of chromosomal instability. The enhancement of chromosomal instability promoted by the presence of the BrdU argues that DNA comprises at least one of the critical targets important for the induction of this end point of genomic instability.

Induction of Chromosomal Aberrations at Fluences of Less Than One HZE Particle per Cell Nucleus

NASA Technical Reports Server (NTRS)

Hada, Megumi; Chappell, Lori J.; Wang, Minli; George, Kerry A.; Cucinotta, Francis A.

2014-01-01

The assumption of a linear dose response used to describe the biological effects of high LET radiation is fundamental in radiation protection methodologies. We investigated the dose response for chromosomal aberrations for exposures corresponding to less than one particle traversal per cell nucleus by high energy and charge (HZE) nuclei. Human fibroblast and lymphocyte cells where irradiated with several low doses of <0.1 Gy, and several higher doses of up to 1 Gy with O (77 keV/ (long-s)m), Si (99 keV/ (long-s)m), Fe (175 keV/ (long-s)m), Fe (195 keV/ (long-s)m) or Fe (240 keV/ (long-s)m) particles. Chromosomal aberrations at first mitosis were scored using fluorescence in situ hybridization (FISH) with chromosome specific paints for chromosomes 1, 2 and 4 and DAPI staining of background chromosomes. Non-linear regression models were used to evaluate possible linear and non-linear dose response models based on these data. Dose responses for simple exchanges for human fibroblast irradiated under confluent culture conditions were best fit by non-linear models motivated by a non-targeted effect (NTE). Best fits for the dose response data for human lymphocytes irradiated in blood tubes were a NTE model for O and a linear response model fit best for Si and Fe particles. Additional evidence for NTE were found in low dose experiments measuring gamma-H2AX foci, a marker of double strand breaks (DSB), and split-dose experiments with human fibroblasts. Our results suggest that simple exchanges in normal human fibroblasts have an important NTE contribution at low particle fluence. The current and prior experimental studies provide important evidence against the linear dose response assumption used in radiation protection for HZE particles and other high LET radiation at the relevant range of low doses.

Factors modifying the response of large animals to low-intensity radiation exposure

NASA Technical Reports Server (NTRS)

Page, N. P.; Still, E. T.

1972-01-01

In assessing the biological response to space radiation, two of the most important modifying factors are dose protraction and dose distribution to the body. Studies are reported in which sheep and swine were used to compare the hematology and lethality response resulting from radiation exposure encountered in a variety of forms, including acute (high dose-rate), chronic (low dose-rate), combinations of acute and chronic, and whether received as a continuous or as fractionated exposure. While sheep and swine are basically similar in response to acute radiation, their sensitivity to chronic irradiation is markedly different. Sheep remain relatively sensitive as the radiation exposure is protracted while swine are more resistant and capable of surviving extremely large doses of chronic irradiation. This response to chronic irradiation correlated well with changes in radiosensitivity and recovery following an acute, sublethal exposure.

Platelet response to increased aspirin dose in patients with persistent platelet aggregation while treated with aspirin 81 mg.

PubMed

Gengo, Fran; Westphal, Erica S; Rainka, Michelle M; Janda, Maria; Robson, Matthew J; Hourihane, J Maurice; Bates, Vernice

2016-04-01

This study demonstrates that patients who are taking 81 mg of aspirin and are nonresponsive benefit from a dose of 162 mg or greater vs a different antiplatelet therapy. We identified 100 patients who were nonresponsive to aspirin 81 mg via whole blood aggregometry and observed how many patients became responsive at a dose of 162 mg or greater. Platelet nonresponsiveness was defined as >10 Ω of resistance to collagen 1 µg/mL and/or an ohms ratio of collagen 1 µg/mL to collagen 5 µg/mL >0.5 and/or >6 Ω to arachidonate. Borderline response was defined as an improvement in 1 but not both of the above criteria. Of the initial 100 patients who were nonresponsive to an aspirin dose of 81 mg, 79% became responsive at a dose of 162 mg or >162 mg. Only 6% did not respond to any increase in dose. We believe that patients treated with low-dose aspirin who have significant risk for secondary vascular events should be individually assessed to determine their antiplatelet response. Those found to have persistent platelet aggregation despite treatment with 81 mg of aspirin have a higher likelihood of obtaining an adequate antiplatelet response at a higher aspirin dose. © 2015, The American College of Clinical Pharmacology.

Ceruletide intravenous dose-response study by a simplified scintigraphic technique

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krishnamurthy, G.T.; Turner, F.E.; Mangham, D.

1985-04-01

The intravenous dose response of a ceruletide diethylamine (ceruletide) was established by a simplified scintigraphic technique where multiple graded doses were given sequentially on a single occasion. The gallbladder volume was presented nongeometrically by /sup 99m/Tc-IDA counts. The mean latent period, ejection period, and ejection rate were similar for all four groups of subjects given 1-20 ng/kg of ceruletide. The ejection fractions were similar to the values when the identical dose of ceruletide was administered sequentially either before or after another dose. A dose of 5 ng/kg produced the most physiologic type of emptying. Intravenous doses of 10 ng/kg andmore » larger caused adverse reactions in 42% of the total doses in the form of abdominal pain, nausea, systolic and diastolic hypotension, or bradycardia. It is concluded that the dose response of a cholecystokininlike agent (ceruletide) can be established reliably by a scintigraphic technique where multiple graded doses are given on a single occasion.« less

Analyzing the dose-dependence of the Saccharomyces cerevisiae global transcriptional response to methyl methanesulfonate and ionizing radiation.

PubMed

Benton, Michael G; Somasundaram, Swetha; Glasner, Jeremy D; Palecek, Sean P

2006-12-01

One of the most crucial tasks for a cell to ensure its long term survival is preserving the integrity of its genetic heritage via maintenance of DNA structure and sequence. While the DNA damage response in the yeast Saccharomyces cerevisiae, a model eukaryotic organism, has been extensively studied, much remains to be elucidated about how the organism senses and responds to different types and doses of DNA damage. We have measured the global transcriptional response of S. cerevisiae to multiple doses of two representative DNA damaging agents, methyl methanesulfonate (MMS) and gamma radiation. Hierarchical clustering of genes with a statistically significant change in transcription illustrated the differences in the cellular responses to MMS and gamma radiation. Overall, MMS produced a larger transcriptional response than gamma radiation, and many of the genes modulated in response to MMS are involved in protein and translational regulation. Several clusters of coregulated genes whose responses varied with DNA damaging agent dose were identified. Perhaps the most interesting cluster contained four genes exhibiting biphasic induction in response to MMS dose. All of the genes (DUN1, RNR2, RNR4, and HUG1) are involved in the Mec1p kinase pathway known to respond to MMS, presumably due to stalled DNA replication forks. The biphasic responses of these genes suggest that the pathway is induced at lower levels as MMS dose increases. The genes in this cluster with a threefold or greater transcriptional response to gamma radiation all showed an increased induction with increasing gamma radiation dosage. Analyzing genome-wide transcriptional changes to multiple doses of external stresses enabled the identification of cellular responses that are modulated by magnitude of the stress, providing insights into how a cell deals with genotoxicity.

Method to determine the position-dependant metal correction factor for dose-rate equivalent laser testing of semiconductor devices

DOEpatents

Horn, Kevin M.

2013-07-09

A method reconstructs the charge collection from regions beneath opaque metallization of a semiconductor device, as determined from focused laser charge collection response images, and thereby derives a dose-rate dependent correction factor for subsequent broad-area, dose-rate equivalent, laser measurements. The position- and dose-rate dependencies of the charge-collection magnitude of the device are determined empirically and can be combined with a digital reconstruction methodology to derive an accurate metal-correction factor that permits subsequent absolute dose-rate response measurements to be derived from laser measurements alone. Broad-area laser dose-rate testing can thereby be used to accurately determine the peak transient current, dose-rate response of semiconductor devices to penetrating electron, gamma- and x-ray irradiation.

The effect of pre-dose on thermally and optically stimulated luminescence from α-Al2O3:C,Mg and α-Al2O3:C.

PubMed

Kalita, J M; Chithambo, M L

2018-06-15

We report the effect of pre-dose on the thermoluminescence (TL) and optically stimulated luminescence (OSL) dose response of α-Al 2 O 3 :C,Mg and α-Al 2 O 3 :C. Before any luminescence measurement, the samples were irradiated with different doses, namely 100, 500 and 1000 Gy to populate the deep electron traps. This is the pre-dose. The results from TL and OSL studies are compared with results from samples used without any pre-measurement dose. The TL glow curves and OSL decay curves of α-Al 2 O 3 :C,Mg recorded after pre-doses of 100, 500 and 1000 Gy are identical to those from a sample used without any pre-dose. Further, the TL and OSL dose response of all α-Al 2 O 3 :C,Mg samples are similar regardless of pre-dose. In comparison, the TL glow curves and OSL decay curves of α-Al 2 O 3 :C are influenced by pre-dose. We conclude that the differences in the TL and OSL dose response of various pre-dosed samples of α-Al 2 O 3 :C are due to the concentration of charge in the deep traps. On the other hand, owing to the lower concentration of such deep traps in α-Al 2 O 3 :C,Mg, the TL or OSL dose responses are not affected by pre-dose in this material. Copyright © 2018 Elsevier Ltd. All rights reserved.

Methylphenidate has nonlinear dose effects on cued response inhibition in adults but not adolescents

PubMed Central

Simon, Nicholas W.; Moghaddam, Bita

2016-01-01

Ongoing development of the dopamine system during adolescence may provide a partial mechanism for behavioral and psychiatric vulnerabilities. Despite early evidence for a hyperactive adolescent dopaminergic system, recent data suggest that adolescent dopamine may be functionally hypoactive compared to in adults. While this distinction has been established in response to dopaminergic drugs and natural rewards, little is known about age-related differences in cognitive efficacy of dopaminergic drugs. Using a recently established Cued Response Inhibition Task, we tested the effects of acute systemic methylphenidate, commonly known as Ritalin, on response inhibition and response initiation in adolescent and adults rats. First, we replicated previous data that adolescents are able to inhibit a response to a cue on par with adults, but are slower to produce a rewarded response after a stop cue. Next, we observed that methylphenidate modulated response inhibition in adult rats, with low dose (0.3 mg/kg) improving inhibition, and high dose (3 mg/kg) impairing performance. This dose-response pattern is commonly observed with psychostimulant cognitive modulation. In adolescents, however, methylphenidate had no effect on response inhibition at any dose. Latency of response initiation after the stop cue was not affected by methylphenidate in either adult or adolescent rats. These data establish that dose-response of a commonly prescribed psychostimulant medication is different in adolescents and adults. They further demonstrate that healthy adolescent response inhibition is not as sensitive to psychostimulants as in adults, supporting the idea that the dopamine system is hypoactive in adolescence. PMID:27431940

No adaptive response is induced by chronic low-dose radiation from Ra-226 in the CHSE/F fish embryonic cell line and the HaCaT human epithelial cell line

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shi, Xiaopei, E-mail: shix22@mcmaster.ca; Mothersi

Purpose: To determine whether chronic low-dose α-particle radiation from Ra-226 over multiple cell generations can lead to an adaptive response in CHSE/F fish embryonic cells or HaCaT human epithelial cells receiving subsequent acute high-dose γ-ray radiation. Methods: CHSE/F and HaCaT cells were exposed to very low doses of Ra-226 in medium for multiple generations prior to being challenged by a higher dose γ-ray radiation. The clonogenic assay was used to test the clonogenic survival of cells with or without being pretreated by radiation from Ra-226. Results: In general, pretreatment with chronic radiation has no significant influence on the reaction ofmore » cells to the subsequent challenge radiation. Compared to unprimed cells, the change in clonogenic survival of primed cells after receiving challenge radiation is mainly due to the influence of the chronic exposure, and there's little adaptive response induced. However at several dose points, pretreatment of CHSE/F fish cells with chronic radiation resulted in a radiosensitive response to a challenge dose of γ-ray radiation, and pretreatment of HaCaT cells resulted in no effect except for a slightly radioresistant response to the challenge radiation which was not significant. Conclusion: The results suggest that chronic low-dose radiation is not effective enough to induce adaptive response. There was a difference between human and fish cells and it may be important to consider results from multiple species before making conclusions about effects of chronic or low doses of radiation in the environment. The term “radiosensitive” or “adaptive” make no judgment about whether such responses are ultimately beneficial or harmful. - Highlights: • No obvious adaptive response is induced by chronic low-dose radiation from Ra-226. • Priming radiation from Ra-226 sensitized CHSE/F cells to the challenge radiation. • Linear model is inconsistent with current work using chronic low-dose radiation.« less

The alanine detector in BNCT dosimetry: Dose response in thermal and epithermal neutron fields

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schmitz, T., E-mail: schmito@uni-mainz.de; Bassler, N.; Blaickner, M.

Purpose: The response of alanine solid state dosimeters to ionizing radiation strongly depends on particle type and energy. Due to nuclear interactions, neutron fields usually also consist of secondary particles such as photons and protons of diverse energies. Various experiments have been carried out in three different neutron beams to explore the alanine dose response behavior and to validate model predictions. Additionally, application in medical neutron fields for boron neutron capture therapy is discussed. Methods: Alanine detectors have been irradiated in the thermal neutron field of the research reactor TRIGA Mainz, Germany, in five experimental conditions, generating different secondary particlemore » spectra. Further irradiations have been made in the epithermal neutron beams at the research reactors FiR 1 in Helsinki, Finland, and Tsing Hua open pool reactor in HsinChu, Taiwan ROC. Readout has been performed with electron spin resonance spectrometry with reference to an absorbed dose standard in a {sup 60}Co gamma ray beam. Absorbed doses and dose components have been calculated using the Monte Carlo codes FLUKA and MCNP. The relative effectiveness (RE), linking absorbed dose and detector response, has been calculated using the Hansen and Olsen alanine response model. Results: The measured dose response of the alanine detector in the different experiments has been evaluated and compared to model predictions. Therefore, a relative effectiveness has been calculated for each dose component, accounting for its dependence on particle type and energy. Agreement within 5% between model and measurement has been achieved for most irradiated detectors. Significant differences have been observed in response behavior between thermal and epithermal neutron fields, especially regarding dose composition and depth dose curves. The calculated dose components could be verified with the experimental results in the different primary and secondary particle fields. Conclusions: The alanine detector can be used without difficulty in neutron fields. The response has been understood with the model used which includes the relative effectiveness. Results and the corresponding discussion lead to the conclusion that application in neutron fields for medical purpose is limited by its sensitivity but that it is a useful tool as supplement to other detectors and verification of neutron source descriptions.« less

Antibody persistence of two pentavalent DTwP-HB-Hib vaccines to the age of 15-18 months, and response to the booster dose of quadrivalent DTwP-Hib vaccine.

PubMed

Sharma, Hitt; Yadav, Sangeeta; Lalwani, Sanjay; Kapre, Subhash; Jadhav, Suresh; Parekh, Sameer; Palkar, Sonali; Ravetkar, Satish; Bahl, Sunil; Kumar, Rakesh; Shewale, Sunil

2013-01-07

Antibody persistence in children following three doses of primary vaccination with diphtheria, tetanus, whole-cell-pertussis (DTwP), hepatitis B, and Haemophilus influenzae type b (Hib) vaccines (SIIL Pentavac vaccine vs. Easyfive(®) of Panacea Biotec), and response to the booster dose of DTwP-Hib (Quadrovax(®)) vaccine. Children who completed their primary immunization were assessed for antibodies at 15-18 months of age, and then given a booster dose of DTwP-Hib vaccine. Reactogenicity and safety of the booster dose was evaluated. Both pentavalent vaccines demonstrated a good immune response at 15-18 months. Following the booster dose, all vaccinated subjects achieved protective titers against diphtheria, tetanus and Hib, whereas the response to pertussis antigen was ~78%. Fever and irritability was noted in 24%, local pain in 51%, and swelling in 36% of the children following booster dose. Primary immunization with either pentavalent vaccine induced an excellent immunity lasting till the second year of life. A booster dose with DTwP-Hib (Quadrovax(®)) vaccine effectuated a good anamnestic response to all vaccine components, being specially strong for Hib in children previously vaccinated with SIIL liquid pentavalent vaccine (Pentavac(®)). Also, the safety profile of SIIL quadrivalent vaccine (Quadrovax(®)) administered as booster dose was acceptable. Copyright © 2012 Elsevier Ltd. All rights reserved.

The impact of the oxygen scavenger on the dose-rate dependence and dose sensitivity of MAGIC type polymer gels

NASA Astrophysics Data System (ADS)

Khan, Muzafar; Heilemann, Gerd; Kuess, Peter; Georg, Dietmar; Berg, Andreas

2018-03-01

Recent developments in radiation therapy aimed at more precise dose delivery along with higher dose gradients (dose painting) and more efficient dose delivery with higher dose rates e.g. flattening filter free (FFF) irradiation. Magnetic-resonance-imaging based polymer gel dosimetry offers 3D information for precise dose delivery techniques. Many of the proposed polymer gels have been reported to exhibit a dose response, measured as relaxation rate ΔR2(D), which is dose rate dependent. A lack of or a reduced dose-rate sensitivity is very important for dosimetric accuracy, especially with regard to the increasing clinical use of FFF irradiation protocols with LINACs at high dose rates. Some commonly used polymer gels are based on Methacrylic-Acid-Gel-Initiated-by-Copper (MAGIC). Here, we report on the dose sensitivity (ΔR2/ΔD) of MAGIC-type gels with different oxygen scavenger concentration for their specific dependence on the applied dose rate in order to improve the dosimetric performance, especially for high dose rates. A preclinical x-ray machine (‘Yxlon’, E  =  200 kV) was used for irradiation to cover a range of dose rates from low \\dot{D} min  =  0.6 Gy min-1 to high \\dot{D} max  =  18 Gy min-1. The dose response was evaluated using R2-imaging of the gel on a human high-field (7T) MR-scanner. The results indicate that all of the investigated dose rates had an impact on the dose response in polymer gel dosimeters, being strongest in the high dose region and less effective for low dose levels. The absolute dose rate dependence \\frac{(Δ R2/Δ D)}{Δ \\dot{D}} of the dose response in MAGIC-type gel is significantly reduced using higher concentrations of oxygen scavenger at the expense of reduced dose sensitivity. For quantitative dose evaluations the relative dose rate dependence of a polymer gel, normalized to its sensitivity is important. Based on this normalized sensitivity the dose rate sensitivity was reduced distinctly using an increased oxygen scavenger concentration with reference to standard MAGIC-type gel formulation at high dose rate levels. The proposed gel composition with high oxygen scavenger concentration exhibits a larger linear active dose response and might be used especially in FFF-radiation applications and preclinical dosimetry at high dose rates. We propose in general to use high dose rates for calibration and evaluation as the change in relative dose sensitivity is reduced at higher dose rates in all of the investigated gel types.

A Comparison of Dose-Response Models for the Parotid Gland in a Large Group of Head-and-Neck Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Houweling, Antonetta C., E-mail: A.Houweling@umcutrecht.n; Philippens, Marielle E.P.; Dijkema, Tim

2010-03-15

Purpose: The dose-response relationship of the parotid gland has been described most frequently using the Lyman-Kutcher-Burman model. However, various other normal tissue complication probability (NTCP) models exist. We evaluated in a large group of patients the value of six NTCP models that describe the parotid gland dose response 1 year after radiotherapy. Methods and Materials: A total of 347 patients with head-and-neck tumors were included in this prospective parotid gland dose-response study. The patients were treated with either conventional radiotherapy or intensity-modulated radiotherapy. Dose-volume histograms for the parotid glands were derived from three-dimensional dose calculations using computed tomography scans. Stimulatedmore » salivary flow rates were measured before and 1 year after radiotherapy. A threshold of 25% of the pretreatment flow rate was used to define a complication. The evaluated models included the Lyman-Kutcher-Burman model, the mean dose model, the relative seriality model, the critical volume model, the parallel functional subunit model, and the dose-threshold model. The goodness of fit (GOF) was determined by the deviance and a Monte Carlo hypothesis test. Ranking of the models was based on Akaike's information criterion (AIC). Results: None of the models was rejected based on the evaluation of the GOF. The mean dose model was ranked as the best model based on the AIC. The TD{sub 50} in these models was approximately 39 Gy. Conclusions: The mean dose model was preferred for describing the dose-response relationship of the parotid gland.« less

Low doses of a neonicotinoid insecticide modify pheromone response thresholds of central but not peripheral olfactory neurons in a pest insect

PubMed Central

Rabhi, Kaouther K.; Deisig, Nina; Demondion, Elodie; Le Corre, Julie; Robert, Guillaume; Tricoire-Leignel, Hélène; Lucas, Philippe; Gadenne, Christophe; Anton, Sylvia

2016-01-01

Insect pest management relies mainly on neurotoxic insecticides, including neonicotinoids, leaving residues in the environment. There is now evidence that low doses of insecticides can have positive effects on pest insects by enhancing various life traits. Because pest insects often rely on sex pheromones for reproduction, and olfactory synaptic transmission is cholinergic, neonicotinoid residues could modify chemical communication. We recently showed that treatments with different sublethal doses of clothianidin could either enhance or decrease behavioural sex pheromone responses in the male moth, Agrotis ipsilon. We investigated now effects of the behaviourally active clothianidin doses on the sensitivity of the peripheral and central olfactory system. We show with extracellular recordings that both tested clothianidin doses do not influence pheromone responses in olfactory receptor neurons. Similarly, in vivo optical imaging does not reveal any changes in glomerular response intensities to the sex pheromone after clothianidin treatments. The sensitivity of intracellularly recorded antennal lobe output neurons, however, is upregulated by a lethal dose 20 times and downregulated by a dose 10 times lower than the lethal dose 0. This correlates with the changes of behavioural responses after clothianidin treatment and suggests the antennal lobe as neural substrate involved in clothianidin-induced behavioural changes. PMID:26842577

Chernobyl Doses. Volume 1. Analysis of Forest Canopy Radiation Response from Multispectral Imagery and the Relationship to Doses

DTIC Science & Technology

1994-09-01

AD-A284 746 Defense Nuclear Agency Alexandria, VA 22310-3398 DNA-TR-92-37-V1 Chernobyl Doses Volume 1-Analysis of Forest Canopy Radiation Response...REPORT DATE 3. REPORT TYPE AND DATES COVERED 940901 Technical 870929- 930930 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS Chernobyl Doses Volume 1-Analysis of...volume of the report Chernobyl Doses presents details of a new, quantitative method for remotely sensing ionizing radiation dose to vegetation

EFFECTS OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN ...

EPA Pesticide Factsheets

While the effect that TCDD has on humoral immunity in the mouse has been well documented, it has not been for the rat. n this study, the effect that TCDD has on the antibody plaque-forming cell (PFC) response to sheep red blood cells (SRBC) in adult female B6C3F1 mice and F344 rats was compared. ice or rats were given a single intraperitoneal injection of TCDD at doses ranging from 0.1 to 30 ug/kg, 7 days prior to intravenous immunization with SRBC. our days later the PFC response to SRBC was determined. ice showed a dose related suppression of the PFC response, with an ED50 of 0.71 ug/kg TCDD. n contrast, TCDD failed to suppress and in fact enhanced the PFC response to SRBC in rats at doses as high as 30 ug/kg. he inability of TCDD to suppress the PFC response in rats was unrelated to hepatic CYP1A1 and CYP1A2 induction which was detectable at doses of 1 and 0.3 ug/kg TCDD, respectively. here was no shift in the time to peak PFC response in rats dosed with TCDD, nor was the failure of TCDD to suppress the PFC response in rats related to gender or strain. henotypic analysis of thymocytes and splenic lymphocytes from TCDD-dosed (i.e., 3, 10 or 30 ug/kg) and SREC-immunized mice and rats revealed that CD4-CD8+ splenocytes were reduced in a dose related manner in rats only and that this reduction in CD4-CD8+ was accompanied by a dose related increase in IgM+ splenocytes. hese results demonstrate species differences in the effect of TCDD on the PFC response to SRBC w

Linear response theory for annealing of radiation damage in semiconductor devices

NASA Technical Reports Server (NTRS)

Litovchenko, Vitaly

1988-01-01

A theoretical study of the radiation/annealing response of MOS ICs is described. Although many experiments have been performed in this field, no comprehensive theory dealing with radiation/annealing response has been proposed. Many attempts have been made to apply linear response theory, but no theoretical foundation has been presented. The linear response theory outlined here is capable of describing a broad area of radiation/annealing response phenomena in MOS ICs, in particular, both simultaneous irradiation and annealing, as well as short- and long-term annealing, including the case when annealing is nearing completion. For the first time, a simple procedure is devised to determine the response function from experimental radiation/annealing data. In addition, this procedure enables us to study the effect of variable temperature and dose rate, effects which are of interest in spaceflight. In the past, the shift in threshold potential due to radiation/annealing has usually been assumed to depend on one variable: the time lapse between an impulse dose and the time of observation. While such a suggestion of uniformity in time is certainly true for a broad range of radiation annealing phenomena, it may not hold for some ranges of the variables of interest (temperature, dose rate, etc.). A response function is projected which is dependent on two variables: the time of observation and the time of the impulse dose. This dependence on two variables allows us to extend the theory to the treatment of a variable dose rate. Finally, the linear theory is generalized to the case in which the response is nonlinear with impulse dose, but is proportional to some impulse function of dose. A method to determine both the impulse and response functions is presented.

Toward a unified approach to dose-response modeling in ecotoxicology.

PubMed

Ritz, Christian

2010-01-01

This study reviews dose-response models that are used in ecotoxicology. The focus lies on clarification of differences and similarities between models, and as a side effect, their different guises in ecotoxicology are unravelled. A look at frequently used dose-response models reveals major discrepancies, among other things in naming conventions. Therefore, there is a need for a unified view on dose-response modeling in order to improve the understanding of it and to facilitate communication and comparison of findings across studies, thus realizing its full potential. This study attempts to establish a general framework that encompasses most dose-response models that are of interest to ecotoxicologists in practice. The framework includes commonly used models such as the log-logistic and Weibull models, but also features entire suites of models as found in various guidance documents. An outline on how the proposed framework can be implemented in statistical software systems is also provided.

Occupational Exposure to Diesel Motor Exhaust and Lung Cancer: A Dose-Response Relationship Hidden by Asbestos Exposure Adjustment? The ICARE Study

PubMed Central

Matrat, Mireille; Guida, Florence; Cénée, Sylvie; Févotte, Joelle; Carton, Matthieu; Cyr, Diane; Menvielle, Gwenn; Paget-Bailly, Sophie; Radoï, Loredana; Schmaus, Annie; Bara, Simona; Velten, Michel; Luce, Danièle; Stücker, Isabelle; The Icare Study Group

2015-01-01

Background. In a French large population-based case-control study we investigated the dose-response relationship between lung cancer and occupational exposure to diesel motor exhaust (DME), taking into account asbestos exposure. Methods. Exposure to DME was assessed by questionnaire. Asbestos was taken into account through a global indicator of exposure to occupational carcinogens or by a specific JEM. Results. We found a crude dose response relationship with most of the indicators of DME exposure, including with the cumulative exposure index. All results were affected by adjustment for asbestos exposure. The dose response relationships between DME and lung cancer were observed among subjects never exposed to asbestos. Conclusions. Exposure to DME and to asbestos is frequently found among the same subjects, which may explain why dose-response relationships in previous studies that adjusted for asbestos exposure were inconsistent. PMID:26425123

Low doses of ionizing radiation to mammalian cells may rather control than cause DNA damage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Feinendegen, L.E.; Bond, V.P.; Sondhaus, C.A.

This report examines the origin of tissue effects that may follow from different cellular responses to low-dose irradiation, using published data. Two principal categories of cellular responses are considered. One response category relates to the probability of radiation-induced DNA damage. The other category consists of low-dose induced metabolic changes that induce mechanisms of DNA damage mitigation, which do not operate at high levels of exposure. Modeled in this way, tissue is treated as a complex adaptive system. The interaction of the various cellular responses results in a net tissue dose-effect relation that is likely to deviate from linearity in themore » low-dose region. This suggests that the LNT hypothesis should be reexamined. This paper aims at demonstrating tissue effects as an expression of cellular responses, both damaging and defensive, in relation to the energy deposited in cell mass, by use of microdosimetric concepts.« less

Complex, non-monotonic dose-response curves with multiple maxima: Do we (ever) sample densely enough?

PubMed

Cvrčková, Fatima; Luštinec, Jiří; Žárský, Viktor

2015-01-01

We usually expect the dose-response curves of biological responses to quantifiable stimuli to be simple, either monotonic or exhibiting a single maximum or minimum. Deviations are often viewed as experimental noise. However, detailed measurements in plant primary tissue cultures (stem pith explants of kale and tobacco) exposed to varying doses of sucrose, cytokinins (BA or kinetin) or auxins (IAA or NAA) revealed that growth and several biochemical parameters exhibit multiple reproducible, statistically significant maxima over a wide range of exogenous substance concentrations. This results in complex, non-monotonic dose-response curves, reminiscent of previous reports of analogous observations in both metazoan and plant systems responding to diverse pharmacological treatments. These findings suggest the existence of a hitherto neglected class of biological phenomena resulting in dose-response curves exhibiting periodic patterns of maxima and minima, whose causes remain so far uncharacterized, partly due to insufficient sampling frequency used in many studies.

Evaluation of ifosfamide salvage therapy for metastatic canine osteosarcoma.

PubMed

Batschinski, K; Dervisis, N G; Kitchell, B E

2014-12-01

A retrospective study was performed to assess toxicity and response rate of ifosfamide salvage treatment for dogs diagnosed with metastatic osteosarcoma (OSA). Dogs diagnosed with OSA and previously treated with standard chemotherapy were included in the study. Nineteen dogs met the inclusion criteria, and 17 dogs were evaluable for response. Ifosfamide doses ranged from 375 to 425 mg m(-2) (median dose 375 mg m(-2)), with a median of two doses administered per dog (range 1-7 doses). The overall response to ifosfamide was 11.8% [complete response (CR) = 1/17, partial response (PR) = 1/17, stable disease (SD) = 2/17, progressive disease (PD) = 13/17]. Two dogs were hospitalized due to ifosfamide toxicosis. The median survival duration from the first dose of ifosfamide to death was 95 days. Ifosfamide was well tolerated, but minor anti-tumour activity was observed. © 2012 Blackwell Publishing Ltd.

The dose-response ratio in electroconvulsive therapy a preliminary study.

PubMed

Price, T R; Mackenzie, T B; Tucker, G J; Culver, C

1978-09-01

To investigate pretreatment patient variables that might correlate with dose-response characteristics of electroconvulsive therapy (ECT) and treatment outcomes, 14 patients were assessed on a daily basis, before and during treatment, using self-report affective scales, three simple paper-and-pencil tests of cognitive function,and finger-tapping speed. From these data, dose-response ratios and treatment outcome measures were derived. The dose-response ratio of ECT was found to correlate with age--the younger the patient, the more favorable the ratio. This finding is discussed in terms of the known relationships between brain monoamine oxidase levels and age, and the established relationship between seizure duration and treatment efficacy. The dose-response ratio over the first two electroconvulsive treatments as well as lesser degrees of initial congnitive and greater degrees of initial affective impairment correlated strongly with greater overall affective improvement. Some clinical and research implications of these findings are discussed.

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose.

PubMed

Lever, Melissa; Lim, Hong-Sheng; Kruger, Philipp; Nguyen, John; Trendel, Nicola; Abu-Shah, Enas; Maini, Philip Kumar; van der Merwe, Philip Anton; Dushek, Omer

2016-10-25

T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose-response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways.

Radiation Dose-Response Relationships and Risk Assessment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Strom, Daniel J.

The notion of a dose-response relationship was probably invented shortly after the discovery of poisons, the invention of alcoholic beverages, and the bringing of fire into a confined space in the forgotten depths of ancient prehistory. The amount of poison or medicine ingested can easily be observed to affect the behavior, health, or sickness outcome. Threshold effects, such as death, could be easily understood for intoxicants, medicine, and poisons. As Paracelsus (1493-1541), the 'father' of modern toxicology said, 'It is the dose that makes the poison.' Perhaps less obvious is the fact that implicit in such dose-response relationships is alsomore » the notion of dose rate. Usually, the dose is administered fairly acutely, in a single injection, pill, or swallow; a few puffs on a pipe; or a meal of eating or drinking. The same amount of intoxicants, medicine, or poisons administered over a week or month might have little or no observable effect. Thus, before the discovery of ionizing radiation in the late 19th century, toxicology ('the science of poisons') and pharmacology had deeply ingrained notions of dose-response relationships. This chapter demonstrates that the notion of a dose-response relationship for ionizing radiation is hopelessly simplistic from a scientific standpoint. While useful from a policy or regulatory standpoint, dose-response relationships cannot possibly convey enough information to describe the problem from a quantitative view of radiation biology, nor can they address societal values. Three sections of this chapter address the concepts, observations, and theories that contribute to the scientific input to the practice of managing risks from exposure to ionizing radiation. The presentation begins with irradiation regimes, followed by responses to high and low doses of ionizing radiation, and a discussion of how all of this can inform radiation risk management. The knowledge that is really needed for prediction of individual risk is presented. The chapter ends with conclusions and recommendations.« less

Harnessing the theoretical foundations of the exponential and beta-Poisson dose-response models to quantify parameter uncertainty using Markov Chain Monte Carlo.

PubMed

Schmidt, Philip J; Pintar, Katarina D M; Fazil, Aamir M; Topp, Edward

2013-09-01

Dose-response models are the essential link between exposure assessment and computed risk values in quantitative microbial risk assessment, yet the uncertainty that is inherent to computed risks because the dose-response model parameters are estimated using limited epidemiological data is rarely quantified. Second-order risk characterization approaches incorporating uncertainty in dose-response model parameters can provide more complete information to decisionmakers by separating variability and uncertainty to quantify the uncertainty in computed risks. Therefore, the objective of this work is to develop procedures to sample from posterior distributions describing uncertainty in the parameters of exponential and beta-Poisson dose-response models using Bayes's theorem and Markov Chain Monte Carlo (in OpenBUGS). The theoretical origins of the beta-Poisson dose-response model are used to identify a decomposed version of the model that enables Bayesian analysis without the need to evaluate Kummer confluent hypergeometric functions. Herein, it is also established that the beta distribution in the beta-Poisson dose-response model cannot address variation among individual pathogens, criteria to validate use of the conventional approximation to the beta-Poisson model are proposed, and simple algorithms to evaluate actual beta-Poisson probabilities of infection are investigated. The developed MCMC procedures are applied to analysis of a case study data set, and it is demonstrated that an important region of the posterior distribution of the beta-Poisson dose-response model parameters is attributable to the absence of low-dose data. This region includes beta-Poisson models for which the conventional approximation is especially invalid and in which many beta distributions have an extreme shape with questionable plausibility. © Her Majesty the Queen in Right of Canada 2013. Reproduced with the permission of the Minister of the Public Health Agency of Canada.

Laser-based irradiation apparatus and method to measure the functional dose-rate response of semiconductor devices

DOEpatents

Horn, Kevin M [Albuquerque, NM

2008-05-20

A broad-beam laser irradiation apparatus can measure the parametric or functional response of a semiconductor device to exposure to dose-rate equivalent infrared laser light. Comparisons of dose-rate response from before, during, and after accelerated aging of a device, or from periodic sampling of devices from fielded operational systems can determine if aging has affected the device's overall functionality. The dependence of these changes on equivalent dose-rate pulse intensity and/or duration can be measured with the apparatus. The synchronized introduction of external electrical transients into the device under test can be used to simulate the electrical effects of the surrounding circuitry's response to a radiation exposure while exposing the device to dose-rate equivalent infrared laser light.

Linearity and reproducibility response of Fricke dosimetry for low energy X-Ray beam

NASA Astrophysics Data System (ADS)

Mantuano, A.; de Amorim, G. J.; David, M. G.; Rosado, P. H. G.; Salata, C.; Magalhães, L. A. G.; deAlmeida, C. E.

2018-03-01

The Fricke dosimeter is the most used, liquid chemical dosimeter. It has been shown to be a feasible option for the absorbed dose standard. The present work aims to determinate a dose-response curve of Fricke solution using different doses and reproducibility test comparing the calculated dose to Fricke solution and Ionizing Chamber. Tests were performed using an X-ray irradiator for biological research at Radiological Science Laboratory (LCR/UERJ). The results showed a linear response to different doses of type A uncertainties from 0.08 to 1.2%. Reproducibility test showed type A uncertainties of 0.16% to the dosimeter.

SU-E-T-264: Preliminary Results On New Optically Stimulated Luminescent Materials for Proton Therapy Dosimetry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Doull, B; Zheng, Y; Procure Proton Therapy Center, Oklahoma City, OK

2014-06-01

Purpose: The objective of this work is to test the premise that luminescence materials with less under-response to proton beams can be identified by testing their dose response to low-LET radiation. The goal is to develop new Optically Stimulated Luminescence (OSL) materials with improved response for proton therapy dosimetry. Methods: We first measured the dose response of new OSL materials, synthesized in our laboratory, to low-LET radiation (beta rays from a {sup 90}Sr/{sup 90}Y source) and selected two materials having different OSL saturation characteristics and good dosimetric properties, namely MgB4O7:Ce,Li and MgO:Li. Commercial Al2O3:C was also used for comparison. Thesemore » materials were then irradiated at several depths along a pristine proton beam. The luminescence responses of the materials, relative to the entrance response, were compared with the depth dose profile measured by a multiple-layer ion chamber. Results: The OSL signals of MgB4O7:Ce,Li and MgO:Li were characterized for signal stability, dose response, and response to a clinical proton beam. The materials were also compared with the commercial Al2O3:C. The signals from both MgB4O7:Ce,Li and MgO:Li were relatively stable after a one day delay following irradiation. The low-LET dose response of the materials showed that, over the dose range investigated (up to ∼800 Gy), MgB4O7:Ce,Li did not saturate, whereas MgO:Li and Al2O3:C saturated at doses of ∼100 Gy. MgB4O7:Ce,Li showed less underresponse to proton beams than MgO:Li and Al2O3:C. Conclusion: In general the material with the highest saturation doses for low-LET radiation (MgB4O7:Ce,Li) showed the least under-response to proton beams, which suggests that it may be possible to develop better OSL materials for proton dosimetry if the dose response can be controlled during synthesis. Nevertheless, the degree in which the response to proton beams can be controlled remains to be determined. The research is funded by the Oklahoma Center for the Advancement of Science and Technology (OCAST), project number HR12-055.« less

Dose-Dependent Pheromone Responses of Ips pini, Orthotomicus latiden (Coleoptera: Scolytidae), and associates in stands of lodgepole pine

Treesearch

Daniel R. Miller; John H. Borden; B. Staffan Lidgren

2005-01-01

We conducted four behavioral choice tests in stands of mature lodgepole pine in British Columbia, from 1988 to 1991, to determine the dose-dependent responses of Orthotomicus latidens (LeConte) and Ips pini (Say) to their respective pheromones. Dose-dependent responses were exhibited by I. pini to (±)-ipsdienol and lanierone, with...

Enhanced Medial Collateral Ligament Healing using Mesenchymal Stem Cells: Dosage Effects on Cellular Response and Cytokine Profile

PubMed Central

Saether, Erin E.; Chamberlain, Connie S.; Leiferman, Ellen M.; Kondratko-Mittnacht, Jaclyn R.; Li, Wan Ju; Brickson, Stacey L.; Vanderby, Ray

2013-01-01

Mesenchymal stem cells (MSCs) have potential therapeutic applications for musculoskeletal injuries due to their ability to differentiate into several tissue cell types and modulate immune and inflammatory responses. These immune-modulatory properties were examined in vivo during early stage rat medial collateral ligament healing. Two different cell doses (low dose 1×106 or high dose 4×106 MSCs) were administered at the time of injury and compared with normal ligament healing at days 5 and 14 post-injury. At both times, the high dose MSC group demonstrated a significant decrease in M2 macrophages compared to controls. At day 14, fewer M1 macrophages were detected in the low dose group compared to the high dose group. These results, along with significant changes in procollagen I, proliferating cells, and endothelialization suggest that MSCs can alter the cellular response during healing in a dose-dependent manner. The higher dose ligaments also had increased expression of several pro-inflammatory cytokines at day 5 (IL-1β, IFNγ, IL-2) and increased expression of IL-12 at day 14. Mechanical testing at day 14 revealed increased failure strength and stiffness in low dose ligaments compared to controls. Based on these improved mechanical properties, MSCs enhanced functional healing when applied at a lower dose. Different doses of MSCs uniquely affected the cellular response and cytokine expression in healing ligaments. Interestingly, the lower dose of cells proved to be most effective in improving functional properties. PMID:24174129

The question of nonlinearity in the dose-response relation between particulate matter air pollution and mortality: can Akaike's Information Criterion be trusted to take the right turn?

PubMed

Roberts, Steven; Martin, Michael A

2006-12-15

The shape of the dose-response relation between particulate matter air pollution and mortality is crucial for public health assessment, and departures of this relation from linearity could have important regulatory consequences. A number of investigators have studied the shape of the particulate matter-mortality dose-response relation and concluded that the relation could be adequately described by a linear model. Some of these researchers examined the hypothesis of linearity by comparing Akaike's Information Criterion (AIC) values obtained under linear, piecewise linear, and spline alternative models. However, at the current time, the efficacy of the AIC in this context has not been assessed. The authors investigated AIC as a means of comparing competing dose-response models, using data from Cook County, Illinois, for the period 1987-2000. They found that if nonlinearities exist, the AIC is not always successful in detecting them. In a number of the scenarios considered, AIC was equivocal, picking the correct simulated dose-response model about half of the time. These findings suggest that further research into the shape of the dose-response relation using alternative model selection criteria may be warranted.

A randomized, double-blind, placebo-controlled, dose-ranging study of lisdexamfetamine dimesylate augmentation for major depressive disorder in adults with inadequate response to antidepressant therapy

PubMed Central

Richards, Cynthia; Iosifescu, Dan V; Mago, Rajnish; Sarkis, Elias; Reynolds, James; Geibel, Brooke; Dauphin, Matthew

2017-01-01

Background: This randomized, double-blind, placebo-controlled study evaluated dose-response relationships of lisdexamfetamine dimesylate when used as augmentation for major depressive disorder in individuals exhibiting inadequate responses to antidepressant monotherapy. Methods: Eligible adults (18–65 years) were assigned to antidepressant monotherapy (escitalopram or venlafaxine extended-release) plus lisdexamfetamine dimesylate-matching placebo during an eight-week single-blind lead-in phase. Participants meeting randomization criteria were randomized (1:1:1:1:1) to eight weeks of lisdexamfetamine dimesylate (10, 30, 50, or 70 mg) or placebo while maintaining antidepressant therapy. Dose-responses for changes from augmentation baseline to week 16/early termination for Montgomery-Åsberg Depression Rating Scale total score (primary efficacy endpoint) and vital signs (systolic and diastolic blood pressure and pulse) were assessed using multiple comparisons procedures with modeling. Results: For Montgomery-Åsberg Depression Rating Scale total score change, no significant dose-responses were observed for any candidate dose-response curve (all p>0.10). In the dose-response evaluable population, least squares mean (90% confidence interval) treatment differences versus placebo for Montgomery-Åsberg Depression Rating Scale total score change at week 16 were −1.4 (−3.9, 1.2), 0.1 (−2.5, 2.7), −0.7 (−3.4, 2.0), and −0.9 (−3.5, 1.6) with 10, 30, 50, and 70 mg lisdexamfetamine dimesylate, respectively. For all vital sign parameters, lisdexamfetamine dimesylate exhibited significant dose-responses for all candidate dose-response curves (all p<0.10), with increases observed as lisdexamfetamine dimesylate dose increased; a linear relationship provided the best fit. Mean±standard deviation changes from augmentation baseline for systolic and diastolic blood pressure and pulse at week 16/early termination were −0.7±9.90 and −0.3±7.24 mm Hg and 0.2±10.57 bpm with placebo and were 1.9±9.47 and 0.8±7.40 mm Hg and 3.6±9.74 bpm with lisdexamfetamine dimesylate (all doses combined). The safety and tolerability profile of lisdexamfetamine dimesylate was consistent with previous studies. Conclusions: Lisdexamfetamine dimesylate augmentation did not provide benefit over placebo in adults with inadequate responses to antidepressant monotherapy based on the assessed efficacy measures. PMID:28857719

Methylphenidate has nonlinear dose effects on cued response inhibition in adults but not adolescents.

PubMed

Simon, Nicholas W; Moghaddam, Bita

2017-01-01

Ongoing development of the dopamine system during adolescence may provide a partial mechanism for behavioral and psychiatric vulnerabilities. Despite early evidence for a hyperactive adolescent dopaminergic system, recent data suggest that adolescent dopamine may be functionally hypoactive compared to in adults. While this distinction has been established in response to dopaminergic drugs and natural rewards, little is known about age-related differences in cognitive efficacy of dopaminergic drugs. Using a recently established Cued Response Inhibition Task, we tested the effects of acute systemic methylphenidate, commonly known as Ritalin, on response inhibition and response initiation in adolescent and adults rats. First, we replicated previous data that adolescents are able to inhibit a response to a cue on par with adults, but are slower to produce a rewarded response after a stop cue. Next, we observed that methylphenidate modulated response inhibition in adult rats, with low dose (0.3mg/kg) improving inhibition, and high dose (3mg/kg) impairing performance. This dose-response pattern is commonly observed with psychostimulant cognitive modulation. In adolescents, however, methylphenidate had no effect on response inhibition at any dose. Latency of response initiation after the stop cue was not affected by methylphenidate in either adult or adolescent rats. These data establish that dose-response of a commonly prescribed psychostimulant medication is different in adolescents and adults. They further demonstrate that healthy adolescent response inhibition is not as sensitive to psychostimulants as in adults, supporting the idea that the dopamine system is hypoactive in adolescence. This article is part of a Special Issue entitled SI: Adolescent plasticity. Copyright © 2016 Elsevier B.V. All rights reserved.

Bradykinin B1 and B2 receptors, tumour necrosis factor α and inflammatory hyperalgesia

PubMed Central

Poole, S; Lorenzetti, B B; Cunha, J M; Cunha, F Q; Ferreira, S H

1999-01-01

The effects of BK agonists and antagonists, and other hyperalgesic/antihyperalgesic drugs were measured (3 h after injection of hyperalgesic drugs) in a model of mechanical hyperalgesia (the end-point of which was indicated by a brief apnoea, the retraction of the head and forepaws, and muscular tremor). DALBK inhibited responses to carrageenin, bradykinin, DABK, and kallidin. Responses to kallidin and DABK were inhibited by indomethacin or atenolol and abolished by the combination of indomethacin+atenolol. DALBK or HOE 140, given 30 min before, but not 2 h after, carrageenin, BK, DABK and kallidin reduced hyperalgesic responses to these agents. A small dose of DABK+a small dose of BK evoked a response similar to the response to a much larger dose of DABK or BK, given alone. Responses to BK were antagonized by HOE 140 whereas DALBK antagonized only responses to larger doses of BK. The combination of a small dose of DALBK with a small dose of HOE 140 abolished the response to BK. The hyperalgesic response to LPS (1 μg) was inhibited by DALBK or HOE 140 and abolished by DALBK+HOE 140. The hyperalgesic response to LPS (5 μg) was not antagonized by DALBK+HOE 140. These data suggest: (a) a predominant role for B2 receptors in mediating hyperalgesic responses to BK and to drugs that stimulate BK release, and (b) activation of the hyperalgesic cytokine cascade independently of both B1 and B2 receptors if the hyperalgesic stimulus is of sufficient magnitude. PMID:10188975

The Key Events Dose-Response Framework: a cross-disciplinary mode-of-action based approach to examining dose-response and thresholds.

PubMed

Julien, Elizabeth; Boobis, Alan R; Olin, Stephen S

2009-09-01

The ILSI Research Foundation convened a cross-disciplinary working group to examine current approaches for assessing dose-response and identifying safe levels of intake or exposure for four categories of bioactive agents-food allergens, nutrients, pathogenic microorganisms, and environmental chemicals. This effort generated a common analytical framework-the Key Events Dose-Response Framework (KEDRF)-for systematically examining key events that occur between the initial dose of a bioactive agent and the effect of concern. Individual key events are considered with regard to factors that influence the dose-response relationship and factors that underlie variability in that relationship. This approach illuminates the connection between the processes occurring at the level of fundamental biology and the outcomes observed at the individual and population levels. Thus, it promotes an evidence-based approach for using mechanistic data to reduce reliance on default assumptions, to quantify variability, and to better characterize biological thresholds. This paper provides an overview of the KEDRF and introduces a series of four companion papers that illustrate initial application of the approach to a range of bioactive agents.

A phase I study of OSI-461 in combination with mitoxantrone in patients with advanced solid tumors potentially responsive to mitoxantrone

PubMed Central

Resta, Lee P.; Pili, Roberto; Eisenberger, Mario A.; Spitz, Avery; King, Serina; Porter, Jennifer; Franke, Amy; Boinpally, Ramesh; Sweeney, Christopher J.

2010-01-01

Purpose To find the maximum tolerated dose (MTD) of OSI-461 in combination with mitoxantrone in patients with advanced solid tumors. Methods This was a Phase I study using cohort dose escalation of OSI-461 dosed orally twice daily in combination with mitoxantrone 12 mg/m2 given on Day 1 of each 21-day cycle. Results OSI-461 dose was escalated to 1,000 mg po bid. One patient experienced a dose-limiting toxicity (DLT). Three patients discontinued the study due to adverse events (AE). Two patients (10%) had a partial response, and ten patients (50%) had stable disease as best response. Conclusion The combination of OSI-461 and mitoxantrone was well tolerated. Dose escalation was stopped because of toxicities in a concurrent Phase I trial. The response rate seen in patients with prostate cancer was comparable to response rates seen in trials of mitoxantrone and prednisone alone, and further studies of the combination of OSI-461 and mitoxantrone were not pursued. PMID:20445979

Radiotherapy dose–response analysis for diffuse large B-cell lymphoma with a complete response to chemotherapy

PubMed Central

2012-01-01

Objective To examine the efficacy of different radiation doses after achievement of a complete response to chemotherapy in diffuse large B-cell lymphoma (DLBCL). Methods Patients with stage I-IV DLBCL treated from 1995–2009 at Duke Cancer Institute who achieved a complete response to chemotherapy were reviewed. In-field control, event-free survival, and overall survival were calculated using the Kaplan-Meier method. Dose response was evaluated by grouping treated sites by delivered radiation dose. Results 105 patients were treated with RT to 214 disease sites. Chemotherapy (median 6 cycles) was R-CHOP (65%), CHOP (26%), R-CNOP (2%), or other (7%). Post-chemotherapy imaging was PET/CT (88%), gallium with CT (1%), or CT only (11%). The median RT dose was 30 Gy (range, 12–40 Gy). The median radiation dose was higher for patients with stage I-II disease compared with patients with stage III-IV disease (30 versus 24.5 Gy, p < 0.001). Five-year in-field control, event-free survival, and overall survival for all patients was 94% (95% CI: 89-99%), 84% (95% CI: 77-92%), and 91% (95% CI: 85-97%), respectively. Six patients developed an in-field recurrence at 10 sites, without a clear dose response. In-field failure was higher at sites ≥ 10 cm (14% versus 4%, p = 0.06). Conclusion In-field control was excellent with a combined modality approach when a complete response was achieved after chemotherapy without a clear radiation dose response. PMID:22720801

Cellular response to low dose radiation: Role of phosphatidylinositol-3 kinase like kinases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Balajee, A.S.; Meador, J.A.; Su, Y.

It is increasingly realized that human exposure either to an acute low dose or multiple chronic low doses of low LET radiation has the potential to cause different types of cancer. Therefore, the central theme of research for DOE and NASA is focused on understanding the molecular mechanisms and pathways responsible for the cellular response to low dose radiation which would not only improve the accuracy of estimating health risks but also help in the development of predictive assays for low dose radiation risks associated with tissue degeneration and cancer. The working hypothesis for this proposal is that the cellularmore » mechanisms in terms of DNA damage signaling, repair and cell cycle checkpoint regulation are different for low and high doses of low LET radiation and that the mode of action of phosphatidylinositol-3 kinase like kinases (PIKK: ATM, ATR and DNA-PK) determines the dose dependent cellular responses. The hypothesis will be tested at two levels: (I) Evaluation of the role of ATM, ATR and DNA-PK in cellular response to low and high doses of low LET radiation in simple in vitro human cell systems and (II) Determination of radiation responses in complex cell microenvironments such as human EpiDerm tissue constructs. Cellular responses to low and high doses of low LET radiation will be assessed from the view points of DNA damage signaling, DNA double strand break repair and cell cycle checkpoint regulation by analyzing the activities (i.e. post-translational modifications and kinetics of protein-protein interactions) of the key target proteins for PI-3 kinase like kinases both at the intra-cellular and molecular levels. The proteins chosen for this proposal are placed under three categories: (I) sensors/initiators include ATM ser1981, ATR, 53BP1, gamma-H2AX, MDC1, MRE11, Rad50 and Nbs1; (II) signal transducers include Chk1, Chk2, FANCD2 and SMC1; and (III) effectors include p53, CDC25A and CDC25C. The primary goal of this proposal is to elucidate the differences in cellular defense mechanisms between low and high doses of low LET radiation and to define the radiation doses where the cellular DNA damage signaling and repair mechanisms tend to shift. This information is critically important to address and advance some of the low dose research program objectives of DOE. The results of this proposed study will lead to a better understanding of the mechanisms for the cellular responses to low and high doses of low LET radiation. Further, systematic analysis of the role of PIKK signaling pathways as a function of radiation dose in tissue microenvironment will provide useful mechanistic information for improving the accuracy of radiation risk assessment for low doses. Knowledge of radiation responses in tissue microenvironment is important for the accurate prediction of ionizing radiation risks associated with cancer and tissue degeneration in humans.« less

Repeated restraint stress lowers the threshold for response to third ventricle CRF administration.

PubMed

Harris, Ruth B S

2017-03-01

Rats and mice exposed to repeated stress or a single severe stress exhibit a sustained increase in energetic, endocrine, and behavioral response to subsequent novel mild stress. This study tested whether the hyper-responsiveness was due to a lowered threshold of response to corticotropin releasing factor (CRF) or an exaggerated response to a standard dose of CRF. Male Sprague-Dawley rats were subjected to 3h of restraint on each of 3 consecutive days (RRS) or were non-restrained controls. RRS caused a temporary hypophagia but a sustained reduction in body weight. Eight days after the end of restraint, rats received increasing third ventricle doses of CRF (0-3.0μg). The lowest dose of CRF (0.25μg) increased corticosterone release in RRS, but not control rats. Higher doses caused the same stimulation of corticosterone in the two groups of rats. Fifteen days after the end of restraint, rats were food deprived during the light period and received increasing third ventricle doses of CRF at the start of the dark period. The lowest dose of CRF inhibited food intake during the first hour following infusion in RRS, but not control rats. All other doses of CRF inhibited food intake to the same degree in both RRS and control rats. The lowered threshold of response to central CRF is consistent with the chronic hyper-responsiveness to CRF and mild stress in RRS rats during the post-restraint period. Copyright © 2016 Elsevier Inc. All rights reserved.

Lemna minor plants chronically exposed to ionising radiation: RNA-seq analysis indicates a dose rate dependent shift from acclimation to survival strategies.

PubMed

Van Hoeck, Arne; Horemans, Nele; Nauts, Robin; Van Hees, May; Vandenhove, Hildegarde; Blust, Ronny

2017-04-01

Ecotoxicological research provides knowledge on ionising radiation-induced responses in different plant species. However, the sparse data currently available are mainly extracted from acute exposure treatments. To provide a better understanding of environmental exposure scenarios, the response to stress in plants must be followed in more natural relevant chronic conditions. We previously showed morphological and biochemical responses in Lemna minor plants continuously exposed for 7days in a dose-rate dependent manner. In this study responses on molecular (gene expression) and physiological (photosynthetic) level are evaluated in L. minor plants exposed to ionising radiation. To enable this, we examined the gene expression profiles of irradiated L. minor plants by using an RNA-seq approach. The gene expression data reveal indications that L. minor plants exposed at lower dose rates, can tolerate the exposure by triggering acclimation responses. In contrast, at the highest dose rate tested, a high number of genes related to antioxidative defense systems, DNA repair and cell cycle were differentially expressed suggesting that only high dose rates of ionising radiation drive L. minor plants into survival strategies. Notably, the photosynthetic process seems to be unaffected in L. minor plants among the tested dose rates. This study, supported by our earlier work, clearly indicates that plants shift from acclimation responses towards survival responses at increasing dose rates of ionising radiation. Copyright © 2017 Elsevier B.V. All rights reserved.

BYSTANDERS, ADAPTIVE RESPONSES AND GENOMIC INSTABILITY - POTENTIAL MODIFIERS OF LOW-DOSE CANCER RESPONSES.

EPA Science Inventory

Bystanders, Adaptive Responses and Genomic Instability -Potential Modifiers ofLow-Dose
Cancer Responses
.
There has been a concerted effort in the field of radiation biology to better understand cellular
responses that could have an impact on the estin1ation of cancer...

Dose Response for Chromosome Aberrations in Human Lymphocytes and Fibroblasts After Exposure to Very Low Dose of High Let Radiation

NASA Technical Reports Server (NTRS)

Hada, M.; George, K.; Chappell, L.; Cucinotta, F. A.

2011-01-01

The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivor with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (0.01 - 0.20 Gy) of 170 MeV/u Si-28 ions or 600 MeV/u Fe-56 ions, including doses where on average less than one direct ion traversal per cell nucleus occurs. Chromosomes were analyzed using the whole-chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). The responses for doses above 0.1 Gy (more than one ion traverses a cell) showed linear dose responses. However, for doses less than 0.1 Gy, both Si-28 ions and Fe-56 ions showed a dose independent response above background chromosome aberrations frequencies. Possible explanations for our results are non-targeted effects due to aberrant cell signaling [1], or delta-ray dose fluctuations [2] where a fraction of cells receive significant delta-ray doses due to the contributions of multiple ion tracks that do not directly traverse cell nuclei where chromosome aberrations are scored.

Long-term Pulmonary Responses to Quadweekly Intermittent Intratracheal Spray Instillations of Magnetite (Fe3O4) Nanoparticles for 52 Weeks in Fischer 344 Rats.

PubMed

Tada, Yukie; Yano, Norio; Takahashi, Hiroshi; Yuzawa, Katsuhiro; Ando, Hiroshi; Kubo, Yoshikazu; Nagasawa, Akemichi; Inomata, Akiko; Ogata, Akio; Nakae, Dai

2013-12-01

Information about potential risks of iron nanomaterials is still limited, while a wide variety of applications are expected. We recently reported acute phase responses of male and female Fischer 344 rats after a single intratracheal spray instillation of Fe3O4 nanoparticles (magnetite), clearly showing dose-dependent pulmonary inflammatory changes (Tada et al., J Toxicol Pathol 25, 233-239, 2012). The present study assessed long-term responses of male and female Fischer 344 rats to multiple administrations of magnetite. Ten-week-old male and female Fischer 344 rats (n=20/group) were exposed to a total of 13 quadweekly intermittent intratracheal spray instillations of magnetite during the experimental period of 52 weeks, at doses of 0, 0.2 (low), 1.0 (medium) and 5.0 (high-dose) mg/kg body weight per administration. Absolute and relative lung weights of the high-dose group were significantly higher than those of the control group. Macroscopically, slight enlargement and scattered black patches were recognized in the lungs and the lung-associated lymph nodes of the high-dose group. Histopathologically, infiltration of macrophages phagocytosing magnetite (all dose groups) and of chronic inflammatory cells (medium- and high-dose males and high-dose females), alveolar bronchiolization and granuloma (high-dose group) were observed. In addition, alveolar hyperplasias were observed in some rats of the high-dose group, and cytoplasmic overexpression of β-catenin protein was immunohistochemically found in such lesions. The present results clearly show that instilled magnetite causes chronic inflammatory responses in the lung. These responses occur in a dose-dependent manner without apparent differences among sexes.

Straightening Beta: Overdispersion of Lethal Chromosome Aberrations following Radiotherapeutic Doses Leads to Terminal Linearity in the Alpha–Beta Model

PubMed Central

Shuryak, Igor; Loucas, Bradford D.; Cornforth, Michael N.

2017-01-01

Recent technological advances allow precise radiation delivery to tumor targets. As opposed to more conventional radiotherapy—where multiple small fractions are given—in some cases, the preferred course of treatment may involve only a few (or even one) large dose(s) per fraction. Under these conditions, the choice of appropriate radiobiological model complicates the tasks of predicting radiotherapy outcomes and designing new treatment regimens. The most commonly used model for this purpose is the venerable linear-quadratic (LQ) formalism as it applies to cell survival. However, predictions based on the LQ model are frequently at odds with data following very high acute doses. In particular, although the LQ predicts a continuously bending dose–response relationship for the logarithm of cell survival, empirical evidence over the high-dose region suggests that the survival response is instead log-linear with dose. Here, we show that the distribution of lethal chromosomal lesions among individual human cells (lymphocytes and fibroblasts) exposed to gamma rays and X rays is somewhat overdispersed, compared with the Poisson distribution. Further, we show that such overdispersion affects the predicted dose response for cell survival (the fraction of cells with zero lethal lesions). This causes the dose response to approximate log-linear behavior at high doses, even when the mean number of lethal lesions per cell is well fitted by the continuously curving LQ model. Accounting for overdispersion of lethal lesions provides a novel, mechanistically based explanation for the observed shapes of cell survival dose responses that, in principle, may offer a tractable and clinically useful approach for modeling the effects of high doses per fraction. PMID:29312888

Phosphoproteomics profiling of human skin fibroblast cells reveals pathways and proteins affected by low doses of ionizing radiation.

PubMed

Yang, Feng; Waters, Katrina M; Miller, John H; Gritsenko, Marina A; Zhao, Rui; Du, Xiuxia; Livesay, Eric A; Purvine, Samuel O; Monroe, Matthew E; Wang, Yingchun; Camp, David G; Smith, Richard D; Stenoien, David L

2010-11-30

High doses of ionizing radiation result in biological damage; however, the precise relationships between long-term health effects, including cancer, and low-dose exposures remain poorly understood and are currently extrapolated using high-dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose-dependent responses to radiation. We have identified 7117 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts 1 h post-exposure. Semi-quantitative label-free analyses were performed to identify phosphopeptides that are apparently altered by radiation exposure. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation-responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatic analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role for MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provide a basis for the systems-level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low-dose radiation exposure on human health.

Phosphoproteomics Profiling of Human Skin Fibroblast Cells Reveals Pathways and Proteins Affected by Low Doses of Ionizing Radiation

PubMed Central

Yang, Feng; Waters, Katrina M.; Miller, John H.; Gritsenko, Marina A.; Zhao, Rui; Du, Xiuxia; Livesay, Eric A.; Purvine, Samuel O.; Monroe, Matthew E.; Wang, Yingchun; Camp, David G.; Smith, Richard D.; Stenoien, David L.

2010-01-01

Background High doses of ionizing radiation result in biological damage; however, the precise relationships between long-term health effects, including cancer, and low-dose exposures remain poorly understood and are currently extrapolated using high-dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose-dependent responses to radiation. Principal Findings We have identified 7117 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts 1 h post-exposure. Semi-quantitative label-free analyses were performed to identify phosphopeptides that are apparently altered by radiation exposure. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation-responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatic analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role for MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Conclusions Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provide a basis for the systems-level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low-dose radiation exposure on human health. PMID:21152398

Synergistic interaction between fentanyl and bupivacaine given intrathecally for labor analgesia.

PubMed

Ngan Kee, Warwick D; Khaw, Kim S; Ng, Floria F; Ng, Karman K L; So, Rita; Lee, Anna

2014-05-01

Lipophilic opioids and local anesthetics are often given intrathecally in combination for labor analgesia. However, the nature of the pharmacologic interaction between these drugs has not been clearly elucidated in humans. Three hundred nulliparous women randomly received 1 of 30 different combinations of fentanyl and bupivacaine intrathecally using a combined spinal-epidural technique for analgesia in the first stage of labor. Visual analogue scale pain scores were recorded for 30 min. Response was defined by percentage decrease in pain score from baseline at 15 and 30 min. Dose-response curves for individual drugs were fitted to a hyperbolic dose-response model using nonlinear regression. The nature of the drug interaction was determined using dose equivalence methodology to compare observed effects of drug combinations with effects predicted by additivity. The derived dose-response models for individual drugs (doses in micrograms) at 15 min were: Effect = 100 × dose / (13.82 + dose) for fentanyl, and Effect = 100 × dose / (1,590 + dose) for bupivacaine. Combinations of fentanyl and bupivacaine produced greater effects than those predicted by additivity at 15 min (P < 0.001) and 30 min (P = 0.015) (mean differences, 9.1 [95% CI, 4.1-14.1] and 6.4 [95% CI, 1.2-11.5] units of the normalized response, respectively), indicating a synergistic interaction. The pharmacologic interaction between intrathecal fentanyl and bupivacaine is synergistic. Characterization and quantification of this interaction provide a theoretical basis and support for the clinical practice of combining intrathecal opioids and local anesthetics.

Properties of model-averaged BMDLs: a study of model averaging in dichotomous response risk estimation.

PubMed

Wheeler, Matthew W; Bailer, A John

2007-06-01

Model averaging (MA) has been proposed as a method of accounting for model uncertainty in benchmark dose (BMD) estimation. The technique has been used to average BMD dose estimates derived from dichotomous dose-response experiments, microbial dose-response experiments, as well as observational epidemiological studies. While MA is a promising tool for the risk assessor, a previous study suggested that the simple strategy of averaging individual models' BMD lower limits did not yield interval estimators that met nominal coverage levels in certain situations, and this performance was very sensitive to the underlying model space chosen. We present a different, more computationally intensive, approach in which the BMD is estimated using the average dose-response model and the corresponding benchmark dose lower bound (BMDL) is computed by bootstrapping. This method is illustrated with TiO(2) dose-response rat lung cancer data, and then systematically studied through an extensive Monte Carlo simulation. The results of this study suggest that the MA-BMD, estimated using this technique, performs better, in terms of bias and coverage, than the previous MA methodology. Further, the MA-BMDL achieves nominal coverage in most cases, and is superior to picking the "best fitting model" when estimating the benchmark dose. Although these results show utility of MA for benchmark dose risk estimation, they continue to highlight the importance of choosing an adequate model space as well as proper model fit diagnostics.

Effects of supplementation with higher levels of manganese and magnesium on immune function.

PubMed

Son, Eun-Wha; Lee, Sung-Ryul; Choi, Hye-Sook; Koo, Hyun-Jung; Huh, Jung-Eun; Kim, Mi-Hyun; Pyo, Suhkneung

2007-06-01

The magnesium (Mg) and manganese (Mn) were evaluated for its effectiveness as an immunomodulator in rats. The treatments were as follows: Group 1, AIN-93M diet (0.05% Mg, 0.001% Mn); Group 2, high-dose Mg (0.1% Mg, 0.001% Mn); and Group 3, high dose Mn (0.05% Mg, 0.01% Mn) (n-12/group). After 12 weeks of supplementation, rats were sacrificed to assess the effect on a range of innate responses (tumoricidal activity, oxidative burst and nitric oxide) and the mitogen-stimulated lymphoproliferative response. Immune function was significantly affected in both the high dose Mg and the Mn group. Lymphocyte proliferative responses and NK cell activity were measured in pooled spleen from each group. The mitogen response of lymphocytes to LPS in the spleen was significantly reduced in high dose Mg-treated groups, whereas the response to ConA was not affected in both high dose minerals-treated groups. The reactive oxygen species level of macrophages was decreased in both groups. These effects were more pronounced in high dose Mg-treated group. Nitric oxide production was also decreased in high dose minerals-treated group. In addition, tumoricidal activities of splenic NK cell and peritoneal macrophage in mineral exposed rats were significantly increased. Moreover, percent death of macrophage was reduced in two groups receiving high dose mineral supplements. Taken together, the present data suggest that high dose trace min erals exert a differential effect on the function of immune cells.

Low dose intranasal oxytocin delivered with Breath Powered device dampens amygdala response to emotional stimuli: A peripheral effect-controlled within-subjects randomized dose-response fMRI trial.

PubMed

Quintana, Daniel S; Westlye, Lars T; Alnæs, Dag; Rustan, Øyvind G; Kaufmann, Tobias; Smerud, Knut T; Mahmoud, Ramy A; Djupesland, Per G; Andreassen, Ole A

2016-07-01

It is unclear if and how exogenous oxytocin (OT) reaches the brain to improve social behavior and cognition and what is the optimal dose for OT response. To better understand the delivery routes of intranasal OT administration to the brain and the dose-response, we compared amygdala response to facial stimuli by means of functional magnetic resonance imaging (fMRI) in four treatment conditions, including two different doses of intranasal OT using a novel Breath Powered device, intravenous (IV) OT, which provided similar concentrations of blood plasma OT, and placebo. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults administering a single-dose of these four treatments. We observed a treatment effect on right amygdala activation during the processing of angry and happy face stimuli, with pairwise comparisons revealing reduced activation after the 8IU low dose intranasal treatment compared to placebo. These data suggest the dampening of amygdala activity in response to emotional stimuli occurs via direct intranasal delivery pathways rather than across the blood-brain barrier via systemically circulating OT. This trial is registered at the U.S. National Institutes of Health clinical trial registry (www.clinicaltrials.gov; NCT01983514) and as EudraCT no. 2013-001608-12. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hormetic Response by Silver Nanoparticles on In Vitro Multiplication of Sugarcane (Saccharum spp. Cv. Mex 69-290) Using a Temporary Immersion System.

PubMed

Bello-Bello, Jericó J; Chavez-Santoscoy, Rocío A; Lecona-Guzmán, Carlos A; Bogdanchikova, Nina; Salinas-Ruíz, Josafhat; Gómez-Merino, Fernando Carlos; Pestryakov, Alexey

2017-01-01

Hormesis is considered a dose-response phenomenon characterized by growth stimulation at low doses and inhibition at high doses. The hormetic response by silver nanoparticles (AgNPs) on in vitro multiplication of sugarcane was evaluated using a temporary immersion system. Sugarcane shoots were used as explants cultured in Murashige and Skoog medium with AgNPs at concentrations of 0, 25, 50, 100, and 200 mg/L. Shoot multiplication rate and length were used to determine hormetic response. Total content of phenolic compounds of sugarcane, mineral nutrition, and reactive oxygen species (ROS) was determined. Results were presented as a dose-response curve. Stimulation phase growth was observed at 50 mg/L AgNPs, whereas inhibition phase was detected at 200 mg/L AgNPs. Mineral nutrient analysis showed changes in macronutrient and micronutrient contents due to the effect of AgNPs. Moreover, AgNPs induced ROS production and increased total phenolic content, with a dose-dependent effect. Results suggested that the production of ROS and mineral nutrition are key mechanisms of AgNP-induced hormesis and that phenolic accumulation was obtained as a response of the plant to stress produced by high doses of AgNPs. Therefore, small doses of AgNPs in the culture medium could be an efficient strategy for commercial micropropagation.

Investigations of putative reproductive toxicity of low-dose exposures to vinclozolin in Wistar rats.

PubMed

Flick, Burkhard; Schneider, Steffen; Melching-Kollmuss, Stephanie; Fussell, Karma C; Gröters, Sibylle; Buesen, Roland; Strauss, Volker; van Ravenzwaay, Bennard

2017-04-01

The current investigation examines whether the fungicide vinclozolin, which has an anti-androgenic mode of action, is capable of disrupting endocrine homeostasis at very low doses. The data generated clarify whether a non-monotonic dose-response relationship exists to enhance the current debate about the regulation of endocrine disruptors. Moreover, it is part of a series of investigations assessing the dose-response relationship of single and combined administration of anti-androgenic substances. A pre-postnatal in vivo study design was chosen which was compliant with regulatory testing protocols. The test design was improved by additional endpoints addressing hormone levels, morphology and histopathological examinations. Doses were chosen to represent an effect level (20 mg/kg bw/d), the current NOAEL (4 mg/kg bw/d), and a dose close to the "ADI" (0.005 mg/kg bw/d) for the detection of a possible non-monotonic dose-response curve. Anti-androgenic changes were observable at the effect level but not at lower exposures. Nipple/areola counts appeared to be the most sensitive measure of effect, followed by male sex organ weights at sexual maturation, and finally gross and histopathological findings. The results indicate the absence of evidence for effects at low or very low dose levels. A non-monotonic dose-response relationship was not evident.

Doses of Nearby Nature Simultaneously Associated with Multiple Health Benefits

PubMed Central

Cox, Daniel T. C.; Shanahan, Danielle F.; Hudson, Hannah L.; Fuller, Richard A.; Anderson, Karen; Hancock, Steven; Gaston, Kevin J.

2017-01-01

Exposure to nature provides a wide range of health benefits. A significant proportion of these are delivered close to home, because this offers an immediate and easily accessible opportunity for people to experience nature. However, there is limited information to guide recommendations on its management and appropriate use. We apply a nature dose-response framework to quantify the simultaneous association between exposure to nearby nature and multiple health benefits. We surveyed ca. 1000 respondents in Southern England, UK, to determine relationships between (a) nature dose type, that is the frequency and duration (time spent in private green space) and intensity (quantity of neighbourhood vegetation cover) of nature exposure and (b) health outcomes, including mental, physical and social health, physical behaviour and nature orientation. We then modelled dose-response relationships between dose type and self-reported depression. We demonstrate positive relationships between nature dose and mental and social health, increased physical activity and nature orientation. Dose-response analysis showed that lower levels of depression were associated with minimum thresholds of weekly nature dose. Nearby nature is associated with quantifiable health benefits, with potential for lowering the human and financial costs of ill health. Dose-response analysis has the potential to guide minimum and optimum recommendations on the management and use of nearby nature for preventative healthcare. PMID:28208789

Doses of Nearby Nature Simultaneously Associated with Multiple Health Benefits.

PubMed

Cox, Daniel T C; Shanahan, Danielle F; Hudson, Hannah L; Fuller, Richard A; Anderson, Karen; Hancock, Steven; Gaston, Kevin J

2017-02-09

Exposure to nature provides a wide range of health benefits. A significant proportion of these are delivered close to home, because this offers an immediate and easily accessible opportunity for people to experience nature. However, there is limited information to guide recommendations on its management and appropriate use. We apply a nature dose-response framework to quantify the simultaneous association between exposure to nearby nature and multiple health benefits. We surveyed ca. 1000 respondents in Southern England, UK, to determine relationships between (a) nature dose type, that is the frequency and duration (time spent in private green space) and intensity (quantity of neighbourhood vegetation cover) of nature exposure and (b) health outcomes, including mental, physical and social health, physical behaviour and nature orientation. We then modelled dose-response relationships between dose type and self-reported depression. We demonstrate positive relationships between nature dose and mental and social health, increased physical activity and nature orientation. Dose-response analysis showed that lower levels of depression were associated with minimum thresholds of weekly nature dose. Nearby nature is associated with quantifiable health benefits, with potential for lowering the human and financial costs of ill health. Dose-response analysis has the potential to guide minimum and optimum recommendations on the management and use of nearby nature for preventative healthcare.

Can reduction of uncertainties in cervix cancer brachytherapy potentially improve clinical outcome?

PubMed

Nesvacil, Nicole; Tanderup, Kari; Lindegaard, Jacob C; Pötter, Richard; Kirisits, Christian

2016-09-01

The aim of this study was to quantify the impact of different types and magnitudes of dosimetric uncertainties in cervix cancer brachytherapy (BT) on tumour control probability (TCP) and normal tissue complication probability (NTCP) curves. A dose-response simulation study was based on systematic and random dose uncertainties and TCP/NTCP models for CTV and rectum. Large patient cohorts were simulated assuming different levels of dosimetric uncertainties. TCP and NTCP were computed, based on the planned doses, the simulated dose uncertainty, and an underlying TCP/NTCP model. Systematic uncertainties of 3-20% and random uncertainties with a 5-30% standard deviation per BT fraction were analysed. Systematic dose uncertainties of 5% lead to a 1% decrease/increase of TCP/NTCP, while random uncertainties of 10% had negligible impact on the dose-response curve at clinically relevant dose levels for target and OAR. Random OAR dose uncertainties of 30% resulted in an NTCP increase of 3-4% for planned doses of 70-80Gy EQD2. TCP is robust to dosimetric uncertainties when dose prescription is in the more flat region of the dose-response curve at doses >75Gy. For OARs, improved clinical outcome is expected by reduction of uncertainties via sophisticated dose delivery and treatment verification. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Radiation Hormesis: Historical Perspective and Implications for Low-Dose Cancer Risk Assessment

PubMed Central

Vaiserman, Alexander M.

2010-01-01

Current guidelines for limiting exposure of humans to ionizing radiation are based on the linear-no-threshold (LNT) hypothesis for radiation carcinogenesis under which cancer risk increases linearly as the radiation dose increases. With the LNT model even a very small dose could cause cancer and the model is used in establishing guidelines for limiting radiation exposure of humans. A slope change at low doses and dose rates is implemented using an empirical dose and dose rate effectiveness factor (DDREF). This imposes usually unacknowledged nonlinearity but not a threshold in the dose-response curve for cancer induction. In contrast, with the hormetic model, low doses of radiation reduce the cancer incidence while it is elevated after high doses. Based on a review of epidemiological and other data for exposure to low radiation doses and dose rates, it was found that the LNT model fails badly. Cancer risk after ordinarily encountered radiation exposure (medical X-rays, natural background radiation, etc.) is much lower than projections based on the LNT model and is often less than the risk for spontaneous cancer (a hormetic response). Understanding the mechanistic basis for hormetic responses will provide new insights about both risks and benefits from low-dose radiation exposure. PMID:20585444

Response to low-dose herbicide selection in self-pollinated Avena fatua.

PubMed

Busi, Roberto; Girotto, Marcelo; Powles, Stephen B

2016-03-01

When applied at the correct plant stage and dose, herbicides are highly toxic to plants. At reduced, low herbicide doses (below the recommended dose) plants can survive and display continuous and quantitative variation in dose-survival responses. Recurrent (directional) selection studies can reveal whether such a phenotypic variation in plant survival response to low herbicide dose is heritable and leads to herbicide resistance. In a common experimental garden study, we have subjected a susceptible population of self-pollinated hexaploid Avena fatua to low-dose recurrent selection with the ACCase-inhibiting herbicide diclofop-methyl for three consecutive generations. Significant differences in response to low-dose diclofop-methyl selection were observed between the selected progenies and parent plants, with a twofold diclofop-methyl resistance and cross-resistance to ALS-inhibiting herbicides. Thus, the capacity of self-pollinated A. fatua to respond to low-dose herbicide selection is marginal, and it is much lower than in cross-pollinated L. rigidum. Lolium rigidum in the same experiment evolved 40-fold diclofop-methyl resistance by progressive enrichment of quantitative resistance-endowing traits. Cross-pollination rate, genetic variation and ploidy levels are identified as possible drivers affecting the contrasting capacity of Avena versus Lolium plants to respond to herbicide selection and the subsequent likelihood of resistance evolution at low herbicide dose usage. © 2015 Society of Chemical Industry.

Pharmacokinetics, pharmacodynamics, and dose-response relationship of repaglinide in type 2 diabetes.

PubMed

Strange, P; Schwartz, S L; Graf, R J; Polvino, W; Weston, I; Marbury, T C; Huang, W C; Goldberg, R B

1999-01-01

The pharmacodynamics and dose-response relationship of repaglinide, a novel oral hypoglycemic agent, were evaluated in steady-state treatment of patients with type 2 diabetes. Efficacy of repaglinide (0.25 mg, 0.5 mg, 1 mg, 2 mg, and 4 mg) was compared to that of placebo in a double-blind, randomized, parallel-group, 4-week dose-response clinical trial in 143 patients. Repaglinide was administered 15 minutes before meals (breakfast, lunch, and dinner). Efficacy of repaglinide therapy was assessed by measuring changes from baseline in mean levels of blood glucose (BGmean), fasting serum glucose (FSG), and mean levels of serum insulin (INSmean). Blood concentrations of repaglinide were proportional to the dose administered. INSmean values increased in all repaglinide treatment groups (by 6.7 to 12.9 microU/mL). All doses of repaglinide significantly decreased values of BGmean and FSG as compared with the placebo group. BGmean values stabilized between the second and third week of repaglinide treatment. A well-defined dose-response relationship was observed for BGmean and FSG values. All doses of repaglinide were well tolerated, and there were no serious adverse events. These findings show that the therapeutic reduction of serum glucose levels produced by repaglinide is dose-dependent for the 0.25- to 4-mg dose range. All doses of repaglinide tested were effective and well tolerated in patients with type 2 diabetes.

Proof of concept and dose estimation with binary responses under model uncertainty.

PubMed

Klingenberg, B

2009-01-30

This article suggests a unified framework for testing Proof of Concept (PoC) and estimating a target dose for the benefit of a more comprehensive, robust and powerful analysis in phase II or similar clinical trials. From a pre-specified set of candidate models, we choose the ones that best describe the observed dose-response. To decide which models, if any, significantly pick up a dose effect, we construct the permutation distribution of the minimum P-value over the candidate set. This allows us to find critical values and multiplicity adjusted P-values that control the familywise error rate of declaring any spurious effect in the candidate set as significant. Model averaging is then used to estimate a target dose. Popular single or multiple contrast tests for PoC, such as the Cochran-Armitage, Dunnett or Williams tests, are only optimal for specific dose-response shapes and do not provide target dose estimates with confidence limits. A thorough evaluation and comparison of our approach to these tests reveal that its power is as good or better in detecting a dose-response under various shapes with many more additional benefits: It incorporates model uncertainty in PoC decisions and target dose estimation, yields confidence intervals for target dose estimates and extends to more complicated data structures. We illustrate our method with the analysis of a Phase II clinical trial. Copyright (c) 2008 John Wiley & Sons, Ltd.

The Use of Mode of Action Information in Risk Assessment: Quantitative Key Events/Dose-Response Framework for Modeling the Dose-Response for Key Events

EPA Science Inventory

The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Act...

The evaluation of the novel pressor activity of gamma-piperidinobutyramide (WY 20051, DF480).

PubMed Central

Alps, B J; Devoy, P W; Waterfall, J F

1976-01-01

1 gamma-Piperidinobutyramide (Wy 20051, DF480) injected intravenously evoked pressor responses in the anaesthetized ganglion blocked rat preparation over the dose range 2.4 x 10(-6)-3.0 x 10(-4) mol/kg. 2 High doses (greater than 3.8 x 10(-5) mol/kg) or even repeated submaximal doses (1.9 x 10(-5) mol/kg) of Wy 20051 caused tachyphylaxis of this pressor response. 3 The noradrenaline pressor-response curve was shifted significantly to the right of the control curve following a dose of Wy 20051 (1.5 x 10(-4) mol/kg cumulative). 4 The dose-response curve for the pressor action of Wy 20051 was potentiated in reserpine-treated anaesthetized rats. In contrast, tyramine-induced pressor responses were abolished. 5 Wy 20051 contracted the guinea-pig isolated aortic spiral preparation (3.8 x 10(-5)-6.0 x 10(-4) mol) and evoked constrictor responses in the perfused mesenteric vasculature preparation of the rat (5.9 x 10(-7)-1.2 x 10(-5) mol). At higher doses the responses were reduced. 6 Wy 20051-induced constrictor responses of the perfused mesentery were unaffected by blockade of alpha-adrenoceptors or by tachyphylaxis of 5-hydroxytryptamine receptors. 7 The time for abolition of Wy 20051-induced constrictor responses of the mesentery in a calcium-free medium was not significantly different from that required for noradrenaline, but was significantly greater than that for KCl (P less than 0.001). 8 Wy 20051 and noradrenaline, but not KCl, evoked constrictor responses in the depolarized rat mesenteric vasculature. 9 The results indicate that Wy 20051 evokes pressor responses which have some of the characteristics of those of noradrenaline. However, the responses are not elicited by an alpha-adrenoceptor mechanism. PMID:3247

A Generalized QMRA Beta-Poisson Dose-Response Model.

PubMed

Xie, Gang; Roiko, Anne; Stratton, Helen; Lemckert, Charles; Dunn, Peter K; Mengersen, Kerrie

2016-10-01

Quantitative microbial risk assessment (QMRA) is widely accepted for characterizing the microbial risks associated with food, water, and wastewater. Single-hit dose-response models are the most commonly used dose-response models in QMRA. Denoting PI(d) as the probability of infection at a given mean dose d, a three-parameter generalized QMRA beta-Poisson dose-response model, PI(d|α,β,r*), is proposed in which the minimum number of organisms required for causing infection, K min , is not fixed, but a random variable following a geometric distribution with parameter 0

Characterization of Changes in Gene Expression and Biochemical Pathways at Low Levels of Benzene Exposure

PubMed Central

Thomas, Reuben; Hubbard, Alan E.; McHale, Cliona M.; Zhang, Luoping; Rappaport, Stephen M.; Lan, Qing; Rothman, Nathaniel; Vermeulen, Roel; Guyton, Kathryn Z.; Jinot, Jennifer; Sonawane, Babasaheb R.; Smith, Martyn T.

2014-01-01

Benzene, a ubiquitous environmental pollutant, causes acute myeloid leukemia (AML). Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC), we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across four airborne concentration ranges (from <1 ppm to >10 ppm) compared with 42 subjects with non-workplace ambient exposure levels. Here, we further characterize these dose-dependent effects with continuous benzene exposure in all 125 study subjects. We estimated air benzene exposure levels in the 42 environmentally-exposed subjects from their unmetabolized urinary benzene levels. We used a novel non-parametric, data-adaptive model selection method to estimate the change with dose in the expression of each gene. We describe non-parametric approaches to model pathway responses and used these to estimate the dose responses of the AML pathway and 4 other pathways of interest. The response patterns of majority of genes as captured by mean estimates of the first and second principal components of the dose-response for the five pathways and the profiles of 6 AML pathway response-representative genes (identified by clustering) exhibited similar apparent supra-linear responses. Responses at or below 0.1 ppm benzene were observed for altered expression of AML pathway genes and CYP2E1. Together, these data show that benzene alters disease-relevant pathways and genes in a dose-dependent manner, with effects apparent at doses as low as 100 ppb in air. Studies with extensive exposure assessment of subjects exposed in the low-dose range between 10 ppb and 1 ppm are needed to confirm these findings. PMID:24786086

Toxicogenomics and cancer risk assessment: a framework for key event analysis and dose-response assessment for nongenotoxic carcinogens.

PubMed

Bercu, Joel P; Jolly, Robert A; Flagella, Kelly M; Baker, Thomas K; Romero, Pedro; Stevens, James L

2010-12-01

In order to determine a threshold for nongenotoxic carcinogens, the traditional risk assessment approach has been to identify a mode of action (MOA) with a nonlinear dose-response. The dose-response for one or more key event(s) linked to the MOA for carcinogenicity allows a point of departure (POD) to be selected from the most sensitive effect dose or no-effect dose. However, this can be challenging because multiple MOAs and key events may exist for carcinogenicity and oftentimes extensive research is required to elucidate the MOA. In the present study, a microarray analysis was conducted to determine if a POD could be identified following short-term oral rat exposure with two nongenotoxic rodent carcinogens, fenofibrate and methapyrilene, using a benchmark dose analysis of genes aggregated in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) biological processes, which likely encompass key event(s) for carcinogenicity. The gene expression response for fenofibrate given to rats for 2days was consistent with its MOA and known key events linked to PPARα activation. The temporal response from daily dosing with methapyrilene demonstrated biological complexity with waves of pathways/biological processes occurring over 1, 3, and 7days; nonetheless, the benchmark dose values were consistent over time. When comparing the dose-response of toxicogenomic data to tumorigenesis or precursor events, the toxicogenomics POD was slightly below any effect level. Our results suggest that toxicogenomic analysis using short-term studies can be used to identify a threshold for nongenotoxic carcinogens based on evaluation of potential key event(s) which then can be used within a risk assessment framework. Copyright © 2010 Elsevier Inc. All rights reserved.

Dose-response plasma appearance of coffee chlorogenic and phenolic acids in adults.

PubMed

Renouf, Mathieu; Marmet, Cynthia; Giuffrida, Francesca; Lepage, Mélissa; Barron, Denis; Beaumont, Maurice; Williamson, Gary; Dionisi, Fabiola

2014-02-01

Coffee contains phenolic compounds, mainly chlorogenic acids (CGAs). Even though coffee intake has been associated with some health benefits in epidemiological studies, the bioavailability of coffee phenolics is not fully understood. We performed a dose-response study measuring plasma bioavailability of phenolics after drinking three increasing, but still nutritionally relevant doses of instant pure soluble coffee. The study design was a one treatment (coffee) three-dose randomized cross-over design, with a washout period of 2 wks between visits. CGAs, phenolic acids, and late-appearing metabolites all increased with increasing ingested dose. Hence, the sum of area under the curve was significantly higher for the medium to low dose, and high to medium dose, by 2.23- and 2.38-fold, respectively. CGAs were not well absorbed in their intact form, regardless of the dose. CGA and phenolic acids appeared rapidly in plasma, indicating an early absorption in the gastrointestinal tract. Late-appearing metabolites were the most abundant, regardless of the dose. This study confirmed previous findings about coffee bioavailability but also showed that coffee phenolics appear in a positive dose-response manner in plasma when drank at nutritionally relevant doses. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Dose-response relationships in a microneutralization test for foot-and-mouth disease viruses.

PubMed Central

Booth, J. C.; Rweyemamu, M. M.; Pay, T. W.

1978-01-01

Two-dimensional quantal microneutralization tests on foot-and-mouth disease viruses, in which neutralizing antibody activity was titrated against a serial range of virus doses, demonstrated a variety of dose-response curves some of which were rectilinear, others clearly curvilinear. Moreover, in the case of the non-linear responses obtained with some antisera, the shape of the curve was such that antibody titres recorded with doses of virus ranging from 10(3)-10(5) TCD50 were closely similar. Studies were carried out on the effect of varying the conditions of the test on the shape of the dose-response curve: significant differences were obtained after treatment of the antiserum-virus mixtures with anti-species globulin, and when the test was assayed in cells of differing susceptibility to infection. PMID:202650

Technical Note: On GAFChromic EBT-XD film and the lateral response artifact.

PubMed

Lewis, David F; Chan, Maria F

2016-02-01

The new radiochromic film, GAFChromic EBT-XD, contains the same active material, lithium-10,12-pentacosadiynoate, as GAFChromic EBT3, but the crystalline form is different. This work investigates the effect of this change on the well-known lateral response artifact when EBT-XD film is digitized on a flatbed scanner. The dose response of a single production lot of EBT-XD was characterized by scanning an unexposed film plus a set of films exposed to doses between 2.5 and 50 Gy using 6 MV photons. To characterize the lateral response artifact, the authors used the unexposed film plus a subset of samples exposed to doses between 20 and 50 Gy. Digital images of these films were acquired at seven discrete lateral locations perpendicular to the scan direction on three Epson 10000XL scanners. Using measurements at the discrete lateral positions, the scanner responses were determined as a function of the lateral position of the film. From the data for each scanner, a set of coefficients were derived whereby measured response values could be corrected to remove the effects of the lateral response artifact. The EBT-XD data were analyzed as in their previous work and compared to results reported for EBT3 in that paper. For films scanned in the same orientation and having equal responses, the authors found that the lateral response artifact for EBT-XD and EBT3 films was remarkably similar. For both films, the artifact increases with increased net response. However, as EBT-XD is less sensitive than EBT3, a greater exposure dose is required to reach the same net response. On this basis, the lower sensitivity of EBT-XD relative to EBT3 results in less net response change for equal exposure and a reduction in the impact of the lateral response artifact. The shape of the crystalline active component in EBT-XD and EBT3 does not affect the fundamental existence of the lateral response artifact when the films are digitized on flatbed scanners. Owing its lower sensitivity, EBT-XD film requires higher dose to reach the same response as EBT3, resulting in lesser impact of the lateral response artifact. For doses >10 Gy, the slopes of the EBT-XD red and green channel dose response curves are greater than the corresponding ones for EBT3. For these two reasons, the authors prefer EBT-XD for doses exceeding about 10 Gy.

Technical Note: On GAFChromic EBT-XD film and the lateral response artifact

PubMed Central

Lewis, David F.

2016-01-01

Purpose: The new radiochromic film, GAFChromic EBT-XD, contains the same active material, lithium-10,12-pentacosadiynoate, as GAFChromic EBT3, but the crystalline form is different. This work investigates the effect of this change on the well-known lateral response artifact when EBT-XD film is digitized on a flatbed scanner. Methods: The dose response of a single production lot of EBT-XD was characterized by scanning an unexposed film plus a set of films exposed to doses between 2.5 and 50 Gy using 6 MV photons. To characterize the lateral response artifact, the authors used the unexposed film plus a subset of samples exposed to doses between 20 and 50 Gy. Digital images of these films were acquired at seven discrete lateral locations perpendicular to the scan direction on three Epson 10000XL scanners. Using measurements at the discrete lateral positions, the scanner responses were determined as a function of the lateral position of the film. From the data for each scanner, a set of coefficients were derived whereby measured response values could be corrected to remove the effects of the lateral response artifact. The EBT-XD data were analyzed as in their previous work and compared to results reported for EBT3 in that paper. Results: For films scanned in the same orientation and having equal responses, the authors found that the lateral response artifact for EBT-XD and EBT3 films was remarkably similar. For both films, the artifact increases with increased net response. However, as EBT-XD is less sensitive than EBT3, a greater exposure dose is required to reach the same net response. On this basis, the lower sensitivity of EBT-XD relative to EBT3 results in less net response change for equal exposure and a reduction in the impact of the lateral response artifact. Conclusions: The shape of the crystalline active component in EBT-XD and EBT3 does not affect the fundamental existence of the lateral response artifact when the films are digitized on flatbed scanners. Owing its lower sensitivity, EBT-XD film requires higher dose to reach the same response as EBT3, resulting in lesser impact of the lateral response artifact. For doses >10 Gy, the slopes of the EBT-XD red and green channel dose response curves are greater than the corresponding ones for EBT3. For these two reasons, the authors prefer EBT-XD for doses exceeding about 10 Gy. PMID:26843228

Immunogenicity and safety of a live attenuated shingles (herpes zoster) vaccine (Zostavax®) in individuals aged ≥ 70 years: a randomized study of a single dose vs. two different two-dose schedules.

PubMed

Vesikari, Timo; Hardt, Roland; Rümke, Hans C; Icardi, Giancarlo; Montero, Jordi; Thomas, Stéphane; Sadorge, Christine; Fiquet, Anne

2013-04-01

Disease protection provided by herpes zoster (HZ) vaccination tends to reduce as age increases. This study was designed to ascertain whether a second dose of the HZ vaccine, Zostavax(®), would increase varicella zoster virus (VZV)-specific immune response among individuals aged ≥ 70 y. Individuals aged ≥ 70 y were randomized to receive HZ vaccine in one of three schedules: a single dose (0.65 mL), two doses at 0 and 1 mo, or two doses at 0 and 3 mo. VZV antibody titers were measured at baseline, 4 weeks after each vaccine dose, and 12 mo after the last dose. In total, 759 participants (mean age 76.1 y) were randomized to receive vaccination. Antibody responses were similar after a single dose or two doses of HZ vaccine [post-dose 2/post-dose 1 geometric mean titer (GMT) ratios for the 1-mo or 3-mo schedules were 1.11, 95% confidence interval (CI) 1.02-1.22 and 0.78, 95% CI 0.73-0.85], respectively). The 12-mo post-dose 2/12-mo post-dose 1 GMT ratio was similar for the 1-mo schedule and for the 3-mo schedule (1.06, 95% CI 0.96-1.17 and 1.08, 95% CI 0.98-1.19, respectively). Similar immune responses were observed in participants aged 70-79 y and those aged ≥ 80 y. HZ vaccine was generally well tolerated, with no evidence of increased adverse event incidence after the second dose with either schedule. Compared with a single-dose regimen, two-dose vaccination did not increase VZV antibody responses among individuals aged ≥ 70 y. Antibody persistence after 12 mo was similar with all three schedules.

DOSE-DEPENDENT TRANSITIONS IN MECHANISMS OF TOXICITY: CASE STUDIES

EPA Science Inventory

Experience with dose response and mechanisms of toxicity has shown that multiple mechanisms may exist for a single agent along the continuum of the full dose-response curve. It is highly likely that critical, limiting steps in any given mechanistic pathway may become overwhelmed ...

A dose-responsive model of smoke inhalation injury. Severity-related alteration in cardiopulmonary function.

PubMed Central

Shimazu, T; Yukioka, T; Hubbard, G B; Langlinais, P C; Mason, A D; Pruitt, B A

1987-01-01

The dose responsiveness of selected physiologic indices was studied in a sheep model of smoke inhalation injury. In this model, graded severity of injury was achieved by changing the contact time with smoke (defined by "unit"), whereas other variables were kept constant. Blood gas and cardiopulmonary indices were measured in 70 sheep, including 12 controls, either 24 or 72 hours after exposure to 3, 6, 9, 12, 15, or 18 units of smoke. A 12-unit dose of smoke was fatal within 72 hours and an 18-unit dose was fatal within 24 hours. The best correlation between smoke dose and response was observed in arterial oxygen tension 24 hours after exposure. At 24 hours, most of the cardiopulmonary indices showed significant change only after a 12-unit exposure. Although the exact shape of the dose-response curve could not be defined, sigmoid or curved linear shape was suggested, reflecting the progressive deterioration. Images Fig. 3. Fig. 4A. Fig. 4B. PMID:3606236

No-threshold dose-response curves for nongenotoxic chemicals: Findings and applications for risk assessment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sheehan, Daniel M.

2006-01-15

We tested the hypothesis that no threshold exists when estradiol acts through the same mechanism as an active endogenous estrogen. A Michaelis-Menten (MM) equation accounting for response saturation, background effects, and endogenous estrogen level fit a turtle sex-reversal data set with no threshold and estimated the endogenous dose. Additionally, 31 diverse literature dose-response data sets were analyzed by adding a term for nonhormonal background; good fits were obtained but endogenous dose estimations were not significant due to low resolving power. No thresholds were observed. Data sets were plotted using a normalized MM equation; all 178 data points were accommodated onmore » a single graph. Response rates from {approx}1% to >95% were well fit. The findings contradict the threshold assumption and low-dose safety. Calculating risk and assuming additivity of effects from multiple chemicals acting through the same mechanism rather than assuming a safe dose for nonthresholded curves is appropriate.« less

An adaptive two-stage dose-response design method for establishing proof of concept.

PubMed

Franchetti, Yoko; Anderson, Stewart J; Sampson, Allan R

2013-01-01

We propose an adaptive two-stage dose-response design where a prespecified adaptation rule is used to add and/or drop treatment arms between the stages. We extend the multiple comparison procedures-modeling (MCP-Mod) approach into a two-stage design. In each stage, we use the same set of candidate dose-response models and test for a dose-response relationship or proof of concept (PoC) via model-associated statistics. The stage-wise test results are then combined to establish "global" PoC using a conditional error function. Our simulation studies showed good and more robust power in our design method compared to conventional and fixed designs.

Dose-response approaches for nuclear receptor-mediated ...

EPA Pesticide Factsheets

A public workshop, organized by a Steering Committee of scientists from government, industry, universities, and research organizations, was held at the National Institute of Environmental Health Sciences (NIEHS) in September, 2010. The workshop explored the dose-response implications of toxicant modes of action (MOA) mediated by nuclear receptors. The dominant paradigm in human health risk assessment has been linear extrapolation without a threshold for cancer, and estimation of sub-threshold doses for non-cancer and (in appropriate cases) cancer endpoints. However, recent publications question the application of dose-response modeling approaches with a threshold. The growing body of molecular toxicology information and computational toxicology tools has allowed for exploration of the presence or absence of subthreshold doses for a number of receptor-mediated MOPs. The workshop explored the development of dose-response approaches for nuclear receptor-mediated liver cancer, within a MOA Human Relevance framework (HRF). Case studies addressed activation of the AHR; the CAR/PXR, and the PPARa. This paper describes the workshop process, key issues discussed, and conclusions. The value of an interactive workshop approach to apply current MOA/HRF frameworks was demonstrated. The results may help direct research on the MOA and dose-response of receptor-based toxicity, since there are commonalities for many receptors in the basic pathways involved for late steps in the

Evaluation of LiF:Mg,Ti (TLD-100) for Intraoperative Electron Radiation Therapy Quality Assurance

PubMed Central

Liuzzi, Raffaele; Savino, Federica; D’Avino, Vittoria; Pugliese, Mariagabriella; Cella, Laura

2015-01-01

Background Purpose of the present work was to investigate thermoluminescent dosimeters (TLDs) response to intraoperative electron radiation therapy (IOERT) beams. In an IOERT treatment, a large single radiation dose is delivered with a high dose-per-pulse electron beam (2–12 cGy/pulse) during surgery. To verify and to record the delivered dose, in vivo dosimetry is a mandatory procedure for quality assurance. The TLDs feature many advantages such as a small detector size and close tissue equivalence that make them attractive for IOERT as in vivo dosimeters. Methods LiF:Mg,Ti dosimeters (TLD-100) were irradiated with different IOERT electron beam energies (5, 7 and 9 MeV) and with a 6 MV conventional photon beam. For each energy, the TLDs were irradiated in the dose range of 0–10 Gy in step of 2Gy. Regression analysis was performed to establish the response variation of thermoluminescent signals with dose and energy. Results The TLD-100 dose-response curves were obtained. In the dose range of 0–10 Gy, the calibration curve was confirmed to be linear for the conventional photon beam. In the same dose region, the quadratic model performs better than the linear model when high dose-per-pulse electron beams were used (F test; p<0.05). Conclusions This study demonstrates that the TLD dose response, for doses ≤10Gy, has a parabolic behavior in high dose-per-pulse electron beams. TLD-100 can be useful detectors for IOERT patient dosimetry if a proper calibration is provided. PMID:26427065

Evaluation of LiF:Mg,Ti (TLD-100) for Intraoperative Electron Radiation Therapy Quality Assurance.

PubMed

Liuzzi, Raffaele; Savino, Federica; D'Avino, Vittoria; Pugliese, Mariagabriella; Cella, Laura

2015-01-01

Purpose of the present work was to investigate thermoluminescent dosimeters (TLDs) response to intraoperative electron radiation therapy (IOERT) beams. In an IOERT treatment, a large single radiation dose is delivered with a high dose-per-pulse electron beam (2-12 cGy/pulse) during surgery. To verify and to record the delivered dose, in vivo dosimetry is a mandatory procedure for quality assurance. The TLDs feature many advantages such as a small detector size and close tissue equivalence that make them attractive for IOERT as in vivo dosimeters. LiF:Mg,Ti dosimeters (TLD-100) were irradiated with different IOERT electron beam energies (5, 7 and 9 MeV) and with a 6 MV conventional photon beam. For each energy, the TLDs were irradiated in the dose range of 0-10 Gy in step of 2 Gy. Regression analysis was performed to establish the response variation of thermoluminescent signals with dose and energy. The TLD-100 dose-response curves were obtained. In the dose range of 0-10 Gy, the calibration curve was confirmed to be linear for the conventional photon beam. In the same dose region, the quadratic model performs better than the linear model when high dose-per-pulse electron beams were used (F test; p<0.05). This study demonstrates that the TLD dose response, for doses ≤10 Gy, has a parabolic behavior in high dose-per-pulse electron beams. TLD-100 can be useful detectors for IOERT patient dosimetry if a proper calibration is provided.

AS03-Adjuvanted, Very-Low-Dose Influenza Vaccines Induce Distinctive Immune Responses Compared to Unadjuvanted High-Dose Vaccines in BALB/c Mice

PubMed Central

Yam, Karen K.; Gupta, Jyotsana; Winter, Kaitlin; Allen, Elizabeth; Brewer, Angela; Beaulieu, Édith; Mallett, Corey P.; Burt, David S.; Ward, Brian J.

2015-01-01

During the 2009–2010 influenza pandemic, an adjuvanted, dose-sparing vaccine was recommended for most Canadians. We hypothesize that differences exist in the responses to AS03-adjuvanted, low antigen (Ag) dose versus unadjuvanted, full-dose vaccines. We investigated the relationship between Ag dose and the oil-in-water emulsion Adjuvant System AS03. BALB/c mice received two IM doses of AS03A or AS03B with exaggerated dilutions of A/Uruguay/716/2007 H3N2 split virion vaccine Ag. Immune responses were assessed 3 weeks after the booster. Unadjuvanted “high” (3 μg) and low-dose (0.03–0.003 μg) vaccines generated similar serum antibody titers and cytokine secretion patterns in restimulated splenocytes. Compared to unadjuvanted “high-dose” vaccination, both AS03A and AS03B-adjuvanted low-dose vaccines tended to elicit higher serum antibody titers, broader induction of cytokine secretion and generated more influenza-specific antibody secreting cells and cytokine-secreting CD4 and CD8 T cells in splenocytes. We show that varying Ag and/or AS03 dose in this influenza vaccination mouse model can strongly influence both the magnitude and pattern of the immune response elicited. These findings are highly relevant given the likelihood of expanded use of adjuvanted, dose-sparing vaccines and raise questions about the use of “standard” doses of vaccines in pre-clinical vaccine studies. PMID:25972874

Evaluating the evidence for non-monotonic dose-response relationships: A systematic literature review and (re-)analysis of in vivo toxicity data in the area of food safety.

PubMed

Varret, C; Beronius, A; Bodin, L; Bokkers, B G H; Boon, P E; Burger, M; De Wit-Bos, L; Fischer, A; Hanberg, A; Litens-Karlsson, S; Slob, W; Wolterink, G; Zilliacus, J; Beausoleil, C; Rousselle, C

2018-01-15

This study aims to evaluate the evidence for the existence of non-monotonic dose-responses (NMDRs) of substances in the area of food safety. This review was performed following the systematic review methodology with the aim to identify in vivo studies published between January 2002 and February 2015 containing evidence for potential NMDRs. Inclusion and reliability criteria were defined and used to select relevant and reliable studies. A set of six checkpoints was developed to establish the likelihood that the data retrieved contained evidence for NMDR. In this review, 49 in vivo studies were identified as relevant and reliable, of which 42 were used for dose-response analysis. These studies contained 179 in vivo dose-response datasets with at least five dose groups (and a control group) as fewer doses cannot provide evidence for NMDR. These datasets were extracted and analyzed using the PROAST software package. The resulting dose-response relationships were evaluated for possible evidence of NMDRs by applying the six checkpoints. In total, 10 out of the 179 in vivo datasets fulfilled all six checkpoints. While these datasets could be considered as providing evidence for NMDR, replicated studies would still be needed to check if the results can be reproduced to rule out that the non-monotonicity was caused by incidental anomalies in that specific study. This approach, combining a systematic review with a set of checkpoints, is new and appears useful for future evaluations of the dose response datasets regarding evidence of non-monotonicity. Published by Elsevier Inc.

TIME COURSE AND DOSE RESPONSE ASSESSMENT OF CHOLINESTERASE (CHE) INHIBITION IN ADULT RATS TREATED ACUTELY WITH CARBARYL, METHOMYL, METHIOCARB, OXAMYL, OR PROPOXUR.

EPA Science Inventory

To compare the toxicity of 5 N-methyl carbamates, the time course and dose response profiles for ChE inhibition were established for each. For the time course comparison, adult male Long Evans rats (n=5 dose group) were dosed orally with either carbaryl (CB; 30 mg/kg in corn oi...

Salmonella Fecal Shedding and Immune Responses are Dose- and Serotype- Dependent in Pigs

PubMed Central

Ivanek, Renata; Österberg, Julia; Gautam, Raju; Sternberg Lewerin, Susanna

2012-01-01

Despite the public health importance of Salmonella infection in pigs, little is known about the associated dynamics of fecal shedding and immunity. In this study, we investigated the transitions of pigs through the states of Salmonella fecal shedding and immune response post-Salmonella inoculation as affected by the challenge dose and serotype. Continuous-time multistate Markov models were developed using published experimental data. The model for shedding had four transient states, of which two were shedding (continuous and intermittent shedding) and two non-shedding (latency and intermittent non-shedding), and one absorbing state representing permanent cessation of shedding. The immune response model had two transient states representing responses below and above the seroconversion level. The effects of two doses [low (0.65×106 CFU/pig) and high (0.65×109 CFU/pig)] and four serotypes (Salmonella Yoruba, Salmonella Cubana, Salmonella Typhimurium, and Salmonella Derby) on the models' transition intensities were evaluated using a proportional intensities model. Results indicated statistically significant effects of the challenge dose and serotype on the dynamics of shedding and immune response. The time spent in the specific states was also estimated. Continuous shedding was on average 10–26 days longer, while intermittent non-shedding was 2–4 days shorter, in pigs challenged with the high compared to low dose. Interestingly, among pigs challenged with the high dose, the continuous and intermittent shedding states were on average up to 10–17 and 3–4 days longer, respectively, in pigs infected with S. Cubana compared to the other three serotypes. Pigs challenged with the high dose of S. Typhimurium or S. Derby seroconverted on average up to 8–11 days faster compared to the low dose. These findings highlight that Salmonella fecal shedding and immune response following Salmonella challenge are dose- and serotype-dependent and that the detection of specific Salmonella strains and immune responses in pigs are time-sensitive. PMID:22523553

Adaptive Responses to Prochloraz Exposure That Alter Dose-Response and Time-Course Behaviors

EPA Science Inventory

Dose response and time-course (DRTC) are, along with exposure, the major determinants of health risk. Adaptive changes within exposed organisms in response to environmental stress are common, and alter DRTC behaviors to minimize the effects caused by stressors. In this project, ...

Characterization and long-term persistence of immune response following two doses of an AS03A-adjuvanted H1N1 influenza vaccine in healthy Japanese adults.

PubMed

Ikematsu, Hideyuki; Nagai, Hideaki; Kawashima, Masahiro; Kawakami, Yasunobu; Tenjinbaru, Kazuyoshi; Li, Ping; Walravens, Karl; Gillard, Paul; Roman, François

2012-02-01

Background Long-term persistence of immune response and safety of two doses of an A/California/07/2009 H1N1 pandemic influenza vaccine adjuvanted with AS03 (an α-tocopherol oil-in-water emulsion-based Adjuvant System) administered 21 d apart was evaluated in Japanese adults [NCT00989612]. Methods One-hundred healthy subjects aged 20-64 y (stratified [1:1] into two age strata 20-40 y and 41-64 y) received 21 d apart, two doses of AS03-adjuvanted 3.75µg haemagglutinin (HA) H1N1 2009 vaccine. Immunogenicity data by haemagglutination inhibition (HI) assay six months after the first vaccine dose (Day 182) and microneutralization assay following each of the two vaccine doses (Days 21 and 42) and at Day 182 are reported here. Results Persistence of strong HI immune response was observed at Day 182 that met the US and European regulatory thresholds for pandemic influenza vaccines (seroprotection rate: 95%; seroconversion rate: 93%; geometric mean fold-rise: 20). The neutralizing antibody response against the A/Netherlands/602/2009 strain (antigenically similar to vaccine-strain) persisted for at least up to Day 182 (vaccine response rate: 76%; geometric mean titer: 114.4) and paralleled the HI immune response at all time points. No marked difference was observed in HI antibody persistence and neutralising antibody response between the two age strata. The vaccine had a clinically-acceptable safety profile. Conclusion Two priming doses of H1N1 2009 pandemic influenza vaccine induced an immune response persisting for at least six months after the first vaccine dose. This could be beneficial in evaluating the importance and effect of vaccination with this AS03-adjuvanted pandemic influenza vaccine.

PET/MRI of Hepatic 90Y Microsphere Deposition Determines Individual Tumor Response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fowler, Kathryn J.; Maughan, Nichole M.; Laforest, Richard

PurposeThe purpose of our study is to determine if there is a relationship between dose deposition measured by PET/MRI and individual lesion response to yttrium-90 ({sup 90}Y) microsphere radioembolization.Materials and Methods26 patients undergoing lobar treatment with {sup 90}Y microspheres underwent PET/MRI within 66 h of treatment and had follow-up imaging available. Adequate visualization of tumor was available in 24 patients, and contours were drawn on simultaneously acquired PET/MRI data. Dose volume histograms (DVHs) were extracted from dose maps, which were generated using a voxelized dose kernel. Similar contours to capture dimensional and volumetric change of tumors were drawn on follow-up imaging.more » Response was analyzed using both RECIST and volumetric RECIST (vRECIST) criteria.ResultsA total of 8 hepatocellular carcinoma (HCC), 4 neuroendocrine tumor (NET), 9 colorectal metastases (CRC) patients, and 3 patients with other metastatic disease met inclusion criteria. Average dose was useful in predicting response between responders and non-responders for all lesion types and for CRC lesions alone using both response criteria (p < 0.05). D70 (minimum dose to 70 % of volume) was also useful in predicting response when using vRECIST. No significant trend was seen in the other tumor types. For CRC lesions, an average dose of 29.8 Gy offered 76.9 % sensitivity and 75.9 % specificity for response.ConclusionsPET/MRI of {sup 90}Y microsphere distribution showed significantly higher DVH values for responders than non-responders in patients with CRC. DVH analysis of {sup 90}Y microsphere distribution following treatment may be an important predictor of response and could be used to guide future adaptive therapy trials.« less

Determinants of Diuretic Responsiveness and Associated Outcomes During Acute Heart Failure Hospitalization: An Analysis From the NHLBI Heart Failure Network Clinical Trials.

PubMed

Kiernan, Michael S; Stevens, Susanna R; Tang, W H Wilson; Butler, Javed; Anstrom, Kevin J; Birati, Edo Y; Grodin, Justin L; Gupta, Divya; Margulies, Kenneth B; LaRue, Shane; Dávila-Román, Victor G; Hernandez, Adrian F; de Las Fuentes, Lisa

2018-03-01

Poor response to loop diuretic therapy is a marker of risk during heart failure hospitalization. We sought to describe baseline determinants of diuretic response and to further explore the relationship between this response and clinical outcomes. Patient data from the National Heart, Lung, and Blood Institute Heart Failure Network ROSE-AHF and CARRESS-HF clinical trials were analyzed to determine baseline determinants of diuretic response. Diuretic efficiency (DE) was defined as total 72-hour fluid output per total equivalent loop diuretic dose. Data from DOSE-AHF was then used to determine if these predictors of DE correlated with response to a high- versus low-dose diuretic strategy. At 72 hours, the high-DE group had median fluid output of 9071 ml (interquartile range: 7240-11775) with median furosemide dose of 320 mg (220-480) compared with 8030 ml (6300-9915) and 840 mg (600-1215) respectively for the low DE group. Cystatin C was independently associated with DE (odds ratio 0.36 per 1mg/L increase; 95% confidence interval: 0.24-0.56; P < 0.001). Independently from baseline characteristics, reduced fluid output, weight loss and DE were each associated with increased 60 day mortality. Among patients with estimated glomerular filtration rate below the median, those randomized to a high-dose strategy had improved symptoms compared with those randomized to a low-dose strategy. Elevated baseline cystatin C, as a biomarker of renal dysfunction, is associated with reduced diuretic response during heart failure hospitalization. Higher loop diuretic doses are required for therapeutic decongestion in patients with renal insufficiency. Poor response identifies a high-risk population. Copyright © 2018 Elsevier Inc. All rights reserved.

A group sequential adaptive treatment assignment design for proof of concept and dose selection in headache trials.

PubMed

Hall, David B; Meier, Ulrich; Diener, Hans-Cristoph

2005-06-01

The trial objective was to test whether a new mechanism of action would effectively treat migraine headaches and to select a dose range for further investigation. The motivation for a group sequential, adaptive, placebo-controlled trial design was (1) limited information about where across the range of seven doses to focus attention, (2) a need to limit sample size for a complicated inpatient treatment and (3) a desire to reduce exposure of patients to ineffective treatment. A design based on group sequential and up and down designs was developed and operational characteristics were explored by trial simulation. The primary outcome was headache response at 2 h after treatment. Groups of four treated and two placebo patients were assigned to one dose. Adaptive dose selection was based on response rates of 60% seen with other migraine treatments. If more than 60% of treated patients responded, then the next dose was the next lower dose; otherwise, the dose was increased. A stopping rule of at least five groups at the target dose and at least four groups at that dose with more than 60% response was developed to ensure that a selected dose would be statistically significantly (p=0.05) superior to placebo. Simulations indicated good characteristics in terms of control of type 1 error, sufficient power, modest expected sample size and modest bias in estimation. The trial design is attractive for phase 2 clinical trials when response is acute and simple, ideally binary, placebo comparator is required, and patient accrual is relatively slow allowing for the collection and processing of results as a basis for the adaptive assignment of patients to dose groups. The acute migraine trial based on this design was successful in both proof of concept and dose range selection.

Gene Profiling Characteristics of Radioadaptive Response in AG01522 Normal Human Fibroblasts

PubMed Central

Hou, Jue; Wang, Fan; Kong, Peizhong; Yu, Peter K. N.; Wang, Hongzhi; Han, Wei

2015-01-01

Radioadaptive response (RAR) in mammalian cells refers to the phenomenon where a low-dose ionizing irradiation alters the gene expression profiles, and protects the cells from the detrimental effects of a subsequent high dose exposure. Despite the completion of numerous experimental studies on RAR, the underlying mechanism has remained unclear. In this study, we aimed to have a comprehensive investigation on the RAR induced in the AG01522 human fibroblasts first exposed to 5 cGy (priming dose) and then followed by 2 Gy (challenge dose) of X-ray through comparisons to those cells that had only received a single 2 Gy dose. We studied how the priming dose affected the expression of gene transcripts, and to identify transcripts or pathways that were associated with the reduced chromosomal damages (in terms of the number of micronuclei) after application of the challenging dose. Through the mRNA and microRNA microarray analyses, the transcriptome alteration in AG01522 cells was examined, and the significantly altered genes were identified for different irradiation procedures using bioinformatics approaches. We observed that a low-dose X-ray exposure produced an alert, triggering and altering cellular responses to defend against subsequent high dose-induced damages, and accelerating the cell repair process. Moreover, the p53 signaling pathway was found to play critial roles in regulating DNA damage responses at the early stage after application of the challenging dose, particularly in the RAR group. Furthermore, microRNA analyses also revealed that cell communication and intercellular signaling transduction played important roles after low-dose irradiation. We conclude that RAR benefits from the alarm mechanisms triggered by a low-dose priming radation dose. PMID:25886619

Imatinib dose reduction in patients with chronic myeloid leukemia in sustained deep molecular response.

PubMed

Cervantes, Francisco; Correa, Juan-Gonzalo; Pérez, Isabel; García-Gutiérrez, Valentín; Redondo, Sara; Colomer, Dolors; Jiménez-Velasco, Antonio; Steegmann, Juan-Luis; Sánchez-Guijo, Fermín; Ferrer-Marín, Francisca; Pereira, Arturo; Osorio, Santiago

2017-01-01

To determine whether a lower imatinib dose could minimize toxicity while maintaining the molecular response (MR), imatinib dose was reduced to 300 mg daily in 43 patients with chronic myeloid leukemia (CML) in sustained deep molecular response to first-line imatinib 400 mg daily. At the time of dose reduction, median duration of the deep response was 4.1 (interquartile range (IQR) 2.2-5.9) years; molecular response was MR 4 , MR 4.5 , and MR 5 of the international scale in 6, 28, and 9 patients, respectively. Toxicity grade was 1, 2, and 3 in 28, 8, and 1 patients, respectively; 6 patients underwent dose reduction without having side effects. With a median of 1.6 (IQR 0.7-3.2) years on imatinib 300 mg daily, only one patient lost the deep molecular response to MR 3 . At the last follow-up, response was MR 3 , MR 4 , MR 4.5 , and MR 5 in 1, 3, 9, and 30 patients, respectively. Toxicity improvement was observed in 23 (62.2 %) of the 37 patients with side effects, decreasing to grade 0 in 20 of them. All but one anemic patients improved (p = 0.01), the median Hb increase in this subgroup of patients being 1 g/dL. In CML patients with sustained deep response to the standard imatinib dose, reducing to 300 mg daily significantly improves tolerability and preserves efficacy.

Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma

PubMed Central

San Miguel, Jesus F.; Weisel, Katja C.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Moreau, Philippe; Banos, Anne; Oriol, Albert; Garderet, Laurent; Cavo, Michele; Ivanova, Valentina; Alegre, Adrian; Martinez-Lopez, Joaquin; Chen, Christine; Renner, Christoph; Bahlis, Nizar Jacques; Yu, Xin; Teasdale, Terri; Sternas, Lars; Jacques, Christian; Zaki, Mohamed H.; Dimopoulos, Meletios A.

2015-01-01

Pomalidomide is a distinct oral IMiD® immunomodulatory agent with direct antimyeloma, stromal-support inhibitory, and immunomodulatory effects. The pivotal, multicenter, open-label, randomized phase 3 trial MM-003 compared pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in 455 patients with refractory or relapsed and refractory multiple myeloma after failure of bortezomib and lenalidomide treatment. Initial results demonstrated significantly longer progression-free survival and overall survival with an acceptable tolerability profile for pomalidomide + low-dose dexamethasone vs high-dose dexamethasone. This secondary analysis describes patient outcomes by treatment history and depth of response. Pomalidomide + low-dose dexamethasone significantly prolonged progression-free survival and favored overall survival vs high-dose dexamethasone for all subgroups analyzed, regardless of prior treatments or refractory status. Both univariate and multivariate analyses showed that no variable relating to either the number (≤ or > 3) or type of prior treatment was a significant predictor of progression-free survival or overall survival. No cross-resistance with prior lenalidomide or thalidomide treatment was observed. Patients achieving a minimal response or better to pomalidomide + low-dose dexamethasone treatment experienced a survival benefit, which was even higher in those achieving at least a partial response (17.2 and 19.9 months, respectively, as compared with 7.5 months for patients with less than minimal response). These data suggest that pomalidomide + low-dose dexamethasone should be considered a standard of care in patients with refractory or relapsed and refractory multiple myeloma regardless of prior treatment. ClinicalTrials.gov: NCT01311687; EudraCT: 2010-019820-30. PMID:26160879

Dose response of bone-targeted enzyme replacement for murine hypophosphatasia.

PubMed

Yadav, Manisha C; Lemire, Isabelle; Leonard, Pierre; Boileau, Guy; Blond, Laurent; Beliveau, Martin; Cory, Esther; Sah, Robert L; Whyte, Michael P; Crine, Philippe; Millán, José Luis

2011-08-01

Hypophosphatasia (HPP) features rickets or osteomalacia from tissue-nonspecific alkaline phosphatase (TNSALP) deficiency due to deactivating mutations within the ALPL gene. Enzyme replacement therapy with a bone-targeted, recombinant TNSALP (sALP-FcD(10), renamed ENB-0040) prevents manifestations of HPP when initiated at birth in TNSALP knockout (Akp2(-/-)) mice. Here, we evaluated the dose-response relationship of ENB-0040 to various phenotypic traits of Akp2(-/-) mice receiving daily subcutaneous (SC) injections of ENB-0040 from birth at 0.5, 2.0, or 8.2mg/kg for 43days. Radiographs, μCT, and histomorphometric analyses documented better bone mineralization with increasing doses of ENB-0040. We found a clear, positive correlation between ENB-0040 dose and prevention of mineralization defects of the feet, rib cage, lower limbs, and jaw bones. According to a dose-response model, the ED(80) (the dose that prevents bone defects in 80% of mice) was 3.2, 2.8 and 2.9mg/kg/day for these sites, respectively. Long bones seemed to respond to lower daily doses of ENB-0040. There was also a positive relationship between ENB-0040 dose and survival. Median survival, body weight, and bone length all improved with increasing doses of ENB-0040. Urinary PP(i) concentrations remained elevated in all treatment groups, indicating that while this parameter is a good biochemical marker for diagnosing HPP in patients, it may not be a good follow up marker for evaluating response to treatment when administering bone-targeted TNSALP to mice. These dose-response relationships strongly support the pharmacological efficacy of ENB-0040 for HPP, and provide the experimental basis for the therapeutic range of ENB-0040 chosen for clinical trials. Copyright © 2011 Elsevier Inc. All rights reserved.

Dose response of bone-targeted enzyme replacement for murine hypophosphatasia

PubMed Central

Yadav, Manisha C.; Lemire, Isabelle; Leonard, Pierre; Boileau, Guy; Blond, Laurent; Beliveau, Martin; Cory, Esther; Sah, Robert L.; Whyte, Michael P.; Crine, Philippe; Millán, José Luis

2011-01-01

Hypophosphatasia (HPP) features rickets or osteomalacia from tissue-nonspecific alkaline phosphatase (TNSALP) deficiency due to deactivating mutations within the ALPL gene. Enzyme replacement therapy with a bone-targeted, recombinant TNSALP (sALP-FcD10, renamed ENB-0040) prevents manifestations of HPP when initiated at birth in TNSALP knockout (Akp2−/−) mice. Here, we evaluated the dose-response relationship of ENB-0040 to various phenotypic traits of Akp2−/− mice receiving daily subcutaneous (SC) injections of ENB-0040 from birth at 0.5, 2.0, or 8.2 mg/kg for 43 days. Radiographs, μCT, and histomorphometric analyses documented better bone mineralization with increasing doses of ENB-0040. We found a clear, positive correlation between ENB-0040 dose and prevention of mineralization defects of the feet, rib cage, lower limbs, and jaw bones. According to a dose-response model, the ED80 (the dose prevents the bone defects in 80% of mice) was 3.2, 2.8 and 2.9 mg/kg/day for these sites, respectively. Long bones seemed to respond to lower daily doses of ENB-0040. There was also a positive relationship between ENB-0040 dose and survival. Median survival, body weight, and bone length all improved with increasing doses of ENB-0040. Urinary PPi concentrations remained elevated in all treatment groups, indicating that while this parameter is a good biochemical marker for diagnosing HPP, it may not be a good follow up marker for evaluating response to treatment when administering bone-targeted TNSALP. These dose-response relationships strongly support the pharmacological efficacy of ENB-0040 for HPP, and provide the experimental basis for the therapeutic range of ENB-0040 chosen for clinical trials. PMID:21458605

Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder.

PubMed

Jakubovski, Ewgeni; Varigonda, Anjali L; Freemantle, Nicholas; Taylor, Matthew J; Bloch, Michael H

2016-02-01

Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder. The authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder. Forty studies involving 10,039 participants were included. Longitudinal modeling (dose-by-time interaction=0.0007, 95% CI=0.0001-0.0013) and endpoint analysis (meta-regression: β=0.00053, 95% CI=0.00018-0.00088, z=2.98) demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects (meta-regression: β=0.00207, 95% CI=0.00071-0.00342, z=2.98) and decreased likelihood of all-cause dropout (meta-regression: β=-0.00093, 95% CI=-0.00165 to -0.00021, z=-2.54). Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents (50 mg of fluoxetine). The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wen, N; Lu, S; Qin, Y

Purpose: To evaluate the dosimetric uncertainty associated with Gafchromic (EBT3) films and establish an absolute dosimetry protocol for Stereotactic Radiosurgery (SRS) and Stereotactic Body Radiotherapy (SBRT). Methods: EBT3 films were irradiated at each of seven different dose levels between 1 and 15 Gy with open fields, and standard deviations of dose maps were calculated at each color channel for evaluation. A scanner non-uniform response correction map was built by registering and comparing film doses to the reference diode array-based dose map delivered with the same doses. To determine the temporal dependence of EBT3 films, the average correction factors of differentmore » dose levels as a function of time were evaluated up to four days after irradiation. An integrated film dosimetry protocol was developed for dose calibration, calibration curve fitting, dose mapping, and profile/gamma analysis. Patient specific quality assurance (PSQA) was performed for 93 SRS/SBRT treatment plans. Results: The scanner response varied within 1% for the field sizes less than 5 × 5 cm{sup 2}, and up to 5% for the field sizes of 10 × 10 cm{sup 2}. The scanner correction method was able to remove visually evident, irregular detector responses found for larger field sizes. The dose response of the film changed rapidly (∼10%) in the first two hours and plateaued afterwards, ∼3% change between 2 and 24 hours. The mean uncertainties (mean of the standard deviations) were <0.5% over the dose range 1∼15Gy for all color channels for the OD response curves. The percentage of points passing the 3%/1mm gamma criteria based on absolute dose analysis, averaged over all tests, was 95.0 ± 4.2. Conclusion: We have developed an absolute film dose dosimetry protocol using EBT3 films. The overall uncertainty has been established to be approximately 1% for SRS and SBRT PSQA. The work was supported by a Research Scholar Grant, RSG-15-137-01-CCE from the American Cancer Society.« less

Testing the dose-response specification in epidemiology: public health and policy consequences for lead.

PubMed

Rothenberg, Stephen J; Rothenberg, Jesse C

2005-09-01

Statistical evaluation of the dose-response function in lead epidemiology is rarely attempted. Economic evaluation of health benefits of lead reduction usually assumes a linear dose-response function, regardless of the outcome measure used. We reanalyzed a previously published study, an international pooled data set combining data from seven prospective lead studies examining contemporaneous blood lead effect on IQ (intelligence quotient) of 7-year-old children (n = 1,333). We constructed alternative linear multiple regression models with linear blood lead terms (linear-linear dose response) and natural-log-transformed blood lead terms (log-linear dose response). We tested the two lead specifications for nonlinearity in the models, compared the two lead specifications for significantly better fit to the data, and examined the effects of possible residual confounding on the functional form of the dose-response relationship. We found that a log-linear lead-IQ relationship was a significantly better fit than was a linear-linear relationship for IQ (p = 0.009), with little evidence of residual confounding of included model variables. We substituted the log-linear lead-IQ effect in a previously published health benefits model and found that the economic savings due to U.S. population lead decrease between 1976 and 1999 (from 17.1 microg/dL to 2.0 microg/dL) was 2.2 times (319 billion dollars) that calculated using a linear-linear dose-response function (149 billion dollars). The Centers for Disease Control and Prevention action limit of 10 microg/dL for children fails to protect against most damage and economic cost attributable to lead exposure.

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCulloch, M; Polan, D; Feng, M

Purpose: Previous studies have shown that radiotherapy treatment for liver metastases causes marked liver hypertrophy in areas receiving low dose and atrophy/fibrosis in areas receiving high dose. The purpose of this work is to develop and evaluate a biomechanical model-based dose-response model to describe these liver responses to SBRT. Methods: In this retrospective study, a biomechanical model-based deformable registration algorithm, Morfeus, was expanded to include dose-based boundary conditions. Liver and tumor volumes were contoured on the planning images and CT/MR images three months post-RT and converted to finite element models. A thermal expansion-based relationship correlating the delivered dose and volumemore » response was generated from 22 patients previously treated. This coefficient, combined with the planned dose, was applied as an additional boundary condition to describe the volumetric response of the liver of an additional cohort of metastatic liver patients treated with SBRT. The accuracy of the model was evaluated based on overall volumetric liver comparisons and the target registration error (TRE) using the average deviations in positions of identified vascular bifurcations on each set of registered images, with a target accuracy of the 2.5mm isotropic dose grid (vector dimension 4.3mm). Results: The thermal expansion coefficient models the volumetric change of the liver to within 3%. The accuracy of Morfeus with dose-expansion boundary conditions a TRE of 5.7±2.8mm compared to 11.2±3.7mm using rigid registration and 8.9±0.28mm using Morfeus with only spatial boundary conditions. Conclusion: A biomechanical model has been developed to describe the volumetric and spatial response of the liver to SBRT. This work will enable the improvement of correlating functional imaging with delivered dose, the mapping of the delivered dose from one treatment onto the planning images for a subsequent treatment, and will further provide information to assist with the biological characterization of patients’ response to radiation.« less

Dose responses for adaption to low doses of (60)Co gamma rays and (3)H beta particles in normal human fibroblasts.

PubMed

Broome, E J; Brown, D L; Mitchel, R E J

2002-08-01

The dose response for adaption to radiation at low doses was compared in normal human fibroblasts (AG1522) exposed to either (60)Co gamma rays or (3)H beta particles. Cells were grown in culture to confluence and exposed at either 37 degrees C or 0 degrees C to (3)H beta-particle or (60)Co gamma-ray adapting doses ranging from 0.1 mGy to 500 mGy. These cells, and unexposed control cells, were allowed to adapt during a fixed 3-h, 37 degrees C incubation prior to a 4-Gy challenge dose of (60)Co gamma rays. Adaption was assessed by measuring micronucleus frequency in cytokinesis-blocked, binucleate cells. No adaption was detected in cells exposed to (60)Co gamma radiation at 37 degrees C after a dose of 0.1 mGy given at a low dose rate or to 500 mGy given at a high dose rate. However, low-dose-rate exposure (1-3 mGy/min) to any dose between 1 and 500 mGy from either radiation, delivered at either temperature, caused cells to adapt and reduced the micronucleus frequency that resulted from the subsequent 4-Gy exposure. Within this dose range, the magnitude of the reduction was the same, regardless of the dose or radiation type. These results demonstrate that doses as low as (on average) about one track per cell (1 mGy) produce the same maximum adaptive response as do doses that deposit many tracks per cell, and that the two radiations were not different in this regard. Exposure at a temperature where metabolic processes, including DNA repair, were inactive (0 degrees C) did not alter the result, indicating that the adaptive response is not sensitive to changes in the accumulation of DNA damage within this range. The results also show that the RBE for low doses of tritium beta-particle radiation is 1, using adaption as the end point.

Low dose radiation interactions with the transformation growth factor (TFG)-beta pathway

NASA Astrophysics Data System (ADS)

Maslowski, Amy Jesse

A major limiting factor for long-term, deep-space missions is the radiation dose to astronauts. Because the dose to the astronauts is a mixed field of low- and high-LET radiation, there is a need to understand the effects of both radiation types on whole tissue; however, there are limited published data on the effects of high-LET (linear-energy-transfer) radiation on tissue. Thus, we designed a perfusion chamber system for rat trachea in order to mimic in vivo respiratory tissue. We successfully maintained the perfused tracheal tissue ex vivo in a healthy and viable condition for up to three days. In addition, this project studied the effects of high-LET Fe particles on the overall transformation growth factor (TGF)-beta response after TGF-beta inactivation and compared the results to the TGF-beta response post x-ray irradiation. It was found that a TGF-beta response could be measured in the perfused tracheal tissue, for x-ray and Fe particle irradiations, despite the high autofluorescent background intrinsic to tissue. However, after comparing the TGF-beta response of x-ray irradiation to High-Z-High-energy (HZE) irradiation, there was not a significant difference in radiation types. The TGF-beta response in x-ray and HZE irradiated perfusion chambers was also measured over time post irradiation. It was found that for 6 hour and 8 hour post irradiation, the TGF-beta response was higher for lower doses of radiation than for higher doses. This is in contrast to the 0 hour fixation which found the TGF-beta response to increase with increased dose. The inverse relationship found for 6 hour and 8 hour fixation times may indicate a threshold response for TGF-beta response; i.e., for low doses, a threshold of dose must be reached for an immediate TGF-beta response, otherwise the tissue responds more slowly to the irradiation damage. This result was unexpected and will require further investigation to determine if the threshold can be determined for the 250 kVp x-rays and 1 Gev Fe particles.

Distinct DC subsets regulate adaptive Th1 and 2 responses during Trichuris muris infection.

PubMed

Demiri, M; Müller-Luda, K; Agace, W W; Svensson-Frej, M

2017-10-01

Low- and high-dose infections with the murine large intestinal nematode Trichuris muris are associated with induction of adaptive Th1 and Th2 responses, respectively, in mesenteric lymph nodes (MLN). Classical dendritic cells (cDC) accumulate in the large intestinal mucosa and MLN upon T. muris infection, yet their role in driving adaptive responses to infection remains largely unknown. We performed low- and high-dose T. muris infections of mice deficient in defined cDC subsets to investigate their role in induction of adaptive immune responses. Mice lacking IRF4-dependent cDC failed to clear a high-dose infection and displayed impaired Th2 responses. Conversely, mice lacking IRF8-dependent cDC cleared a low-dose infection and displayed an impaired Th1 response while increased production of Th2 cytokines. Finally, mice lacking both IRF4- and IRF8-dependent cDC were able to generate a Th2 response and clear a low-dose infection. Collectively, these results suggest that IRF4- and IRF8-dependent cDC act antagonistically during T. muris infection, and demonstrate that intestinal Th2 responses can be generated towards T. muris in the absence of IRF4-dependent cDC. © 2017 John Wiley & Sons Ltd.

Introduction to methodology of dose-response meta-analysis for binary outcome: With application on software.

PubMed

Zhang, Chao; Jia, Pengli; Yu, Liu; Xu, Chang

2018-05-01

Dose-response meta-analysis (DRMA) is widely applied to investigate the dose-specific relationship between independent and dependent variables. Such methods have been in use for over 30 years and are increasingly employed in healthcare and clinical decision-making. In this article, we give an overview of the methodology used in DRMA. We summarize the commonly used regression model and the pooled method in DRMA. We also use an example to illustrate how to employ a DRMA by these methods. Five regression models, linear regression, piecewise regression, natural polynomial regression, fractional polynomial regression, and restricted cubic spline regression, were illustrated in this article to fit the dose-response relationship. And two types of pooling approaches, that is, one-stage approach and two-stage approach are illustrated to pool the dose-response relationship across studies. The example showed similar results among these models. Several dose-response meta-analysis methods can be used for investigating the relationship between exposure level and the risk of an outcome. However the methodology of DRMA still needs to be improved. © 2018 Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd.

Camel molar tooth enamel response to gamma rays using EPR spectroscopy.

PubMed

El-Faramawy, N A; El-Somany, I; Mansour, A; Maghraby, A M; Eissa, H; Wieser, A

2018-03-01

Tooth enamel samples from molar teeth of camel were prepared using a combined procedure of mechanical and chemical tooth treatment. Based on electron paramagnetic resonance (EPR) spectroscopy, the dose response of tooth enamel samples was examined and compared to that of human enamel. The EPR dose response of the tooth enamel samples was obtained through irradiation to gamma doses from 1 Gy up to 100 kGy. It was found that the radiation-induced EPR signal increased linearly with gamma dose for all studied tooth enamel samples, up to about 15 kGy. At higher doses, the dose response curve leveled off. The results revealed that the location of the native signal of camel tooth enamel was similar to that of enamel from human molars at 2.00644, but different from that of enamel from cows and goats. In addition, the peak-to-peak width (ΔH pp ) for human and camel molar teeth was similar. It was also found that the response of camel enamel to gamma radiation was 36% lower than that of human enamel. In conclusion, the results indicate the suitability of camel teeth for retrospective gamma dosimetry.

Quantitative assessment of the dose-response of alkylating agents in DNA repair proficient and deficient ames tester strains.

PubMed

Tang, Leilei; Guérard, Melanie; Zeller, Andreas

2014-01-01

Mutagenic and clastogenic effects of some DNA damaging agents such as methyl methanesulfonate (MMS) and ethyl methanesulfonate (EMS) have been demonstrated to exhibit a nonlinear or even "thresholded" dose-response in vitro and in vivo. DNA repair seems to be mainly responsible for these thresholds. To this end, we assessed several mutagenic alkylators in the Ames test with four different strains of Salmonella typhimurium: the alkyl transferases proficient strain TA1535 (Ogt+/Ada+), as well as the alkyl transferases deficient strains YG7100 (Ogt+/Ada-), YG7104 (Ogt-/Ada+) and YG7108 (Ogt-/Ada-). The known genotoxins EMS, MMS, temozolomide (TMZ), ethylnitrosourea (ENU) and methylnitrosourea (MNU) were tested in as many as 22 concentration levels. Dose-response curves were statistically fitted by the PROAST benchmark dose model and the Lutz-Lutz "hockeystick" model. These dose-response curves suggest efficient DNA-repair for lesions inflicted by all agents in strain TA1535. In the absence of Ogt, Ada is predominantly repairing methylations but not ethylations. It is concluded that the capacity of alkyl-transferases to successfully repair DNA lesions up to certain dose levels contributes to genotoxicity thresholds. Copyright © 2013 Wiley Periodicals, Inc.

SU-C-16A-02: A Beryllium Oxide (BeO) Fibre-Coupled Luminescence Dosimeter for High Dose Rate Brachytherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Santos, A; Institute for Photonics and Advanced Sensing and School of Chem and Phys, Adelaide, South Australia; Mohammadi, M

Purpose: Beryllium oxide (BeO) ceramics have an effective atomic number, zeff ∼7.1, closely matched to water, zeff ∼7.4. The purpose of this study was to evaluate the use of a beryllium oxide (BeO) ceramic fibrecoupled luminescence dosimeter, named RL/OSL BeO FOD, for high dose rate (HDR) brachytherapy dosimetry. In our dosimetry system the radioluminescence (RL) of BeO ceramics is utilized for dose-rate measurements, and the optically stimulated luminescence (OSL) can be read post exposure for accumulated dose measurements. Methods: The RL/OSL BeO FOD consists of a 1 mm diameter × 1 mm long cylinder of BeO ceramic coupled to amore » 15 m long silica-silica optical fibre. The optical fibre is connected to a custom developed portable RL and OSL reader, located outside of the treatment suite. The x-ray energy response was evaluated using superficial x-rays, an Ir-192 source and high energy linear accelerators. The RL/OSL BeO FOD was then characterised for an Ir-192 source, investigating the dose response and angular dependency. A depth dose curve for the Ir-192 source was also measured. Results: The RL/OSL BeO FOD shows an under-response at low energy x-rays as expected. Though at higher x-ray energies, the OSL response continued to increase, while the RL response remained relatively constant. The dose response for the RL is found to be linear up to doses of 15 Gy, while the OSL response becomes more supralinear to doses above 15 Gy. Little angular dependency is observed and the depth dose curve measured agreed within 4% of that calculated based on TG-43. Conclusion: This works shows that the RL/OSL BeO FOD can be useful in HDR dosimetry. With the RL/OSL BeO FODs current size, it is capable of being inserted into intraluminal catheters and interstitial needles to verify HDR treatments.« less

The energy dependence of the lateral dose response functions of detectors with various densities in photon-beam dosimetry.

PubMed

Looe, Hui Khee; Harder, Dietrich; Poppe, Björn

2017-02-07

The lateral dose response function is a general characteristic of the volume effect of a detector used for photon dosimetry in a water phantom. It serves as the convolution kernel transforming the true absorbed dose to water profile, which would be produced within the undisturbed water phantom, into the detector-measured signal profile. The shape of the lateral dose response function characterizes (i) the volume averaging attributable to the detector's size and (ii) the disturbance of the secondary electron field associated with the deviation of the electron density of the detector material from the surrounding water. In previous work, the characteristic dependence of the shape of the lateral dose response function upon the electron density of the detector material was studied for 6 MV photons by Monte Carlo simulation of a wall-less voxel-sized detector (Looe et al 2015 Phys. Med. Biol. 60 6585-07). This study is here continued for 60 Co gamma rays and 15 MV photons in comparison with 6 MV photons. It is found (1) that throughout these photon spectra the shapes of the lateral dose response functions are retaining their characteristic dependence on the detector's electron density, and (2) that their energy-dependent changes are only moderate. This appears as a practical advantage because the lateral dose response function can then be treated as practically invariant across a clinical photon beam in spite of the known changes of the photon spectrum with increasing distance from the beam axis.

Mode of Action (MOA) and Dose-Response Approaches for Nuclear Receptors

EPA Science Inventory

Abstract: The presence of sub-threshold doses for non-cancer and (in appropriate cases) cancer has been the dominant paradigm for the practice of risk assessment, but the application of dose-response modeling approaches that include a threshold have been questioned in a 2009 NRC ...

RISK ASSESSMENT FOR CRYPTOSPORIDIUM: A HIERARCHICAL BAYESIAN ANALYSIS OF HUMAN DOSE-RESPONSE DATA. (R828035)

EPA Science Inventory

Three dose_¯response studies were conducted with healthy volunteers using different Cryptosporidium parvum isolates (IOWA, TAMU, and UCP). The study data were previously analyzed for median infectious dose (ID₅₀) using a simple cumulative perce...

U-SHAPED DOSE-RESPONSE CURVES: THEIR OCCURRENCE AND IMPLICATIONS FOR RISK ASSESSMENT

EPA Science Inventory

A class of curvilinear dose-response relationships in toxicological and epidemiological studies may be roughly described by "U-shaped curves. uch curves reflect an apparent reversal or inversion in the effect of an otherwise toxic agent at a low or intermediate region of the dose...

Early brain response to low-dose radiation exposure involves molecular networks and pathways associated with cognitive functions, advanced aging and Alzheimer's disease.

PubMed

Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco; Wyrobek, Andrew J

2009-01-01

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy and environmental nuclear contamination as well as for Earth-orbit and space missions. Analyses of transcriptome profiles of mouse brain tissue after whole-body irradiation showed that low-dose exposures (10 cGy) induced genes not affected by high-dose radiation (2 Gy) and that low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues and pathways that were specific for brain tissue. Low-dose genes clustered into a saturated network (P < 10(-53)) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified nine neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose irradiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down-regulated in normal human aging and Alzheimer's disease.

Patient adherence to prescribed antimicrobial drug dosing regimens.

PubMed

Vrijens, Bernard; Urquhart, John

2005-05-01

The aim of this article is to review current knowledge about the clinical impact of patients' variable adherence to prescribed anti-infective drug dosing regimens, with the aim of renewing interest and exploration of this important but largely neglected area of therapeutics. Central to the estimation of a patient's adherence to a prescribed drug regimen is a reliably compiled drug dosing history. Electronic monitoring methods have emerged as the virtual 'gold standard' for compiling drug dosing histories in ambulatory patients. Reliably compiled drug dosing histories are consistently downwardly skewed, with varying degrees of under-dosing. In particular, the consideration of time intervals between protease inhibitor doses has revealed that ambulatory patients' variable execution of prescribed dosing regimens is a leading source of variance in viral response. Such analyses reveal the need for a new discipline, called pharmionics, which is the study of how ambulatory patients use prescription drugs. Properly analysed, reliable data on the time-course of patients' actual intake of prescription drugs can eliminate a major source of unallocated variance in drug responses, including the non-response that occurs and is easily misinterpreted when a patient's complete non-execution of a prescribed drug regimen is unrecognized clinically. As such, reliable compilation of ambulatory patients' drug dosing histories has the promise of being a key step in reducing unallocated variance in drug response and in improving the informational yield of clinical trials. It is also the basis for sound, measurement-guided steps taken to improve a patient's execution of a prescribed dosing regimen.

Monte Carlo simulation of the dose response of a novel 2D silicon diode array for use in hybrid MRI-LINAC systems.

PubMed

Gargett, Maegan; Oborn, Brad; Metcalfe, Peter; Rosenfeld, Anatoly

2015-02-01

MRI-guided radiation therapy systems (MRIgRT) are being developed to improve online imaging during treatment delivery. At present, the operation of single point dosimeters and an ionization chamber array have been characterized in such systems. This work investigates a novel 2D diode array, named "magic plate," for both single point calibration and 2D positional performance, the latter being a key element of modern radiotherapy techniques that will be delivered by these systems. geant4 Monte Carlo methods have been employed to study the dose response of a silicon diode array to 6 MV photon beams, in the presence of in-line and perpendicularly aligned uniform magnetic fields. The array consists of 121 silicon diodes (dimensions 1.5 × 1.5 × 0.38 mm(3)) embedded in kapton substrate with 1 cm pitch, spanning a 10 × 10 cm(2) area in total. A geometrically identical, water equivalent volume was simulated concurrently for comparison. The dose response of the silicon diode array was assessed for various photon beam field shapes and sizes, including an IMRT field, at 1 T. The dose response was further investigated at larger magnetic field strengths (1.5 and 3 T) for a 4 × 4 cm(2) photon field size. The magic plate diode array shows excellent correspondence (< ± 1%) to water dose in the in-line orientation, for all beam arrangements and magnetic field strengths investigated. The perpendicular orientation, however, exhibits a dose shift with respect to water at the high-dose-gradient beam edge of jaw-defined fields [maximum (4.3 ± 0.8)% over-response, maximum (1.8 ± 0.8)% under-response on opposing side for 1 T, uncertainty 1σ]. The trend is not evident in areas with in-field dose gradients typical of IMRT dose maps. A novel 121 pixel silicon diode array detector has been characterized by Monte Carlo simulation for its performance inside magnetic fields representative of current prototype and proposed MRI-linear accelerator systems. In the in-line orientation, the silicon dose is directly proportional to the water dose. In the perpendicular orientation, there is a shift in dose response relative to water in the highest dose gradient regions, at the edge of jaw-defined and single-segment MLC fields. The trend was not observed in-field for an IMRT beam. The array is expected to be a valuable tool in MRIgRT dosimetry.

Monte Carlo simulation of the dose response of a novel 2D silicon diode array for use in hybrid MRI–LINAC systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gargett, Maegan, E-mail: mg406@uowmail.edu.au; Rosenfeld, Anatoly; Oborn, Brad

2015-02-15

Purpose: MRI-guided radiation therapy systems (MRIgRT) are being developed to improve online imaging during treatment delivery. At present, the operation of single point dosimeters and an ionization chamber array have been characterized in such systems. This work investigates a novel 2D diode array, named “magic plate,” for both single point calibration and 2D positional performance, the latter being a key element of modern radiotherapy techniques that will be delivered by these systems. Methods: GEANT4 Monte Carlo methods have been employed to study the dose response of a silicon diode array to 6 MV photon beams, in the presence of in-linemore » and perpendicularly aligned uniform magnetic fields. The array consists of 121 silicon diodes (dimensions 1.5 × 1.5 × 0.38 mm{sup 3}) embedded in kapton substrate with 1 cm pitch, spanning a 10 × 10 cm{sup 2} area in total. A geometrically identical, water equivalent volume was simulated concurrently for comparison. The dose response of the silicon diode array was assessed for various photon beam field shapes and sizes, including an IMRT field, at 1 T. The dose response was further investigated at larger magnetic field strengths (1.5 and 3 T) for a 4 × 4 cm{sup 2} photon field size. Results: The magic plate diode array shows excellent correspondence (< ± 1%) to water dose in the in-line orientation, for all beam arrangements and magnetic field strengths investigated. The perpendicular orientation, however, exhibits a dose shift with respect to water at the high-dose-gradient beam edge of jaw-defined fields [maximum (4.3 ± 0.8)% over-response, maximum (1.8 ± 0.8)% under-response on opposing side for 1 T, uncertainty 1σ]. The trend is not evident in areas with in-field dose gradients typical of IMRT dose maps. Conclusions: A novel 121 pixel silicon diode array detector has been characterized by Monte Carlo simulation for its performance inside magnetic fields representative of current prototype and proposed MRI–linear accelerator systems. In the in-line orientation, the silicon dose is directly proportional to the water dose. In the perpendicular orientation, there is a shift in dose response relative to water in the highest dose gradient regions, at the edge of jaw-defined and single-segment MLC fields. The trend was not observed in-field for an IMRT beam. The array is expected to be a valuable tool in MRIgRT dosimetry.« less

Radiation dose response of N channel MOSFET submitted to filtered X-ray photon beam

NASA Astrophysics Data System (ADS)

Gonçalves Filho, Luiz C.; Monte, David S.; Barros, Fabio R.; Santos, Luiz A. P.

2018-01-01

MOSFET can operate as a radiation detector mainly in high-energy photon beams, which are normally used in cancer treatments. In general, such an electronic device can work as a dosimeter from threshold voltage shift measurements. The purpose of this article is to show a new way for measuring the dose-response of MOSFETs when they are under X-ray beams generated from 100kV potential range, which is normally used in diagnostic radiology. Basically, the method consists of measuring the MOSFET drain current as a function of the radiation dose. For this the type of device, it has to be biased with a high value resistor aiming to see a substantial change in the drain current after it has been irradiated with an amount of radiation dose. Two types of N channel device were used in the experiment: a signal transistor and a power transistor. The delivered dose to the device was varied and the electrical curves were plotted. Also, a sensitivity analysis of the power MOSFET response was made, by varying the tube potential of about 20%. The results show that both types of devices have responses very similar, the shift in the electrical curve is proportional to the radiation dose. Unlike the power MOSFET, the signal transistor does not provide a linear function between the dose rate and its drain current. We also have observed that the variation in the tube potential of the X-ray equipment produces a very similar dose-response.

Radiation-induced bystander effect and adaptive response in mammalian cells

NASA Technical Reports Server (NTRS)

Zhou, H.; Randers-Pehrson, G.; Waldren, C. A.; Hei, T. K.

2004-01-01

Two conflicting phenomena, bystander effect and adaptive response, are important in determining the biological responses at low doses of radiation and have the potential to impact the shape of the dose-response relationship. Using the Columbia University charged-particle microbeam and the highly sensitive AL cell mutagenic assay, we show here that non-irradiated cells acquire mutagenesis through direct contact with cells whose nuclei have been traversed with a single alpha particle each. Pretreatment of cells with a low dose of X-rays four hours before alpha particle irradiation significantly decreased this bystander mutagenic response. Results from the present study address some of the fundamental issues regarding both the actual target and radiation dose effect and can contribute to our current understanding in radiation risk assessment. c2004 COSPAR. Published by Elsevier Ltd. All rights reserved.

Induction of Protective CTL Responses in Newborn Mice by a Murine Retrovirus

NASA Astrophysics Data System (ADS)

Sarzotti, Marcella; Robbins, Deanna S.; Hoffman, Paul M.

1996-03-01

The susceptibility of neonates to virus-induced disease is thought to reflect, in part, the immaturity of their immune systems. However, inoculation of newborn mice with low doses of Cas-Br-M murine leukemia virus induced a protective cytotoxic T lymphocyte (CTL) response. The inability of neonates to develop a CTL response to high doses of virus was not the result of immunological immaturity but correlated with the induction of a nonprotective type 2 cytokine response. Thus, the initial viral dose is critical in the development of protective immunity in newborns.

Construction of dose response calibration curves for dicentrics and micronuclei for X radiation in a Serbian population.

PubMed

Pajic, J; Rakic, B; Jovicic, D; Milovanovic, A

2014-10-01

Biological dosimetry using chromosome damage biomarkers is a valuable dose assessment method in cases of radiation overexposure with or without physical dosimetry data. In order to estimate dose by biodosimetry, any biological dosimetry service have to have its own dose response calibration curve. This paper reveals the results obtained after irradiation of blood samples from fourteen healthy male and female volunteers in order to establish biodosimetry in Serbia and produce dose response calibration curves for dicentrics and micronuclei. Taking into account pooled data from all the donors, the resultant fitted curve for dicentrics is: Ydic=0.0009 (±0.0003)+0.0421 (±0.0042)×D+0.0602 (±0.0022)×D(2); and for micronuclei: Ymn=0.0104 (±0.0015)+0.0824 (±0.0050)×D+0.0189 (±0.0017)×D(2). Following establishment of the dose response curve, a validation experiment was carried out with four blood samples. Applied and estimated doses were in good agreement. On this basis, the results reported here give us confidence to apply both calibration curves for future biological dosimetry requirements in Serbia. Copyright © 2014 Elsevier B.V. All rights reserved.

Dose response evaluation of a low-density normoxic polymer gel dosimeter using MRI

NASA Astrophysics Data System (ADS)

Haraldsson, P.; Karlsson, A.; Wieslander, E.; Gustavsson, H.; Bäck, S. Å. J.

2006-02-01

A low-density (~0.6 g cm-3) normoxic polymer gel, containing the antioxidant tetrakis (hydroxymethyl) phosponium (THP), has been investigated with respect to basic absorbed dose response characteristics. The low density was obtained by mixing the gel with expanded polystyrene spheres. The depth dose data for 6 and 18 MV photons were compared with Monte Carlo calculations. A large volume phantom was irradiated in order to study the 3D dose distribution from a 6 MV field. Evaluation of the gel was carried out using magnetic resonance imaging. An approximately linear response was obtained for 1/T2 versus dose in the dose range of 2 to 8 Gy. A small decrease in the dose response was observed for increasing concentrations of THP. A good agreement between measured and Monte Carlo calculated data was obained, both for test tubes and the larger 3D phantom. It was shown that a normoxic polymer gel with a reduced density could be obtained by adding expanded polystyrene spheres. In order to get reliable results, it is very important to have a uniform distribution of the gel and expanded polystyrene spheres in the phantom volume.

TH-E-BRF-03: A Multivariate Interaction Model for Assessment of Hippocampal Vascular Dose-Response and Early Prediction of Radiation-Induced Neurocognitive Dysfunction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farjam, R; Pramanik, P; Srinivasan, A

Purpose: Vascular injury could be a cause of hippocampal dysfunction leading to late neurocognitive decline in patients receiving brain radiotherapy (RT). Hence, our aim was to develop a multivariate interaction model for characterization of hippocampal vascular dose-response and early prediction of radiation-induced late neurocognitive impairments. Methods: 27 patients (17 males and 10 females, age 31–80 years) were enrolled in an IRB-approved prospective longitudinal study. All patients were diagnosed with a low-grade glioma or benign tumor and treated by 3-D conformal or intensity-modulated RT with a median dose of 54 Gy (50.4–59.4 Gy in 1.8− Gy fractions). Six DCE-MRI scans weremore » performed from pre-RT to 18 months post-RT. DCE data were fitted to the modified Toft model to obtain the transfer constant of gadolinium influx from the intravascular space into the extravascular extracellular space, Ktrans, and the fraction of blood plasma volume, Vp. The hippocampus vascular property alterations after starting RT were characterized by changes in the hippocampal mean values of, μh(Ktrans)τ and μh(Vp)τ. The dose-response, Δμh(Ktrans/Vp)pre->τ, was modeled using a multivariate linear regression considering integrations of doses with age, sex, hippocampal laterality and presence of tumor/edema near a hippocampus. Finally, the early vascular dose-response in hippocampus was correlated with neurocognitive decline 6 and 18 months post-RT. Results: The μh(Ktrans) increased significantly from pre-RT to 1 month post-RT (p<0.0004). The multivariate model showed that the dose effect on Δμh(Ktrans)pre->1M post-RT was interacted with sex (p<0.0007) and age (p<0.00004), with the dose-response more pronounced in older females. Also, the vascular dose-response in the left hippocampus of females was significantly correlated with memory function decline at 6 (r = − 0.95, p<0.0006) and 18 (r = −0.88, p<0.02) months post-RT. Conclusion: The hippocampal vascular response to radiation could be sex and age dependent. The early hippocampal vascular dose-response could predict late neurocognitive dysfunction. (Support: NIH-RO1NS064973)« less

TH-C-18A-09: Exam and Patient Parameters Affecting the DNA Damage Response Following CT Studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elgart, S; Adibi, A; Bostani, M

Purpose: To identify exam and patient parameters affecting the biological response to CT studies using in vivo and ex vivo blood samples. Methods: Blood samples were collected under IRB approval from 16 patients undergoing clinically-indicated CT exams. Blood was procured prior to, immediately after and 30minutes following irradiation. A sample of preexam blood was placed on the patient within the exam region for ex vivo analysis. Whole blood samples were fixed immediately following collection and stained for γH2AX to assess DNA damage response (DDR). Median fluorescence of treated samples was compared to non-irradiated control samples for each patient. Patients weremore » characterized by observed biological kinetic response: (a) fast — phosphorylation increased by 2minutes and fell by 30minutes, (b) slow — phosphorylation continued to increase to 30minutes and (c) none — little change was observed or irradiated samples fell below controls. Total dose values were normalized to exam time for an averaged dose-rate in dose/sec for each exam. Relationships between patient biological responses and patient and exam parameters were investigated. Results: A clearer dose response at 30minutes is observed for young patients (<61yoa; R2>0.5) compared to old patients (>61yoa; R{sup 2}<0.11). Fast responding patients were significantly younger than slow responding patients (p<0.05). Unlike in vivo samples, age did not significantly affect the patient response ex vivo. Additionally, fast responding patients received exams with significantly smaller dose-rate than slow responding patients (p<0.05). Conclusion: Age is a significant factor in the biological response suggesting that DDR may be more rapid in a younger population and slower as the population ages. Lack of an agerelated response ex vivo suggests a systemic response to radiation not present when irradiated outside the body. Dose-rate affects the biological response suggesting that patient response may be related to scan timing and dose delivery within an exam protocol. All authors receive(d) funding from a Master Research Agreement from Siemens Healthcare with UCLA Radiological Sciences.« less

Environmental standards for ionizing radiation: theoretical basis for dose-response curves.

PubMed Central

Upton, A C

1983-01-01

The types of injury attributable to ionizing radiation are subdivided, for purposes of risk assessment and radiological protection, into two broad categories: stochastic effects and nonstochastic effects. Stochastic effects are viewed as probablistic phenomena, varying in frequency but not severity as a function of the dose, without any threshold; nonstochastic effects are viewed as deterministic phenomena, varying in both frequency and severity as a function of the dose, with clinical thresholds. Included among stochastic effects are heritable effects (mutations and chromosome aberrations) and carcinogenic effects. Both types of effects are envisioned as unicellular phenomena which can result from nonlethal injury of individual cells, without the necessity of damage to other cells. For the induction of mutations and chromosome aberrations in the low-to-intermediate dose range, the dose-response curve with high-linear energy transfer (LET) radiation generally conforms to a linear nonthreshold relationship and varies relatively little with the dose rate. In contrast, the curve with low-LET radiation generally conforms to a linear-quadratic relationship, rising less steeply than the curve with high-LET radiation and increasing in slope with increasing dose and dose rate. The dose-response curve for carcinogenic effects varies widely from one type of neoplasm to another in the intermediate-to-high dose range, in part because of differences in the way large doses of radiation can affect the promotion and progression of different neoplasms. Information about dose-response relations for low-level irradiation is fragmentary but consistent, in general, with the hypothesis that the neoplastic transformation may result from mutation, chromosome aberration or genetic recombination in a single susceptible cell. PMID:6653536

Randomised controlled trials define shape of dose-response for Pollinex Quattro Birch allergoid immunotherapy.

PubMed

Worm, Margitta; Higenbottam, Tim; Pfaar, Oliver; Mösges, Ralph; Aberer, Werner; Gunawardena, Kulasiri; Wessiepe, Dorothea; Lee, Denise; Kramer, Matthias F; Skinner, Murray; Lees, Bev; Zielen, Stefan

2018-05-19

The Birch Allergoid, Tyrosine Adsorbate, Monophosphoryl Lipid A (POLLINEX ® Quattro Plus 1.0 ml Birch 100%) is an effective, well-tolerated short course subcutaneous immunotherapy. We performed two phase II studies to determine its optimal cumulative dose. The studies were conducted in Germany, Austria and Poland (EudraCT numbers: 2012-004336-28 PQBirch203 and 2015-000984-15 PQBirch204) using a wide range of cumulative doses. In both studies, subjects were administered 6 therapy injections weekly outside the pollen season. Conjunctival Provocation Tests were performed at screening, baseline and 3-4 weeks after completing treatment, to quantify the reduction of Total Symptom Scores (as the primary endpoint) with each cumulative dose. Multiple Comparison Procedure and Modelling analysis was used to test for the dose-response, shape of the curve, and estimation of the median effective dose (ED 50 ), a measure of potency. Statistically significant dose-responses (p<0.01 & 0.001) were seen respectively. The highest cumulative dose in PQBirch204 (27300 standardised units [SU]) approached a plateau. Potency of the PQ Birch was demonstrated by an ED 50 2723 SU, just over half the current dose. Prevalence of treatment-emergent adverse events was similar for active doses, most being short-lived and mild. Compliance was over 85% in all groups. Increasing the cumulative dose of PQ Birch 5.5-fold from 5100 to 27300 SU achieved an absolute point difference from placebo of 1.91, a relative difference 32.3% and an increase of efficacy of 50%, without compromising safety. The cumulative dose-response was confirmed to be curvilinear in shape. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Integration of drug dosing data with physiological data streams using a cloud computing paradigm.

PubMed

Bressan, Nadja; James, Andrew; McGregor, Carolyn

2013-01-01

Many drugs are used during the provision of intensive care for the preterm newborn infant. Recommendations for drug dosing in newborns depend upon data from population based pharmacokinetic research. There is a need to be able to modify drug dosing in response to the preterm infant's response to the standard dosing recommendations. The real-time integration of physiological data with drug dosing data would facilitate individualised drug dosing for these immature infants. This paper proposes the use of a novel computational framework that employs real-time, temporal data analysis for this task. Deployment of the framework within the cloud computing paradigm will enable widespread distribution of individualized drug dosing for newborn infants.

Drug discrimination under two concurrent fixed-interval fixed-interval schedules.

PubMed

McMillan, D E; Li, M

2000-07-01

Pigeons were trained to discriminate 5.0 mg/kg pentobarbital from saline under a two-key concurrent fixed-interval (FI) 100-s FI 200-s schedule of food presentation, and later tinder a concurrent FI 40-s FI 80-s schedule, in which the FI component with the shorter time requirement reinforced responding on one key after drug administration (pentobarbital-biased key) and on the other key after saline administration (saline-biased key). After responding stabilized under the concurrent FI 100-s FI 200-s schedule, pigeons earned an average of 66% (after pentobarbital) to 68% (after saline) of their reinforcers for responding under the FI 100-s component of the concurrent schedule. These birds made an average of 70% of their responses on both the pentobarbital-biased key after the training dose of pentobarbital and the saline-biased key after saline. After responding stabilized under the concurrent FI 40-s FI 80-s schedule, pigeons earned an average of 67% of their reinforcers for responding under the FI 40 component after both saline and the training dose of pentobarbital. These birds made an average of 75% of their responses on the pentobarbital-biased key after the training dose of pentobarbital, but only 55% of their responses on the saline-biased key after saline. In test sessions preceded by doses of pentobarbital, chlordiazepoxide, ethanol, phencyclidine, or methamphetamine, the dose-response curves were similar under these two concurrent schedules. Pentobarbital, chlordiazepoxide, and ethanol produced dose-dependent increases in responding on the pentobarbital-biased key as the doses increased. For some birds, at the highest doses of these drugs, the dose-response curve turned over. Increasing doses of phencyclidine produced increased responding on the pentobarbital-biased key in some, but not all, birds. After methamphetamine, responding was largely confined to the saline-biased key. These data show that pigeons can perform drug discriminations under concurrent schedules in which the reinforcement frequency under the schedule components differs only by a factor of two, and that when other drugs are substituted for the training drugs they produce dose-response curves similar to the curves produced by these drugs under other concurrent interval schedules.

Growth hormone (GH) dosing during catch-up growth guided by individual responsiveness decreases growth response variability in prepubertal children with GH deficiency or idiopathic short stature.

PubMed

Kriström, Berit; Aronson, A Stefan; Dahlgren, Jovanna; Gustafsson, Jan; Halldin, Maria; Ivarsson, Sten A; Nilsson, Nils-Osten; Svensson, Johan; Tuvemo, Torsten; Albertsson-Wikland, Kerstin

2009-02-01

Weight-based GH dosing results in a wide variation in growth response in children with GH deficiency (GHD) or idiopathic short stature (ISS). The hypothesis tested was whether individualized GH doses, based on variation in GH responsiveness estimated by a prediction model, reduced variability in growth response around a set height target compared with a standardized weight-based dose. A total of 153 short prepubertal children diagnosed with isolated GHD or ISS (n = 43) and at least 1 SD score (SDS) below midparental height SDS (MPH(SDS)) were included in this 2-yr multicenter study. The children were randomized to either a standard (43 microg/kg.d) or individualized (17-100 microg/kg.d) GH dose. We measured the deviation of height(SDS) from individual MPH(SDS) (diffMPH(SDS)). The primary endpoint was the difference in the range of diffMPH(SDS) between the two groups. The diffMPH(SDS) range was reduced by 32% in the individualized-dose group relative to the standard-dose group (P < 0.003), whereas the mean diffMPH(SDS) was equal: -0.42 +/- 0.46 and -0.48 +/- 0.67, respectively. Gain in height(SDS) 0-2 yr was equal for the GH-deficient and ISS groups: 1.31 +/- 0.47 and 1.36 +/- 0.47, respectively, when ISS was classified on the basis of maximum GH peak on the arginine-insulin tolerance test or 24-h profile. Individualized GH doses during catch-up growth significantly reduce the proportion of unexpectedly good and poor responders around a predefined individual growth target and result in equal growth responses in children with GHD and ISS.

No regional difference in cisatracurium dose-response and time-course-of-action between patients in China and Bosnia.

PubMed

Dahaba, A A; Suljevic, I; Bornemann, H; Wu, X-M; Metzler, H

2011-03-01

Variability in drug response could result from a variety of genetic and environmental factors that are often hard to define or quantify. A number of studies demonstrated regional geographic variations in potency of neuromuscular blocking agents (NMBAs). The aim of our study was to compare dose-response and time-course-of-action of cisatracurium besylate, an NMBA eliminated via the Hoffman degradation, in two countries with different life habits, diet, and ambient conditions; being Han Chinese in China and Caucasians in Bosnia. Neuromuscular block of cisatracurium 20 µg kg(-1), followed by four incremental 10 µg kg(-1) doses, and the remainder of 100 µg kg(-1) was evaluated using the Relaxometer mechanomyograph (Groningen University, Groningen, The Netherlands). Dose-response curves were created using log-dose-probit-response transformation. There were no significant differences in cisatracurium mean (95% confidence intervals) ED(50), ED(90), and ED(95) (effective doses for 50%, 90%, and 95% first twitch depression) in Caucasian [39.1 (35.7-42.3), 50.6 (45.5-54.3), and 54.4 (49.8-58.9) µg kg(-1)] compared with Chinese patients [39.2 (35.1-43.1), 52.4 (47.9-56.8), and 56.9 (52.8-61.9) µg kg(-1)], respectively. There were no significant differences in mean (sd) Dur(25) and Dur(0.9) (time until 25% first twitch and 0.9 train-of-four ratio recoveries) in Caucasian [47.1 (6.4) and 77.5 (9.1) min)] compared with Chinese patients [(45.9 (4.7) and 72.3 (9.1) min)], respectively. Cisatracurium dose-response relationship and time-course-of-action were not influenced by geographic location. Thus, cisatracurium would not require dose adjustments between patients living in the two geographic locations.

Dose-response assessment for influenza A virus based on data sets of infection with its live attenuated reassortants.

PubMed

Watanabe, Toru; Bartrand, Timothy A; Omura, Tatsuo; Haas, Charles N

2012-03-01

Reported data sets on infection of volunteers challenged with wild-type influenza A virus at graded doses are few. Alternatively, we aimed at developing a dose-response assessment for this virus based on the data sets for its live attenuated reassortants. Eleven data sets for live attenuated reassortants that were fit to beta-Poisson and exponential dose-response models. Dose-response relationships for those reassortants were characterized by pooling analysis of the data sets with respect to virus subtype (H1N1 or H3N2), attenuation method (cold-adapted or avian-human gene reassortment), and human age (adults or children). Furthermore, by comparing the above data sets to a limited number of reported data sets for wild-type virus, we quantified the degree of attenuation of wild-type virus with gene reassortment and estimated its infectivity. As a result, dose-response relationships of all reassortants were best described by a beta-Poisson model. Virus subtype and human age were significant factors determining the dose-response relationship, whereas attenuation method affected only the relationship of H1N1 virus infection to adults. The data sets for H3N2 wild-type virus could be pooled with those for its reassortants on the assumption that the gene reassortment attenuates wild-type virus by at least 63 times and most likely 1,070 times. Considering this most likely degree of attenuation, 10% infectious dose of H3N2 wild-type virus for adults was estimated at 18 TCID50 (95% CI = 8.8-35 TCID50). The infectivity of wild-type H1N1 virus remains unknown as the data set pooling was unsuccessful. © 2011 Society for Risk Analysis.

Efficacy and Safety of Escalation of Adalimumab Therapy to Weekly Dosing in Pediatric Patients with Crohn's Disease.

PubMed

Dubinsky, Marla C; Rosh, Joel; Faubion, William A; Kierkus, Jaroslaw; Ruemmele, Frank; Hyams, Jeffrey S; Eichner, Samantha; Li, Yao; Huang, Bidan; Mostafa, Nael M; Lazar, Andreas; Thakkar, Roopal B

2016-04-01

The efficacy of adalimumab in inducing and maintaining remission in children with moderately to severely active Crohn's disease was shown in the IMAgINE 1 trial (NCT00409682). As per protocol, nonresponders or patients experiencing flare(s) on every other week (EOW) maintenance dosing could escalate to weekly dosing; we aimed to determine the therapeutic benefits of weekly dose escalation in this subpopulation. Week 52 remission and response rates were assessed in patients who escalated to weekly dosing from their previous EOW schedule, which was according to randomized treatment dose (higher dose [HD] adalimumab [≥40 kg, 40 mg EOW; <40 kg, 20 mg EOW] or lower dose [LD; ≥40 kg, 20 mg EOW; <40 kg, 10 mg EOW]). Adverse events were reported for patients remaining on EOW dosing and patients receiving weekly dosing. Escalation to weekly dosing occurred in 48/95 (50.5%) patients randomized to LD and 35/93 (37.6%) patients randomized to HD adalimumab (P = 0.076). Week 52 remission and response rates were 18.8% and 47.9% for patients receiving LD adalimumab weekly and 31.4% and 57.1% for patients receiving HD adalimumab weekly, respectively (LD versus HD, P = 0.19 for remission; P = 0.41 for response). Adverse event rates were similar for patients receiving EOW and weekly adalimumab. Weekly adalimumab dosing was clinically beneficial for children with Crohn's disease who experienced nonresponse or flare on EOW dosing. No increased safety risks were observed with weekly dosing.

Phosphoproteomics profiling of human skin fibroblast cells reveals pathways and proteins affected by low doses of ionizing radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Feng; Waters, Katrina M.; Miller, John H.

2010-11-30

Background: High doses of ionizing radiation result in biological damage, however the precise relationships between long term health effects, including cancer, and low dose exposures remain poorly understood and are currently extrapolated using high dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose dependent responses to radiation. Principle Findings: We have identified 6845 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts one hour post-exposure. Dual statistical analyses based on spectral counts and peakmore » intensities identified 287 phosphopeptides (from 231 proteins) and 244 phosphopeptides (from 182 proteins) that varied significantly following exposure to 2 and 50 cGy respectively. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatics analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role of MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Conlcusions: Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provides a basis for the systems level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low dose radiation exposure on human health.« less

Immunogenicity of the 9-Valent HPV Vaccine Using 2-Dose Regimens in Girls and Boys vs a 3-Dose Regimen in Women.

PubMed

Iversen, Ole-Erik; Miranda, Maria Jose; Ulied, Angels; Soerdal, Terje; Lazarus, Erica; Chokephaibulkit, Kulkanya; Block, Stan L; Skrivanek, Ales; Nur Azurah, Abdul Ghani; Fong, Siew Moy; Dvorak, Vladimir; Kim, Kyung-Hyo; Cestero, Ramon M; Berkovitch, Matitiahu; Ceyhan, Mehmet; Ellison, Misoo C; Ritter, Michael A; Yuan, Shuai S; DiNubile, Mark J; Saah, Alfred J; Luxembourg, Alain

2016-12-13

Human papillomavirus (HPV) infections cause anogenital cancers and warts. The 9-valent HPV vaccine provides protection against 7 high-risk types of HPV responsible for 90% of cervical cancers and 2 other HPV types accounting for 90% of genital warts. To determine whether HPV type-specific antibody responses would be noninferior among girls and boys aged 9 to 14 years after receiving 2 doses of the 9-valent HPV vaccine compared with adolescent girls and young women aged 16 to 26 years receiving 3 doses. Open-label, noninferiority, immunogenicity trial conducted at 52 ambulatory care sites in 15 countries. The study was initiated on December 16, 2013, with the last participant visit for this report on June 19, 2015. Five cohorts were enrolled: (1) girls aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (2) boys aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (3) girls and boys aged 9 to 14 years to receive 2 doses 12 months apart (n = 301); (4) girls aged 9 to 14 years to receive 3 doses over 6 months (n = 301); and (5) a control group of adolescent girls and young women aged 16 to 26 years to receive 3 doses over 6 months (n = 314). Two doses of the 9-valent HPV vaccine administered 6 or 12 months apart or 3 doses administered over 6 months. The primary end point was prespecified as the antibody response against each HPV type assessed 1 month after the last dose using a competitive immunoassay. Each of the three 2-dose regimens was compared with the standard 3-dose schedule in adolescent girls and young women using a noninferiority margin of 0.67 for the ratio of the antibody geometric mean titers. Of the 1518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1474 completed the study and data from 1377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P < .001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received 2 doses 6 months apart; from 1.37 to ∞ to 2.55 to ∞ for boys who received 2 doses 6 months apart; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received 2 doses 12 months apart. Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes. clinicaltrials.gov Identifier: NCT01984697.

Dose/Exposure‐Response Modeling to Support Dosing Recommendation for Phase III Development of Baricitinib in Patients with Rheumatoid Arthritis

PubMed Central

Chua, Laiyi; Ernest, Charles; Macias, William; Rooney, Terence; Tham, Lai San

2017-01-01

Baricitinib is an oral inhibitor of Janus kinases (JAKs), selective for JAK1 and 2. It demonstrated dose‐dependent efficacy in patients with moderate‐to‐severe rheumatoid arthritis (RA) in a phase IIb study up to 24 weeks. Population pharmacokinetic/pharmacodynamic (PopPK/PD) models were developed to characterize concentration‐time profiles and dose/exposure‐response (D/E‐R) relationships for the key efficacy (proportion of patients achieving American College of Rheumatology 20%, 50%, or 70% response rate) and safety endpoints (incidence of anemia) for the phase IIb study. The modeling suggested that 4 mg q.d. was likely to offer the optimum risk/benefit balance, whereas 2 mg q.d. had the potential for adequate efficacy. In addition, at the same total daily dose, a twice‐daily regimen is not expected to provide an advantage over q.d. dosing for the efficacy or safety endpoints. The model‐based simulations formed the rationale for key aspects of dosing, such as dose levels and dosing frequency for phase III development. PMID:28891251

Induction of the immune response suppression in mice inoculated with Candida albicans.

PubMed

Valdez, J C; Mesón, D E; Sirena, A; de Petrino, S F; Eugenia, M; de Jorrat, B B; de Valdex, M G

1986-03-01

There is a controversy in respect to the immunological response (humoral or cellular) concerning the defense against Candida albicans. Candidosis would induce sub-populations of suppressor cells in the host cell-immune response. This report tries to show the effect of different doses of C. albicans (alive or heat-killed) on the expression of cell-mediated and humoral immunity. The effect upon cell immunity was determined by inoculating different lots of singeneic mice, doses of varied concentration of C. albicans and checking for delayed-type hipersensitivity (D.T.H.). D.T.H. was also controlled in syngeneic normal mice which had previously been injected with inoculated mice spleen cells. Humoral immunity was assayed by measuring the induced blastogenesis by Pokeweed Mitogen on spleen mononuclear cells with different doses of C. albicans. Results obtained show that the different doses gave origin to: Suppression of humoral and cell response (10(8) alive); Suppression of only humoral response (10(6) alive); Suppression of cell response and increase of humoral response (10(9) dead); Increase of both responses (10(8) dead).

Thermoluminescence response of flat optical fiber subjected to 9 MeV electron irradiations

NASA Astrophysics Data System (ADS)

Hashim, S.; Omar, S. S. Che; Ibrahim, S. A.; Hassan, W. M. S. Wan; Ung, N. M.; Mahdiraji, G. A.; Bradley, D. A.; Alzimami, K.

2015-01-01

We describe the efforts of finding a new thermoluminescent (TL) media using pure silica flat optical fiber (FF). The present study investigates the dose response, sensitivity, minimum detectable dose and glow curve of FF subjected to 9 MeV electron irradiations with various dose ranges from 0 Gy to 2.5 Gy. The above-mentioned TL properties of the FF are compared with commercially available TLD-100 rods. The TL measurements of the TL media exhibit a linear dose response over the delivered dose using a linear accelerator. We found that the sensitivity of TLD-100 is markedly 6 times greater than that of FF optical fiber. The minimum detectable dose was found to be 0.09 mGy for TLD-100 and 8.22 mGy for FF. Our work may contribute towards the development of a new dosimeter for personal monitoring purposes.

Accounting for shared and unshared dosimetric uncertainties in the dose response for ultrasound-detected thyroid nodules after exposure to radioactive fallout.

PubMed

Land, Charles E; Kwon, Deukwoo; Hoffman, F Owen; Moroz, Brian; Drozdovitch, Vladimir; Bouville, André; Beck, Harold; Luckyanov, Nicholas; Weinstock, Robert M; Simon, Steven L

2015-02-01

Dosimetic uncertainties, particularly those that are shared among subgroups of a study population, can bias, distort or reduce the slope or significance of a dose response. Exposure estimates in studies of health risks from environmental radiation exposures are generally highly uncertain and thus, susceptible to these methodological limitations. An analysis was published in 2008 concerning radiation-related thyroid nodule prevalence in a study population of 2,994 villagers under the age of 21 years old between August 1949 and September 1962 and who lived downwind from the Semipalatinsk Nuclear Test Site in Kazakhstan. This dose-response analysis identified a statistically significant association between thyroid nodule prevalence and reconstructed doses of fallout-related internal and external radiation to the thyroid gland; however, the effects of dosimetric uncertainty were not evaluated since the doses were simple point "best estimates". In this work, we revised the 2008 study by a comprehensive treatment of dosimetric uncertainties. Our present analysis improves upon the previous study, specifically by accounting for shared and unshared uncertainties in dose estimation and risk analysis, and differs from the 2008 analysis in the following ways: 1. The study population size was reduced from 2,994 to 2,376 subjects, removing 618 persons with uncertain residence histories; 2. Simulation of multiple population dose sets (vectors) was performed using a two-dimensional Monte Carlo dose estimation method; and 3. A Bayesian model averaging approach was employed for evaluating the dose response, explicitly accounting for large and complex uncertainty in dose estimation. The results were compared against conventional regression techniques. The Bayesian approach utilizes 5,000 independent realizations of population dose vectors, each of which corresponds to a set of conditional individual median internal and external doses for the 2,376 subjects. These 5,000 population dose vectors reflect uncertainties in dosimetric parameters, partly shared and partly independent, among individual members of the study population. Risk estimates for thyroid nodules from internal irradiation were higher than those published in 2008, which results, to the best of our knowledge, from explicitly accounting for dose uncertainty. In contrast to earlier findings, the use of Bayesian methods led to the conclusion that the biological effectiveness for internal and external dose was similar. Estimates of excess relative risk per unit dose (ERR/Gy) for males (177 thyroid nodule cases) were almost 30 times those for females (571 cases) and were similar to those reported for thyroid cancers related to childhood exposures to external and internal sources in other studies. For confirmed cases of papillary thyroid cancers (3 in males, 18 in females), the ERR/Gy was also comparable to risk estimates from other studies, but not significantly different from zero. These findings represent the first reported dose response for a radiation epidemiologic study considering all known sources of shared and unshared errors in dose estimation and using a Bayesian model averaging (BMA) method for analysis of the dose response.

Spectral calibration of EBT3 and HD-V2 radiochromic film response at high dose using 20 MeV proton beams

NASA Astrophysics Data System (ADS)

Feng, Yiwei; Tiedje, Henry F.; Gagnon, Katherine; Fedosejevs, Robert

2018-04-01

Radiochromic film is used extensively in many medical, industrial, and scientific applications. In particular, the film is used in analysis of proton generation and in high intensity laser-plasma experiments where very high dose levels can be obtained. The present study reports calibration of the dose response of Gafchromic EBT3 and HD-V2 radiochromic films up to high exposure densities. A 2D scanning confocal densitometer system is employed to carry out accurate optical density measurements up to optical density 5 on the exposed films at the peak spectral absorption wavelengths. Various wavelengths from 400 to 740 nm are also scanned to extend the practical dose range of such films by measuring the response at wavelengths removed from the peak response wavelengths. Calibration curves for the optical density versus exposure dose are determined and can be used for quantitative evaluation of measured doses based on the measured optical densities. It was found that blue and UV wavelengths allowed the largest dynamic range though at some trade-off with overall accuracy.

The threshold vs LNT showdown: Dose rate findings exposed flaws in the LNT model part 1. The Russell-Muller debate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Calabrese, Edward J., E-mail: edwardc@schoolph.uma

This paper assesses the discovery of the dose-rate effect in radiation genetics and how it challenged fundamental tenets of the linear non-threshold (LNT) dose response model, including the assumptions that all mutational damage is cumulative and irreversible and that the dose-response is linear at low doses. Newly uncovered historical information also describes how a key 1964 report by the International Commission for Radiological Protection (ICRP) addressed the effects of dose rate in the assessment of genetic risk. This unique story involves assessments by two leading radiation geneticists, Hermann J. Muller and William L. Russell, who independently argued that the report'smore » Genetic Summary Section on dose rate was incorrect while simultaneously offering vastly different views as to what the report's summary should have contained. This paper reveals occurrences of scientific disagreements, how conflicts were resolved, which view(s) prevailed and why. During this process the Nobel Laureate, Muller, provided incorrect information to the ICRP in what appears to have been an attempt to manipulate the decision-making process and to prevent the dose-rate concept from being adopted into risk assessment practices. - Highlights: • The discovery of radiation dose rate challenged the scientific basis of LNT. • Radiation dose rate occurred in males and females. • The dose rate concept supported a threshold dose-response for radiation.« less

Determining the behavioural dose-response relationship of marine mammals to air gun noise and source proximity.

PubMed

Dunlop, Rebecca A; Noad, Michael J; McCauley, Robert D; Scott-Hayward, Lindsay; Kniest, Eric; Slade, Robert; Paton, David; Cato, Douglas H

2017-08-15

The effect of various anthropogenic sources of noise (e.g. sonar, seismic surveys) on the behaviour of marine mammals is sometimes quantified as a dose-response relationship, where the probability of an animal behaviourally 'responding' (e.g. avoiding the source) increases with 'dose' (or received level of noise). To do this, however, requires a definition of a 'significant' response (avoidance), which can be difficult to quantify. There is also the potential that the animal 'avoids' not only the source of noise but also the vessel operating the source, complicating the relationship. The proximity of the source is an important variable to consider in the response, yet difficult to account for given that received level and proximity are highly correlated. This study used the behavioural response of humpback whales to noise from two different air gun arrays (20 and 140 cubic inch air gun array) to determine whether a dose-response relationship existed. To do this, a measure of avoidance of the source was developed, and the magnitude (rather than probability) of this response was tested against dose. The proximity to the source, and the vessel itself, was included within the one-analysis model. Humpback whales were more likely to avoid the air gun arrays (but not the controls) within 3 km of the source at levels over 140 re. 1 µPa 2  s -1 , meaning that both the proximity and the received level were important factors and the relationship between dose (received level) and response is not a simple one. © 2017. Published by The Company of Biologists Ltd.

Paradox effects of binge drinking on response inhibition processes depending on mental workload.

PubMed

Stock, Ann-Kathrin; Riegler, Lea; Chmielewski, Witold X; Beste, Christian

2016-06-01

Binge drinking is an increasing problem in Western societies, but we are still only beginning to unravel the effects of binge drinking on a cognitive level. While common sense suggests that all cognitive functions are compromised during high-dose ethanol intoxication, several studies suggest that the effects might instead be rather specific. Moreover, some results suggest that the degrees of automaticity and complexity of cognitive operations during response control modulate effects of binge drinking. However, this has not been tested in detail. In the current study, we therefore parametrically modulate cognitive/"mental" workload during response inhibition and examine the effects of high-dose ethanol intoxication (~1.1 ‰) in n = 18 male participants. The results suggest that detrimental effects of high-dose ethanol intoxication strongly depend on the complexity of processes involved in response inhibition. The results revealed strong effects (η (2) = .495) and are in line with findings showing that even high doses of ethanol have very specific effects on a cognitive level. Opposed to common sense, more complex cognitive operations seem to be less affected by a high-dose ethanol intoxication. Complementing this, high-dose ethanol intoxication is increasingly detrimental for action control, as stronger automated response tendencies are in charge and need to be controlled. Binge-like ethanol intoxication may take a heavier toll on cognitive control processes than on automated responses/response tendencies. Therefore, ethanol effects are more pronounced in supposedly "easier" control conditions because those facilitate the formation of automated response tendencies.

Influence of sex and age on febrile responses to peripheral and central administration of pyrogens in the rabbit

PubMed Central

Lipton, J. M.; Ticknor, C. B.

1979-01-01

1. Intravenous injections of leucocytic pyrogen in doses of 15, 30 and 60 μl./kg caused febrile reactions in male rabbits that were related to age of the animal: rabbits under 2 yr of age developed fevers that were related to dose of pyrogen, while rabbits 2-3 yr old showed large febrile responses which were not dose-related. 2. Female rabbits of comparable ages generally showed smaller febrile reactions to I.V. leucocytic pyrogen, and still older females (3-5 yr) developed fever only after the largest dose. 3. Dose-related febrile responses to 2·5, 5 and 10 μl. leucocytic pyrogen given intracerebroventricularly (I.C.V.) were greater in male rabbits 1-3 yr old than in females of comparable age. Female rabbits 3-5 yr old showed dose-related fevers that were smaller than those of younger animals of both sexes. 4. There were no major differences in response to 125, 250 and 500 ng PGE2, given I.C.V., between male and female rabbits under 2 yr of age. Females 2-3 yr of age had greater responses to PGE2 than males of comparable age whilst the oldest females showed smaller responses. 5. It is concluded that the febrile response of the rabbit to peripheral and central leucocytic pyrogen varies with both age and sex. Differences in sensitivity of central fever controls to endogenous pyrogen in animals of different ages and sexes may account for the different responses to peripheral pyrogen. PMID:521933

Influence of sex and age on febrile responses to peripheral and central administration of pyrogens in the rabbit.

PubMed

Lipton, J M; Ticknor, C B

1979-10-01

1. Intravenous injections of leucocytic pyrogen in doses of 15, 30 and 60 mul./kg caused febrile reactions in male rabbits that were related to age of the animal: rabbits under 2 yr of age developed fevers that were related to dose of pyrogen, while rabbits 2-3 yr old showed large febrile responses which were not dose-related.2. Female rabbits of comparable ages generally showed smaller febrile reactions to I.V. leucocytic pyrogen, and still older females (3-5 yr) developed fever only after the largest dose.3. Dose-related febrile responses to 2.5, 5 and 10 mul. leucocytic pyrogen given intracerebroventricularly (I.C.V.) were greater in male rabbits 1-3 yr old than in females of comparable age. Female rabbits 3-5 yr old showed dose-related fevers that were smaller than those of younger animals of both sexes.4. There were no major differences in response to 125, 250 and 500 ng PGE(2), given I.C.V., between male and female rabbits under 2 yr of age. Females 2-3 yr of age had greater responses to PGE(2) than males of comparable age whilst the oldest females showed smaller responses.5. It is concluded that the febrile response of the rabbit to peripheral and central leucocytic pyrogen varies with both age and sex. Differences in sensitivity of central fever controls to endogenous pyrogen in animals of different ages and sexes may account for the different responses to peripheral pyrogen.

Low-dose (10-Gy) total skin electron beam therapy for cutaneous T-cell lymphoma: an open clinical study and pooled data analysis.

PubMed

Kamstrup, Maria R; Gniadecki, Robert; Iversen, Lars; Skov, Lone; Petersen, Peter Meidahl; Loft, Annika; Specht, Lena

2015-05-01

Cutaneous T-cell lymphomas (CTCLs) are dominated by mycosis fungoides (MF) and Sézary syndrome (SS), and durable disease control is a therapeutic challenge. Standard total skin electron beam therapy (TSEBT) is an effective skin-directed therapy, but the possibility of retreatments is limited to 2 to 3 courses in a lifetime due to skin toxicity. This study aimed to determine the clinical effect of low-dose TSEBT in patients with MF and SS. In an open clinical study, 21 patients with MF/SS stages IB to IV were treated with low-dose TSEBT over <2.5 weeks, receiving a total dose of 10 Gy in 10 fractions. Data from 10 of these patients were published previously but were included in the current pooled data analysis. Outcome measures were response rate, duration of response, and toxicity. The overall response rate was 95% with a complete cutaneous response or a very good partial response rate (<1% skin involvement with patches or plaques) documented in 57% of the patients. Median duration of overall cutaneous response was 174 days (5.8 months; range: 60-675 days). TSEBT-related acute adverse events (grade 1 or 2) were observed in 60% of patients. Low-dose (10-Gy) TSEBT offers a high overall response rate and is relatively safe. With this approach, reirradiation at times of relapse or progression is likely to be less toxic than standard dose TSEBT. It remains to be established whether adjuvant and combination treatments can prolong the beneficial effects of low-dose TSEBT. Copyright © 2015 Elsevier Inc. All rights reserved.

X-ray-induced bystander responses reduce spontaneous mutations in V79 cells

PubMed Central

Maeda, Munetoshi; Kobayashi, Katsumi; Matsumoto, Hideki; Usami, Noriko; Tomita, Masanori

2013-01-01

The potential for carcinogenic risks is increased by radiation-induced bystander responses; these responses are the biological effects in unirradiated cells that receive signals from the neighboring irradiated cells. Bystander responses have attracted attention in modern radiobiology because they are characterized by non-linear responses to low-dose radiation. We used a synchrotron X-ray microbeam irradiation system developed at the Photon Factory, High Energy Accelerator Research Organization, KEK, and showed that nitric oxide (NO)-mediated bystander cell death increased biphasically in a dose-dependent manner. Here, we irradiated five cell nuclei using 10 × 10 µm2 5.35 keV X-ray beams and then measured the mutation frequency at the hypoxanthine-guanosine phosphoribosyl transferase (HPRT) locus in bystander cells. The mutation frequency with the null radiation dose was 2.6 × 10–5 (background level), and the frequency decreased to 5.3 × 10–6 with a dose of approximately 1 Gy (absorbed dose in the nucleus of irradiated cells). At high doses, the mutation frequency returned to the background level. A similar biphasic dose-response effect was observed for bystander cell death. Furthermore, we found that incubation with 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), a specific scavenger of NO, suppressed not only the biphasic increase in bystander cell death but also the biphasic reduction in mutation frequency of bystander cells. These results indicate that the increase in bystander cell death involves mechanisms that suppress mutagenesis. This study has thus shown that radiation-induced bystander responses could affect processes that protect the cell against naturally occurring alterations such as mutations. PMID:23660275

Low-Dose (10-Gy) Total Skin Electron Beam Therapy for Cutaneous T-Cell Lymphoma: An Open Clinical Study and Pooled Data Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kamstrup, Maria R., E-mail: mkam0004@bbh.regionh.dk; Gniadecki, Robert; Iversen, Lars

2015-05-01

Purpose: Cutaneous T-cell lymphomas (CTCLs) are dominated by mycosis fungoides (MF) and Sézary syndrome (SS), and durable disease control is a therapeutic challenge. Standard total skin electron beam therapy (TSEBT) is an effective skin-directed therapy, but the possibility of retreatments is limited to 2 to 3 courses in a lifetime due to skin toxicity. This study aimed to determine the clinical effect of low-dose TSEBT in patients with MF and SS. Methods and Materials: In an open clinical study, 21 patients with MF/SS stages IB to IV were treated with low-dose TSEBT over <2.5 weeks, receiving a total dose of 10 Gymore » in 10 fractions. Data from 10 of these patients were published previously but were included in the current pooled data analysis. Outcome measures were response rate, duration of response, and toxicity. Results: The overall response rate was 95% with a complete cutaneous response or a very good partial response rate (<1% skin involvement with patches or plaques) documented in 57% of the patients. Median duration of overall cutaneous response was 174 days (5.8 months; range: 60-675 days). TSEBT-related acute adverse events (grade 1 or 2) were observed in 60% of patients. Conclusions: Low-dose (10-Gy) TSEBT offers a high overall response rate and is relatively safe. With this approach, reirradiation at times of relapse or progression is likely to be less toxic than standard dose TSEBT. It remains to be established whether adjuvant and combination treatments can prolong the beneficial effects of low-dose TSEBT.« less

2D dosimetry in a proton beam with a scintillating GEM detector

NASA Astrophysics Data System (ADS)

Seravalli, E.; de Boer, M. R.; Geurink, F.; Huizenga, J.; Kreuger, R.; Schippers, J. M.; van Eijk, C. W. E.

2009-06-01

A two-dimensional position-sensitive dosimetry system based on a scintillating gas detector is being developed for pre-treatment verification of dose distributions in particle therapy. The dosimetry system consists of a chamber filled with an Ar/CF4 scintillating gas mixture, inside which two gas electron multiplier (GEM) structures are mounted (Seravalli et al 2008b Med. Phys. Biol. 53 4651-65). Photons emitted by the excited Ar/CF4 gas molecules during the gas multiplication in the GEM holes are detected by a mirror-lens-CCD camera system. The intensity distribution of the measured light spot is proportional to the 2D dose distribution. In this work, we report on the characterization of the scintillating GEM detector in terms of those properties that are of particular importance in relative dose measurements, e.g. response reproducibility, dose dependence, dose rate dependence, spatial and time response, field size dependence, response uniformity. The experiments were performed in a 150 MeV proton beam. We found that the detector response is very stable for measurements performed in succession (σ = 0.6%) and its response reproducibility over 2 days is about 5%. The detector response was found to be linear with the dose in the range 0.05-19 Gy. No dose rate effects were observed between 1 and 16 Gy min-1 at the shallow depth of a water phantom and 2 and 38 Gy min-1 at the Bragg peak depth. No field size effects were observed in the range 120-3850 mm2. A signal rise and fall time of 2 µs was recorded and a spatial response of <=1 mm was measured.

Physics must join with biology in better assessing risk from low-dose irradiation.

PubMed

Feinendegen, L E; Neumann, R D

2005-01-01

This review summarises the complex response of mammalian cells and tissues to low doses of ionising radiation. This thesis encompasses induction of DNA damage, and adaptive protection against both renewed damage and against propagation of damage from the basic level of biological organisation to the clinical expression of detriment. The induction of DNA damage at low radiation doses apparently is proportional to absorbed dose at the physical/chemical level. However, any propagation of such damage to higher levels of biological organisation inherently follows a sigmoid function. Moreover, low-dose-induced inhibition of damage propagation is not linear, but instead follows a dose-effect function typical for adaptive protection, after an initial rapid rise it disappears at doses higher than approximately 0.1-0.2 Gy to cells. The particular biological response duality at low radiation doses precludes the validity of the linear-no-threshold hypothesis in the attempt to relate absorbed dose to cancer. In fact, theory and observation support not only a lower cancer incidence than expected from the linear-no-threshold hypothesis, but also a reduction of spontaneously occurring cancer, a hormetic response, in the healthy individual.

MAGIC with formaldehyde applied to dosimetry of HDR brachytherapy source

NASA Astrophysics Data System (ADS)

Marques; T; Fernandes; J; Barbi; G; Nicolucci; P; Baffa; O

2009-05-01

The use of polymer gel dosimeters in brachytherapy can allow the determination of three-dimensional dose distributions in large volumes and with high spatial resolution if an adequate calibration process is performed. One of the major issues in these experiments is the polymer gel response dependence on dose rate when high dose rate sources are used and the doses in the vicinity of the sources are to be determinated. In this study, the response of a modified MAGIC polymer gel with formaldehyde around an Iridium-192 HDR brachytherapy source is presented. Experimental results obtained with this polymer gel were compared with ionization chamber measurements and with Monte Carlo simulation with PENELOPE. A maximum difference of 3.10% was found between gel dose measurements and Monte Carlo simulation at a radial distance of 18 mm from the source. The results obtained show that the gel's response is strongly influenced by dose rate and that a different calibration should be used for the vicinity of the source and for regions of lower dose rates. The results obtained in this study show that, provided the proper calibration is performed, MAGIC with formaldehyde can be successfully used to accurate determinate dose distributions form high dose rate brachytherapy sources.

Chromosomal Aberrations in DNA Repair Defective Cell Lines: Comparisons of Dose Rate and Radiation Quality

NASA Technical Reports Server (NTRS)

George, K. A.; Hada, M.; Patel, Z.; Huff, J.; Pluth, J. M.; Cucinotta, F. A.

2009-01-01

Chromosome aberration yields were assessed in DNA double-strand break repair (DSB) deficient cells after acute doses of gamma-rays or high-LET iron nuclei, or low dose-rate (0.018 Gy/hr) gamma-rays. We studied several cell lines including fibroblasts deficient in ATM (product of the gene that is mutated in ataxia telangiectasia patients) or NBS (product of the gene mutated in the Nijmegen breakage syndrome), and gliomablastoma cells that are proficient or lacking in DNA-dependent protein kinase, DNA-PK activity. Chromosomes were analyzed using the fluorescence in-situ hybridization (FISH) chromosome painting method in cells at the first division post-irradiation and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). Gamma radiation induced higher yields of both simple and complex exchanges in the DSB repair defective cells than in the normal cells. The quadratic dose-response terms for both chromosome exchange types were significantly higher for the ATM and NBS defective lines than for normal fibroblasts. However, the linear dose-response term was significantly higher only for simple exchanges in the NBS cells. Large increases in the quadratic dose response terms indicate the important roles of ATM and NBS in chromatin modifications that facilitate correct DSB repair and minimize aberration formation. Differences in the response of AT and NBS deficient cells at lower doses suggests important questions about the applicability of observations of radiation sensitivity at high dose to low dose exposures. For all iron nuclei irradiated cells, regression models preferred purely linear and quadratic dose responses for simple and complex exchanges, respectively. All the DNA repair defective cell lines had lower Relative biological effectiveness (RBE) values than normal cells, the lowest being for the DNA-PK-deficient cells, which was near unity. To further investigate the sensitivity differences for low and low high doses, we performed chronic low dose-rate irradiation, and have begun studies with ATM and Nibrin inhibitors and siRNA knockout of these proteins. Results support the conclusion that for the endpoint of simple chromosomal aberrations (translocation or dicentrics), the increased radiation sensitivity of AT cells found at high doses (>1 Gy) does not carry over to low doses or doserates, while NBS cells show increased sensitivity for both high and low dose exposures.

Clonidine Reduces Nociceptive Responses in Mouse Orofacial Formalin Model: Potentiation by Sigma-1 Receptor Antagonist BD1047 without Impaired Motor Coordination.

PubMed

Yoon, Seo-Yeon; Kang, Suk-Yun; Kim, Hyun-Woo; Kim, Hyung-Chan; Roh, Dae-Hyun

2015-01-01

Although the administration of clonidine, an alpha-2 adrenoceptor agonist, significantly attenuates nociception and hyperalgesia in several pain models, clinical trials of clonidine are limited by its side effects such as drowsiness, hypotension and sedation. Recently, we determined that the sigma-1 receptor antagonist BD1047 dose-dependently reduced nociceptive responses in a mouse orofacial formalin model. Here we examined whether intraperitoneal injection of clonidine suppressed the nociceptive responses in the orofacial formalin test, and whether co-administration with BD1047 enhances lower-dose clonidine-induced anti-nociceptive effects without the disruption of motor coordination and blood pressure. Formalin (5%, 10 µL) was subcutaneously injected into the right upper lip, and the rubbing responses with the ipsilateral fore- or hind-paw were counted for 45 min. Clonidine (10, 30 or 100 µg/kg) was intraperitoneally administered 30 min before formalin injection. Clonidine alone dose-dependently reduced nociceptive responses in both the first and second phases. Co-localization for alpha-2A adrenoceptors and sigma-1 receptors was determined in trigeminal ganglion cells. Interestingly, the sub-effective dose of BD1047 (3 mg/kg) significantly potentiated the anti-nociceptive effect of lower-dose clonidine (10 or 30 µg/kg) in the second phase. In particular, the middle dose of clonidine (30 µg/kg) in combination with BD1047 produced an anti-nociceptive effect similar to that of the high-dose clonidine, but without a significant motor dysfunction or hypotension. In contrast, mice treated with the high dose of clonidine developed severe impairment in motor coordination and blood pressure. These data suggest that a combination of low-dose clonidine with BD1047 may be a novel and safe therapeutic strategy for orofacial pain management.

Time and dose-response effects of honokiol on UVB-induced skin cancer development.

PubMed

Guillermo, Ruth F; Chilampalli, Chandeshwari; Zhang, Xiaoying; Zeman, David; Fahmy, Hesham; Dwivedi, Chandradhar

2012-06-01

Honokiol has shown chemopreventive effects in chemically-induced and UVB-induced skin cancer in mice. In this investigation, we assessed the time-effects of a topical low dose of honokiol (30 μg), and then the effects of different honokiol doses (30, 45, and 60 μg) on a UVB-induced skin cancer model to find an optimal dose and time for desirable chemopreventive effects. UVB radiation (30 mJ/cm(2), 5 days/week for 25 or 27 weeks) was used to induce skin carcinogenesis in SKH-1 mice. For the time-response experiment 30 μg honokiol in acetone was applied topically to the animals before the UVB exposure (30 min, 1 h, and 2 h) and after the UVB exposure (immediately, 30 min, and 1 h). Control groups were treated with acetone. For the dose-response study, animals were treated topically with acetone or honokiol (30, 45, and 60 μg) one hour before the UVB exposure. In the time-response experiment, honokiol inhibited skin tumor multiplicity by 49-58% while reducing tumor volumes by 70-89%. In the dose-response study, honokiol (30, 45, and 60 μg) significantly decreased skin tumor multiplicity by 36-78% in a dose-dependent manner, while tumor area was reduced by 76-94%. Honokiol (60 μg) significantly reduced tumor incidence by 40% as compared to control group. Honokiol applied in very low doses (30 μg) either before or after UVB radiation shows chemopreventive effects. Honokiol (30, 45, and 60 μg) prevents UVB-induced skin cancer in a dose-dependent manner. Honokiol can be an effective chemopreventive agent against skin cancer.

Analysis of Dose Response for Circulatory Disease After Radiotherapy for Benign Disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Little, Mark P., E-mail: mark.little@nih.gov; Kleinerman, Ruth A.; Stovall, Marilyn

Purpose: To assess the shape of the dose-response for various circulatory disease endpoints, and modifiers by age and time since exposure. Methods and Materials: This was an analysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by circulatory disease endpoint (ischemic heart, cerebrovascular, other circulatory disease). Results: There were significant excess risks for all circulatory disease, with an excess relative risk Gy{sup -1} of 0.082 (95% CI 0.031-0.140), and ischemic heart disease, with an excess relative risk Gy{sup -1} of 0.102 (95% CI 0.039-0.174) (both p = 0.01), and indications of excess risk for stroke. Theremore » were no statistically significant (p > 0.2) differences between risks by endpoint, and few indications of curvature in the dose-response. There were significant (p < 0.001) modifications of relative risk by time since exposure, the magnitude of which did not vary between endpoints (p > 0.2). Risk modifications were similar if analysis was restricted to patients receiving radiation, although the relative risks were slightly larger and the risk of stroke failed to be significant. The slopes of the dose-response were generally consistent with those observed in the Japanese atomic bomb survivors and in occupationally and medically exposed groups. Conclusions: There were excess risks for a variety of circulatory diseases in this dataset, with significant modification of risk by time since exposure. The consistency of the dose-response slopes with those observed in radiotherapeutically treated groups at much higher dose, as well as in lower dose-exposed cohorts such as the Japanese atomic bomb survivors and nuclear workers, implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.« less

Low dose evaluation of the antiandrogen flutamide following a Mode of Action approach.

PubMed

Sarrabay, A; Hilmi, C; Tinwell, H; Schorsch, F; Pallardy, M; Bars, R; Rouquié, D

2015-12-15

The dose-response characterization of endocrine mediated toxicity is an on-going debate which is controversial when exploring the nature of the dose-response curve and the effect at the low-end of the curve. To contribute to this debate we have assessed the effects of a wide range of dose levels of the antiandrogen flutamide (FLU) on 7-week male Wistar rats. FLU was administered by oral gavage at doses of 0, 0.001, 0.01, 0.1, 1 and 10mg/kg/day for 28 days. To evaluate the reproducibility, the study was performed 3 times. The molecular initiating event (MIE; AR antagonism), the key events (LH increase, Leydig cell proliferation and hyperplasia increases) and associated events involved in the mode of action (MOA) of FLU induced testicular toxicity were characterized to address the dose response concordance. Results showed no effects at low doses (<0.1mg/kg/day) for the different key events studied. The histopathological changes (Leydig cell hyperplasia) observed at 1 and 10mg/kg/day were associated with an increase in steroidogenesis gene expression in the testis from 1mg/kg/day, as well as an increase in testosterone blood level at 10mg/kg/day. Each key event dose-response was in good concordance with the MOA of FLU on the testis. From the available results, only monotonic dose-response curves were observed for the MIE, the key events, associated events and in effects observed in other sex related tissues. All the results, so far, show that the reference endocrine disruptor FLU induces threshold effects in a standard 28-day toxicity study on adult male rats. Copyright © 2015 Elsevier Inc. All rights reserved.

Ketamine modulation of the haemodynamic response to spreading depolarization in the gyrencephalic swine brain

PubMed Central

Santos, Edgar; Schöll, Michael; Kunzmann, Kevin; Stock, Christian; Silos, Humberto; Unterberg, Andreas W; Sakowitz, Oliver W

2016-01-01

Spreading depolarization (SD) generates significant alterations in cerebral haemodynamics, which can have detrimental consequences on brain function and integrity. Ketamine has shown an important capacity to modulate SD; however, its impact on SD haemodynamic response is incompletely understood. We investigated the effect of two therapeutic ketamine dosages, a low-dose of 2 mg/kg/h and a high-dose of 4 mg/kg/h, on the haemodynamic response to SD in the gyrencephalic swine brain. Cerebral blood volume, pial arterial diameter and cerebral blood flow were assessed through intrinsic optical signal imaging and laser-Doppler flowmetry. Our findings indicate that frequent SDs caused a persistent increase in the baseline pial arterial diameter, which can lead to a diminished capacity to further dilate. Ketamine infused at a low-dose reduced the hyperemic/vasodilative response to SD; however, it did not alter the subsequent oligemic/vasoconstrictive response. This low-dose did not prevent the baseline diameter increase and the diminished dilative capacity. Only infusion of ketamine at a high-dose suppressed SD and the coupled haemodynamic response. Therefore, the haemodynamic response to SD can be modulated by continuous infusion of ketamine. However, its use in pathological models needs to be explored to corroborate its possible clinical benefit. PMID:27126324

Ketamine modulation of the haemodynamic response to spreading depolarization in the gyrencephalic swine brain.

PubMed

Sánchez-Porras, Renán; Santos, Edgar; Schöll, Michael; Kunzmann, Kevin; Stock, Christian; Silos, Humberto; Unterberg, Andreas W; Sakowitz, Oliver W

2017-05-01

Spreading depolarization (SD) generates significant alterations in cerebral haemodynamics, which can have detrimental consequences on brain function and integrity. Ketamine has shown an important capacity to modulate SD; however, its impact on SD haemodynamic response is incompletely understood. We investigated the effect of two therapeutic ketamine dosages, a low-dose of 2 mg/kg/h and a high-dose of 4 mg/kg/h, on the haemodynamic response to SD in the gyrencephalic swine brain. Cerebral blood volume, pial arterial diameter and cerebral blood flow were assessed through intrinsic optical signal imaging and laser-Doppler flowmetry. Our findings indicate that frequent SDs caused a persistent increase in the baseline pial arterial diameter, which can lead to a diminished capacity to further dilate. Ketamine infused at a low-dose reduced the hyperemic/vasodilative response to SD; however, it did not alter the subsequent oligemic/vasoconstrictive response. This low-dose did not prevent the baseline diameter increase and the diminished dilative capacity. Only infusion of ketamine at a high-dose suppressed SD and the coupled haemodynamic response. Therefore, the haemodynamic response to SD can be modulated by continuous infusion of ketamine. However, its use in pathological models needs to be explored to corroborate its possible clinical benefit.

The effect of an inhaled neutral endopeptidase inhibitor, thiorphan, on airway responses to neurokinin A in normal humans in vivo.

PubMed

Cheung, D; Bel, E H; Den Hartigh, J; Dijkman, J H; Sterk, P J

1992-06-01

Neuropeptides such as neurokinin A (NKA) have been proposed as important mediators of bronchoconstriction and airway hyperresponsiveness in asthma. Inhaled NKA causes bronchoconstriction in patients with asthma, but not in normal subjects. This is possibly due to the activity of an endogenous neuropeptide-degrading enzyme: neutral endopeptidase (NEP). We investigated whether a NEP-inhibitor, thiorphan, reveals bronchoconstriction to NKA or NKA-induced changes in airway responsiveness to methacholine in normal humans in vivo. Eight normal male subjects participated in a double-blind crossover study, using thiorphan as pretreatment to NKA challenge. Dose-response curves to inhaled NKA (8 to 1,000 micrograms/ml, 0.5 ml/dose) were recorded on 2 randomized days 1 wk apart, and methacholine tests were performed 48 h before and 24 h after the NKA challenge. Ten minutes prior to NKA challenge the subjects inhaled either thiorphan (2.5 mg/ml, 0.5 ml) or placebo. To detect a possible nonspecific effect of thiorphan, we investigated the effect of the same pretreatment with thiorphan or placebo on the dose-response curve to methacholine in a separate set of experiments. The response was measured by the flow from standardized partial expiratory flow-volume curves (V40p), expressed in percent fall from baseline. NKA log dose-response curves were analyzed using the area under the curve (AUC) and the response to the highest dose of 1,000 micrograms/ml (V40p,1000). The methacholine dose-response curves were characterized by their position (PC40V40p) and the maximal-response plateau (MV40p). Baseline V40p was not affected by either pretreatment (p greater than 0.15).(ABSTRACT TRUNCATED AT 250 WORDS)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, P; Kuo, L; Yorke, E

Purpose: To develop a biological modeling strategy which incorporates the response observed on the mid-treatment PET/CT into a dose escalation design for adaptive radiotherapy of non-small-cell lung cancer. Method: FDG-PET/CT was acquired midway through standard fractionated treatment and registered to pre-treatment planning PET/CT to evaluate radiation response of lung cancer. Each mid-treatment PET voxel was assigned the median SUV inside a concentric 1cm-diameter sphere to account for registration and imaging uncertainties. For each voxel, the planned radiation dose, pre- and mid-treatment SUVs were used to parameterize the linear-quadratic model, which was then utilized to predict the SUV distribution after themore » full prescribed dose. Voxels with predicted post-treatment SUV≥2 were identified as the resistant target (response arm). An adaptive simultaneous integrated boost was designed to escalate dose to the resistant target as high as possible, while keeping prescription dose to the original target and lung toxicity intact. In contrast, an adaptive target volume was delineated based only on the intensity of mid-treatment PET/CT (intensity arm), and a similar adaptive boost plan was optimized. The dose escalation capability of the two approaches was compared. Result: Images of three patients were used in this planning study. For one patient, SUV prediction indicated complete response and no necessary dose escalation. For the other two, resistant targets defined in the response arm were multifocal, and on average accounted for 25% of the pre-treatment target, compared to 67% in the intensity arm. The smaller response arm targets led to a 6Gy higher mean target dose in the adaptive escalation design. Conclusion: This pilot study suggests that adaptive dose escalation to a biologically resistant target predicted from a pre- and mid-treatment PET/CT may be more effective than escalation based on the mid-treatment PET/CT alone. More plans and ultimately clinical protocols are needed to validate this approach. MSKCC has a research agreement with Varian Medical System.« less

TU-D-201-07: Severity Indication in High Dose Rate Brachytherapy Emergency Response Procedure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, K; Rustad, F

Purpose: Understanding the corresponding dose to different staff during the High Dose Rate (HDR) Brachytherapy emergency response procedure could help to develop a strategy in efficiency and effective action. In this study, the variation and risk analysis methodology was developed to simulation the HDR emergency response procedure based on severity indicator. Methods: A GammaMedplus iX HDR unit from Varian Medical System was used for this simulation. The emergency response procedure was decomposed based on risk management methods. Severity indexes were used to identify the impact of a risk occurrence on the step including dose to patient and dose to operationmore » staff by varying the time, HDR source activity, distance from the source to patient and staff and the actions. These actions in 7 steps were to press the interrupt button, press emergency shutoff switch, press emergency button on the afterloader keypad, turn emergency hand-crank, remove applicator from the patient, disconnect transfer tube and move afterloader from the patient, and execute emergency surgical recovery. Results: Given the accumulated time in second at the assumed 7 steps were 15, 5, 30, 15, 180, 120, 1800, and the dose rate of HDR source is 10 Ci, the accumulated dose in cGy to patient at 1cm distance were 188, 250, 625, 813, 3063, 4563 and 27063, and the accumulated exposure in rem to operator at outside the vault, 1m and 10cm distance were 0.0, 0.0, 0.1, 0.1, 22.6, 37.6 and 262.6. The variation was determined by the operators in action at different time and distance from the HDR source. Conclusion: The time and dose were estimated for a HDR unit emergency response procedure. It provided information in making optimal decision during the emergency procedure. Further investigation would be to optimize and standardize the responses for other emergency procedure by time-spatial-dose severity function.« less

Dose-response relationship between dietary magnesium intake and cardiovascular mortality: A systematic review and dose-based meta-regression analysis of prospective studies.

PubMed

Fang, Xin; Liang, Chun; Li, Mei; Montgomery, Scott; Fall, Katja; Aaseth, Jan; Cao, Yang

2016-12-01

Although epidemiology studies have reported the relationship, including a dose-response relationship, between dietary magnesium intake and risk of cardiovascular disease (CVD), the risk for CVD mortality is inconclusive and the evidence for a dose-response relationship has not been summarized. We conducted a systematic review and meta-analysis of prospective studies to summarize the evidence regarding the association of dietary magnesium intake with risk of CVD mortality and describe their dose-response relationship. We identified relevant studies by searching major scientific literature databases and grey literature resources from their inception to August 2015, and reviewed references lists of retrieved articles. We included population-based studies that reported mortality risks, i.e. relative risks (RRs), odds ratios (ORs) or hazard ratios (HRs) of CVD mortality or cause-specific CVD death. Linear dose-response relationships were assessed using random-effects meta-regression. Potential nonlinear associations were evaluated using restricted cubic splines. Out of 3002 articles, 9 articles from 8 independent studies met the eligibility criteria. These studies comprised 449,748 individuals and 10,313 CVD deaths. Compared with the lowest dietary magnesium consumption group in the population, the risk of CVD mortality was reduced by 16% in women and 8% in men. No significant linear dose-response relationship was found between increment in dietary magnesium intake and CVD mortality across all the studies. After adjusting for age and BMI, the risk of CVD mortality was reduced by 24-25% per 100mg/d increment in dietary magnesium intake in women of all the participants and in all the US participants. Although the combined data confirm the role of dietary magnesium intake in reducing CVD mortality, the dose-response relationship was only found among women and in US population. Copyright © 2016 Elsevier GmbH. All rights reserved.

Dose-Response Relationship between Dietary Magnesium Intake and Risk of Type 2 Diabetes Mellitus: A Systematic Review and Meta-Regression Analysis of Prospective Cohort Studies.

PubMed

Fang, Xin; Han, Hedong; Li, Mei; Liang, Chun; Fan, Zhongjie; Aaseth, Jan; He, Jia; Montgomery, Scott; Cao, Yang

2016-11-19

The epidemiological evidence for a dose-response relationship between magnesium intake and risk of type 2 diabetes mellitus (T2D) is sparse. The aim of the study was to summarize the evidence for the association of dietary magnesium intake with risk of T2D and evaluate the dose-response relationship. We conducted a systematic review and meta-analysis of prospective cohort studies that reported dietary magnesium intake and risk of incident T2D. We identified relevant studies by searching major scientific literature databases and grey literature resources from their inception to February 2016. We included cohort studies that provided risk ratios, i.e., relative risks (RRs), odds ratios (ORs) or hazard ratios (HRs), for T2D. Linear dose-response relationships were assessed using random-effects meta-regression. Potential nonlinear associations were evaluated using restricted cubic splines. A total of 25 studies met the eligibility criteria. These studies comprised 637,922 individuals including 26,828 with a T2D diagnosis. Compared with the lowest magnesium consumption group in the population, the risk of T2D was reduced by 17% across all the studies; 19% in women and 16% in men. A statistically significant linear dose-response relationship was found between incremental magnesium intake and T2D risk. After adjusting for age and body mass index, the risk of T2D incidence was reduced by 8%-13% for per 100 mg/day increment in dietary magnesium intake. There was no evidence to support a nonlinear dose-response relationship between dietary magnesium intake and T2D risk. The combined data supports a role for magnesium in reducing risk of T2D, with a statistically significant linear dose-response pattern within the reference dose range of dietary intake among Asian and US populations. The evidence from Europe and black people is limited and more prospective studies are needed for the two subgroups.

High proportions of regulatory B and T cells are associated with decreased cellular responses to pH1N1 influenza vaccine in HIV-infected children and youth (IMPAACT P1088)

PubMed Central

Weinberg, Adriana; Muresan, Petronella; Fenton, Terence; Richardson, Kelly; Dominguez, Teresa; Bloom, Anthony; Petzold, Elizabeth; Anthony, Patricia; Cunningham, Coleen K.; Spector, Stephen A.; Nachman, Sharon; Siberry, George K.; Handelsman, Edward; Flynn, Patricia M.

2013-01-01

HIV-infected individuals have poor responses to inactivated influenza vaccines. To evaluate the potential role of regulatory T (Treg) and B cells (Breg), we analyzed their correlation with humoral and cell-mediated immune (CMI) responses to pandemic influenza (pH1N1) monovalent vaccine in HIV-infected children and youth. Seventy-four HIV-infected, 4- to 25-y old participants in a 2-dose pH1N1 vaccine study had circulating and pH1N1-stimulated Treg and Breg measured by flow cytometry at baseline, post-dose 1 and post-dose 2. Concomitantly, CMI was measured by ELISPOT and flow cytometry; and antibodies by hemagglutination inhibition (HAI). At baseline, most of the participants had pH1N1-specific IFNγ ELISPOT responses, whose magnitude positively correlated with the baseline pH1N1, but not with seasonal H1N1 HAI titers. pH1N1-specific IFNγ ELISPOT responses did not change post-dose 1 and significantly decreased post-dose 2. In contrast, circulating CD4+CD25+% and CD4+FOXP3+% Treg increased after vaccination. The decrease in IFNγ ELISPOT results was marginally associated with higher pH1N1-specific CD19+FOXP3+ and CD4+TGFβ+% Breg and Treg, respectively. In contrast, increases in HAI titers post-dose 1 were associated with significantly higher circulating CD19+CD25+% post-dose 1, whereas increases in IFNγ ELISPOT results post-dose 1 were associated with higher circulating CD4+/C8+CD25+FOXP3+%. In conclusion, in HIV-infected children and youth, influenza-specific Treg and Breg may contribute to poor responses to vaccination. However, robust humoral and CMI responses to vaccination may result in increased circulating Treg and/or Breg, establishing a feed-back mechanism. PMID:23370281

Long-term persistence of humoral and cellular immune responses induced by an AS03A-adjuvanted H1N1 2009 influenza vaccine: an open-label, randomized study in adults aged 18-60 years and older.

PubMed

Van Damme, Pierre; Kafeja, Froukje; Bambure, Vinod; Hanon, Emmanuel; Moris, Philippe; Roman, François; Gillard, Paul

2013-07-01

This manuscript presents data on the persistence of Hemagglutination Inhibition (HI) immune response against the A/California/7/2009 strain, six and 12 mo after adults received one dose (n = 138) or two doses (n = 102; 21 d apart) of a 3.75 µg Hemagglutinin antigen AS03-adjuvanted H1N1 2009 vaccine (NCT00968526). Two hundred forty subjects (18-60 y: 120;>60 y: 120) were vaccinated. Immunogenicity end points were based on the European licensure criteria for pandemic influenza vaccines. Exploratory analyses assessed the cell-mediated immune response (CMI) up to Month 12 and the influence of previous influenza vaccination on persistence of immune response. At Month 6, the CHMP criteria were met in subjects aged 18-60 y who received one or two vaccine doses and in subjects aged>60 y who received two vaccine doses. At Month 12, the CHMP criteria were met only in subjects aged 18-60 y who received two vaccine doses. Persistence of HI immune response against the vaccine strain was higher in subjects without prior influenza vaccination. Exploratory analyses showed that two doses of the H1N1 2009 vaccine induced persistence of H1N1-specific CD4+ T cells up to Month 6 and memory B cells up to Month 12. In conclusion, HI immune responses persisted up to 12 mo after vaccination with one-dose and two-dose regimens of the AS03-adjuvanted 3.75 µg HA H1N1 2009 pandemic influenza vaccine, although not all three CHMP guidance criteria for both groups were met at Month 6 and Month 12. The CD4+ T cell and B cell responses also persisted up to Month 12.

The characterization of oxotremorine-induced hypothermic response in the rat.

PubMed

Ryan, P M; Kelly, J P; Chambers, P L; Leonard, B E

1996-11-01

Oxotremorine is a muscarinic receptor agonist that induces a variety of physiological and behavioural effects including hypothermia in mice. These effects are antagonized dose-dependently by classical anticholinergic compounds such as atropine. Although the oxotremorine-induced hypothermic response has been demonstrated in mice, few studies of the effects of this muscarinic agonist have been made in the rat. The following studies were made in male Sprague Dawley rats: 1. an investigation of the dose-response relationship between oxotremorine and hypothermia; 2. an examination of the effect of housing on the oxotremorine-induced hypothermic response, and 3, an investigation of the acute administration of various doses of atropine sulphate on the hypothermia caused by oxotremorine. The results indicate that the dose-response relationship between oxotremorine and the antagonism of hypothermia is similar in rat as it is in mice. The results also showed that this effect did not occur in group-housed animals.

Simulated response of a multi-element thick gas electron multiplier-based microdosimeter to high energy neutrons.

PubMed

Moslehi, Amir; Raisali, Gholamreza

2018-07-01

The response of a microdosimeter for neutrons above 14 MeV is investigated. The mean quality factors and dose-equivalents are determined using lineal energy distributions calculated by Monte Carlo simulations (Geant4 toolkit). From 14 MeV to 5 GeV, the mean quality factors were found to vary between 6.00 and 9.30 and the dose-equivalents were in agreement with the true ambient dose-equivalent at the depth of 10 mm inside the ICRU sphere, H * (10). An energy-independent dose-equivalent response around a median value of 0.86 within 22% uncertainty was obtained. Therefore, the microdosimeter is appropriate for dose-equivalent measurement of high-energy neutrons. Copyright © 2018 Elsevier Ltd. All rights reserved.

Alectinib Dose Escalation Re-induces Central Nervous System Responses in ALK-Positive Non-Small Cell Lung Cancer (NSCLC) Patients Relapsing on Standard Dose Alectinib

PubMed Central

Gainor, Justin F.; Chi, Andrew S.; Logan, Jennifer; Hu, Ranliang; Oh, Kevin S.; Brastianos, Priscilla K.; Shih, Helen A.; Shaw, Alice T.

2015-01-01

The central nervous system (CNS) is an important and increasingly recognized site of treatment failure in ALK-positive, non-small cell lung cancer (NSCLC) patients receiving ALK inhibitors. In this report, we describe two ALK-positive patients who experienced initial improvements in CNS metastases on standard-dose alectinib (600 mg twice daily), but subsequently recurred with symptomatic leptomeningeal metastases. Both patients were dose-escalated to alectinib 900 mg twice daily, resulting in repeat clinical and radiographic responses. Our results suggest that dose intensification of alectinib may be necessary to overcome incomplete ALK inhibition in the CNS and prolong the durability of responses in patients with CNS metastases, particularly those with leptomeningeal carcinomatosis. PMID:26845119

Dose response of CRM197 and tetanus toxoid-conjugated Haemophilus influenzae type b vaccines.

PubMed

Huebner, Robin E; Nicol, Mark; Mothupi, Rosalia; Käyhty, Helena; Mbelle, Nontombi; Khomo, Esther; Klugman, Keith P

2004-12-21

High vaccine cost has limited use of conjugate vaccines in the developing world where the disease burden is greatest. Fixed fractional doses of Haemophilus influenzae type b (Hib) vaccines have been shown to be immunogenic, but dose responses of these vaccines in humans are needed to determine the lowest immunogenic dose as an option for lowering vaccine cost. We randomized children to receive one of five doses (0.625, 1.25, 2.5, 5.0 and 10 microg) of either a diphtheria CRM197 or tetanus toxoid-conjugated Hib vaccine. The children received a primary three-dose series at 6, 10, and 14 weeks of age and a booster dose at 9 months. Anti-PRP IgG antibodies were measured at each vaccination, at 18 weeks, and at one week following the booster dose. Concentrations of > or =1.25 microg of HibCRM197 vaccine produced mean anti-PRP responses at 18 weeks of > or =5.72 microg/ml and > or =0.15 microg/ml was achieved in >98% of the children with at least 79% reaching anti-PRP concentrations of > or =1.0 microg/ml. Concentrations of > or =1.25 microg of Hib-tetanus vaccine produced mean anti-PRP responses at 18 weeks of > or =8.63 microg/ml and > or =0.15 microg/ml was achieved in 100% of the children with at least 88.9% reaching anti-PRP concentrations of > or =1.0 microg/ml. While mean antibody concentrations after either vaccine decreased over time, the proportion of children with antibody levels of > or =0.15 microg/ml had not changed significantly at the 9 month measurement. Immunologic memory was demonstrated by significant increases in mean antibody concentrations one week after the booster dose for doses > or =1.25 microg of HibCRM197 and Hib-tetanus to mean concentrations > or =37.71 and 16.07 microg/ml, respectively. There were no differences in antibody responses for vaccine doses > or =1.25 microg of the same vaccine or between the same concentrations of the two different vaccines. Our data suggest that doses of these vaccines of > or =1.25 microg may be sufficient to stimulate an immune response that offers both short and longer term protection from invasive Hib disease.

Effects of luteinizing hormone-releasing hormone and arginine-vasotocin on the sperm-release response of Günther's Toadlet, Pseudophryne guentheri

PubMed Central

2010-01-01

Background Luteinizing hormone-releasing hormone (LHRH) is an exogenous hormone commonly used to induce spermiation in anuran amphibians. Over the past few decades, the LHRH dose administered to individuals and the frequency of injection has been highly variable. The sperm-release responses reported have been correspondingly diverse, highlighting a need to quantify dose-response relationships on a species-specific basis. This study on the Australian anuran Pseudophryne guentheri first evaluated the spermiation response of males administered one of five LHRHa doses, and second, determined whether AVT administered in combination with the optimal LHRHa dose improved sperm-release. Methods Male toadlets were administered a single dose of 0, 1, 2, 4 or 8 micrograms/g body weight of LHRHa. A 4 micrograms/g dose of AVT was administered alone or in combination with 2 micrograms/g LHRHa. Spermiation responses were evaluated at 3, 7 and 12 h post hormone administration (PA), and sperm number and viability were quantified using fluorescent microscopy. Results LHRHa administration was highly effective at inducing spermiation in P. guentheri, with 100% of hormone-treated males producing sperm during the experimental period. The number of sperm released in response to 2 micrograms/g LHRHa was greater than all other doses administered and sperm viability was highest in the 1 microgram/g treatment. The administration of AVT alone or in combination with LHRHa resulted in the release of significantly lower sperm numbers. Conclusion Overall, results from this study suggest that in P. guentheri, LHRHa is effective at inducing spermiation, but that AVT inhibits sperm-release. PMID:21059269

Implementation of radiochromic film dosimetry protocol for volumetric dose assessments to various organs during diagnostic CT procedures

PubMed Central

Brady, Samuel; Yoshizumi, Terry; Toncheva, Greta; Frush, Donald

2010-01-01

Purpose: The authors present a means to measure high-resolution, two-dimensional organ dose distributions in an anthropomorphic phantom of heterogeneous tissue composition using XRQA radiochromic film. Dose distributions are presented for the lungs, liver, and kidneys to demonstrate the organ volume dosimetry technique. XRQA film response accuracy was validated using thermoluminescent dosimeters (TLDs). Methods: XRQA film and TLDs were first exposed at the center of two CTDI head phantoms placed end-to-end, allowing for a simple cylindrical phantom of uniform scatter material for verification of film response accuracy and sensitivity in a computed tomography (CT) exposure geometry; the TLD and film dosimeters were exposed separately. In a similar manner, TLDs and films were placed between cross-sectional slabs of a 5 yr old anthropomorphic phantom’s thorax and abdomen regions. The anthropomorphic phantom was used to emulate real pediatric patient geometry and scatter conditions. The phantom consisted of five different tissue types manufactured to attenuate the x-ray beam within 1%–3% of normal tissues at CT beam energies. Software was written to individually calibrate TLD and film dosimeter responses for different tissue attenuation factors, to spatially register dosimeters, and to extract dose responses from film for TLD comparison. TLDs were compared to film regions of interest extracted at spatial locations corresponding to the TLD locations. Results: For the CTDI phantom exposure, the film and TLDs measured an average difference in dose response of 45% (SD±2%). Similar comparisons within the anthropomorphic phantom also indicated a consistent difference, tracking along the low and high dose regions, for the lung (28%) (SD±8%) and liver and kidneys (15%) (SD±4%). The difference between the measured film and TLD dose values was due to the lower response sensitivity of the film that arose when the film was oriented with its large surface area parallel to the main axis of the CT beam. The consistency in dose response difference allowed for a tissue specific correction to be applied. Once corrected, the average film response agreed to better than 3% (SD±2%) for the CTDI scans, and for the anthropomorphic phantom scans: 3% (SD±3%) for the lungs, 5% (SD±3%) for the liver, and 4% (SD±3%) for the kidneys. Additionally, XRQA film measured a heterogeneous dose distribution within the organ volumes. The extent of the dose distribution heterogeneity was not measurable with the TLDs due to the limitation on the number of TLDs loadable in the regions of the phantom organs. In this regard, XRQA film demonstrated an advantage over the TLD method by discovering a 15% greater maximum dose to lung in a region unmeasured by TLDs. Conclusions: The films demonstrated a lower sensitivity to absorbed dose measurements due to the geometric inefficiency of measuring dose from a beam situated end-on to the film. Once corrected, the film demonstrated equivalent dose measurement accuracy as TLD detectors with the added advantage of relatively simple measurement of high-resolution dose distributions throughout organ volumes. PMID:20964198

Different dose rate-dependent responses of human melanoma cells and fibroblasts to low dose fast neutrons.

PubMed

Dionet, Claude; Müller-Barthélémy, Melanie; Marceau, Geoffroy; Denis, Jean-Marc; Averbeck, Dietrich; Gueulette, John; Sapin, Vincent; Pereira, Bruno; Tchirkov, Andrei; Chautard, Emmanuel; Verrelle, Pierre

2016-09-01

To analyze the dose rate influence in hyper-radiosensitivity (HRS) of human melanoma cells to very low doses of fast neutrons and to compare to the behaviour of normal human skin fibroblasts. We explored different neutron dose rates as well as possible implication of DNA double-strand breaks (DSB), apoptosis, and energy-provider adenosine-triphosphate (ATP) levels during HRS. HRS in melanoma cells appears only at a very low dose rate (VLDR), while a high dose rate (HDR) induces an initial cell-radioresistance (ICRR). HRS does not seem to be due either to DSB or to apoptosis. Both phenomena (HRS and ICRR) appear to be related to ATP availability for triggering cell repair. Fibroblast survival after neutron irradiation is also dose rate-dependent but without HRS. Melanoma cells or fibroblasts exert their own survival behaviour at very low doses of neutrons, suggesting that in some cases there is a differential between cancer and normal cells radiation responses. Only the survival of fibroblasts at HDR fits the linear no-threshold model. This new insight into human cell responses to very low doses of neutrons, concerns natural radiations, surroundings of accelerators, proton-therapy devices, flights at high altitude. Furthermore, ATP inhibitors could increase HRS during high-linear energy transfer (high-LET) irradiation.

Immunogenicity and safety of a quadrivalent meningococcal polysaccharide CRM conjugate vaccine in infants and toddlers.

PubMed

Tregnaghi, Miguel; Lopez, Pio; Stamboulian, Daniel; Graña, Gabriela; Odrljin, Tatjana; Bedell, Lisa; Dull, Peter M

2014-09-01

This phase III study assessed the safety and immunogenicity of MenACWY-CRM, a quadrivalent meningococcal conjugate vaccine, administered with routine vaccines starting at 2 months of age. Healthy infants received MenACWY-CRM in a two- or three-dose primary infant series plus a single toddler dose. In addition, a two-dose toddler catch-up series was evaluated. Immune responses to MenACWY-CRM were assessed for serum bactericidal activity with human complement (hSBA). Reactogenicity and safety results were collected systematically. After a full infant/toddler series or two-dose toddler catch-up series, MenACWY-CRM elicited immune responses against the four serogroups in 94-100% of subjects. Noninferiority of the two- versus three-dose MenACWY-CRM infant dosing regimen was established for geometric mean titers for all serogroups. Following the three-dose infant primary series, 89-98% of subjects achieved an hSBA ≥ 8 across all serogroups. Immune responses to concomitant routine vaccines given with MenACWY-CRM were noninferior to responses to routine vaccines alone, except for pertactin after the two-dose infant series. Noninferiority criteria were met for all concomitant antigens after the three-dose infant series. MenACWY-CRM vaccination regimens in infants and toddlers were immunogenic and well tolerated. No clinically meaningful effects of concomitant administration with routine infant and toddler vaccines were observed. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Evaluation of Clostridium novyi-NT spores in dogs with naturally occurring tumors.

PubMed

Krick, Erika L; Sorenmo, Karin U; Rankin, Shelley C; Cheong, Ian; Kobrin, Barry; Thornton, Katherine; Kinzler, Kenneth W; Vogelstein, Bert; Zhou, Shibin; Diaz, Luis A

2012-01-01

To establish the maximum tolerated dose of Clostridium novyi-NT spores in tumor-bearing dogs and evaluate spore germination within tumors and tumor response. 6 client-owned dogs. A standard dose-escalation study was planned, with maximum tolerated dose defined as the highest dose at which 0 or 1 of 6 dogs had dose-limiting toxicoses (DLT). Dogs received 1 dose of C. novyi-NT spores i.v.. Toxicoses were graded and interventions performed according to specific guidelines. Grade 3 or higher toxicosis or any toxicosis combination that substantially affected patient status was considered DLT. Clinical response was measured by use of response evaluation criteria in solid tumors at 28 days. The first 2 dogs had DLT. The dose was decreased. Two of the next 4 dogs had DLT; therefore, dose administration was stopped because the study endpoint had been reached. The most common toxicosis was fever (n = 6 dogs). Two dogs developed abscesses (1 within a nasal carcinoma and 1 splenic abscess) attributable to C. novyi-NT infection; both required surgical intervention. Clostridium novyi-NT was cultured from 1 of 6 tumors. Five dogs were available for response assessment (4 had stable disease; 1 had progressive disease). Results indicated that C. novyi-NT can germinate within tumors of dogs. Toxicosis, although common and sometimes severe, was manageable with treatment. Further studies in dogs with superficial tumors may allow for continued dose escalation and provide information for use in clinical trials in veterinary and human oncology.

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

PubMed Central

Lever, Melissa; Lim, Hong-Sheng; Kruger, Philipp; Nguyen, John; Trendel, Nicola; Abu-Shah, Enas; Maini, Philip Kumar; van der Merwe, Philip Anton

2016-01-01

T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose–response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways. PMID:27702900

Safety and immunogenicity of a novel quadrivalent meningococcal CRM-conjugate vaccine given concomitantly with routine vaccinations in infants.

PubMed

Klein, Nicola P; Reisinger, Keith S; Johnston, William; Odrljin, Tatjana; Gill, Christopher J; Bedell, Lisa; Dull, Peter

2012-01-01

In phase II studies, MenACWY-CRM elicited robust immunologic responses in young infants. We now present results from our pivotal phase III infant immunogenicity/safety study. In this open-label phase III study, we randomized full-term 2-month-old infants to 4 doses of MenACWY-CRM coadministered with routine vaccines at 2, 4, 6, and 12 months of age or with routine vaccines alone. We monitored for local and systemic reactions and serious adverse events among all study participants and evaluated for sufficiency of the immune responses to MenACWY-CRM through serum bactericidal activity assay with human complement. Bactericidal antibodies were present in 94% to 100% of subjects against each of the serogroups in MenACWY-CRM after the 4-dose series and were 67% to 97% after the first 3 doses. Geometric mean titers were higher after the fourth dose of MenACWY-CRM compared with a single dose of MenACWY-CRM at 12 months of age for all serogroups (range of ratios, 4.5-38). Responses to 3 doses of routine vaccines coadministered with MenACWY-CRM were noninferior to routine vaccinations alone, except for small differences in pneumococcal serotype 6B responses after dose 3 but not dose 4 and pertactin after dose 3. Inclusion of MenACWY-CRM did not affect the safety or reactogenicity profiles of the routine infant vaccine series. A 4-dose series of MenACWY-CRM was highly immunogenic and well tolerated in young infants, and it can be coadministered with routine infant vaccines. Substantial immunity was conferred after the first 3 doses administered at 2, 4, and 6 months of age.

Immunogenicity and safety of 1 vs 2 doses of quadrivalent meningococcal conjugate vaccine in youth infected with human immunodeficiency virus.

PubMed

Lujan-Zilbermann, Jorge; Warshaw, Meredith G; Williams, Paige L; Spector, Stephen A; Decker, Michael D; Abzug, Mark J; Heckman, Barb; Manzella, Adam; Kabat, Bill; Jean-Philippe, Patrick; Nachman, Sharon; Siberry, George K

2012-10-01

To compare the immunogenicity of 1 vs 2 doses of meningococcal polysaccharide conjugate vaccine (MCV4) in youth infected with human immunodeficiency virus (HIV). P1065 was a phase I/II immunogenicity and safety trial of MCV4 in 324 youth infected with HIV performed at 27 sites of the International Maternal Pediatric Adolescent AIDS Clinical Trials Group network in the US. At entry subjects received 1 dose of MCV4. At 24 weeks, those with screening cluster of differentiation 4 (CD4)% ≥ 15 were randomized to receive a second dose or not, and all with screening CD4% <15 received a second dose. Immunogenicity was evaluated as the proportion of subjects with a ≥ 4-fold rise from entry in serum bactericidal antibody against each meningococcal serogroup (SG) at weeks 28 and 72. Logistic regression models adjusting for HIV disease severity were used to evaluate the effect of 1 vs 2 MCV4 doses among those with screening CD4% ≥ 15. Subjects randomized to receive 2 vs 1 MCV4 dose had significantly higher response rates to all SGs at week 28 and to all except Neisseria meningitidis SG Y at week 72, with adjusted ORs of 2.5-5.6. In 31 subjects with screening CD4% <15 who received 2 MCV4 doses, response rates ranged from 22%-55% at week 28 and 6%-28% at week 72. In youth infected with HIV with a CD4% ≥ 15, a second dose of MCV4 given 6 months after the initial dose significantly improves response rates at 28 and 72 weeks. Subjects with CD4% <15 at entry had lower response rates despite 2 doses of MCV4. Copyright © 2012 Mosby, Inc. All rights reserved.

Low doses of six toxicants change plant size distribution in dense populations of Lactuca sativa.

PubMed

Belz, Regina G; Patama, Marjo; Sinkkonen, Aki

2018-08-01

Toxicants are known to have negligible or stimulatory, i.e. hormetic, effects at low doses below those that decrease the mean response of a plant population. Our earlier observations indicated that at such low toxicant doses the growth of very fast- and slow-growing seedlings is selectively altered, even if the population mean remains constant. Currently, it is not known how common these selective low-dose effects are, whether they are similar among fast- and slow-growing seedlings, and whether they occur concurrently with hormetic effects. We tested the response of Lactuca sativa in complete dose-response experiments to six different toxicants at doses that did not decrease population mean and beyond. The tested toxicants were IAA, parthenin, HHCB, 4-tert-octylphenol, glyphosate, and pelargonic acid. Each experiment consisted of 14,400-16,800 seedlings, 12-14 concentrations, 24 replicates per concentration and 50 germinated seeds per replicate. We analyzed the commonness of selective low-dose effects and explored if toxic effects and hormetic stimulation among fast- and slow-growing individuals occurred at the same concentrations as they occur at the population level. Irrespective of the observed response pattern and toxicant, selective low-dose effects were found. Toxin effects among fast-growing individuals usually started at higher doses compared to the population mean, while the opposite was found among slow-growing individuals. Very low toxin exposures tended to homogenize plant populations due to selective effects, while higher, but still hormetic doses tended to heterogenize plant populations. Although the extent of observed size segregation varied with the specific toxin tested, we conclude that a dose-dependent alteration in size distribution of a plant population may generally apply for many toxin exposures. Copyright © 2018 Elsevier B.V. All rights reserved.

Hematopoietic responses under protracted exposures to low daily dose gamma irradiation

NASA Astrophysics Data System (ADS)

Seed, T. M.; Fritz, T. E.; Tolle, D. V.; Jackson, W. E.

In attempting to evaluate the possible health consequences of chronic ionizing radiation exposure during extended space travel (e.g., Mars Mission), ground-based experimental studies of the clinical and pathological responses of canines under low daily doses of 60Co gamma irradiation (0.3-26.3 cGy d -1) have been examined. Specific reference was given to responses of the blood forming system. Results suggest that the daily dose rate of 7.5 cGy d -1 represents a threshold below which the hematopoietic system can retain either partial or full trilineal cell-producing capacity (erythropoiesis, myelopoiesis, and megakaryopoiesis) for extended periods of exposure (> 1yr). Trilineal capacity was fully retained for several years of exposure at the lowest dose-rate tested (0.3 cGy d -1) but was completely lost within several hundred days at the highest dose-rate (26.3 cGy d -1). Retention of hematopoietic capacity under chronic exposure has been demonstrated to be mediated by hematopoietic progenitors with acquired radioresistance and repair functions, altered cytogenetics, and cell-cycle characteristics. Radiological, biological, and temporal parameters responsible for these vital acquisitions by hematopoietic progenitors have been partially characterized. These parameters, along with threshold responses, are described and discussed in relation to potential health risks of the space traveler under chronic stress of low-dose irradiation.

Early Dose Response to Yttrium-90 Microsphere Treatment of Metastatic Liver Cancer by a Patient-Specific Method Using Single Photon Emission Computed Tomography and Positron Emission Tomography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Campbell, Janice M.; Department of Radiation Oncology, Wayne State University, Detroit, MI; Wong, C. Oliver

2009-05-01

Purpose: To evaluate a patient-specific single photon emission computed tomography (SPECT)-based method of dose calculation for treatment planning of yttrium-90 ({sup 90}Y) microsphere selective internal radiotherapy (SIRT). Methods and Materials: Fourteen consecutive {sup 90}Y SIRTs for colorectal liver metastasis were retrospectively analyzed. Absorbed dose to tumor and normal liver tissue was calculated by partition methods with two different tumor/normal liver vascularity ratios: an average 3:1 and a patient-specific ratio derived from pretreatment technetium-99m macroaggregated albumin SPECT. Tumor response was quantitatively evaluated from fluorine-18 fluoro-2-deoxy-D-glucose positron emission tomography scans. Results: Positron emission tomography showed a significant decrease in total tumor standardizedmore » uptake value (average, 52%). There was a significant difference in the tumor absorbed dose between the average and specific methods (p = 0.009). Response vs. dose curves fit by linear and linear-quadratic modeling showed similar results. Linear fit r values increased for all tumor response parameters with the specific method (+0.20 for mean standardized uptake value). Conclusion: Tumor dose calculated with the patient-specific method was more predictive of response in liver-directed {sup 90}Y SIRT.« less

Stimulation versus inhibition--bioactivity of parthenin, a phytochemical from Parthenium hysterophorus L.

PubMed

Belz, Regina G

2007-09-30

Parthenium hysterophorus L. is an invasive weed that biosynthesizes several phytochemicals. The sesquiterpene lactone parthenin receives most attention regarding allelopathy of the plant or potential herbicidal properties. Since parthenin exhibits dose-dependent phytotoxicity with low dose stimulation, this study investigated the occurrence and temporal features of parthenin hormesis in Sinapis arvensis L. sprayed with parthenin under semi-natural conditions. Dose/response studies showed that the occurrence and the magnitude of hormesis depended on climatic conditions and the parameter measured. Within the tested dose range, stimulatory responses were only observed under less-stressful conditions and were most pronounced for leaf area growth [138 % of control; 13 days after treatment (DAT)]. Temporal assessment of leaf area development showed that doses causing a stimulatory response at the end of the experiment (< 0.42 +/- 0.04 kg/ha; 13 DAT) were initially inhibitory up to ED(50) values (2 DAT). This clearly demonstrated an over-compensatory response. Inhibition of leaf area at 13 DAT reached ED(50) values on average at 0.62 +/-0.12 kg/ha, and S. arvensis was completely inhibited at doses exceeding 1.81 +/-0.56 kg/ha (ED(90)). Based on these findings, implications of parthenin hormesis are discussed with respect to allelopathy of P. hysterophorus and exploitation of growth stimulatory responses in agriculture.

Use of mode of action data to inform a dose-response assessment for bladder cancer following exposure to inorganic arsenic.

PubMed

Gentry, P R; Yager, J W; Clewell, R A; Clewell, H J

2014-10-01

In the recent National Research Council report on conducting a dose-response assessment for inorganic arsenic, the committee remarked that mode of action data should be used, to the extent possible, to extrapolate below the observed range for epidemiological studies to inform the shape of the dose-response curve. Recent in vitro mode of action studies focused on understanding the development of bladder cancer following exposure to inorganic arsenic provide data to inform the dose-response curve. These in vitro data, combined with results of bladder cancer epidemiology studies, inform the dose-response curve in the low-dose region, and include values for both pharmacokinetic and pharmacodynamic variability. Integration of these data provides evidence of a range of concentrations of arsenic for which no effect on the bladder would be expected. Specifically, integration of these results suggest that arsenic exposures in the range of 7-43 ppb in drinking water are exceedingly unlikely to elicit changes leading to key events in the development of cancer or noncancer effects in bladder tissue. These findings are consistent with the lack of evidence for bladder cancer following chronic ingestion of arsenic water concentrations <100 ppb in epidemiological studies. Copyright © 2014 Elsevier Ltd. All rights reserved.

A Reanalysis of Curvature in the Dose Response for Cancer and Modifications by Age at Exposure Following Radiation Therapy for Benign Disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Little, Mark P., E-mail: mark.little@nih.gov; Stovall, Marilyn; Smith, Susan A.

Purpose: To assess the shape of the dose response for various cancer endpoints and modifiers by age and time. Methods and Materials: Reanalysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by cancer endpoint (stomach, pancreas, lung, leukemia, all other). Results: There are statistically significant (P<.05) excess risks for all cancer and for lung cancer and borderline statistically significant risks for stomach cancer (P=.07), and leukemia (P=.06), with excess relative risks Gy{sup -1} of 0.024 (95% confidence interval [CI] 0.011, 0.039), 0.559 (95% CI 0.221, 1.021), 0.042 (95% CI -0.002, 0.119), and 1.087 (95% CI -0.018,more » 4.925), respectively. There is statistically significant (P=.007) excess risk of pancreatic cancer when adjusted for dose-response curvature. General downward curvature is apparent in the dose response, statistically significant (P<.05) for all cancers, pancreatic cancer, and all other cancers (ie, other than stomach, pancreas, lung, leukemia). There are indications of reduction in relative risk with increasing age at exposure (for all cancers, pancreatic cancer), but no evidence for quadratic variations in relative risk with age at exposure. If a linear-exponential dose response is used, there is no significant heterogeneity in the dose response among the 5 endpoints considered or in the speed of variation of relative risk with age at exposure. The risks are generally consistent with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers. Conclusions: There are excess risks for various malignancies in this data set. Generally there is a marked downward curvature in the dose response and significant reduction in relative risk with increasing age at exposure. The consistency of risks with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.« less

Local tumor control probability modeling of primary and secondary lung tumors in stereotactic body radiotherapy.

PubMed

Guckenberger, Matthias; Klement, Rainer J; Allgäuer, Michael; Andratschke, Nicolaus; Blanck, Oliver; Boda-Heggemann, Judit; Dieckmann, Karin; Duma, Marciana; Ernst, Iris; Ganswindt, Ute; Hass, Peter; Henkenberens, Christoph; Holy, Richard; Imhoff, Detlef; Kahl, Henning K; Krempien, Robert; Lohaus, Fabian; Nestle, Ursula; Nevinny-Stickel, Meinhard; Petersen, Cordula; Semrau, Sabine; Streblow, Jan; Wendt, Thomas G; Wittig, Andrea; Flentje, Michael; Sterzing, Florian

2016-03-01

To evaluate whether local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) varies between lung metastases of different primary cancer sites and between primary non-small cell lung cancer (NSCLC) and secondary lung tumors. A retrospective multi-institutional (n=22) database of 399 patients with stage I NSCLC and 397 patients with 525 lung metastases was analyzed. Irradiation doses were converted to biologically effective doses (BED). Logistic regression was used for local tumor control probability (TCP) modeling and the second-order bias corrected Akaike Information Criterion was used for model comparison. After median follow-up of 19 months and 16 months (n.s.), local tumor control was observed in 87.7% and 86.7% of the primary and secondary lung tumors (n.s.), respectively. A strong dose-response relationship was observed in the primary NSCLC and metastatic cohort but dose-response relationships were not significantly different: the TCD90 (dose to achieve 90% TCP; BED of maximum planning target volume dose) estimates were 176 Gy (151-223) and 160 Gy (123-237) (n.s.), respectively. The dose-response relationship was not influenced by the primary cancer site within the metastatic cohort. Dose-response relationships for local tumor control in SBRT were not different between lung metastases of various primary cancer sites and between primary NSCLC and lung metastases. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Clinical efficacy and safety following dose tapering of ciclosporin in cats with hypersensitivity dermatitis.

PubMed

Roberts, Elizabeth S; Tapp, Tiffany; Trimmer, Ann; Roycroft, Linda; King, Stephen

2016-11-01

Objectives This study was designed to evaluate the efficacy and safety of reducing ciclosporin (CsA) dosing frequency from daily to every other day (EOD) or twice a week (TW) according to clinical response in cats with hypersensitivity dermatitis (HD) and treated with CsA. Methods One hundred and ninety-one cats with HD were given 7 mg/kg CsA daily for at least 4 weeks. Depending on clinical response, the dosing frequency was tapered from daily to EOD over the next 4 weeks and further to TW for an additional 4 weeks. Safety was evaluated through physical examinations, clinical pathology and the monitoring of adverse events (AEs). Results The majority of cats were able to have their dose of CsA tapered to either EOD (15.5%) or TW (62.9%) according to the clinical response. Observed AEs were most frequently mild and self-limiting vomiting and diarrhea. A higher percentage of AEs occurred with daily administration (73%) compared with other dosing regimens (27%). Conclusions and relevance Following 4 weeks of daily dosing at 7 mg/kg, CsA may be tapered to EOD or TW while maintaining the desired therapeutic response in cats with HD. Additionally, CsA appears to be well tolerated with fewer AEs at EOD or TW dosing. Establishing the lowest effective dosing frequency of CsA improves the drug's safety profile.

Dose-response relationship for light intensity and ocular and electroencephalographic correlates of human alertness

NASA Technical Reports Server (NTRS)

Cajochen, C.; Zeitzer, J. M.; Czeisler, C. A.; Dijk, D. J.

2000-01-01

Light can elicit both circadian and acute physiological responses in humans. In a dose response protocol men and women were exposed to illuminances ranging from 3 to 9100 lux for 6.5 h during the early biological night after they had been exposed to <3 lux for several hours. Light exerted an acute alerting response as assessed by a reduction in the incidence of slow-eye movements, a reduction of EEG activity in the theta-alpha frequencies (power density in the 5-9 Hz range) as well as a reduction in self-reported sleepiness. This alerting response was positively correlated with the degree of melatonin suppression by light. In accordance with the dose response function for circadian resetting and melatonin suppression, the responses of all three indices of alertness to variations in illuminance were consistent with a logistic dose response curve. Half of the maximum alerting response to bright light of 9100 lux was obtained with room light of approximately 100 lux. This sensitivity to light indicates that variations in illuminance within the range of typical, ambient, room light (90-180 lux) can have a significant impact on subjective alertness and its electrophysiologic concomitants in humans during the early biological night.

Assessing the response to opioids in cancer patients: a methodological proposal and the results.

PubMed

Corli, O; Roberto, A; Greco, M T; Montanari, M

2015-07-01

The efficacy of treatment with opioids in cancer pain is variable. To evaluate this variability, we (1) applied two parameters, changes in pain intensity (PI) and opioid daily doses (DDs), to distinguish different responses to opioids. The need to switch to another opioid was recorded. We then (2) evaluated the distribution of the responses depending on these parameters, alone and taken together, in cancer patients with pain. The cutoffs between positive and negative responses related to PI and DD were defined on the basis of the literature. For PI, responders were patients who obtained simultaneously a decrease of 30% or more and a final score ≤4 points (numerical rating scale 0 to 10). For DD changes, we applied the opioid escalation index percentage, a positive response corresponding to a dose increase ≤5%. These criteria were applied to 201 cancer patients treated with WHO step III "strong" opioids for 21 days. The results were mainly analyzed case by case. Of the patients, 63.7% obtained a positive analgesic response and 80.1% a dose-related positive response. Combining the parameters, the response was double positive in 55.2% of cases, double negative in 11.4%, a good analgesic response with a large dose escalation in 8.5%, and no pain relief with a stable dose in 24.9%. Switches were made 21 times, 15 because of the lack of analgesia. Different degrees of response to opioids were observed, PI and DD changes both contributing. Only over half the patients had a full positive response.

Optically stimulated luminescence (OSL) of carbon-doped aluminum oxide (Al{sub 2}O{sub 3}:C) for film dosimetry in radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schembri, V.; Heijmen, B. J. M.

2007-06-15

Introduction and Purpose: Conventional x-ray films and radiochromic films have inherent challenges for high precision radiotherapy dosimetry. Here we have investigated basic characteristics of optically stimulated luminescence (OSL) of irradiated films containing carbon-doped aluminum oxide (Al{sub 2}O{sub 3}:C) for dosimetry in therapeutic photon and electron beams. Materials and Methods: The OSL films consist of a polystyrene sheet, with a top layer of a mixture of single crystals of Al{sub 2}O{sub 3}:C, ground into a powder, and a polyester base. The total thickness of the films is 0.3 mm. Measurements have been performed in a water equivalent phantom, using 4, 6,more » 10, and 18 MV photon beams, and 6-22 MeV electron beams. The studies include assessment of the film response (acquired OSL signal/delivered dose) on delivered dose (linearity), dose rate (1-6 Gy/min), beam quality, field size and depth (6 MV, ranges 4x4-30x30 cm{sup 2}, d{sub max}-35 cm). Doses have been derived from ionization chamber measurements. OSL films have also been compared with conventional x-ray and GafChromic films for dosimetry outside the high dose area, with a high proportion of low dose scattered photons. In total, 787 OSL films have been irradiated. Results: Overall, the OSL response for electron beams was 3.6% lower than for photon beams. Differences between the various electron beam energies were not significant. The 6 and 18 MV photon beams differed in response by 4%. No response dependencies on dose rate were observed. For the 6 MV beam, the field size and depth dependencies of the OSL response were within {+-}2.5%. The observed inter-film response variation for films irradiated with the same dose varied from 1% to 3.2% (1 SD), depending on the measurement day. At a depth of 20 cm, 5 cm outside the 20x20 cm{sup 2} 6 and 18 MV beams, an over response of 17% was observed. In contrast to GafChromic and conventional x-ray films, the response of the Al{sub 2}O{sub 3}:C films is linear in the clinically relevant dose range 0-200 cGy. Conclusions: Measurement of the OSL signal of irradiated films containing Al{sub 2}O{sub 3}:C is a promising technique for film dosimetry in radiotherapy with no or small response variations with dose rate, beam quality, field size and depth, and a linear response from 0 to 200 cGy.« less

Dose Response Effects of Lisdexamfetamine Dimesylate Treatment in Adults with ADHD: An Exploratory Study

ERIC Educational Resources Information Center

Faraone, Stephen V.; Spencer, Thomas J.; Kollins, Scott H.; Glatt, Stephen J.; Goodman, David

2012-01-01

Objective: To explore dose-response effects of lisdexamfetamine dimesylate (LDX) treatment for ADHD. Method: This was a 4-week, randomized, double-blinded, placebo-controlled, parallel-group, forced-dose titration study in adult participants, aged 18 to 55 years, meeting "Diagnostic and Statistical Manual of Mental Disorders" (4th ed., text rev.)…

Dose-Response Issues Concerning the Relations between Regular Physical Activity and Health.

ERIC Educational Resources Information Center

Rankinen, Tuomo; Bouchard, Claude

2002-01-01

This paper categorizes the many benefits of physical activity, offering information concerning the type of dose necessary to get that benefit. In 2000, Health Canada and the United States Centers for Disease Control and Prevention, along with other agencies, sponsored a symposium to determine whether there was a dose-response relationship between…

Non-Targeted Effects and the Dose Response for Heavy Ion Tumorigenesis

NASA Technical Reports Server (NTRS)

Chappell, Lori J.; Cucinotta, Francis A.

2010-01-01

There is no human epidemiology data available to estimate the heavy ion cancer risks experienced by astronauts in space. Studies of tumor induction in mice are a necessary step to estimate risks to astronauts. Previous experimental data can be better utilized to model dose response for heavy ion tumorigenesis and plan future low dose studies.

OSLD energy response performance and dose accuracy at 24 - 1250 keV: Comparison with TLD-100H and TLD-100

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kadir, A. B. A.; Priharti, W.; Samat, S. B.

OSLD was evaluated in terms of energy response and accuracy of the measured dose in comparison with TLD-100H and TLD-100. The OSLD showed a better energy response performance for H{sub p}(10) whereas for H{sub p}(0.07), TLD-100H is superior than the others. The OSLD dose accuracy is comparable with the other two dosimeters since it fulfilled the requirement of the ICRP trumpet graph analysis.

IRIS Toxicological Review of 1,2,3-Trichloropropane (External ...

EPA Pesticide Factsheets

EPA conducted a peer review of the scientific basis supporting the human health hazard and dose-response assessment of 1,2,3-trichloropropane (TCP) that once finalized will appear on the Integrated Risk Information System (IRIS) database. Peer review is meant to ensure that science is used credibly and appropriately in derivation of the dose-response assessments and toxicological characterization. This Tox Review provides scientific support and rationale for the hazard and dose-response assessment pertaining to chronic exposure to 1,2,3-trichloropropane.

Modified Maxium Likelihood Estimation Method for Completely Separated and Quasi-Completely Separated Data for a Dose-Response Model

DTIC Science & Technology

2015-08-01

McCullagh, P.; Nelder, J.A. Generalized Linear Model , 2nd ed.; Chapman and Hall: London, 1989. 7. Johnston, J. Econometric Methods, 3rd ed.; McGraw...FOR A DOSE-RESPONSE MODEL ECBC-TN-068 Kyong H. Park Steven J. Lagan RESEARCH AND TECHNOLOGY DIRECTORATE August 2015 Approved for public release...Likelihood Estimation Method for Completely Separated and Quasi-Completely Separated Data for a Dose-Response Model 5a. CONTRACT NUMBER 5b. GRANT

High dose Intravenous Anti-D Immune Globulin is More Effective and Safe in Indian Paediatric Patients of Immune Thrombocytopenic Purpura

PubMed Central

Jena, Rabindra Kumar; Swain, Kali Prasanna

2016-01-01

Introduction Immune Thrombocytopenia (ITP) is characterised by an autoimmune antibody-mediated destruction of platelets and impaired platelet production. Few controlled trials exist to guide management of patients with ITP in Indian scenario for which patients require an individualized approach. Anti-D (Rho (D) immune globulin) at a higher dose can prove to be a cost effective and safe alternative for Indian patients with ITP. Aim To compare the safety and efficacy of higher dose (75μg/kg) intravenous Anti-D immune globulin against the standard dose of 50μg/kg for the management of ITP in Indian patients. Materials and Methods One hundred and sixty four children with newly diagnosed ITP between 4-14 years were randomly selected for inclusion and were treated with 50μg/kg (standard dose) or 75μg /kg (higher dose) of Anti-D to compare the efficacy and safety of higher dose intravenous anti-D immune globulin. Efficacy of Anti-D was measured in terms of rate of response and median time to response for increase in platelet counts. Any adverse event was noted. A decrease in haemoglobin concentration suggested accompanying haemolysis. Results Seventy one out of 84 patients treated with Anti-D at 75μg/kg produced complete response (85%) with median time of response being 2.5 days. On the contrary, 45 patients (70%) patients treated with 50μg/kg had complete response. However, there was no significant increase in haemolysis with higher dose. A significant correlation was found between dose and peak increase in platelet count measured at 7th day following administration. However, there was no relationship between the decrease in haemoglobin and the dose given, or between the increase in platelet count and fall in haemoglobin. Conclusion A 75μg/kg dose of Anti-D is more effective with acceptable side effect in comparison to 50μg dose for treatment of newly diagnosed Indian patients of ITP. PMID:28208873

'Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jetten, Marlon J.A.; Gaj, Stan; Ruiz-Aracama, Ainhoa

2012-03-15

Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure acetaminophen exposure after profound liver toxicity has already occurred. Furthermore, these tests do not provide mechanistic information. Here, 'omics techniques (global analysis of metabolomic/gene-expression responses) may provide additional insight. To better understand acetaminophen-induced responses at low doses, we evaluated the effects of (sub-)therapeutic acetaminophen doses on metabolite formation and global gene-expression changes (including, for the first time, full-genome humanmore » miRNA expression changes) in blood/urine samples from healthy human volunteers. Many known and several new acetaminophen-metabolites were detected, in particular in relation to hepatotoxicity-linked, oxidative metabolism of acetaminophen. Transcriptomic changes indicated immune-modulating effects (2 g dose) and oxidative stress responses (4 g dose). For the first time, effects of acetaminophen on full-genome human miRNA expression have been considered and confirmed the findings on mRNA level. 'Omics techniques outperformed clinical chemistry tests and revealed novel response pathways to acetaminophen in humans. Although no definitive conclusion about potential immunotoxic effects of acetaminophen can be drawn from this study, there are clear indications that the immune system is triggered even after intake of low doses of acetaminophen. Also, oxidative stress-related gene responses, similar to those seen after high dose acetaminophen exposure, suggest the occurrence of possible pre-toxic effects of therapeutic acetaminophen doses. Possibly, these effects are related to dose-dependent increases in levels of hepatotoxicity-related metabolites. -- Highlights: ► 'Omics techniques outperformed classic clinical chemistry tests. ► Metabolomic analyses led to the detection of five new acetaminophen metabolites. ► Low dose APAP changed immune and oxidative stress related gene expression in blood. ► APAP-induced full-genome human blood miRNA profiles were assessed for the first time.« less

Probiotic Lactobacillus rhamnosus GG Enhanced Th1 Cellular Immunity but Did Not Affect Antibody Responses in a Human Gut Microbiota Transplanted Neonatal Gnotobiotic Pig Model

PubMed Central

Wen, Ke; Tin, Christine; Wang, Haifeng; Yang, Xingdong; Li, Guohua; Giri-Rachman, Ernawati; Kocher, Jacob; Bui, Tammy; Clark-Deener, Sherrie; Yuan, Lijuan

2014-01-01

This study aims to establish a human gut microbiota (HGM) transplanted gnotobiotic (Gn) pig model of human rotavirus (HRV) infection and diarrhea, and to verify the dose-effects of probiotics on HRV vaccine-induced immune responses. Our previous studies using the Gn pig model found that probiotics dose-dependently regulated both T cell and B cell immune responses induced by rotavirus vaccines. We generated the HGM transplanted neonatal Gn pigs through daily feeding of neonatal human fecal suspension to germ-free pigs for 3 days starting at 12 hours after birth. We found that attenuated HRV (AttHRV) vaccination conferred similar overall protection against rotavirus diarrhea and virus shedding in Gn pigs and HGM transplanted Gn pigs. HGM promoted the development of the neonatal immune system, as evidenced by the significantly enhanced IFN-γ producing T cell responses and reduction of regulatory T cells and their cytokine production in the AttHRV-vaccinated pigs. The higher dose Lactobacillus rhamnosus GG (LGG) feeding (14 doses, up to 109 colony-forming-unit [CFU]/dose) effectively increased the LGG counts in the HGM Gn pig intestinal contents and significantly enhanced HRV-specific IFN-γ producing T cell responses to the AttHRV vaccine. Lower dose LGG (9 doses, up to 106 CFU/dose) was ineffective. Neither doses of LGG significantly improved the protection rate, HRV-specific IgA and IgG antibody titers in serum, or IgA antibody titers in intestinal contents compared to the AttHRV vaccine alone, suggesting that an even higher dose of LGG is needed to overcome the influence of the microbiota to achieve the immunostimulatory effect in the HGM pigs. This study demonstrated that HGM Gn pig is an applicable animal model for studying immune responses to rotavirus vaccines and can be used for studying interventions (i.e., probiotics and prebiotics) that may enhance the immunogenicity and protective efficacy of vaccines through improving the gut microbiota. PMID:24722168

An evaluation of some pertinent parameters that influence the dosimetric performance of synthetic diamond detectors

NASA Astrophysics Data System (ADS)

Ade, N.; Nam, T. L.; Mhlanga, S. H.

2013-05-01

Although the near-tissue equivalence of diamond allows the direct measurement of dose for clinical applications without the need for energy-corrections, it is often cited that diamond detectors require pre-irradiation, a procedure necessary to stabilize the response or sensitivity of a diamond detector before dose measurements. In addition it has been pointed out that the relative dose measured with a diamond detector requires dose rate dependence correction and that the angular dependence of a detector could be due to its mechanical design or to the intrinsic angular sensitivity of the detection process. While the cause of instability of response has not been meticulously investigated, the issue of dose rate dependence correction is uncertain as some studies ignored it but reported good results. The aims of this study were therefore to investigate, in particular (1) the major cause of the unstable response of diamond detectors requiring pre-irradiation; (2) the influence of dose rate dependence correction in relative dose measurements; and (3) the angular dependence of the diamond detectors. The study was conducted with low-energy X-rays and electron therapy beams on HPHT and CVD synthesized diamonds. Ionization chambers were used for comparative measurements. Through systematic investigations, the major cause of the unstable response of diamond detectors requiring the recommended pre-irradiation step was isolated and attributed to the presence and effects of ambient light. The variation in detector's response between measurements in light and dark conditions could be as high as 63% for a CVD diamond. Dose rate dependence parameters (Δ values) of 0.950 and 1.035 were found for the HPHT and CVD diamond detectors, respectively. Without corrections based on dose rate dependence, the relative differences between depth-doses measured with the diamond detectors and a Markus chamber for exposures to 7 and 14 MeV electron beams were within 2.5%. A dose rate dependence correction using the Δ values obtained seemed to worsen the performance of the HPHT sample (up to about 3.3%) but it had a marginal effect on the performance of the CVD sample. In addition, the angular response of the CVD diamond detector was shown to be comparable with that of a cylindrical chamber. This study concludes that once the responses of the diamond detectors have been stabilised and they are properly shielded from ambient light, pre-irradiation prior to each measurement is not required. Also, the relative dose measured with the diamond detectors do not require dose rate dependence corrections as the required correction is only marginal and could have no dosimetric significance.

AN EXTRACT OF PENICILLIUM CHRYSOGENUM INDUCES DOSE-DEPENDENT ALLERGIC ASTHMA RESPONSES IN MICE

EPA Science Inventory

Rationale: Penicillium chrysogenum, a common indoor mold, is known to have several allergens and can induce allergic responses in a mouse model of allergic penicilliosis. Our hypothesis is that soluble components of P. chrysogenum (PCE) can dose-dependently induce responses typ...

Pharmacogenetic Predictors of Methylphenidate Dose-Response in Attention-Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Froehlich, Tanya E.; Epstein, Jeffery N.; Nick, Todd G.; Melguizo Castro, Maria S.; Stein, Mark A.; Brinkman, William B.; Graham, Amanda J.; Langberg, Joshua M.; Kahn, Robert S.

2011-01-01

Objective: Because of significant individual variability in attention-deficit/hyperactivity disorder (ADHD) medication response, there is increasing interest in identifying genetic predictors of treatment effects. This study examined the role of four catecholamine-related candidate genes in moderating methylphenidate (MPH) dose-response. Method:…

Depth dose and off-axis characteristics of TLD in therapeutic pion beams.

PubMed

Hogstrom, K R; Irifune, T

1980-07-01

The thermoluminescent (TL) response of LiF (TLD-100, TLD-600, TLD-700) and Li2B4O7 (TLD-800) has been measured as a function of depth and off-axis position in a therapeutic negative-pion beam in order to evaluate their usefulness in pion radiotherapy. TLD-100, TLD-600, and TLD-800 have been shown to be of little use as in vivo dosemeters because the neutron kerma relative to that in tissue changes grossly with depth. The neutron source comes primarily from pion absorption in the lead-alloy collimator. The 200 degrees C TLD-700 response agrees well with the depth dose spectra, except for small changes due to the varying linear energy transfer (LET) distributions. This variation can be partially accounted for by incorporating the known LET response of LiF. The 260 degrees C peak of TLD-700 has been found to be approximately four times more sensitive than the 200 degrees C peak to high LET dose. Using a simple model of the LET responses, the measured 200 degrees C and 260 degrees C peaks predict total dose within +/- 4% and high LET dose within +/- 50%, therefore indicating TLD-700 to be a good in vivo dosemeter for total dose but only an indicator of high LET dose.

A dose related response of 6-OHDA on chicken spectral sensitivity and oscillatory potentials of recording electroretinograms.

PubMed

Li, X; Schaeffel, F; Konrad, K; Eberhart, Z

1996-10-01

To further study the contribution of dopamine system to the local growth controlling mechanisms, a dose related response of 6-hydroxydopamine (6-OHDA) was studied by recording electroretinograms (ERGs). The spectral sensitivity of the b-waves and spectral efficiency function of oscillatory potentials (OPs) including OP1, OP2 and OP3 in 4 different doses group were measured. The effect of ascorbate that must be contained in solution of 6-OHDA was first tested with the spectral sensitivity of the b-waves and a correlation between response of the OPs and age, as well as a difference in both own eyes was analyzed for determining an intra-subject and inter-subject variance. An enhanced response was found in OP1, OP2 with doses of 175 micrograms and OP3 with dose of 150 micrograms, and the effect of OPs was mainly in wavelength from 620 nm to 480 nm. No significant increase was found in the spectral sensitivity of the b-waves. The dose 200 micrograms seemed to be toxic to the retina estimated by both spectral sensitivity of the b-waves and spectral efficiency function of the OPs. The dose 175 micrograms and 150 micrograms of 6-OHDA yielded an effect on the chicken retina.

Exposure time independent summary statistics for assessment of drug dependent cell line growth inhibition.

PubMed

Falgreen, Steffen; Laursen, Maria Bach; Bødker, Julie Støve; Kjeldsen, Malene Krag; Schmitz, Alexander; Nyegaard, Mette; Johnsen, Hans Erik; Dybkær, Karen; Bøgsted, Martin

2014-06-05

In vitro generated dose-response curves of human cancer cell lines are widely used to develop new therapeutics. The curves are summarised by simplified statistics that ignore the conventionally used dose-response curves' dependency on drug exposure time and growth kinetics. This may lead to suboptimal exploitation of data and biased conclusions on the potential of the drug in question. Therefore we set out to improve the dose-response assessments by eliminating the impact of time dependency. First, a mathematical model for drug induced cell growth inhibition was formulated and used to derive novel dose-response curves and improved summary statistics that are independent of time under the proposed model. Next, a statistical analysis workflow for estimating the improved statistics was suggested consisting of 1) nonlinear regression models for estimation of cell counts and doubling times, 2) isotonic regression for modelling the suggested dose-response curves, and 3) resampling based method for assessing variation of the novel summary statistics. We document that conventionally used summary statistics for dose-response experiments depend on time so that fast growing cell lines compared to slowly growing ones are considered overly sensitive. The adequacy of the mathematical model is tested for doxorubicin and found to fit real data to an acceptable degree. Dose-response data from the NCI60 drug screen were used to illustrate the time dependency and demonstrate an adjustment correcting for it. The applicability of the workflow was illustrated by simulation and application on a doxorubicin growth inhibition screen. The simulations show that under the proposed mathematical model the suggested statistical workflow results in unbiased estimates of the time independent summary statistics. Variance estimates of the novel summary statistics are used to conclude that the doxorubicin screen covers a significant diverse range of responses ensuring it is useful for biological interpretations. Time independent summary statistics may aid the understanding of drugs' action mechanism on tumour cells and potentially renew previous drug sensitivity evaluation studies.

Exposure time independent summary statistics for assessment of drug dependent cell line growth inhibition

PubMed Central

2014-01-01

Background In vitro generated dose-response curves of human cancer cell lines are widely used to develop new therapeutics. The curves are summarised by simplified statistics that ignore the conventionally used dose-response curves’ dependency on drug exposure time and growth kinetics. This may lead to suboptimal exploitation of data and biased conclusions on the potential of the drug in question. Therefore we set out to improve the dose-response assessments by eliminating the impact of time dependency. Results First, a mathematical model for drug induced cell growth inhibition was formulated and used to derive novel dose-response curves and improved summary statistics that are independent of time under the proposed model. Next, a statistical analysis workflow for estimating the improved statistics was suggested consisting of 1) nonlinear regression models for estimation of cell counts and doubling times, 2) isotonic regression for modelling the suggested dose-response curves, and 3) resampling based method for assessing variation of the novel summary statistics. We document that conventionally used summary statistics for dose-response experiments depend on time so that fast growing cell lines compared to slowly growing ones are considered overly sensitive. The adequacy of the mathematical model is tested for doxorubicin and found to fit real data to an acceptable degree. Dose-response data from the NCI60 drug screen were used to illustrate the time dependency and demonstrate an adjustment correcting for it. The applicability of the workflow was illustrated by simulation and application on a doxorubicin growth inhibition screen. The simulations show that under the proposed mathematical model the suggested statistical workflow results in unbiased estimates of the time independent summary statistics. Variance estimates of the novel summary statistics are used to conclude that the doxorubicin screen covers a significant diverse range of responses ensuring it is useful for biological interpretations. Conclusion Time independent summary statistics may aid the understanding of drugs’ action mechanism on tumour cells and potentially renew previous drug sensitivity evaluation studies. PMID:24902483

EPR/alanine dosimetry for two therapeutic proton beams

NASA Astrophysics Data System (ADS)

Marrale, Maurizio; Carlino, Antonio; Gallo, Salvatore; Longo, Anna; Panzeca, Salvatore; Bolsi, Alessandra; Hrbacek, Jan; Lomax, Tony

2016-02-01

In this work the analysis of the electron paramagnetic resonance (EPR) response of alanine pellets exposed to two different clinical proton beams employed for radiotherapy is performed. One beam is characterized by a passive delivery technique and is dedicated to the eyes treatment (OPTIS2 beam line). Alanine pellets were irradiated with a 70 MeV proton beam corresponding to 35 mm range in eye tissue. We investigated how collimators with different sizes and shape used to conform the dose to the planned target volume influence the delivered dose. For this purpose we performed measurements with varying the collimator size (Output Factor) and the results were compared with those obtained with other dosimetric techniques (such as Markus chamber and diode detector). This analysis showed that the dosimeter response is independent of collimator diameter if this is larger than or equal to 10 mm. The other beam is characterized by an active spot-scanning technique, the Gantry1 beam line (maximum energy 230 MeV), and is used to treat deep-seated tumors. The dose linearity of alanine response in the clinical dose range was tested and the alanine dose response at selected locations in depth was measured and compared with the TPS planned dose in a quasi-clinical scenario. The alanine response was found to be linear in the dose in the clinical explored range (from 10 to 70 Gy). Furthermore, a depth dose profile in a quasi-clinical scenario was measured and compared to the dose computed by the Treatment Planning System PSIPLAN. The comparison of calibrated proton alanine measurements and TPS dose shows a difference under 1% in the SOBP and a "quenching" effect up to 4% in the distal part of SOBP. The positive dosimetric characteristics of the alanine pellets confirm the feasibility to use these detectors for "in vivo" dosimetry in clinical proton beams.

The linearized multistage model and the future of quantitative risk assessment.

PubMed

Crump, K S

1996-10-01

The linearized multistage (LMS) model has for over 15 years been the default dose-response model used by the U.S. Environmental Protection Agency (USEPA) and other federal and state regulatory agencies in the United States for calculating quantitative estimates of low-dose carcinogenic risks from animal data. The LMS model is in essence a flexible statistical model that can describe both linear and non-linear dose-response patterns, and that produces an upper confidence bound on the linear low-dose slope of the dose-response curve. Unlike its namesake, the Armitage-Doll multistage model, the parameters of the LMS do not correspond to actual physiological phenomena. Thus the LMS is 'biological' only to the extent that the true biological dose response is linear at low dose and that low-dose slope is reflected in the experimental data. If the true dose response is non-linear the LMS upper bound may overestimate the true risk by many orders of magnitude. However, competing low-dose extrapolation models, including those derived from 'biologically-based models' that are capable of incorporating additional biological information, have not shown evidence to date of being able to produce quantitative estimates of low-dose risks that are any more accurate than those obtained from the LMS model. Further, even if these attempts were successful, the extent to which more accurate estimates of low-dose risks in a test animal species would translate into improved estimates of human risk is questionable. Thus, it does not appear possible at present to develop a quantitative approach that would be generally applicable and that would offer significant improvements upon the crude bounding estimates of the type provided by the LMS model. Draft USEPA guidelines for cancer risk assessment incorporate an approach similar to the LMS for carcinogens having a linear mode of action. However, under these guidelines quantitative estimates of low-dose risks would not be developed for carcinogens having a non-linear mode of action; instead dose-response modelling would be used in the experimental range to calculate an LED10* (a statistical lower bound on the dose corresponding to a 10% increase in risk), and safety factors would be applied to the LED10* to determine acceptable exposure levels for humans. This approach is very similar to the one presently used by USEPA for non-carcinogens. Rather than using one approach for carcinogens believed to have a linear mode of action and a different approach for all other health effects, it is suggested herein that it would be more appropriate to use an approach conceptually similar to the 'LED10*-safety factor' approach for all health effects, and not to routinely develop quantitative risk estimates from animal data.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lewis, David F., E-mail: rcfilmconsulting@gmail.com; Chan, Maria F.

Purpose: The new radiochromic film, GAFChromic EBT-XD, contains the same active material, lithium-10,12-pentacosadiynoate, as GAFChromic EBT3, but the crystalline form is different. This work investigates the effect of this change on the well-known lateral response artifact when EBT-XD film is digitized on a flatbed scanner. Methods: The dose response of a single production lot of EBT-XD was characterized by scanning an unexposed film plus a set of films exposed to doses between 2.5 and 50 Gy using 6 MV photons. To characterize the lateral response artifact, the authors used the unexposed film plus a subset of samples exposed to dosesmore » between 20 and 50 Gy. Digital images of these films were acquired at seven discrete lateral locations perpendicular to the scan direction on three Epson 10000XL scanners. Using measurements at the discrete lateral positions, the scanner responses were determined as a function of the lateral position of the film. From the data for each scanner, a set of coefficients were derived whereby measured response values could be corrected to remove the effects of the lateral response artifact. The EBT-XD data were analyzed as in their previous work and compared to results reported for EBT3 in that paper. Results: For films scanned in the same orientation and having equal responses, the authors found that the lateral response artifact for EBT-XD and EBT3 films was remarkably similar. For both films, the artifact increases with increased net response. However, as EBT-XD is less sensitive than EBT3, a greater exposure dose is required to reach the same net response. On this basis, the lower sensitivity of EBT-XD relative to EBT3 results in less net response change for equal exposure and a reduction in the impact of the lateral response artifact. Conclusions: The shape of the crystalline active component in EBT-XD and EBT3 does not affect the fundamental existence of the lateral response artifact when the films are digitized on flatbed scanners. Owing its lower sensitivity, EBT-XD film requires higher dose to reach the same response as EBT3, resulting in lesser impact of the lateral response artifact. For doses >10 Gy, the slopes of the EBT-XD red and green channel dose response curves are greater than the corresponding ones for EBT3. For these two reasons, the authors prefer EBT-XD for doses exceeding about 10 Gy.« less

Characterization of the aggregation responses of camel platelets.

PubMed

Al Ghumlas, Abeer K; Gader, Abdel Galil M Abdel

2013-09-01

Despite evidence of active hemostasis, camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation. The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists, and to characterize the receptor that mediates the aggregation response to adenosine diphosphate (ADP), the most potent agonist for camel platelets known so far. Aggregation studies were performed with platelet-rich plasma (PRP) in response to multiple doses or combinations of ADP, epinephrine (EPN), collagen, and arachidonic acid (AA). Aggregation responses to ADP were performed before and after the addition of the ADP receptor (P2Y12) antagonist Clopidogrel. Camel platelets responded to ADP at doses higher than the standard dose for human platelets, and to combinations of EPN and other agonists, while no aggregation was elicited with EPN or AA alone. Clopidogrel blocked the ADP-induced aggregation responses in a dose-dependent fashion in vitro. Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP, but not AA or EPN. Irreversible aggregation of camel platelets could also be triggered by a combination of EPN and ADP, and collagen and AA. Inhibition with clopidogrel suggests that camel platelets express the ADP receptor, P2Y12. Understanding platelet function in camels will add to the understanding of platelet function in health and disease. © 2013 American Society for Veterinary Clinical Pathology.

Nilotinib dose-optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd.

PubMed

Hughes, Timothy P; Munhoz, Eduardo; Aurelio Salvino, Marco; Ong, Tee Chuan; Elhaddad, Alaa; Shortt, Jake; Quach, Hang; Pavlovsky, Carolina; Louw, Vernon J; Shih, Lee-Yung; Turkina, Anna G; Meillon, Luis; Jin, Yu; Acharya, Sandip; Dalal, Darshan; Lipton, Jeffrey H

2017-10-01

The Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Extending Molecular Responses (ENESTxtnd) study was conducted to evaluate the kinetics of molecular response to nilotinib in patients with newly diagnosed chronic myeloid leukaemia in chronic phase and the impact of novel dose-optimization strategies on patient outcomes. The ENESTxtnd protocol allowed nilotinib dose escalation (from 300 to 400 mg twice daily) in the case of suboptimal response or treatment failure as well as dose re-escalation for patients with nilotinib dose reductions due to adverse events. Among 421 patients enrolled in ENESTxtnd, 70·8% (95% confidence interval, 66·2-75·1%) achieved major molecular response (BCR-ABL1 ≤ 0·1% on the International Scale) by 12 months (primary endpoint). By 24 months, 81·0% of patients achieved major molecular response, including 63·6% (56 of 88) of those with dose escalations for lack of efficacy and 74·3% (55 of 74) of those with dose reductions due to adverse events (including 43 of 54 patients with successful re-escalation). The safety profile of nilotinib was consistent with prior studies. The most common non-haematological adverse events were headache, rash, and nausea; cardiovascular events were reported in 4·5% of patients (grade 3/4, 3·1%). The study was registered at clinicaltrials.gov (NCT01254188). © 2017 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

Characterization of a novel two dimensional diode array the "magic plate" as a radiation detector for radiation therapy treatment.

PubMed

Wong, J H D; Fuduli, I; Carolan, M; Petasecca, M; Lerch, M L F; Perevertaylo, V L; Metcalfe, P; Rosenfeld, A B

2012-05-01

Intensity modulated radiation therapy (IMRT) utilizes the technology of multileaf collimators to deliver highly modulated and complex radiation treatment. Dosimetric verification of the IMRT treatment requires the verification of the delivered dose distribution. Two dimensional ion chamber or diode arrays are gaining popularity as a dosimeter of choice due to their real time feedback compared to film dosimetry. This paper describes the characterization of a novel 2D diode array, which has been named the "magic plate" (MP). It was designed to function as a 2D transmission detector as well as a planar detector for dose distribution measurements in a solid water phantom for the dosimetric verification of IMRT treatment delivery. The prototype MP is an 11 × 11 detector array based on thin (50 μm) epitaxial diode technology mounted on a 0.6 mm thick Kapton substrate using a proprietary "drop-in" technology developed by the Centre for Medical Radiation Physics, University of Wollongong. A full characterization of the detector was performed, including radiation damage study, dose per pulse effect, percent depth dose comparison with CC13 ion chamber and build up characteristics with a parallel plane ion chamber measurements, dose linearity, energy response and angular response. Postirradiated magic plate diodes showed a reproducibility of 2.1%. The MP dose per pulse response decreased at higher dose rates while at lower dose rates the MP appears to be dose rate independent. The depth dose measurement of the MP agrees with ion chamber depth dose measurements to within 0.7% while dose linearity was excellent. MP showed angular response dependency due to the anisotropy of the silicon diode with the maximum variation in angular response of 10.8% at gantry angle 180°. Angular dependence was within 3.5% for the gantry angles ± 75°. The field size dependence of the MP at isocenter agrees with ion chamber measurement to within 1.1%. In the beam perturbation study, the surface dose increased by 12.1% for a 30 × 30 cm(2) field size at the source to detector distance (SDD) of 80 cm whilst the transmission for the MP was 99%. The radiation response of the magic plate was successfully characterized. The array of epitaxial silicon based detectors with "drop-in" packaging showed properties suitable to be used as a simplified multipurpose and nonperturbing 2D radiation detector for radiation therapy dosimetric verification.

Sensitivity calibration procedures in optical-CT scanning of BANG 3 polymer gel dosimeters

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Y.; Wuu, Cheng-Shie; Maryanski, Marek J.

2010-02-15

The dose response of the BANG 3 polymer gel dosimeter (MGS Research Inc., Madison, CT) was studied using the OCTOPUS laser CT scanner (MGS Research Inc., Madison, CT). Six 17 cm diameter and 12 cm high Barex cylinders, and 18 small glass vials were used to house the gel. The gel phantoms were irradiated with 6 and 10 MV photons, as well as 12 and 16 MeV electrons using a Varian Clinac 2100EX. Three calibration methods were used to obtain the dose response curves: (a) Optical density measurements on the 18 glass vials irradiated with graded doses from 0 tomore » 4 Gy using 6 or 10 MV large field irradiations; (b) optical-CT scanning of Barex cylinders irradiated with graded doses (0.5, 1, 1.5, and 2 Gy) from four adjacent 4x4 cm{sup 2} photon fields or 6x6 cm{sup 2} electron fields; and (c) percent depth dose (PDD) comparison of optical-CT scans with ion chamber measurements for 6x6 cm{sup 2}, 12 and 16 MeV electron fields. The dose response of the BANG 3 gel was found to be linear and energy independent within the uncertainties of the experimental methods (about 3%). The slopes of the linearly fitted dose response curves (dose sensitivities) from the four field irradiations (0.0752{+-}3%, 0.0756{+-}3%, 0.0767{+-}3%, and 0.0759{+-}3% cm{sup -1} Gy{sup -1}) and the PDD matching methods (0.0768{+-}3% and 0.0761{+-}3% cm{sup -1} Gy{sup -1}) agree within 2.2%, indicating a good reproducibility of the gel dose response within phantoms of the same geometry. The dose sensitivities from the glass vial approach are different from those of the cylindrical Barex phantoms by more than 30%, owing probably to the difference in temperature inside the two types of phantoms during gel formation and irradiation, and possible oxygen contamination of the glass vial walls. The dose response curve obtained from the PDD matching approach with 16 MeV electron field was used to calibrate the gel phantom irradiated with the 12 MeV, 6x6 cm{sup 2} electron field. Three-dimensional dose distributions from the gel measurement and the Eclipse planning system (Varian Corporation, Palo Alto, CA) were compared and evaluated using 3% dose difference and 2 mm distance-to-agreement criteria.« less

Intravenous Nicotine Self-Administration in Smokers: Dose-Response Function and Sex Differences.

PubMed

Jensen, Kevin P; DeVito, Elise E; Valentine, Gerald; Gueorguieva, Ralitza; Sofuoglu, Mehmet

2016-07-01

Sex differences in the sensitivity to nicotine may influence vulnerability to tobacco dependence. The goal of this study was to investigate the dose-response function for the reinforcing and subjective effects of intravenous nicotine in male and female smokers. Tobacco-dependent subjects (12 male and 14 female) participated in four experimental sessions in which they received sample infusions of saline and nicotine (0.1, 0.2, 0.3, or 0.4 mg doses) in a randomized double-blind crossover design. During each session, subjects first received the sample infusions, and heart rate (HR), blood pressure, and subjective stimulatory, pleasurable and aversive responses were monitored. Immediately following the sample infusions, subjects self-administered either nicotine or saline in six double-blind forced-choice trials. A sex by dose interaction was observed in the nicotine choice paradigm. Nicotine self-administration rate was negatively correlated with nicotine dose in males (males displayed choice preference for low doses of nicotine over high doses of nicotine), but no significant relationship between dose and choice preference was evident in females. Relative to placebo, sample doses of nicotine increased heart rate and blood pressure, and induced stimulatory, pleasurable, and aversive subjective effects. Diastolic blood pressure increased dose dependently in males, but not in females. These findings, which demonstrate sex differences in nicotine self-administration for doses that are near to the reinforcement threshold, suggest that male and female smokers may respond differently to the changes in nicotine doses available for self-administration.

Effect of hypothalamic neuropeptides on corticotrophin release from quarters of rat anterior pituitary gland in vitro.

PubMed

Nicholson, S A; Adrian, T E; Gillham, B; Jones, M T; Bloom, S R

1984-02-01

The effect of six hypothalamic peptides on the basal release of ACTH and that induced by arginine vasopressin (AVP) or by ovine corticotrophin releasing factor (oCRF) from fragments of the rat anterior pituitary gland incubated in vitro was investigated. Dose-response curves to AVP and to oCRF were obtained, and the response to a low dose of oCRF was potentiated by a low dose of AVP. Basal release of ACTH was not affected by any of the peptides in concentrations in the range 10(-12) to 10(-6) mol/l, and only substance P (SP) and somatostatin (SRIF) inhibited significantly the response to oCRF in a dose-related manner. The responses to a range of doses of oCRF or AVP were reduced by 10(-8) and 10(-6) mol SP or SRIF/l, and to a greater extent by the higher dose. Except in the case of 10(-6) mol SRIF/l on the response to AVP, the response was not further diminished by preincubation of the tissue with the peptide before the stimulating agent was added. The inhibition of the responses to AVP or oCRF by 10(-9) mol SP/l was not potentiated by its combination with either 5 X 10(-10) or 10(-8) mol SRIF/l; the inhibitory effects were merely additive. The results suggest that although SRIF and SP are able to modulate the release of ACTH from the anterior pituitary gland, they do so only at a high concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Surface effects on the radiation response of nanoporous Au foams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fu, E. G.; Caro, M.; Wang, Y. Q.

2012-11-05

We report on an experimental and simulation campaign aimed at exploring the radiation response of nanoporous Au (np-Au) foams. We find different defect accumulation behavior by varying radiation dose-rate in ion-irradiated np-Au foams. Stacking fault tetrahedra are formed when np-Au foams are irradiated at high dose-rate, but they do not seem to be formed in np-Au at low dose-rate irradiation. A model is proposed to explain the dose-rate dependent defect accumulation based on these results.

Chimpanzee Adenovirus Vector Ebola Vaccine.

PubMed

Ledgerwood, Julie E; DeZure, Adam D; Stanley, Daphne A; Coates, Emily E; Novik, Laura; Enama, Mary E; Berkowitz, Nina M; Hu, Zonghui; Joshi, Gyan; Ploquin, Aurélie; Sitar, Sandra; Gordon, Ingelise J; Plummer, Sarah A; Holman, LaSonji A; Hendel, Cynthia S; Yamshchikov, Galina; Roman, Francois; Nicosia, Alfredo; Colloca, Stefano; Cortese, Riccardo; Bailer, Robert T; Schwartz, Richard M; Roederer, Mario; Mascola, John R; Koup, Richard A; Sullivan, Nancy J; Graham, Barney S

2017-03-09

The unprecedented 2014 epidemic of Ebola virus disease (EVD) prompted an international response to accelerate the availability of a preventive vaccine. A replication-defective recombinant chimpanzee adenovirus type 3-vectored ebolavirus vaccine (cAd3-EBO), encoding the glycoprotein from Zaire and Sudan species, that offers protection in the nonhuman primate model, was rapidly advanced into phase 1 clinical evaluation. We conducted a phase 1, dose-escalation, open-label trial of cAd3-EBO. Twenty healthy adults, in sequentially enrolled groups of 10 each, received vaccination intramuscularly in doses of 2×10 10 particle units or 2×10 11 particle units. Primary and secondary end points related to safety and immunogenicity were assessed throughout the first 8 weeks after vaccination; in addition, longer-term vaccine durability was assessed at 48 weeks after vaccination. In this small study, no safety concerns were identified; however, transient fever developed within 1 day after vaccination in two participants who had received the 2×10 11 particle-unit dose. Glycoprotein-specific antibodies were induced in all 20 participants; the titers were of greater magnitude in the group that received the 2×10 11 particle-unit dose than in the group that received the 2×10 10 particle-unit dose (geometric mean titer against the Zaire antigen at week 4, 2037 vs. 331; P=0.001). Glycoprotein-specific T-cell responses were more frequent among those who received the 2×10 11 particle-unit dose than among those who received the 2×10 10 particle-unit dose, with a CD4 response in 10 of 10 participants versus 3 of 10 participants (P=0.004) and a CD8 response in 7 of 10 participants versus 2 of 10 participants (P=0.07) at week 4. Assessment of the durability of the antibody response showed that titers remained high at week 48, with the highest titers in those who received the 2×10 11 particle-unit dose. Reactogenicity and immune responses to cAd3-EBO vaccine were dose-dependent. At the 2×10 11 particle-unit dose, glycoprotein Zaire-specific antibody responses were in the range reported to be associated with vaccine-induced protective immunity in challenge studies involving nonhuman primates, and responses were sustained to week 48. Phase 2 studies and efficacy trials assessing cAd3-EBO are in progress. (Funded by the Intramural Research Program of the National Institutes of Health; VRC 207 ClinicalTrials.gov number, NCT02231866 .).

Accounting for Shared and Unshared Dosimetric Uncertainties in the Dose Response for Ultrasound-Detected Thyroid Nodules after Exposure to Radioactive Fallout

PubMed Central

Hoffman, F. Owen; Moroz, Brian; Drozdovitch, Vladimir; Bouville, André; Beck, Harold; Luckyanov, Nicholas; Weinstock, Robert M.; Simon, Steven L.

2015-01-01

Dosimetic uncertainties, particularly those that are shared among subgroups of a study population, can bias, distort or reduce the slope or significance of a dose response. Exposure estimates in studies of health risks from environmental radiation exposures are generally highly uncertain and thus, susceptible to these methodological limitations. An analysis was published in 2008 concerning radiation-related thyroid nodule prevalence in a study population of 2,994 villagers under the age of 21 years old between August 1949 and September 1962 and who lived downwind from the Semi-palatinsk Nuclear Test Site in Kazakhstan. This dose-response analysis identified a statistically significant association between thyroid nodule prevalence and reconstructed doses of fallout-related internal and external radiation to the thyroid gland; however, the effects of dosimetric uncertainty were not evaluated since the doses were simple point “best estimates”. In this work, we revised the 2008 study by a comprehensive treatment of dosimetric uncertainties. Our present analysis improves upon the previous study, specifically by accounting for shared and unshared uncertainties in dose estimation and risk analysis, and differs from the 2008 analysis in the following ways: 1. The study population size was reduced from 2,994 to 2,376 subjects, removing 618 persons with uncertain residence histories; 2. Simulation of multiple population dose sets (vectors) was performed using a two-dimensional Monte Carlo dose estimation method; and 3. A Bayesian model averaging approach was employed for evaluating the dose response, explicitly accounting for large and complex uncertainty in dose estimation. The results were compared against conventional regression techniques. The Bayesian approach utilizes 5,000 independent realizations of population dose vectors, each of which corresponds to a set of conditional individual median internal and external doses for the 2,376 subjects. These 5,000 population dose vectors reflect uncertainties in dosimetric parameters, partly shared and partly independent, among individual members of the study population. Risk estimates for thyroid nodules from internal irradiation were higher than those published in 2008, which results, to the best of our knowledge, from explicitly accounting for dose uncertainty. In contrast to earlier findings, the use of Bayesian methods led to the conclusion that the biological effectiveness for internal and external dose was similar. Estimates of excess relative risk per unit dose (ERR/Gy) for males (177 thyroid nodule cases) were almost 30 times those for females (571 cases) and were similar to those reported for thyroid cancers related to childhood exposures to external and internal sources in other studies. For confirmed cases of papillary thyroid cancers (3 in males, 18 in females), the ERR/Gy was also comparable to risk estimates from other studies, but not significantly different from zero. These findings represent the first reported dose response for a radiation epidemiologic study considering all known sources of shared and unshared errors in dose estimation and using a Bayesian model averaging (BMA) method for analysis of the dose response. PMID:25574587

Metronidazole and 5-aminosalicylic acid enhance the contractile activity of histaminergic agonists on the guinea-pig isolated ileum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Winbery, S.L.; Barker, L.A.

1986-03-01

The effects of metronidazole and 5-aminosalicylic acid (5-ASA) on histamine receptor-effector systems in the small intestine and right atrium of the guinea pig were studied. In an apparently all-or-none manner, both caused a sinistral shift in dose-response curves for the phasic component of the contractile response to histamine at H1 receptors on the ileum. In the presence of either, the EC50 value for histamine was reduced from 0.07 to about 0.03 microM. Similarly, in an apparently all-or-none fashion, both produced an elevation in the dose-response curve for the actions of dimaprit at H2-receptors in the ileum; the response to allmore » doses was increased about 30% with no significant change in the EC50 value. Metronidazole and 5-ASA did not alter dose-response curves for the tonic contractile response to histamine or curves generated by the cumulative addition of histamine. Also, neither altered the positive chronotropic response on isolated right atria or the phasic contractile response on isolated segments of jejunum and duodenum to histamine or dimaprit. Likewise, neither altered dose-response curves for the direct action of carbamylcholine at muscarinic receptors or for the indirect actions of dimethylphenylpiperazinium on the ileum. The effects of 5-ASA or metronidazole on the response to histamine could be prevented as well as reversed by scopolamine or tetrodotoxin. The results suggest that metronidazole and 5-ASA enhance the actions of histamine and dimaprit on the ileum by an action on myenteric plexus neurons.« less

COMPUTATIONAL MODELING OF SIGNALING PATHWAYS MEDIATING CELL CYCLE AND APOPTOTIC RESPONSES TO IONIZING RADIATION MEDIATED DNA DAMAGE

EPA Science Inventory

Demonstrated of the use of a computational systems biology approach to model dose response relationships. Also discussed how the biologically motivated dose response models have only limited reference to the underlying molecular level. Discussed the integration of Computational S...

The Key Events Dose-Response Framework: A cross-Disciplinary Mode-of-Action Based Approach to Examining Does-Response and Thresholds

EPA Science Inventory

the ILSI Research Foundation conveded a cross-disciplinary working group to examine current approaches for assessing dose-response and identifying safe levels of intake or exposure for four categoreis of bioactive agents: food allergens, nutrients, pathogenic microorganisms, and ...

A system for electron therapy dosimetry surveys with thermoluminescence dosimeters.

PubMed

Soares, C G; Ehrlich, M; Padikal, T N; Gromadzki, Z C

1982-11-01

Radiation-therapy dosimetry surveys employing thermoluminescence dosimeters (TLDs) are now being considered for high-energy electron beams. Using a system of individually calibrated pressed LiF TLDs in a water and a polystyrene phantom, we established that the distortions of depth-dose distributions in non-conducting materials previously observed at high absorbed doses and high dose rates were not detectable in the present geometry at doses and dose rates as much as 40 times higher than those employed in radiation therapy. The system was then used to measure TLD response in water and in polystyrene in the nominal electron-energy range from 7 to 18 MeV. In the water phantom, the well-known trend for TLD response to decrease with increasing electron energy was observed. In the polystyrene phantom, TLD response was found to be independent of electron energy.

Ultra Low-Dose Radiation: Stress Responses and Impacts Using Rice as a Grass Model

PubMed Central

Rakwal, Randeep; Agrawal, Ganesh Kumar; Shibato, Junko; Imanaka, Tetsuji; Fukutani, Satoshi; Tamogami, Shigeru; Endo, Satoru; Sahoo, Sarata Kumar; Masuo, Yoshinori; Kimura, Shinzo

2009-01-01

We report molecular changes in leaves of rice plants (Oryza sativa L. - reference crop plant and grass model) exposed to ultra low-dose ionizing radiation, first using contaminated soil from the exclusion zone around Chernobyl reactor site. Results revealed induction of stress-related marker genes (Northern blot) and secondary metabolites (LC-MS/MS) in irradiated leaf segments over appropriate control. Second, employing the same in vitro model system, we replicated results of the first experiment using in-house fabricated sources of ultra low-dose gamma (γ) rays and selected marker genes by RT-PCR. Results suggest the usefulness of the rice model in studying ultra low-dose radiation response/s. PMID:19399245

The dose-response of Harshaw TLD-700H.

PubMed

Velbeck, K J; Luo, L Z; Ramlo, M J; Rotunda, J E

2006-01-01

Harshaw TLD-700H (7LiF:Mg,Cu,P) was previously characterised for low- to high-dose ranges from 1 microGy to 20 Gy. This paper describes the studies and results of dose-response and linearity at much higher doses. TLD-700H is a near perfect dosimetric material with near tissue equivalence, flat energy response, and the ability to measure beta, gamma and X rays. These new results extend the applicability of Harshaw TLD-700H into more dosimetric measurement environments. The simple glow curve structure provides insignificant fade, eliminating special oven preparation methods experienced by other materials. The work presented in this paper quantifies the performance of Harshaw TLD-700H in extended ranges.

SU-F-J-86: Method to Include Tissue Dose Response Effect in Deformable Image Registration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, J; Liang, J; Chen, S

Purpose: Organ changes shape and size during radiation treatment due to both mechanical stress and radiation dose response. However, the dose response induced deformation has not been considered in conventional deformable image registration (DIR). A novel DIR approach is proposed to include both tissue elasticity and radiation dose induced organ deformation. Methods: Assuming that organ sub-volume shrinkage was proportional to the radiation dose induced cell killing/absorption, the dose induced organ volume change was simulated applying virtual temperature on each sub-volume. Hence, both stress and heterogeneity temperature induced organ deformation. Thermal stress finite element method with organ surface boundary condition wasmore » used to solve deformation. Initial boundary correspondence on organ surface was created from conventional DIR. Boundary condition was updated by an iterative optimization scheme to minimize elastic deformation energy. The registration was validated on a numerical phantom. Treatment dose was constructed applying both the conventional DIR and the proposed method using daily CBCT image obtained from HN treatment. Results: Phantom study showed 2.7% maximal discrepancy with respect to the actual displacement. Compared with conventional DIR, subvolume displacement difference in a right parotid had the mean±SD (Min, Max) to be 1.1±0.9(−0.4∼4.8), −0.1±0.9(−2.9∼2.4) and −0.1±0.9(−3.4∼1.9)mm in RL/PA/SI directions respectively. Mean parotid dose and V30 constructed including the dose response induced shrinkage were 6.3% and 12.0% higher than those from the conventional DIR. Conclusion: Heterogeneous dose distribution in normal organ causes non-uniform sub-volume shrinkage. Sub-volume in high dose region has a larger shrinkage than the one in low dose region, therefore causing more sub-volumes to move into the high dose area during the treatment course. This leads to an unfavorable dose-volume relationship for the normal organ. Without including this effect in DIR, treatment dose in normal organ could be underestimated affecting treatment evaluation and planning modification. Acknowledgement: Partially Supported by Elekta Research Grant.« less

Ranitidine Can Potentiate The Prokinetic Effect Of Itopride At Low Doses- An In Vitro Study.

PubMed

Butt, Aroosa Ishtiaq; Khan, Bushra Tayyaba; Khan, Asma; Khan, Qamar-Uz-Zaman

2017-01-01

Gastroparesis and GERD occur concomitantly in 40 percent of the cases. Prokinetic drugs and acid blockers are employed as the main treatment modality. Ranitidine is an acid blocker with additional prokinetic activity and Itopride is a known prokinetic drug. This study was designed to observe the synergistic potentiating prokinetic effect of Ranitidine on itopride on isolated duodenum of rabbits. Ranitidine (10-5-10-3) and itopride (10-6-10-5) were added in increasing concentrations to isolated duodenum of rabbits and contractions were recorded on PowerLab Data acquisition unit AHK/214. Cumulative dose response curves were constructed. The potentiating prokinetic effect of Ranitidine on itopride was seen by using a fixed dose of ranitidine and cumulatively enhancing doses of itopride on iWorx. Ranitidine and itopride produced a dose dependent reversible contraction of the isolated tissue of rabbits with ranitidine showing a max response of 0.124mV and itopride showing a maximum response of 0.131mV. Ranitidine was able to potentiate the prokinetic effect of itopride at low doses but at high dose the effect began to wane off. Ranitidine and itopride produce a statistically significant synergistic potentiating prokinetic effect at low doses in vitro.

Transcriptomic Dose-Response Analysis for Mode of Action ...

EPA Pesticide Factsheets

Microarray and RNA-seq technologies can play an important role in assessing the health risks associated with environmental exposures. The utility of gene expression data to predict hazard has been well documented. Early toxicogenomics studies used relatively high, single doses with minimal replication. Thus, they were not useful in understanding health risks at environmentally-relevant doses. Until the past decade, application of toxicogenomics in dose response assessment and determination of chemical mode of action has been limited. New transcriptomic biomarkers have evolved to detect chemical hazards in multiple tissues together with pathway methods to study biological effects across the full dose response range and critical time course. Comprehensive low dose datasets are now available and with the use of transcriptomic benchmark dose estimation techniques within a mode of action framework, the ability to incorporate informative genomic data into human health risk assessment has substantially improved. The key advantage to applying transcriptomic technology to risk assessment is both the sensitivity and comprehensive examination of direct and indirect molecular changes that lead to adverse outcomes. Book Chapter with topic on future application of toxicogenomics technologies for MoA and risk assessment

Integrated analysis of genetic variation and gene expression reveals novel variant for increased warfarin dose requirement in African Americans.

PubMed

Hernandez, W; Gamazon, E R; Aquino-Michaels, K; Smithberger, E; O'Brien, T J; Harralson, A F; Tuck, M; Barbour, A; Cavallari, L H; Perera, M A

2017-04-01

Essentials Genetic variants controlling gene regulation have not been explored in pharmacogenomics. We tested liver expression quantitative trait loci for association with warfarin dose response. A novel predictor for increased warfarin dose response in African Americans was identified. Precision medicine must take into account population-specific variation in gene regulation. Background Warfarin is commonly used to control and prevent thromboembolic disorders. However, because of warfarin's complex dose-requirement relationship, safe and effective use is challenging. Pharmacogenomics-guided warfarin dosing algorithms that include the well-established VKORC1 and CYP2C9 polymorphisms explain only a small proportion of inter-individual variability in African Americans (AAs). Objectives We aimed to assess whether transcriptomic analyses could be used to identify regulatory variants associated with warfarin dose response in AAs. Patients/Methods We identified a total of 56 expression quantitative trait loci (eQTLs) for CYP2C9, VKORC1 and CALU derived from human livers and evaluated their association with warfarin dose response in two independent AA warfarin patient cohorts. Results We found that rs4889606, a strong cis-eQTL for VKORC1 (log 10 Bayes Factor = 12.02), is significantly associated with increased warfarin daily dose requirement (β = 1.1; 95% confidence interval [CI] 0.46 to 1.8) in the discovery cohort (n = 305) and in the replication cohort (β = 1.04; 95% CI 0.33 -1.7; n = 141) after conditioning on relevant covariates and the VKORC1 -1639G>A (rs9923231) variant. Inclusion of rs4889606 genotypes, along with CYP2C9 alleles, rs9923231 genotypes and clinical variables, explained 31% of the inter-patient variability in warfarin dose requirement. We demonstrate different linkage disequilibrium patterns in the region encompassing rs4889606 and rs9923231 between AAs and European Americans, which may explain the increased dose requirement found in AAs. Conclusion Our approach of interrogating eQTLs identified in liver has revealed a novel predictor of warfarin dose response in AAs. Our work highlights the utility of leveraging information from regulatory variants mapped in the liver to uncover novel variants associated with drug response and the importance of population-specific research. © 2017 International Society on Thrombosis and Haemostasis.

A dose of nature: Tree cover, stress reduction, and gender differences

Treesearch

Bin Jiang; Chun-Yen Chang; William C. Sullivan

2014-01-01

Although it is well established that exposure to nearby nature can help reduce stress in individuals, the shape of the dose-response curve is entirely unclear. To establish this dose-response curve, we recruited 160 individuals for a laboratory experiment. Participants engaged in the Trier Social Stress Test (TSST) to induce psychological stress, and were then randomly...

Temporal aspects of tumorigenic response to individual and mixed carcinogens. [Response of mouse skin to benzo(a)pyrene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Albert, R.E.; Burns, F.J.

1976-02-01

Results are reported from experiments that involved either single or multiple doses of benzo(a)pyrene in mouse skin followed by prolonged observation. Preliminary results indicate linearity in dose and time and no evidence of recovery or enhancement for multiple doses of initiator given for extended periods of time. (auth)

Pretreatment of low dose radiation reduces radiation-induced apoptosis in mouse lymphoma (EL4) cells.

PubMed

Kim, J H; Hyun, S J; Yoon, M Y; Ji, Y H; Cho, C K; Yoo, S Y

1997-06-01

Induction of an adaptive response to ionizing radiation in mouse lymphoma (EL4) cells was studied by using cell survival fraction and apoptotic nucleosomal DNA fragmentation as biological end points. Cells in early log phase were pre-exposed to low dose of gamma-rays (0.01 Gy) 4 or 20 hrs prior to high dose gamma-ray (4, 8 and 12 Gy for cell survival fraction analysis; 8 Gy for DNA fragmentation analysis) irradiation. Then cell survival fractions and the extent of DNA fragmentation were measured. Significant adaptive response, increase in cell survival fraction and decrease in the extent of DNA fragmentation were induced when low and high dose gamma-ray irradiation time interval was 4 hr. Addition of protein or RNA synthesis inhibitor, cycloheximide or 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole (DRFB), respectively during adaptation period, the period from low dose gamma-ray irradiation to high dose gamma-ray irradiation, was able to inhibit the induction of adaptive response, which is the reduction of the extent DNA fragmentation in irradiated EL4 cells. These data suggest that the induction of adaptive response to ionizing radiation in EL4 cells required both protein and RNA synthesis.

On the origin of the visible light responsible for proton dose measurement using plastic optical fibers

NASA Astrophysics Data System (ADS)

Darafsheh, Arash; Taleei, Reza; Kassaee, Alireza; Finlay, Jarod C.

2017-03-01

We experimentally and by means of Monte Carlo simulations investigated the origin of the visible signal responsible for proton therapy dose measurement using bare plastic optical fibers. Experimentally, the fiber optic probe, embedded in tissue-mimicking plastics, was irradiated with a proton beam produced by a proton therapy cyclotron and the luminescence spectroscopy was performed by a CCD-coupled spectrograph to analyze the emission spectrum of the fiber tip. Monte Carlo simulations were performed using FLUKA Monte Carlo code to stochastically simulate radiation transport, ionizing radiation dose deposition, and optical emission of Čerenkov radiation. The spectroscopic study of proton-irradiated plastic fibers showed a continuous spectrum with shape different from that of Čerenkov radiation. The Monte Carlo simulations confirmed that the amount of the generated Čerenkov light does not follow the radiation absorbed dose in a medium. Our results show that the origin of the optical signal responsible for the proton dose measurement using bare optical fibers is not Čerenkov radiation. Our results point toward a connection between the scintillation of the plastic material of the fiber and the origin of the signal responsible for dose measurement.

Quantitative structure - mesothelioma potency model ...

EPA Pesticide Factsheets

Cancer potencies of mineral and synthetic elongated particle (EP) mixtures, including asbestos fibers, are influenced by changes in fiber dose composition, bioavailability, and biodurability in combination with relevant cytotoxic dose-response relationships. A unique and comprehensive rat intra-pleural (IP) dose characterization data set with a wide variety of EP size, shape, crystallographic, chemical, and bio-durability properties facilitated extensive statistical analyses of 50 rat IP exposure test results for evaluation of alternative dose pleural mesothelioma response models. Utilizing logistic regression, maximum likelihood evaluations of thousands of alternative dose metrics based on hundreds of individual EP dimensional variations within each test sample, four major findings emerged: (1) data for simulations of short-term EP dose changes in vivo (mild acid leaching) provide superior predictions of tumor incidence compared to non-acid leached data; (2) sum of the EP surface areas (ÓSA) from these mildly acid-leached samples provides the optimum holistic dose response model; (3) progressive removal of dose associated with very short and/or thin EPs significantly degrades resultant ÓEP or ÓSA dose-based predictive model fits, as judged by Akaike’s Information Criterion (AIC); and (4) alternative, biologically plausible model adjustments provide evidence for reduced potency of EPs with length/width (aspect) ratios 80 µm. Regar

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy, environmental nuclear contamination, as well as earth orbit and space missions. Analyses of transcriptome profiles of murine brain tissue after whole-body radiation showed that low-dose exposures (10 cGy) induced genes not affected by high dose (2 Gy), and low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues, and pathways that were brain tissue specific. Low-dose genes clustered into a saturated networkmore » (p < 10{sup -53}) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified 9 neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose radiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down regulated in normal human aging and Alzheimer's disease.« less

Experimental evaluation of a MOSFET dosimeter for proton dose measurements.

PubMed

Kohno, Ryosuke; Nishio, Teiji; Miyagishi, Tomoko; Hirano, Eriko; Hotta, Kenji; Kawashima, Mitsuhiko; Ogino, Takashi

2006-12-07

The metal oxide semiconductor field-effect transistor (MOSFET) dosimeter has been widely studied for use as a dosimeter for patient dose verification. The major advantage of this detector is its size, which acts as a point dosimeter, and also its ease of use. The commercially available TN502RD MOSFET dosimeter manufactured by Thomson and Nielsen has never been used for proton dosimetry. Therefore we used the MOSFET dosimeter for the first time in proton dose measurements. In this study, the MOSFET dosimeter was irradiated with 190 MeV therapeutic proton beams. We experimentally evaluated dose reproducibility, linearity, fading effect, beam intensity dependence and angular dependence for the proton beam. Furthermore, the Bragg curve and spread-out Bragg peak were also measured and the linear-energy transfer (LET) dependence of the MOSFET response was investigated. Many characteristics of the MOSFET response for proton beams were the same as those for photon beams reported in previous papers. However, the angular MOSFET responses at 45, 90, 135, 225, 270 and 315 degrees for proton beams were over-responses of about 15%, and moreover the MOSFET response depended strongly on the LET of the proton beam. This study showed that the angular dependence and LET dependence of the MOSFET response must be considered very carefully for quantitative proton dose evaluations.

Development of UV-B screening compounds in response to variation in ambient levels of UV-B radiation

NASA Astrophysics Data System (ADS)

Sullivan, Joe H.; Xu, Chenping; Gao, Wei; Slusser, James R.

2005-08-01

The induction of UV-B screening compounds in response to exposure to UV-B radiation is a commonly reported response and is generally considered to be an adaptive response of plants for protection from UVinduced damage. However, a number of questions remain to be answered including the importance of qualitative and localization differences among species in providing protection, indirect consequences of changes in leaf secondary chemistry on ecological processes and the dose response of metabolite accumulation. In this study we utilized UV monitoring data provided on site by the USDA UV-B Monitoring and Research Program to monitor the changes in UV-screening compounds in soybeans under a range of UV-B levels due to natural variation in ambient UV-B radiation. Soybean cultivars Essex, Clark and Clark-magenta, an isoline of Clark that produces minimal levels of flavonols, were grown beneath shelters covered either with polyester to block most UV-B radiation or teflon which is nearly transparent in the UV range and harvested at regular intervals for pigment and protein analysis. Daily levels of weighted UV-B varied from <1 to >7 kJ m-2. Increases in UV-screening compounds showed a positive dose response to UV-B radiation in all cultivars with Essex showing the steepest dose response. UV-A also induced screening compounds in all species The hydroxycinnimates of the magenta isoline showed a steep dose response to UV-A and a rather constant (non dose specific) but small additional increment in response to UV-B. The Clark isoline, which produced primarily the flavonol quercetin, showed a dose response to UV-B intermediate between that of Clark-magenta and Essex. All three cultivars show similar tolerance to UV-B in field conditions indicating that UV-induced pigment production is adequate to protect them from excessive UV-B damage.

Mutations induced in Tradescantia by small doses of X-rays and neutrons - Analysis of dose-response curves.

NASA Technical Reports Server (NTRS)

Sparrow, A. H.; Underbrink, A. G.; Rossi, H. H.

1972-01-01

Dose-response curves for pink somatic mutations in Tradescantia stamen hairs were analyzed after neutron and X-ray irradiation with doses ranging from a fraction of a rad to the region of saturation. The dose-effect relation for neutrons indicates a linear dependence from 0.01 to 8 rads; between 0.25 and 5 rads, a linear dependence is indicated for X-rays also. As a consequence the relative biological effectiveness reaches a constant value (about 50) at low doses. The observations are in good agreement with the predictions of the theory of dual radiation action and support its interpretation of the effects of radiation on higher organisms. The doubling dose of X-rays was found to be nearly 1 rad.

Alternative Reinforcer Response Cost Impacts Methamphetamine Choice in Humans

PubMed Central

Bennett, J. Adam; Stoops, William W.; Rush, Craig R.

2012-01-01

Methamphetamine use disorders are a persistent public health concern. Behavioral treatments have demonstrated that providing access to non-drug alternative reinforcers reduces methamphetamine use. The purpose of this human laboratory experiment was to determine how changes in response cost for non-drug alternative reinforcers influenced methamphetamine choice. Seven subjects with past year histories of recreational stimulant use completed a placebo-controlled, crossover, double-blind protocol in which they first sampled doses of oral methamphetamine (0, 8 or 16 mg) and completed a battery of subject-rated and physiological measures. During subsequent sessions, subjects then made eight discrete choices between 1/8th of the sampled dose and an alternative reinforcer ($0.25). The response cost to earn a methamphetamine dose was always 500 responses (FR500). The response cost for the alternative reinforcer varied across sessions (FR500, FR1000, FR2000, FR3000). Methamphetamine functioned as a positive reinforcer and produced prototypical stimulant-like effects (e.g., elevated blood pressure, increased ratings of “Stimulated”). Choice for doses over money was sensitive to changes in response cost for alternative reinforcers in that more doses were taken at higher FR values than at lower FR values. Placebo choices changed as a function of alternative reinforcer response cost to a greater degree than active methamphetamine choices. These findings suggest that manipulating the effort necessary to earn alternative reinforcers could impact methamphetamine use. PMID:23046851

Bias of phencyclidine discrimination by the schedule of reinforcement.

PubMed Central

McMillan, D E; Wenger, G R

1984-01-01

Pigeons, trained to discriminate phencyclidine from saline under a procedure requiring the bird to track the location of a color, received cumulative doses of phencyclidine, pentobarbital, or d-amphetamine with a variety of schedules of reinforcement in effect (across phases). When the same second-order schedules were used to reinforce responding after either saline or phencyclidine administration, stimulus control by phencyclidine did not depend on the schedule parameter. When different second-order schedules were used that biased responding toward the phencyclidine-correlated key color, pigeons responded on the phencyclidine-correlated key at lower doses of phencyclidine and pentobarbital than when the second-order schedule biased responding toward the saline key color. A similar but less marked effect was obtained with d-amphetamine. Attempts to produce bias by changing reinforcement magnitude (duration of food availability) were less successful. A signal-detection analysis of dose-effect curves for phencyclidine under two of the second-order schedules employed suggested that at low doses of phencyclidine, response bias is a major determinant of responding. As doses were increased, position preferences occurred and response bias decreased; at higher doses both response bias and position preference decreased and discriminability increased. With low doses of pentobarbital, responding again was biased but increasing doses produced position preference with only small increases in discriminability. At low doses of d-amphetamine responding also was biased, but bias did not decrease consistently with dose nor did discriminability increase. These experiments suggest that the schedule of reinforcement can be used to bias responding toward or away from making the drug-correlated response in drug discrimination experiments, and that signal-detection analysis and analysis of responding at a position can be used to separate the discriminability of the drug state from other effects of the drug on responding. PMID:6481300

Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma.

PubMed

Rangwala, Reshma; Leone, Robert; Chang, Yunyoung C; Fecher, Leslie A; Schuchter, Lynn M; Kramer, Amy; Tan, Kay-See; Heitjan, Daniel F; Rodgers, Glenda; Gallagher, Maryann; Piao, Shengfu; Troxel, Andrea B; Evans, Tracey L; DeMichele, Angela M; Nathanson, Katherine L; O'Dwyer, Peter J; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; Amaravadi, Ravi K

2014-08-01

Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.

Maintained cocaine self-administration is determined by quantal responses: implications for the measurement of antagonist potency.

PubMed

Norman, Andrew B; Tabet, Michael R; Norman, Mantana K; Tsibulsky, Vladimir L

2014-02-01

The change in frequency of cocaine self-administration as a function of the unit dose is widely assumed to represent a graded pharmacodynamic response. Alternatively, a pharmacological theory states that during maintained self-administration, a quantal response occurs at a minimum maintained cocaine concentration (satiety threshold). Rats self-administered cocaine at unit doses spanning an 8-fold range from 0.75 to 6 µmol/kg. Despite an approximately 7-fold difference in the interinjection intervals, there were no differences in the plasma cocaine concentration at the time of lever press across this range of unit doses, consistent with the satiety threshold representing an equiactive cocaine concentration. Because self-administration always occurs when cocaine concentrations decline back to the satiety threshold, this behavior represents a process of automatic back titration of equiactive agonist concentrations. Therefore, the lower frequency of self-administration at higher unit doses is caused by an increase in the duration of the cocaine-induced satiety response, and the graded dose-frequency relationship is due to cocaine pharmacokinetics. After the interinjection intervals at a particular unit dose were stable, rats were injected with the competitive D₁-like dopamine receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390; 15 nmol/kg intravenously) and the session continued. At all cocaine unit doses, SCH23390 accelerated self-administration with a concomitant increase in the calculated satiety threshold, and these equiactive cocaine concentration ratios were independent of the cocaine unit dose. Therefore, the measurement of antagonist potency requires only a single unit dose of cocaine, selected on the basis of convenience, and using multiple cocaine unit doses is redundant.

Responses to simulated nitrogen deposition by the neotropical epiphytic orchid Laelia speciosa

PubMed Central

Díaz-Álvarez, Edison A.; Lindig-Cisneros, Roberto

2015-01-01

Potential ecophysiological responses to nitrogen deposition, which is considered to be one of the leading causes for global biodiversity loss, were studied for the endangered endemic Mexican epiphytic orchid, Laelia speciosa, via a shadehouse dose-response experiment (doses were 2.5, 5, 10, 20, 40, and 80 kg N ha−1 yr−1) in order to assess the potential risk facing this orchid given impending scenarios of nitrogen deposition. Lower doses of nitrogen of up to 20 kg N ha yr−1, the dose that led to optimal plant performance, acted as fertilizer. For instance, the production of leaves and pseudobulbs were respectively 35% and 36% greater for plants receiving 20 kg N ha yr−1 than under any other dose. Also, the chlorophyll content and quantum yield peaked at 0.66 ± 0.03 g m−2 and 0.85 ± 0.01, respectively, for plants growing under the optimum dose. In contrast, toxic effects were observed at the higher doses of 40 and 80 kg N ha yr−1. The δ13C for leaves averaged −14.7 ± 0.2‰ regardless of the nitrogen dose. In turn, δ15N decreased as the nitrogen dose increased from 0.9 ± 0.1‰ under 2.5 kg N ha−1yr−1 to −3.1 ± 0.2‰ under 80 kg N ha−1yr−1, indicating that orchids preferentially assimilate NH4+ rather than NO3− of the solution under higher doses of nitrogen. Laelia speciosa showed a clear response to inputs of nitrogen, thus, increasing rates of atmospheric nitrogen deposition can pose an important threat for this species. PMID:26131375

Dose-Response Relationship between Radiation Dose and Loco-regional Control in Patients with Stage II-III Esophageal Cancer Treated with Definitive Chemoradiotherapy.

PubMed

Kim, Hyun Ju; Suh, Yang-Gun; Lee, Yong Chan; Lee, Sang Kil; Shin, Sung Kwan; Cho, Byung Chul; Lee, Chang Geol

2017-07-01

The correlation between radiation dose and loco-regional control (LRC) was evaluated in patients with stage II-III esophageal cancer treated with definitive concurrent chemoradiotherapy (CRT). Medical records of 236 stage II-III esophageal cancer patients treated with definitive CRT at Yonsei Cancer Center between 1994 and 2013 were retrospectively reviewed. Among these, 120 received a radiation dose of < 60 Gy (standard-dose group), while 116 received ≥ 60 Gy (high-dose group). The median doses of radiation in the standard- and high-dose groups were 50.4 and 63 Gy, respectively. Concurrent 5-fluorouracil/cisplatin chemotherapy was administered to most patients. There were no differences in patient characteristics between the two groups except for high Karnofsky performance status and lower-thoracic lesions being more prevalent in the standard-dose group. The median progression-free survival (PFS) and overall survival (OS) times were 13.2 months and 26.2 months, respectively. Patients in the high-dose group had significantly better 2-year LRC (69.1% vs. 50.3%, p=0.002), median PFS (16.7 months vs. 11.7 months, p=0.029), and median OS (35.1 months vs. 22.3 months, p=0.043). Additionally, LRC exhibited a dose-response relationship and the complete response rate was significantly higher in the high-dose group (p=0.006). There were no significant differences in treatment-related toxicities between the groups. A higher radiation dose (> 60 Gy) is associated with increased LRC, PFS, and OS in patients with stage II-III esophageal cancer treated with definitive CRT.

Evaluation of Clostridium novyi–NT spores in dogs with naturally occurring tumors

PubMed Central

Krick, Erika L.; Sorenmo, Karin U.; Rankin, Shelley C.; Cheong, Ian; Kobrin, Barry; Thornton, Katherine; Kinzler, Kenneth W.; Vogelstein, Bert; Zhou, Shibin; Diaz, Luis A.

2015-01-01

Objective To establish the maximum tolerated dose of Clostridium novyi–NT spores in tumor-bearing dogs and evaluate spore germination within tumors and tumor response. Animals 6 client-owned dogs. Procedures A standard dose-escalation study was planned, with maximum tolerated dose defined as the highest dose at which 0 or 1 of 6 dogs had dose-limiting toxicoses (DLT). Dogs received 1 dose of C novyi–NT spores IV. Toxicoses were graded and interventions performed according to specific guidelines. Grade 3 or higher toxicosis or any toxicosis combination that substantially affected patient status was considered DLT. Clinical response was measured by use of response evaluation criteria in solid tumors at 28 days. Results The first 2 dogs had DLT. The dose was decreased. Two of the next 4 dogs had DLT; therefore, dose administration was stopped because the study endpoint had been reached. The most common toxicosis was fever (n = 6 dogs). Two dogs developed abscesses (1 within a nasal carcinoma and 1 splenic abscess) attributable to C novyi–NT infection; both required surgical intervention. Clostridium novyi–NT was cultured from 1 of 6 tumors. Five dogs were available for response assessment (4 had stable disease; 1 had progressive disease). Conclusions and Clinical Relevance Results indicated that C novyi–NT can germinate within tumors of dogs. Toxicosis, although common and sometimes severe, was manageable with treatment. Further studies in dogs with superficial tumors may allow for continued dose escalation and provide information for use in clinical trials in veterinary and human oncology. PMID:22204296

Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers.

PubMed

Lehmann-Che, Jacqueline; André, Fabrice; Desmedt, Christine; Mazouni, Chafika; Giacchetti, Sylvie; Turpin, Elisabeth; Espié, Marc; Plassa, Louis-François; Marty, Michel; Bertheau, Philippe; Sotiriou, Christos; Piccart, Martine; Symmans, W Fraser; Pusztai, Lajos; de Thé, Hugues

2010-01-01

The predictive value of p53 for the efficacy of front-line anthracycline-based chemotherapy regimens has been a matter of significant controversy. Anthracyclines are usually combined with widely different doses of alkylating agents, which may significantly modulate tumor response to these combinations. We analyzed three series of de novo stage II-III breast cancer patients treated front line with anthracycline-based regimens of various cyclophosphamide dose intensities: 65 patients with estrogen receptor (ER)(-) tumors treated with anthracyclines alone (Institut Jules Bordet, Brussels), 51 unselected breast cancer patients treated with intermediate doses of cyclophosphamide (MD Anderson Cancer Center, Houston, TX), and 128 others treated with a dose-dense anthracycline-cyclophosphamide combination (St. Louis, Paris). After chemotherapy and surgery, pathologic complete response (pCR) was evaluated. p53 status was determined by a yeast functional assay on the pretreatment tumor sample. In a multivariate analysis of the pooled results, a lack of ER expression and high-dose cyclophosphamide administration were associated with a higher likelihood of pCR. A sharp statistical interaction was detected between p53 status and cyclophosphamide dose intensity. Indeed, when restricting our analysis to patients with ER(-) tumors, we confirmed that a mutant p53 status was associated with anthracycline resistance, but found that p53 inactivation was required for response to the dose-intense alkylating regimen. The latter allowed very high levels of pCR in triple-negative tumors. Thus, our data strongly suggest that cyclophosphamide dose intensification in ER(-) p53-mutated breast cancer patients could significantly improve their response.

A comparative assessment of the duration of action of amlodipine and nifedipine GITS in normotensive subjects.

PubMed

Ueda, S; Meredith, P A; Howie, C A; Elliott, H L

1993-12-01

1 This study in normotensive subjects compared the duration and consistency of action of amlodipine (5 mg) and nifedipine GITS (60 mg) by assessment of the attenuation of pressor responses to noradrenaline and angiotensin II. 2 Both drugs significantly attenuated pressor responses to both vasoconstrictors at 6 and 24 h post-dose with rightward shifts of up to 2.3-fold in the dose-response curves. 3 There was significantly less pharmacokinetic variability with amlodipine: for example, intra-subject variability was 33% with amlodipine and 59% with nifedipine GITS. 4 There were no significant differences in the pressor dose ratios up to 48 h post-dose with amlodipine whereas there was a significant and progressive reduction in the pressor dose ratios with nifedipine. 5 These results suggest that both drugs are broadly comparable as once daily treatments but amlodipine displayed less intra- and inter-subject variability and provided a significantly more sustained effect with a reserve of pharmacological activity up to 48 h post-dose.

Influence of sensitization on the discriminative stimulus effects of methylphenidate in mice.

PubMed

McGovern, Robin; Luderman, Lauryn; Knecht, Kelly; Griffin, William C

2014-12-01

Methylphenidate (MPH) remains an important therapy for attention-deficit hyperactivity disorder, but aspects of its pharmacology remain unclear. In the present study, we used a regimen of MPH (8 mg/kg daily×14 days) in C57BL/6J mice to determine whether establishing locomotor sensitization to MPH influenced the acquisition and the dose-response function of MPH in a classic drug discrimination procedure. MPH-sensitized mice (SENS group) showed enhanced locomotor activity to the 8 mg/kg exposure dose as well as a 2 mg/kg dose before discrimination training. However, the SENS mice did not acquire discrimination of either a low dose (2 mg/kg) or a higher dose (4 mg/kg) of MPH any more rapidly than the CTRL mice. Further, during generalization testing, the dose-response functions for the SENS and CTRL mice were identical. Therefore, we did not find that previous exposure to MPH, which produced a sensitized locomotor response, facilitated MPH discrimination.

Immune modulation with high-dose heat-shock protein gp96: therapy of murine autoimmune diabetes and encephalomyelitis.

PubMed

Chandawarkar, Rajiv Y; Wagh, Mihir S; Kovalchin, Joseph T; Srivastava, Pramod

2004-04-01

Immunization with heat-shock protein (HSP) gp96 elicits protective immunity to the cancer or virus-infected cells from which it is derived. Low doses of gp96 generate immunity, while doses 10 times the immunizing dose do not. We show here that injection of high doses of gp96 generates CD4(+) T cells that down-regulate a variety of ongoing immune responses. Immunization with high doses of gp96 prevents myelin basic protein- or proteolipid protein-induced autoimmune encephalomyelitis in SJL mice and the onset of diabetes in non-obese diabetic mice. The suppression of immune response can be adoptively transferred with CD4(+) cells and does not partition with the CD25 phenotype. The immunomodulatory properties of gp96 (and possibly other HSP) may be used for antigen-specific activation or suppression of cellular immune responses. The latter may form the basis for novel immunotherapies for autoimmune diseases.

GENERAL CONSIDERATIONS OF DOSE-EFFECT AND DOSE-RESPONSE RELATIONSHIPS

EPA Science Inventory

ABSTRACT In 2003, the International Union of Pure and Applied chemistry (IUPAC) issued a glossary of terms that included the defi nition of dose-effect and doseresponse relationships (Nordberg et al., 2004). Dose effect relationship is defined as an association between dose and...

Dose requirements of alfentanil to eliminate autonomic responses during rapid-sequence induction with thiopental 4 mg/kg and rocuronium 0.6 mg/kg.

PubMed

Abou-Arab, Mohammad H; Rostrup, Morten; Heier, Tom

2016-12-01

Opioids are integral part of anesthesia induction, but information on optimal dosing is limited. We aimed to determine doses of alfentanil needed to eliminate increases in 5 autonomic response variables (plasma concentrations of epinephrine, norepinephrine and vasopressin, arterial blood pressure [ABP], and heart rate) during rapid-sequence induction of anesthesia with thiopental 4 mg/kg and rocuronium 0.6 mg/kg. Prospective, randomized, observer-blinded, interventional clinical study. Large academic institution. Eighty-four healthy patients, aged 18 to 55 years, received 1 of 7 assessor-blinded doses of alfentanil (0, 10, 20, 30, 40, 50, and 60 μg/kg) together with thiopental 4 mg/kg and rocuronium 0.6 mg/kg, administered in rapid succession (15 seconds). Laryngoscopy was initiated 40 seconds after rocuronium, and tracheal intubation was concluded within 15 seconds thereafter. An indwelling radial artery catheter was used for hemodynamic monitoring and blood sampling. Relationships between alfentanil dose and response variables were tested with linear regression, and the influence of covariates (sex, body weight, and age) was determined. Alfentanil dose needed to prevent increases in ABP >10% above baseline with 95% probability was estimated with logistic regression. Significant relationships were determined between alfentanil dose and response variables. Clinically interesting influence of covariates was not found. Alfentanil 55 μg/kg was needed to prevent increases in ABP postintubation >10% above baseline with 95% probability. One individual needed a bolus of vasopressor postintubation. Optimal control of autonomic responses during rapid-sequence induction was achieved with clinically relevant doses of alfentanil in healthy patients anesthetized with thiopental 4 mg/kg and rocuronium 0.6 mg/kg. Copyright © 2016 Elsevier Inc. All rights reserved.

A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia: Metformin with induction chemotherapy of vincristine, dexamethasone, PEG-asparaginase, and doxorubicin.

PubMed

Trucco, Matteo; Barredo, Julio C; Goldberg, John; Leclerc, Gilles M; Hale, Gregory A; Gill, Jonathan; Setty, Bhuvana; Smith, Tiffany; Lush, Richard; Lee, Jae K; Reed, Damon R

2018-06-01

Acute lymphoblastic leukemia (ALL) remains a major cause of death in children. AMP-activated protein kinase (AMPK) affects the unfolded protein response (UPR), leading to increased vulnerability to endoplasmic reticulum (ER) stress in ALL cells. In vitro, metformin causes ALL cell death via AMPK-mediated inhibition of the UPR. It was evaluated whether ER stress could be induced in relapsed ALL through a phase I study investigating the safety and feasibility of metformin in combination with relapse induction chemotherapy. Metformin was administered twice daily for 28 days in addition to vincristine, dexamethasone, PEG-asparaginase and doxorubicin (VXLD). Dose escalation of metformin was evaluated using a 3+3 design. Pharmacokinetics (PK), pharmacodynamic (PD) evaluation of the AMPK and ER stress/UPR pathways, and treatment response were assessed. Fourteen patients were enrolled; all were evaluable for toxicity. The recommended phase 2 dose (RP2D) was Dose level 2, 1,000 mg/m 2 /day. A single dose-limiting toxicity (DLT), hypoglycemia with acidosis, was observed at the RP2D and two DLTs, diarrhea and acidosis, were observed at Dose Level 3. Nine patients were evaluable for response as defined by the protocol, receiving at least 85% of planned metformin doses. Five complete remissions, one partial response, and one stable disease were observed. PD evaluation showed induction of ER stress, activation of AMPK, and inhibition of the UPR. The VXLD with metformin was tolerable with a RP2D for metformin of 1,000 mg/m 2 /day and yielded responses in a heavily pretreated population. ER stress was induced and toxicities attributable to metformin occurred in all dose levels. © 2018 Wiley Periodicals, Inc.

An investigation into the selectivity of a novel series of benzoquinolizines for alpha 2-adrenoceptors in vivo.

PubMed Central

Paciorek, P. M.; Pierce, V.; Shepperson, N. B.; Waterfall, J. F.

1984-01-01

The potencies and selectivities of a novel series of benzoquinolizines for the alpha 2-adrenoceptor have been investigated in the rat in comparison with yohimbine and indoramin. Peripheral postjunctional alpha 2- and alpha 1-adrenoceptor blockade was measured as the reversal of B-HT 933 and methoxamine-induced pressor responses, respectively, in the pithed rat. Peripheral prejunctional alpha 2-adrenoceptor blockade was measured as the reversal of B-HT 933-induced inhibition of an electrically evoked tachycardia in the pithed rat. Central alpha 2-adrenoceptor blockade was measured as a reversal of the hypotension induced in anaesthetized rats by central (i.c.v.) administration of clonidine. Wy 25309, Wy 26392, Wy 26703 and yohimbine (0.3-3 mg kg-1 i.v.) evoked dose-dependent shifts to the right of the dose-response curves to B-HT 933 whilst having minimal effects on the methoxamine dose-response curve. The selectivity for alpha 2-adrenoceptors increased with the dose of antagonist administered. In general, the order of selectivity was Wy 25309 greater than Wy 26392 greater than Wy 26703 greater than yohimbine. Indoramin (1 mg kg-1 i.v.) shifted the methoxamine pressor dose-response curve to the right without affecting the B-HT 933 dose-response curves, confirming its selective alpha 1-antagonist activity. Peripheral administration of all three benzoquinolizines (1-100 micrograms kg-1 i.v.) led to a dose-dependent reversal of the hypotension evoked by central administration of clonidine (500 ng i.c.v.). The reversal was incomplete, higher doses causing a further decrease in blood pressure. (ABSTRACT TRUNCATED AT 250 WORDS) PMID:6329385

Clinical application of a nomogram based on age, serum FSH and AMH to select the FSH starting dose in IVF/ICSI cycles: a retrospective two-centres study.

PubMed

Papaleo, Enrico; Zaffagnini, Stefano; Munaretto, Maria; Vanni, Valeria Stella; Rebonato, Giorgia; Grisendi, Valentina; Di Paola, Rossana; La Marca, Antonio

2016-12-01

To externally validate a nomogram based on ovarian reserve markers as a tool to optimize the FSH starting dose in IVF/ICSI cycles. A two-centres retrospective study including 398 infertile women undergoing their first IVF/ICSI cycle (June 2013-June 2014). IVF data were retrieved from two independent IVF centres in Italy (San Raffaele Hospital, Centre 1; Verona Hospital, Centre 2). A central lab for the routine measurement of AMH and FSH was used for both centres. All women were treated based on physical and hormonal characteristics according to locally adopted protocols. The nomogram was then retrospectively applied to the patients comparing the calculated starting dose to the one actually given. In Centre 1, 64/131 women (48.8%) had an ovarian response below the target. While 45 of these patients were treated with a maximal FSH starting dose (≥225 IU), n=19/131 (14.5%) were treated with a submaximal dose. The vast majority of them (n=17/19) would have received a higher FSH starting dose by using the nomogram. Seventeen patients (n=17/131) had hyper response and about half of them would have been treated with a reduced FSH starting dose according to the nomogram. In Centre 2, 142/267 patients (53.2%) had an ovarian response below the target. While 136 of these were treated with a maximal FSH starting dose (≥225 IU), n=6/267 were treated with a submaximal dose. The majority of them (n=5/6) would have received a higher FSH starting dose. Thirty-two (n=32/267) patients had hyper response and more than half of them would have been treated with a reduced FSH dose. In both Centres, applying the nomogram would have resulted in more appropriate FSH starting doses compared to the the ones actually given based on clinicians choices. The use of an objective algorithm based on patient's age, serum FSH and AMH levels may thus be an effective advice on the selection of the tailored FSH starting dose. Hence, the use of this easily available nomogram could increase the proportion of patients achieving the optimal ovarian response. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cellular and Humoral Responses to a Second Dose of Herpes Zoster Vaccine Administered 10 Years After the First Dose Among Older Adults.

PubMed

Levin, Myron J; Schmader, Kenneth E; Pang, Lei; Williams-Diaz, Angela; Zerbe, Gary; Canniff, Jennifer; Johnson, Michael J; Caldas, Yupanqui; Cho, Alice; Lang, Nancy; Su, Shu-Chih; Parrino, Janie; Popmihajlov, Zoran; Weinberg, Adriana

2016-01-01

Herpes zoster vaccine (ZV) was administered as a second dose to 200 participants ≥ 70 years old who had received a dose of ZV ≥ 10 years previously (NCT01245751). Varicella zoster virus (VZV) antibody titers (measured by a VZV glycoprotein-based enzyme-linked immunosorbent assay [gpELISA]) and levels of interferon γ (IFN-γ) and interleukin 2 (IL-2; markers of VZV-specific cell-mediated immunity [CMI], measured by means of ELISPOT analysis) in individuals aged ≥ 70 years who received a booster dose of ZV were compared to responses of 100 participants aged 50-59 years, 100 aged 60-69 years, and 200 aged ≥ 70 years who received their first dose of ZV. The study was powered to demonstrate noninferiority of the VZV antibody response at 6 weeks in the booster-dose group, compared with the age-matched first-dose group. Antibody responses were similar at baseline and after vaccination across all age and treatment groups. Both baseline and postvaccination VZV-specific CMI were lower in the older age groups. Peak gpELISA titers and their fold rise from baseline generally correlated with higher baseline and postvaccination VZV-specific CMI. IFN-γ and IL-2 results for subjects ≥ 70 years old were significantly higher at baseline and after vaccination in the booster-dose group, compared with the first-dose group, indicating that a residual effect of ZV on VZV-specific CMI persisted for ≥ 10 years and was enhanced by the booster dose. These findings support further investigation of ZV administration in early versus later age and of booster doses for elderly individuals at an appropriate interval after initial immunization against HZ. NCT01245751. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Identification of Differential Gene Expression Patterns after Acute Exposure to High and Low Doses of Low-LET Ionizing Radiation in a Reconstituted Human Skin Tissue

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tilton, Susan C.; Markillie, Lye Meng; Hays, Spencer

Our goal here was to identify dose and temporal dependent radiation responses in a complex tissue, reconstituted human skin. Direct sequencing of RNA (RNA-seq) was used to quantify altered transcripts following exposure to 0.1, 2 and 10 Gy of ionizing radiation at 3 and 8 hours. These doses include a low dose in the range of some medical diagnostic procedures (0.1 Gy), a dose typically received during radiotherapy (2.0 Gy) and a lethal dose (10 Gy). These doses could be received after an intentional or accidental radiation exposure and biomarkers are needed to rapidly and accurately triage exposed individuals. Amore » total of 1701 genes were deemed to be significantly affected by high dose radiation exposure with the majority of genes affected at 10 Gy. A group of 29 genes including GDF15, BBC3, PPM1D, FDXR, GADD45A, MDM2, CDKN1A, TP53INP1, CYCSP27, SESN1, SESN2, PCNA, and AEN were similarly altered at both 2 and 10 Gy, but not 0.1 Gy, at multiple time points. A much larger group of up regulated genes, including those involved in inflammatory responses, was significantly altered only after a 10 Gy exposure. At high doses, down regulated genes were associated with cell cycle regulation and exhibited an apparent linear response between 2 and 10 Gy. While only a handful of genes were significantly affected by 0.1 Gy exposure using stringent statistical filters, groups of related genes regulating cell cycle progression and inflammatory responses consistently exhibited opposite trends in their regulation compared to the high dose exposures. Differential regulation of PLK1 signaling at low and high doses was confirmed using qRT-PCR. These results indicate that some alterations in gene expression are qualitatively different at low and high doses of radiation in this model system.« less

A comparison of two doses of omeprazole in the treatment of equine gastric ulcer syndrome: a blinded, randomised, clinical trial.

PubMed

Sykes, B W; Sykes, K M; Hallowell, G D

2014-07-01

Studies on omeprazole have reported that doses as low as 0.7 mg/kg bwt per os are potent suppressors of acid production. Yet, to date, no studies have compared treatment efficacy of different doses in clinical cases of equine gastric ulceration. Furthermore, no studies have been performed to compare the healing response of the squamous and glandular mucosa to acid suppression therapy. To compare: 1) the efficacy of 2 doses of omeprazole in the treatment of primary squamous and glandular gastric ulceration; and 2) the healing response of primary squamous and glandular gastric ulceration to acid suppression therapy. A blinded, randomised, dose-response clinical trial. Twenty Thoroughbred racehorses with grade ≥2/4 glandular ulceration were identified on gastroscopy. Seventeen horses also had grade ≥2/4 squamous ulceration. Horses were randomly assigned to one of 2 groups. Horses received either 2.0 g (high dose: 4.0 mg/kg bwt) or 0.8 g (low dose: 1.6 mg/kg bwt) of oral omeprazole per os once daily. Gastroscopy was repeated at 28-35 days. Time and dose significantly affected grades of squamous (P<0.0001, P = 0.02) and glandular (P = 0.006 and 0.005) ulceration. Data analysis did not support our hypothesis that the lower dose would have similar effects (i.e. be noninferior) to the higher dose when considering ulcer healing and ulcer improvement. Improvement was more likely with the high dose for the squamous (P = 0.05) but not glandular (P = 0.4) mucosa. The percentage of glandular ulcers that improved was less than squamous ulcers (P = 0.02). The results suggest that a dose-response exists for the treatment of both squamous and glandular ulcers. Improvement of glandular ulcers was not as complete as observed with squamous ulcers and current equine gastric ulcer syndrome treatment recommendations may not be appropriate for glandular disease. © 2013 EVJ Ltd.

Dose- and time-dependence of the host-mediated response to paclitaxel therapy: a mathematical modeling approach.

PubMed

Benguigui, Madeleine; Alishekevitz, Dror; Timaner, Michael; Shechter, Dvir; Raviv, Ziv; Benzekry, Sebastien; Shaked, Yuval

2018-01-05

It has recently been suggested that pro-tumorigenic host-mediated processes induced in response to chemotherapy counteract the anti-tumor activity of therapy, and thereby decrease net therapeutic outcome. Here we use experimental data to formulate a mathematical model describing the host response to different doses of paclitaxel (PTX) chemotherapy as well as the duration of the response. Three previously described host-mediated effects are used as readouts for the host response to therapy. These include the levels of circulating endothelial progenitor cells in peripheral blood and the effect of plasma derived from PTX-treated mice on migratory and invasive properties of tumor cells in vitro . A first set of mathematical models, based on basic principles of pharmacokinetics/pharmacodynamics, did not appropriately describe the dose-dependence and duration of the host response regarding the effects on invasion. We therefore provide an alternative mathematical model with a dose-dependent threshold, instead of a concentration-dependent one, that describes better the data. This model is integrated into a global model defining all three host-mediated effects. It not only precisely describes the data, but also correctly predicts host-mediated effects at different doses as well as the duration of the host response. This mathematical model may serve as a tool to predict the host response to chemotherapy in cancer patients, and therefore may be used to design chemotherapy regimens with improved therapeutic outcome by minimizing host mediated effects.

Spectral correction factors for conventional neutron dosemeters used in high-energy neutron environments.

PubMed

Lee, K W; Sheu, R J

2015-04-01

High-energy neutrons (>10 MeV) contribute substantially to the dose fraction but result in only a small or negligible response in most conventional moderated-type neutron detectors. Neutron dosemeters used for radiation protection purpose are commonly calibrated with (252)Cf neutron sources and are used in various workplace. A workplace-specific correction factor is suggested. In this study, the effect of the neutron spectrum on the accuracy of dose measurements was investigated. A set of neutron spectra representing various neutron environments was selected to study the dose responses of a series of Bonner spheres, including standard and extended-range spheres. By comparing (252)Cf-calibrated dose responses with reference values based on fluence-to-dose conversion coefficients, this paper presents recommendations for neutron field characterisation and appropriate correction factors for responses of conventional neutron dosemeters used in environments with high-energy neutrons. The correction depends on the estimated percentage of high-energy neutrons in the spectrum or the ratio between the measured responses of two Bonner spheres (the 4P6_8 extended-range sphere versus the 6″ standard sphere). © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Predicting cancer rates in astronauts from animal carcinogenesis studies and cellular markers

NASA Technical Reports Server (NTRS)

Williams, J. R.; Zhang, Y.; Zhou, H.; Osman, M.; Cha, D.; Kavet, R.; Cuccinotta, F.; Dicello, J. F.; Dillehay, L. E.

1999-01-01

The radiation space environment includes particles such as protons and multiple species of heavy ions, with much of the exposure to these radiations occurring at extremely low average dose-rates. Limitations in databases needed to predict cancer hazards in human beings from such radiations are significant and currently do not provide confidence that such predictions are acceptably precise or accurate. In this article, we outline the need for animal carcinogenesis data based on a more sophisticated understanding of the dose-response relationship for induction of cancer and correlative cellular endpoints by representative space radiations. We stress the need for a model that can interrelate human and animal carcinogenesis data with cellular mechanisms. Using a broad model for dose-response patterns which we term the "subalpha-alpha-omega (SAO) model", we explore examples in the literature for radiation-induced cancer and for radiation-induced cellular events to illustrate the need for data that define the dose-response patterns more precisely over specific dose ranges, with special attention to low dose, low dose-rate exposure. We present data for multiple endpoints in cells, which vary in their radiosensitivity, that also support the proposed model. We have measured induction of complex chromosome aberrations in multiple cell types by two space radiations, Fe-ions and protons, and compared these to photons delivered at high dose-rate or low dose-rate. Our data demonstrate that at least three factors modulate the relative efficacy of Fe-ions compared to photons: (i) intrinsic radiosensitivity of irradiated cells; (ii) dose-rate; and (iii) another unspecified effect perhaps related to reparability of DNA lesions. These factors can produce respectively up to at least 7-, 6- and 3-fold variability. These data demonstrate the need to understand better the role of intrinsic radiosensitivity and dose-rate effects in mammalian cell response to ionizing radiation. Such understanding is critical in extrapolating databases between cellular response, animal carcinogenesis and human carcinogenesis, and we suggest that the SAO model is a useful tool for such extrapolation.

Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment.

PubMed

Ranganath, Lakshminarayan R; Milan, Anna M; Hughes, Andrew T; Dutton, John J; Fitzgerald, Richard; Briggs, Michael C; Bygott, Helen; Psarelli, Eftychia E; Cox, Trevor F; Gallagher, James A; Jarvis, Jonathan C; van Kan, Christa; Hall, Anthony K; Laan, Dinny; Olsson, Birgitta; Szamosi, Johan; Rudebeck, Mattias; Kullenberg, Torbjörn; Cronlund, Arvid; Svensson, Lennart; Junestrand, Carin; Ayoob, Hana; Timmis, Oliver G; Sireau, Nicolas; Le Quan Sang, Kim-Hanh; Genovese, Federica; Braconi, Daniela; Santucci, Annalisa; Nemethova, Martina; Zatkova, Andrea; McCaffrey, Judith; Christensen, Peter; Ross, Gordon; Imrich, Richard; Rovensky, Jozef

2016-02-01

Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid (HGA) in AKU but the dose-response relationship has not been previously studied. Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4 weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of nitisinone. A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mmol for the no treatment or 1 mg, 2 mg, 4 mg and 8 mg doses, respectively. For the most efficacious dose, 8 mg daily, this corresponds to a mean reduction of u-HGA24 of 98.8% compared with baseline. An increase in tyrosine levels was seen at all doses but the dose-response relationship was less clear than the effect on HGA. Despite tyrosinaemia, there were no safety concerns and no serious adverse events were reported over the 4 weeks of nitisinone therapy. In this study in patients with AKU, nitisinone therapy decreased urinary HGA excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range. EudraCT number: 2012-005340-24. Registered at ClinicalTrials.gov: NCTO1828463. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

A randomized dose-response trial of aerobic exercise and health-related quality of life in colon cancer survivors.

PubMed

Brown, Justin C; Damjanov, Nevena; Courneya, Kerry S; Troxel, Andrea B; Zemel, Babette S; Rickels, Michael R; Ky, Bonnie; Rhim, Andrew D; Rustgi, Anil K; Schmitz, Kathryn H

2018-04-01

To examine the dose-response effects of aerobic exercise on health-related quality of life (HRQoL) among colon cancer survivors. Thirty-nine stage I to III colon cancer survivors were randomized to 1 of 3 groups: usual-care control, 150 min·wk -1 of aerobic exercise (low-dose) and 300 min·wk -1 of aerobic exercise (high-dose) for 6 months. HRQoL outcomes included the Short Form (SF)-36 physical and mental component summary, Functional Assessment of Cancer Therapy-Colorectal, Pittsburgh Sleep Quality Index, Fear of Cancer Recurrence Inventory, Fatigue Symptom Inventory, and North Central Cancer Treatment Group bowel function questionnaire, assessed at baseline and post intervention. The primary hypothesis was that exercise would improve HRQoL outcomes in a dose-response fashion, such that high-dose aerobic exercise would yield the largest improvements in HRQoL outcomes. Over 6 months, the low-dose group completed 141 ± 10 min·wk -1 of aerobic exercise, and the high-dose group completed 247 ± 11 min·wk -1 of aerobic exercise. Over 6 months, exercise improved the physical component summary score of the SF-36 (P trend  = 0.002), the Functional Assessment of Cancer Therapy-Colorectal (P trend  = 0.025), the Pittsburgh Sleep Quality Index (P trend  = 0.049), and the Fatigue Symptom Inventory (P trend  = 0.045) in a dose-response fashion. Between-group standardized mean difference effects sizes for the above-described findings were small to moderate in magnitude (0.35-0.75). No dose-response effects were observed for the mental component summary score of the SF-36, the Fear of Cancer Recurrence Inventory, or bowel function. Higher doses of aerobic exercise, up to 300 min·wk -1 , improve multiple HRQoL outcomes among stage I to III colon cancer survivors. These findings provide evidence that aerobic exercise may provide multiple health benefits for colon cancer survivors. Copyright © 2018 John Wiley & Sons, Ltd.

Study of thermoluminescence response of purple to violet amethyst quartz from Balikesir, Turkey

NASA Astrophysics Data System (ADS)

Nur, N.; Yeğingil, Z.; Topaksu, M.; Kurt, K.; Doğan, T.; Sarıgül, N.; Yüksel, M.; Altunal, V.; Özdemir, A.; Güçkan, V.; Günay, I.

2015-09-01

In thermoluminescence (TL) dosimetry, the phosphor amethyst quartz as a thermoluminescent, appears to be one of the materials arousing the highest interest. In this study the dosimetric characteristics of natural amethyst quartz crystals collected from Balikesir-Dursunbey (Turkey) were investigated for the purpose of determination of the general properties that phosphors should have in order to be useful for thermoluminescence dosimetry. The natural thermoluminescence was drained by annealing the powder samples at 450 °C for 1.5 h. The effects of high temperature annealing, dose response curves, glow curves after a postirradiation annealing, reusability of the samples and storage of trapped electrons in dark at room temperature were clarified through irradiating the samples with the desired exposures by 90Sr/90Y beta particles. Isothermal annealing before and after irradiation was found to have a definite effect upon the TL glow curve of amethyst crystal powder. The same sample varied in sensitivity depending upon its previous thermal and radiation history. The peak heights of the glow peaks were examined with respect to dose response at dose levels between 1 Gy and 5 kGy. The intermediate temperature (IT) and high temperature (HT) peaks of 230 °C and 300 °C, respectively, exhibit dose-response curves as superlinear when dose is on the logarithmic scale except the dose response of 300 °C peak for the dose values of 1 < D < 20 Gy in which linear dose response was acquired. At the end of the storage time between exposure and readout which was about one month at room temperature, the emitted light reduction was 14% comparing to the initial state. Repeating the measurements of the same sample, exposed with 0.1, 0.5, 0.8 and 1 kGy beta exposures, resulted in between 4% and 11% increase in the TL sensitivity of the material.

Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: a dose escalation and pharmacologic study.

PubMed

Phuphanich, Surasak; Baker, Sharyn D; Grossman, Stuart A; Carson, Kathryn A; Gilbert, Mark R; Fisher, Joy D; Carducci, Michael A

2005-04-01

We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 muM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme-inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants.

Final Report - Epigenetics of low dose radiation effects in an animal model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kovalchuk, Olga

This project sought mechanistic understanding of the epigenetic response of tissues as well as the consequences of those responses, when induced by low dose irradiation in a well-established model system (mouse). Based on solid and extensive preliminary data we investigated the molecular epigenetic mechanisms of in vivo radiation responses, particularly – effects of low, occupationally relevant radiation exposures on the genome stability and adaptive response in mammalian tissues and organisms. We accumulated evidence that low dose irradiation altered epigenetic profiles and impacted radiation target organs of the exposed animals. The main long-term goal was to dissect the epigenetic basis ofmore » induction of the low dose radiation-induced genome instability and adaptive response and the specific fundamental roles of epigenetic changes (i.e. DNA methylation, histone modifications and miRNAs) in their generation. We hypothesized that changes in global and regional DNA methylation, global histone modifications and regulatory microRNAs played pivotal roles in the generation and maintenance low-dose radiation-induced genome instability and adaptive response. We predicted that epigenetic changes influenced the levels of genetic rearrangements (transposone reactivation). We hypothesized that epigenetic responses from low dose irradiation were dependent on exposure regimes, and would be greatest when organisms are exposed in a protracted/fractionated manner: fractionated exposures > acute exposures. We anticipated that the epigenetic responses were correlated with the gene expression levels. Our immediate objectives were: • To investigate the exact nature of the global and locus-specific DNA methylation changes in the LDR exposed cells and tissues and dissect their roles in adaptive response • To investigate the roles of histone modifications in the low dose radiation effects and adaptive response • To dissect the roles of regulatory microRNAs and their targets in low dose radiation effects and adaptive response • To correlate the levels of epigenetic changes with genetic rearrangement levels and gene expression patterns. In sum, we determined the precise global and locus-specific DNA methylation patterns in the LDR-exposed cells and tissues of mice, and to correlated DNA methylation changes with the gene expression patterns and manifestations of genome instability. We also determined the alterations of global histone modification pattern in the LDR exposed tissues. Additionally, we established the nature of microRNAome changes in the LDR exposed tissue. In this study we for the first time found that LDR exposure caused profound tissue-specific epigenetic changes in the exposed tissues. We established that LDR exposure affect methylation of repetitive elements in the murine genome, causes changes in histone methylation, acetylation and phosphorylation. Importantly, we found that LDR causes profound and persistent effects on small RNA profiles and gene expression, and that miRNAs are excellent biomarkers of LDR exposure. Furthermore, we extended our analysis and studied LDR effects in rat tissues and human tissues and cell lines. There we also analyzed LDR-induced gene expression, DNA methylation and miRNA changes. Our datasets laid foundation for several new research projects aimed to understand molecular underpinnings of low dose radiation responses, and biological repercussions of low dose radiation effects and radiation carcinogenesis.« less

Hematopoietic responses under protracted exposures to low daily dose gamma irradiation.

PubMed

Seed, T M; Fritz, T E; Tolle, D V; Jackson, W E

2002-01-01

In attempting to evaluate the possible health consequences of chronic ionizing radiation exposure during extended space travel (e.g., Mars Mission), ground-based experimental studies of the clinical and pathological responses of canines under low daily doses of 60Co gamma irradiation (0.3-26.3 cGy d-1) have been examined. Specific reference was given to responses of the blood forming system. Results suggest that the daily dose rate of 7.5 cGy d-1 represents a threshold below which the hematopoietic system can retain either partial or full trilineal cell-producing capacity (erythropoiesis, myelopoiesis, and megakaryopoiesis) for extended periods of exposure (>1 yr). Trilineal capacity was fully retained for several years of exposure at the lowest dose-rate tested (0.3 cGy d-1) but was completely lost within several hundred days at the highest dose-rate (26.3 cGy d-1). Retention of hematopoietic capacity under chronic exposure has been demonstrated to be mediated by hematopoietic progenitors with acquired radioresistance and repair functions, altered cytogenetics, and cell-cycle characteristics. Radiological, biological, and temporal parameters responsible for these vital acquisitions by hematopoietic progenitors have been partially characterized. These parameters, along with threshold responses, are described and discussed in relation to potential health risks of the space traveler under chronic stress of low-dose irradiation. Published by Elsevier Science Ltd on behalf of COSPAR.

Stimulation Versus Inhibition—Bioactivity of Parthenin, A Phytochemical From Parthenium hysterophorus L.

PubMed Central

Belz, Regina G.

2008-01-01

Parthenium hysterophorus L. is an invasive weed that biosynthesizes several phytochemi-cals. The sesquiterpene lactone parthenin receives most attention regarding allelopathy of the plant or potential herbicidal properties. Since parthenin exhibits dose-dependent phy-totoxicity with low dose stimulation, this study investigated the occurrence and temporal features of parthenin hormesis in Sinapis arvensis L. sprayed with parthenin under semi-natural conditions. Dose/response studies showed that the occurrence and the magnitude of hormesis depended on climatic conditions and the parameter measured. Within the tested dose range, stimulatory responses were only observed under less-stressful conditions and were most pronounced for leaf area growth [138 % of control; 13 days after treatment (DAT)]. Temporal assessment of leaf area development showed that doses causing a stimulatory response at the end of the experiment (< 0.42 ± 0.04 kg/ha; 13 DAT) were initially inhibitory up to ED50 values (2 DAT). This clearly demonstrated an over-compensatory response. Inhibition of leaf area at 13 DAT reached ED50 values on average at 0.62 ±0.12 kg/ha, and S. arvensis was completely inhibited at doses exceeding 1.81 ±0.56 kg/ha (ED90). Based on these findings, implications of parthenin hormesis are discussed with respect to allelopathy of P. hysterophorus and exploitation of growth stimulatory responses in agriculture. PMID:18648571

Exercise-Induced Dose-Response Alterations in Adiponectin and Leptin Levels Are Dependent on Body Fat Changes in Women at Risk for Breast Cancer.

PubMed

Sturgeon, Kathleen; Digiovanni, Laura; Good, Jerene; Salvatore, Domenick; Fenderson, Desiré; Domchek, Susan; Stopfer, Jill; Galantino, Mary Lou; Bryan, Cathy; Hwang, Wei-Ting; Schmitz, Kathryn

2016-08-01

Dysregulation of adipokines, such as adiponectin and leptin, is associated with a variety of chronic diseases, including cancer. Physical activity protects against breast cancer and one of the mechanisms which may underlie this association is exercise-induced changes in adipokine levels. The WISER Sister Trial was a three-armed randomized controlled trial in premenopausal women (n = 137) with an elevated risk for breast cancer. A 5-menstrual-cycle-long dosed aerobic exercise intervention compared low-dose exercise (150 min/wk; n = 44) or high-dose exercise (300 min/wk; n = 48) with a control group asked to maintain usual activity levels (n = 45). Exercise intensity progressed to and was maintained at 70% to 80% of age predicted heart rate max. Body composition and adipokine levels were measured at baseline and follow-up. We observed significant linear trends for increased fitness capacity (Δ%: -2.0% control, 10.1% low dose, 13.1% high dose), decreased fat tissue-to-total tissue mass (Δ%: 0.7% control, -2.9% low dose, -3.7% high dose), increased body fat adjusted adiponectin (Δ%: -0.6% control, 0.6% low dose, 0.9% high dose), and decreased body fat adjusted leptin (Δ%: 0.7% control, -8.2% low dose, -10.2% high dose). In this randomized clinical trial of premenopausal women at risk for breast cancer, we demonstrate a dose-response effect of exercise on adiponectin and leptin and that dose response is dependent on changes in body fat. Improved adipokine levels, achieved by aerobic exercise training-induced decreases in body fat, may decrease breast cancer risk for high-risk premenopausal women. Cancer Epidemiol Biomarkers Prev; 25(8); 1195-200. ©2016 AACR. ©2016 American Association for Cancer Research.

IRIS Toxicological Review of Acrylamide (External Review ...

EPA Pesticide Factsheets

EPA has conducted a peer review by EPA’s Science Advisory Board (SAB) of the scientific basis supporting the human health hazard and dose-response assessment of acrylamide that once finalized will appear on the Integrated Risk Information System (IRIS) database. Peer review is meant to ensure that the science is used credibly and appropriately in derivation of the dose-response assessments and toxicological characterization. The draft Toxicological Review of Acrylamide provides scientific support and rationale for the hazard identification and dose-response assessment pertaining to a chronic exposure to acrylamide.

Dramatic response to high-dose icotinib in a lung adenocarcinoma patient after erlotinib failure.

PubMed

Guan, Yin; Zhao, Hong; Meng, Jing; Yan, Xiang; Jiao, ShunChang

2014-02-01

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) retreatment is rarely administered for non-small cell lung cancer (NSCLC) patients who did not respond to previous TKI treatment. A high dose of TKI may overcome resistance to the standard dose of TKI and have different effectiveness toward cancer compared with the standard dose of TKI. This manuscript describes a dramatic and durable response to high-dose icotinib in a NSCLC patient who did not respond to a previous standard dose of erlotinib. The treatment extended the life of the patient for one additional year. A higher dose of icotinib deserves further study not only for patients whose therapy failed with the standard dose of TKI but also for newly diagnosed NSCLC patients with a sensitive mutation. Serial mutation testing during disease development is necessary for analysis and evaluation of EGFR TKI treatment. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Mixed-effects Gaussian process functional regression models with application to dose-response curve prediction.

PubMed

Shi, J Q; Wang, B; Will, E J; West, R M

2012-11-20

We propose a new semiparametric model for functional regression analysis, combining a parametric mixed-effects model with a nonparametric Gaussian process regression model, namely a mixed-effects Gaussian process functional regression model. The parametric component can provide explanatory information between the response and the covariates, whereas the nonparametric component can add nonlinearity. We can model the mean and covariance structures simultaneously, combining the information borrowed from other subjects with the information collected from each individual subject. We apply the model to dose-response curves that describe changes in the responses of subjects for differing levels of the dose of a drug or agent and have a wide application in many areas. We illustrate the method for the management of renal anaemia. An individual dose-response curve is improved when more information is included by this mechanism from the subject/patient over time, enabling a patient-specific treatment regime. Copyright © 2012 John Wiley & Sons, Ltd.

Measuring and statistically testing the size of the effect of a chemical compound on a continuous in-vitro pharmacological response through a new statistical model of response detection limit

PubMed Central

Diaz, Francisco J.; McDonald, Peter R.; Pinter, Abraham; Chaguturu, Rathnam

2018-01-01

Biomolecular screening research frequently searches for the chemical compounds that are most likely to make a biochemical or cell-based assay system produce a strong continuous response. Several doses are tested with each compound and it is assumed that, if there is a dose-response relationship, the relationship follows a monotonic curve, usually a version of the median-effect equation. However, the null hypothesis of no relationship cannot be statistically tested using this equation. We used a linearized version of this equation to define a measure of pharmacological effect size, and use this measure to rank the investigated compounds in order of their overall capability to produce strong responses. The null hypothesis that none of the examined doses of a particular compound produced a strong response can be tested with this approach. The proposed approach is based on a new statistical model of the important concept of response detection limit, a concept that is usually neglected in the analysis of dose-response data with continuous responses. The methodology is illustrated with data from a study searching for compounds that neutralize the infection by a human immunodeficiency virus of brain glioblastoma cells. PMID:24905187

The effect of selective 5-hydroxytryptamine uptake inhibitors on 5-methoxy-N,N-dimethyltryptamine-induced ejaculation in the rat.

PubMed Central

Rényi, L.

1986-01-01

The ejaculatory response and the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (3 mg kg-1 i.p.) were studied following acute and repeated treatment of rats with the selective uptake inhibitors of 5-HT, fluoxetine, zimeldine, alaproclate, and citalopram. The oral doses used were based on the respective ED50 values for uptake inhibition. Acute doses of fluoxetine and zimeldine significantly reduced the ejaculatory response when given 48 h before 5-MeODMT. This blockade was prevented by treatment of the rats with the postsynaptic 5-HT receptor antagonist methergoline. An acute dose of fluoxetine given 7 and 14 days before 5-MeODMT significantly enhanced the ejaculatory response. On day 24, the response returned to the control level. Repeated treatment every second day (5 times over 9 days and 10 times over 19 days) with fluoxetine caused a longer blockade of the ejaculatory response and the sensitization of the response came later than after an acute dose. Parallel with the ejaculatory response three other components of the 5-HT behavioural syndrome also decreased significantly. Acute doses of alaproclate and citalopram significantly blocked the ejaculatory response at 1 h, but they failed to affect the response at any other time point after either acute or repeated treatment. Neither did these drugs attentuate the 5-HT syndrome. It is concluded that acute and repeated treatment of rats with different selective 5-HT uptake inhibitors does not produce a common alteration in 5-HT2-receptor functions. PMID:2939912

Dose-dependent pheromone responses of mountain pine beetle in stands of lodgepole pine

Treesearch

Daniel R. Miller; B. Staffan Lindgren; John H. Borden

2005-01-01

We conducted seven behavioral choice tests with Lindgren multiple-funnel traps in stands of mature lodgepole pine in British Columbia, from 1988 to 1994, to determine the dosedependent responses of the mountain pine beetle, Dendroctonus ponderosae Hopkins, to its pheromones. Amultifunctional dose-dependent response was exhibited by D. ...

Modeling and regression analysis of semiochemical dose-response curves of insect antennal reception and behavior

USDA-ARS?s Scientific Manuscript database

Dose-response curves with semiochemicals are reported in many articles in insect chemical ecology regarding neurophysiology and behavioral bioassays. Most such curves are shown in figures where the x-axis has order of magnitude increases in dosages versus responses on the y-axis represented by point...

Development of the dose-response relationship for human toxoplasma gondii infection associated with meat consumption

USDA-ARS?s Scientific Manuscript database

Toxoplasma gondii is a protozoan parasite that is responsible for approximately 24% of deaths attributed to foodborne pathogens in the United States.A substantial portion of human T. gondii infections may be acquired through the consumption of meats. The dose-response relationship for human exposure...

Effect of some blocking drugs on the pressor response to physostigmine in the rat

PubMed Central

Gokhale, S. D.; Gulati, O. D.; Joshi, N. Y.

1963-01-01

Bretylium and guanethidine blocked the pressor effect of physostigmine and potentiated the responses to adrenaline and noradrenaline on the blood pressure of the rat. Morphine and atropine in small doses blocked the pressor effect of physostigmine without interfering with the actions of adrenaline and noradrenaline. Chlorpromazine in small doses (0.5 to 2.5 mg/kg) blocked the pressor effect of physostigmine and potentiated the responses to noradrenaline whilst those to adrenaline remained unaltered. 3,6-Di(3-diethylaminopropoxy)pyridazine di(methiodide) (Win 4981) blocked the pressor effect of physostigmine and, in its early stages, this block was partially reversed by choline chloride. N-Diethylaminoethyl-N-isopentyl-N'N'-diisopropylurea (P-286), in a dose that reduced the effect of dimethylphenylpiperazinium, had no effect on the pressor response to physostigmine or on the responses to adrenaline and noradrenaline. Hexamethonium, even in large doses (100 mg/kg), only blocked partially the effect of physostigmine while mecamylamine produced a complete block; the responses to adrenaline and noradrenaline were potentiated in both instances. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6 PMID:14081658

Systematic review with dose-response meta-analyses between vitamin B-12 intake and European Micronutrient Recommendations Aligned's prioritized biomarkers of vitamin B-12 including randomized controlled trials and observational studies in adults and elderly persons.

PubMed

Dullemeijer, Carla; Souverein, Olga W; Doets, Esmée L; van der Voet, Hilko; van Wijngaarden, Janneke P; de Boer, Waldo J; Plada, Maria; Dhonukshe-Rutten, Rosalie A M; In 't Veld, Paulette H; Cavelaars, Adrienne E J M; de Groot, Lisette C P G M; van 't Veer, Pieter

2013-02-01

Many randomized controlled trials (RCTs) and observational studies have provided information on the association between vitamin B-12 intake and biomarkers. The use of these data to estimate dose-response relations provides a useful means to summarize the body of evidence. We systematically reviewed studies that investigated vitamin B-12 intake and biomarkers of vitamin B-12 status and estimated dose-response relations with the use of a meta-analysis. This systematic review included all RCTs, prospective cohort studies, nested case-control studies, and cross-sectional studies in healthy adult populations published through January 2010 that supplied or measured dietary vitamin B-12 intake and measured vitamin B-12 status as serum or plasma vitamin B-12, methylmalonic acid (MMA), or holotranscobalamin. We calculated an intake-status regression coefficient ( ) for each individual study and calculated the overall pooled and SE ( ) by using random-effects meta-analysis on a double-log scale. The meta-analysis of observational studies showed a weaker slope of dose-response relations than the meta-analysis of RCTs. The pooled dose-response relation of all studies between vitamin B-12 intake and status indicated that a doubling of the vitamin B-12 intake increased vitamin B-12 concentrations by 11% (95% CI: 9.4%, 12.5%). This increase was larger for studies in elderly persons (13%) than in studies in adults (8%). The dose-response relation between vitamin B-12 intake and MMA concentrations indicated a decrease in MMA of 7% (95% CI: -10%, -4%) for every doubling of the vitamin B-12 intake. The assessment of risk of bias within individual studies and across studies indicated risk that was unlikely to seriously alter these results. The obtained dose-response estimate between vitamin B-12 intake and status provides complementary evidence to underpin recommendations for a vitamin B-12 intake of populations.

REDUCING UNCERTAINTY IN AIR TOXICS RISK ASSESSMENT: A MECHANISTIC EXPOSURE-DOSE-RESPONSE (EDR) MODEL FOR ASSESSING THE ACUTE NEUROTOXICITY OF VOLATILE ORGANIC COMPOUNDS (VOCS) BASED UPON A RECEPTOR-MEDIATED MODE OF ACTION

EPA Science Inventory

SUMMARY: The major accomplishment of NTD’s air toxics program is the development of an exposure-dose- response model for acute exposure to volatile organic compounds (VOCs), based on momentary brain concentration as the dose metric associated with acute neurological impairments...

Consequences of synergy between environmental carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Berenbaum, M.C.

1985-12-01

As it is generally impossible to determine dose-response relationships for carcinogens at the low concentrations in which they occur in the environment, risk-benefit considerations are by consensus based on the linear, no-threshold model, on the assumption that this represents the worst case. However, this assumption does not take into account the possibility of synergistic interactions between carcinogens. It is shown here that, as a result of such interactions, the dose-response curve for added risk due to any individual carcinogen will generally be steeper at lower doses than at higher doses, and consequently the risk at low environmental levels will bemore » higher than would be expected from a linear response. Moreover, this excess risk at low doses is shown to increase as the general level of environmental carcinogens rises and, independently of this effect, it may also increase with the number of carcinogens present.« less

Alectinib Dose Escalation Reinduces Central Nervous System Responses in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer Relapsing on Standard Dose Alectinib.

PubMed

Gainor, Justin F; Chi, Andrew S; Logan, Jennifer; Hu, Ranliang; Oh, Kevin S; Brastianos, Priscilla K; Shih, Helen A; Shaw, Alice T

2016-02-01

The central nervous system (CNS) is an important and increasingly recognized site of treatment failure in anaplastic lymphoma kinase (ALK)-positive, non-small cell lung cancer (NSCLC) patients receiving ALK inhibitors. In this report, we describe two ALK-positive patients who experienced initial improvements in CNS metastases on standard dose alectinib (600 mg twice daily), but who subsequently experienced recurrences with symptomatic leptomeningeal metastases. Both patients were dose-escalated to alectinib 900 mg twice daily, resulting in repeat clinical and radiographic responses. Our results suggest that dose intensification of alectinib may be necessary to overcome incomplete ALK inhibition in the CNS and prolong the durability of responses in patients with CNS metastases, particularly those with leptomeningeal carcinomatosis. Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Modeling the effect of boost timing in murine irradiated sporozoite prime-boost vaccines

PubMed Central

Zhang, Min; Herrero, Miguel A.; Acosta, Francisco J.; Tsuji, Moriya

2018-01-01

Vaccination with radiation-attenuated sporozoites has been shown to induce CD8+ T cell-mediated protection against pre-erythrocytic stages of malaria. Empirical evidence suggests that successive inoculations often improve the efficacy of this type of vaccines. An initial dose (prime) triggers a specific cellular response, and subsequent inoculations (boost) amplify this response to create a robust CD8+ T cell memory. In this work we propose a model to analyze the effect of T cell dynamics on the performance of prime-boost vaccines. This model suggests that boost doses and timings should be selected according to the T cell response elicited by priming. Specifically, boosting during late stages of clonal contraction would maximize T cell memory production for vaccines using lower doses of irradiated sporozoites. In contrast, single-dose inoculations would be indicated for higher vaccine doses. Experimental data have been obtained that support theoretical predictions of the model. PMID:29329308

Comparison of the relative airways and systemic potencies of inhaled fenoterol and salbutamol in asthmatic patients.

PubMed Central

Lipworth, B. J.; Newnham, D. M.; Clark, R. A.; Dhillon, D. P.; Winter, J. H.; McDevitt, D. G.

1995-01-01

BACKGROUND--There is controversy as to the relative safety of fenoterol and salbutamol. No differences have been found in the relative cardiac beta 1/beta 2 receptor activity of inhaled fenoterol and salbutamol in normal subjects. These initial findings have been extended by comparing the respective potencies of equivalent doses by weight of fenoterol and salbutamol in asthmatic subjects, in terms of airways and systemic responses. METHODS--Eighteen asthmatic patients of mean (SD) age 40 (14) years and a forced expiratory volume in one second (FEV1)% predicted of 56 (14)% (1.97 (0.66)1) were randomised to inhale fenoterol (100 micrograms/puff or 200 micrograms/puff), salbutamol, or placebo (100 micrograms/puff or 200 micrograms/puff) on three separate days. Dose-response curves were constructed using cumulative doses of 100 micrograms, 200 micrograms, 400 micrograms, 1000 micrograms, 2000 micrograms, and 4000 micrograms, and airways and systemic responses were measured 20 minutes after each dose with 40 minute increments. Dose ratios for the relative potency of fenoterol versus salbutamol were calculated from the dose-response curves using regression analysis of parallel slopes. RESULTS--There was no difference in bronchodilator potency between fenoterol and salbutamol (as median dose ratio): FEV1 1.1 (95% CI 0.4 to 4.6). In contrast, dose ratios for systemic responses showed that fenoterol was more potent than salbutamol: serum potassium 3.7 (95% CI 2.0 to 6.0), tremor 5.7 (95% CI 1.4 to 10.2), heart rate 1.6 (95% CI 1.0 to 2.3). At a conventional dose of 200 micrograms the only difference in response between the two drugs was observed for tremor (as mean difference): 0.23 log units (95% CI 0.06 to 0.41 log units). CONCLUSIONS--There was no difference in the bronchodilator potency between fenoterol and salbutamol on a microgram equivalent basis. In contrast, systemic potency was greater with fenoterol, although this difference was not clinically relevant at conventional dosages up to 200 micrograms. PMID:7886650

Dose-Response Relationship between Dietary Magnesium Intake and Risk of Type 2 Diabetes Mellitus: A Systematic Review and Meta-Regression Analysis of Prospective Cohort Studies

PubMed Central

Fang, Xin; Han, Hedong; Li, Mei; Liang, Chun; Fan, Zhongjie; Aaseth, Jan; He, Jia; Montgomery, Scott; Cao, Yang

2016-01-01

The epidemiological evidence for a dose-response relationship between magnesium intake and risk of type 2 diabetes mellitus (T2D) is sparse. The aim of the study was to summarize the evidence for the association of dietary magnesium intake with risk of T2D and evaluate the dose-response relationship. We conducted a systematic review and meta-analysis of prospective cohort studies that reported dietary magnesium intake and risk of incident T2D. We identified relevant studies by searching major scientific literature databases and grey literature resources from their inception to February 2016. We included cohort studies that provided risk ratios, i.e., relative risks (RRs), odds ratios (ORs) or hazard ratios (HRs), for T2D. Linear dose-response relationships were assessed using random-effects meta-regression. Potential nonlinear associations were evaluated using restricted cubic splines. A total of 25 studies met the eligibility criteria. These studies comprised 637,922 individuals including 26,828 with a T2D diagnosis. Compared with the lowest magnesium consumption group in the population, the risk of T2D was reduced by 17% across all the studies; 19% in women and 16% in men. A statistically significant linear dose-response relationship was found between incremental magnesium intake and T2D risk. After adjusting for age and body mass index, the risk of T2D incidence was reduced by 8%–13% for per 100 mg/day increment in dietary magnesium intake. There was no evidence to support a nonlinear dose-response relationship between dietary magnesium intake and T2D risk. The combined data supports a role for magnesium in reducing risk of T2D, with a statistically significant linear dose-response pattern within the reference dose range of dietary intake among Asian and US populations. The evidence from Europe and black people is limited and more prospective studies are needed for the two subgroups. PMID:27869762

Spatial Prediction of Coxiella burnetii Outbreak Exposure via Notified Case Counts in a Dose-Response Model.

PubMed

Brooke, Russell J; Kretzschmar, Mirjam E E; Hackert, Volker; Hoebe, Christian J P A; Teunis, Peter F M; Waller, Lance A

2017-01-01

We develop a novel approach to study an outbreak of Q fever in 2009 in the Netherlands by combining a human dose-response model with geostatistics prediction to relate probability of infection and associated probability of illness to an effective dose of Coxiella burnetii. The spatial distribution of the 220 notified cases in the at-risk population are translated into a smooth spatial field of dose. Based on these symptomatic cases, the dose-response model predicts a median of 611 asymptomatic infections (95% range: 410, 1,084) for the 220 reported symptomatic cases in the at-risk population; 2.78 (95% range: 1.86, 4.93) asymptomatic infections for each reported case. The low attack rates observed during the outbreak range from (Equation is included in full-text article.)to (Equation is included in full-text article.). The estimated peak levels of exposure extend to the north-east from the point source with an increasing proportion of asymptomatic infections further from the source. Our work combines established methodology from model-based geostatistics and dose-response modeling allowing for a novel approach to study outbreaks. Unobserved infections and the spatially varying effective dose can be predicted using the flexible framework without assuming any underlying spatial structure of the outbreak process. Such predictions are important for targeting interventions during an outbreak, estimating future disease burden, and determining acceptable risk levels.

Respiratory Toxicity of Dimethyl Sulfoxide.

PubMed

Takeda, Kotaro; Pokorski, Mieczyslaw; Sato, Yutaka; Oyamada, Yoshitaka; Okada, Yasumasa

2016-01-01

Dimethyl sulfoxide (DMSO) is one of the most commonly used solvents for hydrophobic substances in biological experiments. In addition, the compound exhibits a plethora of bioactivities, which makes it of potential pharmacological use of its own. The influence on respiration, and thus on arterial blood oxygenation, of DMSO is unclear, contentious, and an area of limited study. Thus, in the present investigation we set out to determine the influence on lung ventilation of cumulated doses of DMSO in the amount of 0.5, 1.5, 3.5, 7.5, and 15.5 g/kg; each dose given intraperitoneally at 1 h interval in conscious mice. Ventilation and its responses to 7 % hypoxia (N(2) balanced) were recorded in a whole body plethsymograph. We demonstrate a dose-dependent inhibitory effect of DMSO on lung ventilation and its hypoxic responsiveness, driven mostly by changes in the tidal component. The maximum safe dose of DMSO devoid of meaningful consequences for respiratory function was 3.5 g/kg. The dose of 7.5 g/kg of DMSO significantly dampened respiration, with yet well preserved hyperventilatory response to hypoxia. The highest dose of 15.5 g/kg severely impaired ventilation and its responses. The study delineates the safety profile of DMSO regarding the respiratory function which is essential for maintaining proper tissue oxygenation. Caution should be exercised concerning dose concentration of DMSO.

Distinguishing dose, focus, and blur for lithography characterization and control

NASA Astrophysics Data System (ADS)

Ausschnitt, Christopher P.; Brunner, Timothy A.

2007-03-01

We derive a physical model to describe the dependence of pattern dimensions on dose, defocus and blur. The coefficients of our model are constants of a given lithographic process. Model inversion applied to dimensional measurements then determines effective dose, defocus and blur for wafers patterned with the same process. In practice, our approach entails the measurement of proximate grating targets of differing dose and focus sensitivity. In our embodiment, the measured attribute of one target is exclusively sensitive to dose, whereas the measured attributes of a second target are distinctly sensitive to defocus and blur. On step-and-scan exposure tools, z-blur is varied in a controlled manner by adjusting the across slit tilt of the image plane. The effects of z-blur and x,y-blur are shown to be equivalent. Furthermore, the exposure slit width is shown to determine the tilt response of the grating attributes. Thus, the response of the measured attributes can be characterized by a conventional focus-exposure matrix (FEM), over which the exposure tool settings are intentionally changed. The model coefficients are determined by a fit to the measured FEM response. The model then fully defines the response for wafers processed under "fixed" dose, focus and blur conditions. Model inversion applied to measurements from the same targets on all such wafers enables the simultaneous determination of effective dose and focus/tilt (DaFT) at each measurement site.

Evaluation of cytotoxicity and radiation enhancement using 1.9 nm gold particles: potential application for cancer therapy

PubMed Central

Butterworth, K T; Coulter, J A; Jain, S; Forker, J; McMahon, S J; Schettino, G; Prise, K M; Currell, F J; Hirst, D G

2010-01-01

High atomic number (Z) materials such as gold preferentially absorb kilovoltage x-rays compared to soft tissue and may be used to achieve local dose enhancement in tumours during treatment with ionizing radiation. Gold nanoparticles have been demonstrated as radiation dose enhancing agents in vivo and in vitro. In the present study, we used multiple endpoints to characterize the cellular cytotoxic response of a range of cell lines to 1.9 nm gold particles and measured dose modifying effects following transient exposure at low concentrations. Gold nanoparticles caused significant levels of cell type specific cytotoxicity, apoptosis and increased oxidative stress. When used as dose modifying agents, dose enhancement factors varied between the cell lines investigated with the highest enhancement being 1.9 in AGO-1522B cells at a nanoparticle concentration of 100 μg ml−1. This study shows exposure to 1.9 nm gold particles to induce a range of cell line specific responses including decreased clonogenic survival, increased apoptosis and induction of DNA damage which may be mediated through the production of reactive oxygen species. This is the first study involving 1.9 nm nanometre sized particles to report multiple cellular responses which impact on the radiation dose modifying effect. The findings highlight the need for extensive characterization of responses to gold nanoparticles when assessing dose enhancing potential in cancer therapy. PMID:20601762

X IRRADIATION AND THE SECONDARY RESPONSE TO TETANUS TOXOID IN MICE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crook, J.C.; Ford, C.E.

1962-04-01

In 1952 it was recommended that wounded soldiers who had been actively immunized should be given a dose of tetanus toxoid and not tetanus antiserum as had been the practice previously. However, in the event of nuclear warfare, wounded soldiers might be exposed to irradiation, which would be detrimental to toxoid treatment since irradiation inhibits antibody formation. To investigate the problem, male PCT mice were immunized with two doses of tetanus toxoid at a 8- week interval, and their immune response to the second dose was tested by challenge with tetanus toxin 14 days later. Whole-body x irradiation with 35more » days before the second dose of toxoid to 7 days after. The criterion of inhibition of immune response was the percentage of deaths and paralyzed survivals occurring on the eighth day. The secondary response to tetanus toxoid was shown to be radiosensitive and to depend largely on the dose of radiation; a dose of 500 rad produced approximates 50% inhibition. Radiation given from 35 days to 1 day before the second dose of tetanus toxoid prcduced most inhibition; when given 2 days after the second dose it was less effective, and it was ineffective when given 5 or 7 days after. In the 200-rad experiment there was no evidence of inhibition at all. It is concluded that the wounded soldier should receive a booster dose of tetanus toxoid as soon as possible after wounding and probable irradiation from an atomic weapon. If a delay of a day or two occurred, the irradiated soldier might be at a stage of marked inhibition of his secondary response. If it is assumed that these findings are capable of extrapolation to man, he would not be capable of responding fully to any active immunizing procedures for a period of a few weeks at least after irradiation. (BBB)« less

A priming dose of protons alters the early cardiac cellular and molecular response to 56Fe irradiation

NASA Astrophysics Data System (ADS)

Ramadan, Samy S.; Sridharan, Vijayalakshmi; Koturbash, Igor; Miousse, Isabelle R.; Hauer-Jensen, Martin; Nelson, Gregory A.; Boerma, Marjan

2016-02-01

Purpose: Recent evidence suggests that the heart may be injured by ionizing radiation at lower doses than was previously thought. This raises concerns about the cardiovascular risks from exposure to radiation during space travel. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we here examined the effects of a ;priming; dose of protons on the cardiac cellular and molecular response to a ;challenge; dose of 56Fe in a mouse model. Methods: Male C57BL/6 mice at 10 weeks of age were exposed to sham-irradiation, 0.1 Gy of protons (150 MeV), 0.5 Gy of 56Fe (600 MeV/n), or 0.1 Gy of protons 24 hours prior to 0.5 Gy of 56Fe. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine protein markers of cardiac remodeling, inflammatory infiltration, and cell death. Results: Exposure to 56Fe caused an increase in expression of α-smooth muscle cell actin, collagen type III, the inflammatory cell markers mast cell tryptase, CD2 and CD68, the endothelial glycoprotein thrombomodulin, and cleaved caspase 3. Of all proteins investigated, protons at a dose of 0.1 Gy induced a small increase only in cleaved caspase 3 levels. On the other hand, exposure to protons 24 hours before 56Fe prevented all of the responses to 56Fe. Conclusions: This study shows that a low dose of protons may prime the heart to respond differently to a subsequent challenge dose of heavy ions. Further investigation is required to identify responses at additional time points, consequences for cardiac function, threshold dose levels, and mechanisms by which a proton priming dose may alter the response to heavy ions.

A New Method for Synthesizing Radiation Dose-Response Data From Multiple Trials Applied to Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Diez, Patricia; Vogelius, Ivan S.; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792

2010-07-15

Purpose: A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. nonrandomized) and risk group (low vs. intermediate-high). Methods and Materials: Nine published prostate cancer dose escalation studies including 6,539 patients were identified in the MEDLINE and CINAHL databases and reviewed to assess the relationship between dose and biochemical control. A novel method of analysis is presented in which the normalized dose-response gradient, {gamma}{sub 50}, is estimated for each study and subsequently synthesized across studies. Our method does not assume that biochemical control rates are directly comparable between studies.more » Results: Nonrandomized studies produced a statistically significantly higher {gamma}{sub 50} than randomized studies for intermediate- to high-risk patients ({gamma}{sub 50} = 1.63 vs. {gamma}{sub 50} = 0.93, p = 0.03) and a borderline significantly higher ({gamma}{sub 50} = 1.78 vs. {gamma}{sub 50} = 0.56, p = 0.08) for low-risk patients. No statistically significant difference in {gamma}{sub 50} was found between low- and intermediate- to high-risk patients (p = 0.31). From the pooled data of low and intermediate- to high-risk patients in randomized trials, we obtain the overall best estimate of {gamma}{sub 50} = 0.84 with 95% confidence interval 0.54-1.15. Conclusions: Nonrandomized studies overestimate the steepness of the dose-response curve as compared with randomized trials. This is probably the result of stage migration, improved treatment techniques, and a shorter follow-up in higher dose patients that were typically entered more recently. This overestimation leads to inflated expectations regarding the benefit from dose-escalation and could lead to underpowered clinical trials. There is no evidence of a steeper dose response for intermediate- to high-risk compared with low-risk patients.« less

A priming dose of protons alters the early cardiac cellular and molecular response to (56)Fe irradiation.

PubMed

Ramadan, Samy S; Sridharan, Vijayalakshmi; Koturbash, Igor; Miousse, Isabelle R; Hauer-Jensen, Martin; Nelson, Gregory A; Boerma, Marjan

2016-02-01

Recent evidence suggests that the heart may be injured by ionizing radiation at lower doses than was previously thought. This raises concerns about the cardiovascular risks from exposure to radiation during space travel. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we here examined the effects of a "priming" dose of protons on the cardiac cellular and molecular response to a "challenge" dose of (56)Fe in a mouse model. Male C57BL/6 mice at 10 weeks of age were exposed to sham-irradiation, 0.1 Gy of protons (150 MeV), 0.5 Gy of (56)Fe (600 MeV/n), or 0.1 Gy of protons 24 hours prior to 0.5 Gy of (56)Fe. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine protein markers of cardiac remodeling, inflammatory infiltration, and cell death. Exposure to (56)Fe caused an increase in expression of α-smooth muscle cell actin, collagen type III, the inflammatory cell markers mast cell tryptase, CD2 and CD68, the endothelial glycoprotein thrombomodulin, and cleaved caspase 3. Of all proteins investigated, protons at a dose of 0.1 Gy induced a small increase only in cleaved caspase 3 levels. On the other hand, exposure to protons 24 hours before (56)Fe prevented all of the responses to (56)Fe. This study shows that a low dose of protons may prime the heart to respond differently to a subsequent challenge dose of heavy ions. Further investigation is required to identify responses at additional time points, consequences for cardiac function, threshold dose levels, and mechanisms by which a proton priming dose may alter the response to heavy ions. Copyright © 2015 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.

A priming dose of protons alters the early cardiac cellular and molecular response to 56Fe irradiation

PubMed Central

Ramadan, Samy S.; Sridharan, Vijayalakshmi; Koturbash, Igor; Miousse, Isabelle R.; Hauer-Jensen, Martin; Nelson, Gregory A.; Boerma, Marjan

2015-01-01

Purpose Recent evidence suggests that the heart may be injured by ionizing radiation at lower doses than was previously thought. This raises concerns about the cardiovascular risks from exposure to radiation during space travel. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we here examined the effects of a “priming” dose of protons on the cardiac cellular and molecular response to a “challenge” dose of 56Fe in a mouse model. Methods Male C57BL/6 mice at 10 weeks of age were exposed to sham-irradiation, 0.1 Gy of protons (150 MeV), 0.5 Gy of 56Fe (600 MeV/n), or 0.1 Gy of protons 24 hours prior to 0.5 Gy of 56Fe. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine protein markers of cardiac remodeling, inflammatory infiltration, and cell death. Results Exposure to 56Fe caused an increase in expression of α-smooth muscle cell actin, collagen type III, the inflammatory cell markers mast cell tryptase, CD2 and CD68, the endothelial glycoprotein thrombomodulin, and cleaved caspase 3. Of all proteins investigated, protons at a dose of 0.1 Gy induced a small increase only in cleaved caspase 3 levels. On the other hand, exposure to protons 24 hours before 56Fe prevented all of the responses to 56Fe. Conclusions This study shows that a low dose of protons may prime the heart to respond differently to a subsequent challenge dose of heavy ions. Further investigation is required to identify responses at additional time points, consequences for cardiac function, threshold dose levels, and mechanisms by which a proton priming dose may alter the response to heavy ions. PMID:26948008

Pseudomonas aeruginosa dose response and bathing water infection.

PubMed

Roser, D J; van den Akker, B; Boase, S; Haas, C N; Ashbolt, N J; Rice, S A

2014-03-01

Pseudomonas aeruginosa is the opportunistic pathogen mostly implicated in folliculitis and acute otitis externa in pools and hot tubs. Nevertheless, infection risks remain poorly quantified. This paper reviews disease aetiologies and bacterial skin colonization science to advance dose-response theory development. Three model forms are identified for predicting disease likelihood from pathogen density. Two are based on Furumoto & Mickey's exponential 'single-hit' model and predict infection likelihood and severity (lesions/m2), respectively. 'Third-generation', mechanistic, dose-response algorithm development is additionally scoped. The proposed formulation integrates dispersion, epidermal interaction, and follicle invasion. The review also details uncertainties needing consideration which pertain to water quality, outbreaks, exposure time, infection sites, biofilms, cerumen, environmental factors (e.g. skin saturation, hydrodynamics), and whether P. aeruginosa is endogenous or exogenous. The review's findings are used to propose a conceptual infection model and identify research priorities including pool dose-response modelling, epidermis ecology and infection likelihood-based hygiene management.

Radiotherapy Dose Fractionation under Parameter Uncertainty

NASA Astrophysics Data System (ADS)

Davison, Matt; Kim, Daero; Keller, Harald

2011-11-01

In radiotherapy, radiation is directed to damage a tumor while avoiding surrounding healthy tissue. Tradeoffs ensue because dose cannot be exactly shaped to the tumor. It is particularly important to ensure that sensitive biological structures near the tumor are not damaged more than a certain amount. Biological tissue is known to have a nonlinear response to incident radiation. The linear quadratic dose response model, which requires the specification of two clinically and experimentally observed response coefficients, is commonly used to model this effect. This model yields an optimization problem giving two different types of optimal dose sequences (fractionation schedules). Which fractionation schedule is preferred depends on the response coefficients. These coefficients are uncertainly known and may differ from patient to patient. Because of this not only the expected outcomes but also the uncertainty around these outcomes are important, and it might not be prudent to select the strategy with the best expected outcome.

Dose-Response Relation between Work Hours and Cardiovascular Disease Risk: Findings from the Panel Study of Income Dynamics

PubMed Central

Conway, Sadie H.; Pompeii, Lisa A.; Roberts, Robert E.; Follis, Jack L.; Gimeno, David

2015-01-01

Objectives To examine the presence of a dose-response relationship between work hours and incident cardiovascular disease (CVD) in a representative sample of U.S. workers. Methods Retrospective cohort study of 1,926 individuals from the Panel Study of Income Dynamics (1986–2011) employed for at least 10 years. Restricted cubic spline regression was used to estimate the dose-response relationship of work hours with CVD. Results A dose-response relationship was observed in which an average workweek of 46 hours or more for at least 10 years was associated with increased risk of CVD. Compared to working 45 hours per week, working an additional 10 hours per week or more for at least 10 years increased CVD risk by at least 16%. Conclusions Working more than 45 work hours per week for at least 10 years may be an independent risk factor for CVD. PMID:26949870

Radiological characteristics of MRI-based VIP polymer gel under carbon beam irradiation

NASA Astrophysics Data System (ADS)

Maeyama, T.; Fukunishi, N.; Ishikawa, K. L.; Furuta, T.; Fukasaku, K.; Takagi, S.; Noda, S.; Himeno, R.; Fukuda, S.

2015-02-01

We study the radiological characteristics of VIP polymer gel dosimeters under carbon beam irradiation with energy of 135 and 290 AMeV. To evaluate dose response of VIP polymer gels, the transverse (or spin-spin) relaxation rate R2 of the dosimeters measured by magnetic resonance imaging (MRI) as a function of linear energy transfer (LET), rather than penetration depth, as is usually done in previous reports. LET is evaluated by use of the particle transport simulation code PHITS. Our results reveal that the dose response decreases with increasing dose-averaged LET and that the dose response-LET relation also varies with incident carbon beam energy. The latter can be explained by taking into account the contribution from fragmentation products.

Predicting in vivo cardiovascular properties of β-blockers from cellular assays: a quantitative comparison of cellular and cardiovascular pharmacological responses

PubMed Central

Baker, Jillian G.; Kemp, Philip; March, Julie; Fretwell, Laurice; Hill, Stephen J.; Gardiner, Sheila M.

2011-01-01

β-Adrenoceptor antagonists differ in their degree of partial agonism. In vitro assays have provided information on ligand affinity, selectivity, and intrinsic efficacy. However, the extent to which these properties are manifest in vivo is less clear. Conscious freely moving rats, instrumented for measurement of heart rate (β1; HR) and hindquarters vascular conductance (β2; HVC) were used to measure receptor selectivity and ligand efficacy in vivo. CGP 20712A caused a dose-dependent decrease in basal HR (P<0.05, ANOVA) at 5 doses between 6.7 and 670 μg/kg (i.v.) and shifted the dose-response curve for isoprenaline to higher agonist concentrations without altering HVC responses. In contrast, at doses of 67 μg/kg (i.v.) and above, ICI 118551 substantially reduced the HVC response to isoprenaline without affecting HR responses. ZD 7114, xamoterol, and bucindolol significantly increased basal HR (ΔHR: +122±12, +129±11, and +59±11 beats/min, respectively; n=6), whereas other β-blockers caused significant reductions (all at 2 mg/kg i.v.). The agonist effects of xamoterol and ZD 7114 were equivalent to that of the highest dose of isoprenaline. Bucindolol, however, significantly antagonized the response to the highest doses isoprenaline. An excellent correlation was obtained between in vivo and in vitro measures of β1-adrenoceptor efficacy (R2=0.93; P<0.0001).—Baker, J. G., Kemp, P., March, J., Fretwell, L., Hill, S. J., Gardiner, S. M. Predicting in vivo cardiovascular properties of β-blockers from cellular assays: a quantitative comparison of cellular and cardiovascular pharmacological responses. PMID:21865315

Evaluation of a toxicogenomic approach to the local lymph node assay (LLNA).

PubMed

Boverhof, Darrell R; Gollapudi, B Bhaskar; Hotchkiss, Jon A; Osterloh-Quiroz, Mandy; Woolhiser, Michael R

2009-02-01

Genomic technologies have the potential to enhance and complement existing toxicology endpoints; however, assessment of these approaches requires a systematic evaluation including a robust experimental design with genomic endpoints anchored to traditional toxicology endpoints. The present study was conducted to assess the sensitivity of genomic responses when compared with the traditional local lymph node assay (LLNA) endpoint of lymph node cell proliferation and to evaluate the responses for their ability to provide insights into mode of action. Female BALB/c mice were treated with the sensitizer trimellitic anhydride (TMA), following the standard LLNA dosing regimen, at doses of 0.1, 1, or 10% and traditional tritiated thymidine ((3)HTdR) incorporation and gene expression responses were monitored in the auricular lymph nodes. Additional mice dosed with either vehicle or 10% TMA and sacrificed on day 4 or 10, were also included to examine temporal effects on gene expression. Analysis of (3)HTdR incorporation revealed TMA-induced stimulation indices of 2.8, 22.9, and 61.0 relative to vehicle with an EC(3) of 0.11%. Examination of the dose-response gene expression responses identified 9, 833, and 2122 differentially expressed genes relative to vehicle for the 0.1, 1, and 10% TMA dose groups, respectively. Calculation of EC(3) values for differentially expressed genes did not identify a response that was more sensitive than the (3)HTdR value, although a number of genes displayed comparable sensitivity. Examination of temporal responses revealed 1760, 1870, and 953 differentially expressed genes at the 4-, 6-, and 10-day time points respectively. Functional analysis revealed many responses displayed dose- and time-specific induction patterns within the functional categories of cellular proliferation and immune response, including numerous immunoglobin genes which were highly induced at the day 10 time point. Overall, these experiments have systematically illustrated the potential utility of genomic endpoints to enhance the LLNA and support further exploration of this approach through examination of a more diverse array of chemicals.

Spinal action of neurokinins producing cardiovascular responses in the conscious freely moving rat: evidence for a NK-1 receptor mechanism.

PubMed

Hasséssian, H; Drapeau, G; Couture, R

1988-12-01

This study was initiated to characterize the receptors which mediate the cardiovascular responses elicited by the intrathecal (i.th.) administration of neurokinins (NK) in the conscious freely moving rat. The dose response profile for substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) was determined over 0.065-65 nmol doses of the peptides. After i.th. administration at the T8-T10 thoracic level, only SP elicited a dose dependent pressor response. However, all NK elicited a dose dependent increase in heart rate (HR), and the following rank order of potency was observed: SP greater than NKA greater than NKB. SP (6.5 nmol) produced cardiovascular responses markedly greater than an equimolar dose of any of the seven SP fragments which were studied. The C-terminal sequences SP (4-11), [pGlu5]SP (5-11), [pGlu6]SP (6-11), and SP (7-11), as a group were slightly more potent than the N-terminal fragments, SP (1-4), SP (1-7) and SP (1-9) which were almost inactive. The NK-1 receptor selective agonists [Pro9, Met(O2)11]SP and [beta-Ala4, Sar9, Met(O2)11]SP (4-11), produced pressor and positive chronotropic responses equal to or greater in intensity than SP. With up to 6.5 nmol of the NK-2 receptor selective agonist [Nle10]NKA (4-10), no dose dependent cardiovascular response was produced and the NK-3 receptor selective agonist senktide (succinyl-[Asp6, MePhe8]SP (6-11], produced neither a cardiac nor pressor response when 6.5 nmol was administered. These results are consistent with the hypothesis that, receptors of the NK-1 subtype mediate the cardiovascular responses evoked by the spinal action of NK.

Durable responses and reversible toxicity of high-dose interleukin-2 treatment of melanoma and renal cancer in a Community Hospital Biotherapy Program.

PubMed

Payne, Roxanne; Glenn, Lyn; Hoen, Helena; Richards, Beverley; Smith, John W; Lufkin, Robert; Crocenzi, Todd S; Urba, Walter J; Curti, Brendan D

2014-01-01

High-dose interleukin-2 (IL-2) has been FDA-approved for over 20 years, but it is offered only at a small number of centers with expertise in its administration. We analyzed the outcomes of patients receiving high-dose IL-2 in relation to the severity of toxicity to ascertain if response or survival were adversely affected. A retrospective analysis of the outcomes of 500 patients with metastatic renal cell carcinoma (RCC) (n = 186) or melanoma (n = 314) treated with high-dose IL-2 between 1997 and 2012 at Providence Cancer Center was performed. IL-2 was administered at a dose of 600,000 international units per kg by IV bolus every 8 hours for up to 14 doses. A second cycle was administered 16 days after the first and patients with tumor regression could receive additional cycles. Survival and anti-tumor response were analyzed by diagnosis, severity of toxicity, number of IL-2 cycles and subsequent therapy. The objective response rate in melanoma was 28% (complete 12% and partial 16%), and in RCC was 24% (complete 7% and partial 17%). The 1-, 2- and 3-year survivals were 59%, 41% and 31%, for melanoma and 75%, 56% and 44%, for RCC, respectively. The proportion of patients with complete or partial response in both melanoma and RCC was higher in patients who a) required higher phenylephrine doses to treat hypotension (p < 0.003), b) developed acidosis (bicarbonate < 19 mmol (p < 0.01)), or c) thrombocytopenia (<50, 50-100, >100,000 platelets; p < 0.025). The proportion achieving a complete or partial response was greater in patients with melanoma who received 5 or more compared with 4 or fewer IL-2 cycles (p < 0.0001). The incidence of death from IL-2 was less than 1% and was not higher in patients who required phenylephrine. High-dose IL-2 can be administered safely; severe toxicity including hypotension is reversible and can be managed in a community hospital. The tumor response and survival reported here are superior to the published literature and support treating patients to their individualized maximum tolerated dose. IL-2 should remain part of the treatment paradigm in selected patients with melanoma and RCC.

The Dose Response Relationship for Radiation Carcinogenesis

NASA Astrophysics Data System (ADS)

Hall, Eric

2008-03-01

Recent surveys show that the collective population radiation dose from medical procedures in the U.S. has increased by 750% in the past two decades. It would be impossible to imagine the practice of medicine today without diagnostic and therapeutic radiology, but nevertheless the widespread and rapidly increasing use of a modality which is a known human carcinogen is a cause for concern. To assess the magnitude of the problem it is necessary to establish the shape of the dose response relationship for radiation carcinogenesis. Information on radiation carcinogenesis comes from the A-bomb survivors, from occupationally exposed individuals and from radiotherapy patients. The A-bomb survivor data indicates a linear relationship between dose and the risk of solid cancers up to a dose of about 2.5 Sv. The lowest dose at which there is a significant excess cancer risk is debatable, but it would appear to be between 40 and 100 mSv. Data from the occupation exposure of nuclear workers shows an excess cancer risk at an average dose of 19.4 mSv. At the other end of the dose scale, data on second cancers in radiotherapy patients indicates that cancer risk does not continue to rise as a linear function of dose, but tends towards a plateau of 40 to 60 Gy, delivered in a fractionated regime. These data can be used to estimate the impact of diagnostic radiology at the low dose end of the dose response relationship, and the impact of new radiotherapy modalities at the high end of the dose response relationship. In the case of diagnostic radiology about 90% of the collective population dose comes from procedures (principally CT scans) which involve doses at which there is credible evidence of an excess cancer incidence. While the risk to the individual is small and justified in a symptomatic patient, the same is not true of some screening procedures is asymptomatic individuals, and in any case the huge number of procedures must add up to a potential public health problem. In the case of radiation oncology, modern innovations such as Intensity Modulated Radiation Oncology or Proton Therapy both result in a substantial total-body dose to the patient, which must result in an increased incidence of second cancers. The technology exists to reduce these total body doses and the problem needs to be addressed.

Low-dose radiation attenuates chemical mutagenesis in vivo.

PubMed

Kakinuma, Shizuko; Yamauchi, Kazumi; Amasaki, Yoshiko; Nishimura, Mayumi; Shimada, Yoshiya

2009-09-01

The biological effects of low-dose radiation are not only of social concern but also of scientific interest. The radioadaptive response, which is defined as an increased radioresistance by prior exposure to low-dose radiation, has been extensively studied both in vitro and in vivo. Here we briefly review the radioadaptive response with respect to mutagenesis, survival rate, and carcinogenesis in vivo, and introduce our recent findings of cross adaptation in mouse thymic cells, that is, the suppressive effect of repeated low-dose radiation on mutation induction by the alkylating agent N-ethyl-N-nitrosourea.

Pilot Study: Unique Response of Bone Tissue During an Investigation of Radio-Adaptive Effects in Mice

NASA Technical Reports Server (NTRS)

Sibonga, J. D.; Iwaniec, U.; Wu, H.

2011-01-01

PURPOSE: We obtained bone tissue to evaluate the collateral effects of experiments designed to investigate molecular mechanisms of radio-adaptation in a mouse model. Radio-adaptation describes a process by which the prior exposure to low dose radiation can protect against the toxic effect of a subsequent high dose exposure. In the radio-adaptation experiments, C57Bl/6 mice were exposed to either a Sham or a priming Low Dose (5 cGy) of Cs-137 gamma rays before being exposed to either a Sham or High Dose (6 Gy) 24 hours later. ANALYSIS: Bone tissue were obtained from two experiments where mice were sacrificed at 3 days (n=3/group, 12 total) and at 14 days (n=6/group, 24 total) following high dose exposure. Tissues were analyzed to 1) evaluate a radio-adaptive response in bone tissue and 2) describe cellular and microstructural effects for two skeletal sites with different rates of bone turnover. One tibia and one lumbar vertebrae (LV2), collected at the 3-day time-point, were analyzed by bone histomorphometry and micro-CT to evaluate the cellular response and any evidence of microarchitectural impact. Likewise, tibia and LV2, collected at the 14-day time-point, were analyzed by micro-CT alone to evaluate resulting changes to bone structure and microarchitecture. The data were analyzed by 2-way ANOVA to evaluate the effects of the priming low dose radiation, of the high dose radiation, and of any interaction between the priming low and high doses of radiation. Bone histomorphometry was performed in the cancellous bone (aka trabecular bone) compartments of the proximal tibial metaphysis and of LV2. RESULTS: Cellular Response @ 3 Days The priming Low Dose radiation decreased osteoblast-covered bone perimeter in the proximal tibia and the total cell density in the bone marrow in the LV2. High Dose radiation, regardless of prior exposure to priming dose, dramatically reduced total cell density in bone marrow of both the long bone and vertebra. However, in the proximal tibia, High Dose radiation increased the osteoclast-covered bone perimeters, the density of adipocytes in bone marrow, and the area of bone marrow occupied by fat cells -- while in the LV2, adipocytes were rare and not stimulated by High Dose radiation. In an unexpected response, High Dose radiation dramatically increased (10-fold) osteoblast-covered bone perimeter in the LV2.

Probability Distribution of Dose and Dose-Rate Effectiveness Factor for use in Estimating Risks of Solid Cancers From Exposure to Low-Let Radiation.

PubMed

Kocher, David C; Apostoaei, A Iulian; Hoffman, F Owen; Trabalka, John R

2018-06-01

This paper presents an analysis to develop a subjective state-of-knowledge probability distribution of a dose and dose-rate effectiveness factor for use in estimating risks of solid cancers from exposure to low linear energy transfer radiation (photons or electrons) whenever linear dose responses from acute and chronic exposure are assumed. A dose and dose-rate effectiveness factor represents an assumption that the risk of a solid cancer per Gy at low acute doses or low dose rates of low linear energy transfer radiation, RL, differs from the risk per Gy at higher acute doses, RH; RL is estimated as RH divided by a dose and dose-rate effectiveness factor, where RH is estimated from analyses of dose responses in Japanese atomic-bomb survivors. A probability distribution to represent uncertainty in a dose and dose-rate effectiveness factor for solid cancers was developed from analyses of epidemiologic data on risks of incidence or mortality from all solid cancers as a group or all cancers excluding leukemias, including (1) analyses of possible nonlinearities in dose responses in atomic-bomb survivors, which give estimates of a low-dose effectiveness factor, and (2) comparisons of risks in radiation workers or members of the public from chronic exposure to low linear energy transfer radiation at low dose rates with risks in atomic-bomb survivors, which give estimates of a dose-rate effectiveness factor. Probability distributions of uncertain low-dose effectiveness factors and dose-rate effectiveness factors for solid cancer incidence and mortality were combined using assumptions about the relative weight that should be assigned to each estimate to represent its relevance to estimation of a dose and dose-rate effectiveness factor. The probability distribution of a dose and dose-rate effectiveness factor for solid cancers developed in this study has a median (50th percentile) and 90% subjective confidence interval of 1.3 (0.47, 3.6). The harmonic mean is 1.1, which implies that the arithmetic mean of an uncertain estimate of the risk of a solid cancer per Gy at low acute doses or low dose rates of low linear energy transfer radiation is only about 10% less than the mean risk per Gy at higher acute doses. Data were also evaluated to define a low acute dose or low dose rate of low linear energy transfer radiation, i.e., a dose or dose rate below which a dose and dose-rate effectiveness factor should be applied in estimating risks of solid cancers.

[Characterization of a diode system for in vivo dosimetry with electron beams].

PubMed

Ragona, R; Rossetti, V; Lucio, F; Anglesio, S; Giglioli, F R

2001-10-01

Current quality assurance regulation stresses the basic role of in vivo dosimetry. Our study evaluates the usefulness and reliability of semiconductor diodes in determining the electron absorbed dose. P-type EDE semiconductor detectors were irradiated with electron beams of different energies produced by a CGR Saturn Therac 20. The diode and ionization chamber response were compared, and effect of energy value, collimator opening, source skin distance and gantry angle on diode response was studied. Measurements show a maximum increment of about 20% in diode response increasing the beam energy (6-20 MeV). The response also increases with: collimator opening, reaching 5% with field sizes larger than 10x10 cm2 (with the exception of 20 MeV energy); SSD increase (with a maximum of 8% for 20 MeV); transversal gantry incidence, compared with the diode longitudinal axis; it does not affect the response in the interval of +/- 45 degrees. Absorbed dose attenuation at dmax, due to the presence of diode on the axis of the beam as a function of electron energy was also determined : the maximum attenuation value is 15% in 6 MeV electron beams. A dose calculation algorithm, taking into account diode response dependence was outlined. In vivo dosimetry was performed in 92 fields for 80 patients, with an agreement of +/-4 % (1 SD) between prescribed and measured dose. It is possible to use the EDE semiconductor detectors on a quality control program of dose delivery for electron beam therapy, but particular attention should be paid to the beam incidence angle and diode dose attenuation.

Dose-response relationships for environmentally mediated infectious disease transmission models

PubMed Central

Eisenberg, Joseph N. S.

2017-01-01

Environmentally mediated infectious disease transmission models provide a mechanistic approach to examining environmental interventions for outbreaks, such as water treatment or surface decontamination. The shift from the classical SIR framework to one incorporating the environment requires codifying the relationship between exposure to environmental pathogens and infection, i.e. the dose–response relationship. Much of the work characterizing the functional forms of dose–response relationships has used statistical fit to experimental data. However, there has been little research examining the consequences of the choice of functional form in the context of transmission dynamics. To this end, we identify four properties of dose–response functions that should be considered when selecting a functional form: low-dose linearity, scalability, concavity, and whether it is a single-hit model. We find that i) middle- and high-dose data do not constrain the low-dose response, and different dose–response forms that are equally plausible given the data can lead to significant differences in simulated outbreak dynamics; ii) the choice of how to aggregate continuous exposure into discrete doses can impact the modeled force of infection; iii) low-dose linear, concave functions allow the basic reproduction number to control global dynamics; and iv) identifiability analysis offers a way to manage multiple sources of uncertainty and leverage environmental monitoring to make inference about infectivity. By applying an environmentally mediated infectious disease model to the 1993 Milwaukee Cryptosporidium outbreak, we demonstrate that environmental monitoring allows for inference regarding the infectivity of the pathogen and thus improves our ability to identify outbreak characteristics such as pathogen strain. PMID:28388665

Alcohol consumption impairs stimulus- and error-related processing during a Go/No-Go Task.

PubMed

Easdon, Craig; Izenberg, Aaron; Armilio, Maria L; Yu, He; Alain, Claude

2005-12-01

Alcohol consumption has been shown to increase the number of errors in tasks that require a high degree of cognitive control, such as a go/no-go task. The alcohol-related decline in performance may be related to difficulties in maintaining attention on the task at hand and/or deficits in inhibiting a prepotent response. To test these two accounts, we investigated the effects of alcohol on stimulus- and response-locked evoked potentials recorded during a go/no-go task that involved the withholding of key presses to rare targets. All participants performed the task prior to drinking and were then assigned randomly to either a control, low-dose, or moderate-dose treatment. Both doses of alcohol increased the number of errors relative to alcohol-free performance. Success in withholding a prepotent response was associated with an early-enhanced stimulus-locked negativity at inferior parietal sites, which was delayed when participants failed to inhibit the motor command. Moreover, low and moderate doses of alcohol reduced N170 and P3 amplitudes during go, no-go, and error trials. In comparison with the correct responses, errors generated large response-locked negative (Ne) and positive (Pe) waves at central sites. Both doses of alcohol reduced the Ne amplitude whereas the Pe amplitude decreased only after moderate doses of alcohol. These results are consistent with the interpretation that behavioral disinhibition following alcohol consumption involved alcohol-induced deficits in maintaining and allocating attention thereby affecting the processing of incoming stimuli and the recognition that an errant response has been made.

A 3-lever discrimination procedure reveals differences in the subjective effects of low and high doses of MDMA.

PubMed

Harper, David N; Langen, Anna-Lena; Schenk, Susan

2014-01-01

Drug discrimination studies have suggested that the subjective effects of low doses of (±)3,4-methylenedioxymethamphetamine (MDMA) are readily differentiated from those of d-amphetamine (AMPH) and that the discriminative stimulus properties are mediated by serotonergic and dopaminergic mechanisms, respectively. Previous studies, however, have primarily examined responses to doses that do not produce substantial increases in extracellular dopamine. The present study determined whether doses of MDMA that produce increases in synaptic dopamine would also produce subjective effects that were more like AMPH and were sensitive to pharmacological manipulation of D1-like receptors. A three-lever drug discrimination paradigm was used. Rats were trained to respond on different levers following saline, AMPH (0.5mg/kg, IP) or MDMA (1.5mg/kg, IP) injections. Generalization curves were generated for a range of different doses of both drugs and the effect of the D1-like antagonist, SCH23390 on the discriminative stimulus effects of different doses of MDMA was determined. Rats accurately discriminated MDMA, AMPH and saline. Low doses of MDMA produced almost exclusive responding on the MDMA lever but at doses of 3.0mg/kg MDMA or higher, responding shifted to the AMPH lever. The AMPH response produced by higher doses of MDMA was attenuated by pretreatment with SCH23390. The data suggest that low doses and higher doses of MDMA produce distinct discriminative stimuli. The shift to AMPH-like responding following administration of higher doses of MDMA, and the decrease in this response following administration of SCH23390 suggests a dopaminergic component to the subjective experience of MDMA at higher doses. Copyright © 2013 Elsevier Inc. All rights reserved.

Modeling low-dose mortality and disease incubation period of inhalational anthrax in the rabbit.

PubMed

Gutting, Bradford W; Marchette, David; Sherwood, Robert; Andrews, George A; Director-Myska, Alison; Channel, Stephen R; Wolfe, Daniel; Berger, Alan E; Mackie, Ryan S; Watson, Brent J; Rukhin, Andrey

2013-07-21

There is a need to advance our ability to conduct credible human risk assessments for inhalational anthrax associated with exposure to a low number of bacteria. Combining animal data with computational models of disease will be central in the low-dose and cross-species extrapolations required in achieving this goal. The objective of the current work was to apply and advance the competing risks (CR) computational model of inhalational anthrax where data was collected from NZW rabbits exposed to aerosols of Ames strain Bacillus anthracis. An initial aim was to parameterize the CR model using high-dose rabbit data and then conduct a low-dose extrapolation. The CR low-dose attack rate was then compared against known low-dose rabbit data as well as the low-dose curve obtained when the entire rabbit dose-response data set was fitted to an exponential dose-response (EDR) model. The CR model predictions demonstrated excellent agreement with actual low-dose rabbit data. We next used a modified CR model (MCR) to examine disease incubation period (the time to reach a fever >40 °C). The MCR model predicted a germination period of 14.5h following exposure to a low spore dose, which was confirmed by monitoring spore germination in the rabbit lung using PCR, and predicted a low-dose disease incubation period in the rabbit between 14.7 and 16.8 days. Overall, the CR and MCR model appeared to describe rabbit inhalational anthrax well. These results are discussed in the context of conducting laboratory studies in other relevant animal models, combining the CR/MCR model with other computation models of inhalational anthrax, and using the resulting information towards extrapolating a low-dose response prediction for man. Published by Elsevier Ltd.

Proton dose distribution measurements using a MOSFET detector with a simple dose-weighted correction method for LET effects.

PubMed

Kohno, Ryosuke; Hotta, Kenji; Matsuura, Taeko; Matsubara, Kana; Nishioka, Shie; Nishio, Teiji; Kawashima, Mitsuhiko; Ogino, Takashi

2011-04-04

We experimentally evaluated the proton beam dose reproducibility, sensitivity, angular dependence and depth-dose relationships for a new Metal Oxide Semiconductor Field Effect Transistor (MOSFET) detector. The detector was fabricated with a thinner oxide layer and was operated at high-bias voltages. In order to accurately measure dose distributions, we developed a practical method for correcting the MOSFET response to proton beams. The detector was tested by examining lateral dose profiles formed by protons passing through an L-shaped bolus. The dose reproducibility, angular dependence and depth-dose response were evaluated using a 190 MeV proton beam. Depth-output curves produced using the MOSFET detectors were compared with results obtained using an ionization chamber (IC). Since accurate measurements of proton dose distribution require correction for LET effects, we developed a simple dose-weighted correction method. The correction factors were determined as a function of proton penetration depth, or residual range. The residual proton range at each measurement point was calculated using the pencil beam algorithm. Lateral measurements in a phantom were obtained for pristine and SOBP beams. The reproducibility of the MOSFET detector was within 2%, and the angular dependence was less than 9%. The detector exhibited a good response at the Bragg peak (0.74 relative to the IC detector). For dose distributions resulting from protons passing through an L-shaped bolus, the corrected MOSFET dose agreed well with the IC results. Absolute proton dosimetry can be performed using MOSFET detectors to a precision of about 3% (1 sigma). A thinner oxide layer thickness improved the LET in proton dosimetry. By employing correction methods for LET dependence, it is possible to measure absolute proton dose using MOSFET detectors.

Ifosfamide in the treatment of recurrent or disseminated lung cancer: a phase II study of two dose schedules.

PubMed

Costanzi, J J; Gagliano, R; Loukas, D; Panettiere, F J; Hokanson, J A

1978-05-01

Ifosfamide was administered to 21 patients with recurrent or disseminated lung cancer at a dose of 4.0 gm/M2 iv every 3 weeks. The response rate was 33% with an additional 14% showing no response or stable disease. At a dose of 1.2 gm/M2 daily for 5 days every 4 weeks, 57% of 14 patients responded with 35% showing no response or stable disease. The majority of the patients (28) had epidermoid carcinoma. Two (7%) had complete response with 9 (32%) showing partial responses. Other responses included 1/2 oat cell carcinomas and 3/6 large cell undifferentiated carcinomas. Toxicity was equal in both regimens for nausea, vomiting, increased serum LDH and neutropenia but the 5 day program had significantly less hemorrhagic cystitis. Survival was greatly influenced by response. There was no statistical difference in overall length of response between responders and the non responding/stable disease patients. But these two groups had a very significant survival advantage when compared to those patients with increasing disease. Similarly, there was a significant improvement in response duration for the low dosage regimen. Therefore, the low dose 5 day regimen is recommended because of its response rate, it has less hemorrhagic cystitis and it has better patient acceptance in that it can be given as an outpatient and does not require a Foley catheter.

Cancer Dose-Response Assessment for Polychlorinated Biphenyls (PCBs) and Application to Environmental Mixtures

EPA Pesticide Factsheets

This report updates the cancer dose-response assessment for PCBs and shows how information on toxicity, disposition, and environmental processes can be considered together to evaluate health risks from PCB mixtures in the environment.

Exercise and sport performance with low doses of caffeine.

PubMed

Spriet, Lawrence L

2014-11-01

Caffeine is a popular work-enhancing supplement that has been actively researched since the 1970s. The majority of research has examined the effects of moderate to high caffeine doses (5-13 mg/kg body mass) on exercise and sport. These caffeine doses have profound effects on the responses to exercise at the whole-body level and are associated with variable results and some undesirable side effects. Low doses of caffeine (<3 mg/kg body mass, ~200 mg) are also ergogenic in some exercise and sport situations, although this has been less well studied. Lower caffeine doses (1) do not alter the peripheral whole-body responses to exercise; (2) improve vigilance, alertness, and mood and cognitive processes during and after exercise; and (3) are associated with few, if any, side effects. Therefore, the ergogenic effect of low caffeine doses appears to result from alterations in the central nervous system. However, several aspects of consuming low doses of caffeine remain unresolved and suffer from a paucity of research, including the potential effects on high-intensity sprint and burst activities. The responses to low doses of caffeine are also variable and athletes need to determine whether the ingestion of ~200 mg of caffeine before and/or during training and competitions is ergogenic on an individual basis.

Optimal design of clinical trials with biologics using dose-time-response models.

PubMed

Lange, Markus R; Schmidli, Heinz

2014-12-30

Biologics, in particular monoclonal antibodies, are important therapies in serious diseases such as cancer, psoriasis, multiple sclerosis, or rheumatoid arthritis. While most conventional drugs are given daily, the effect of monoclonal antibodies often lasts for months, and hence, these biologics require less frequent dosing. A good understanding of the time-changing effect of the biologic for different doses is needed to determine both an adequate dose and an appropriate time-interval between doses. Clinical trials provide data to estimate the dose-time-response relationship with semi-mechanistic nonlinear regression models. We investigate how to best choose the doses and corresponding sample size allocations in such clinical trials, so that the nonlinear dose-time-response model can be precisely estimated. We consider both local and conservative Bayesian D-optimality criteria for the design of clinical trials with biologics. For determining the optimal designs, computer-intensive numerical methods are needed, and we focus here on the particle swarm optimization algorithm. This metaheuristic optimizer has been successfully used in various areas but has only recently been applied in the optimal design context. The equivalence theorem is used to verify the optimality of the designs. The methodology is illustrated based on results from a clinical study in patients with gout, treated by a monoclonal antibody. Copyright © 2014 John Wiley & Sons, Ltd.

Characterization of MOSFET detectors for in vivo dosimetry in interventional radiology and for dose reconstruction in case of overexposure.

PubMed

Bassinet, Céline; Huet, Christelle; Baumann, Marion; Etard, Cécile; Réhel, Jean-Luc; Boisserie, Gilbert; Debroas, Jacques; Aubert, Bernard; Clairand, Isabelle

2013-04-01

As MOSFET (Metal Oxide Semiconductor Field Effect Transistor) detectors allow dose measurements in real time, the interest in these dosimeters is growing. The aim of this study was to investigate the dosimetric properties of commercially available TN-502RD-H MOSFET silicon detectors (Best Medical Canada, Ottawa, Canada) in order to use them for in vivo dosimetry in interventional radiology and for dose reconstruction in case of overexposure. Reproducibility of the measurements, dose rate dependence, and dose response of the MOSFET detectors have been studied with a Co source. Influence of the dose rate, frequency, and pulse duration on MOSFET responses has also been studied in pulsed x-ray fields. Finally, in order to validate the integrated dose given by MOSFET detectors, MOSFETs and TLDs (LiF:Mg,Cu,P) were fixed on an Alderson-Rando phantom in the conditions of an interventional neuroradiology procedure, and their responses have been compared. The results of this study show the suitability of MOSFET detectors for in vivo dosimetry in interventional radiology and for dose reconstruction in case of accident, provided a well-corrected energy dependence, a pulse duration equal to or higher than 10 ms, and an optimized contact between the detector and the skin of the patient are achieved.

Estimation of low-dose radiation-responsive proteins in the absence of genomic instability in normal human fibroblast cells.

PubMed

Yim, Ji-Hye; Yun, Jung Mi; Kim, Ji Young; Nam, Seon Young; Kim, Cha Soon

2017-11-01

Low-dose radiation has various biological effects such as adaptive responses, low-dose hypersensitivity, as well as beneficial effects. However, little is known about the particular proteins involved in these effects. Here, we sought to identify low-dose radiation-responsive phosphoproteins in normal fibroblast cells. We assessed genomic instability and proliferation of fibroblast cells after γ-irradiation by γ-H2AX foci and micronucleus formation analyses and BrdU incorporation assay, respectively. We screened fibroblast cells 8 h after low-dose (0.05 Gy) γ-irradiation using Phospho Explorer Antibody Microarray and validated two differentially expressed phosphoproteins using Western blotting. Cell proliferation proceeded normally in the absence of genomic instability after low-dose γ-irradiation. Phospho antibody microarray analysis and Western blotting revealed increased expression of two phosphoproteins, phospho-NFκB (Ser536) and phospho-P70S6K (Ser418), 8 h after low-dose radiation. Our findings suggest that low-dose radiation of normal fibroblast cells activates the expression of phospho-NFκB (Ser536) and phospho-P70S6K (Ser418) in the absence of genomic instability. Therefore, these proteins may be involved in DNA damage repair processes.

Treatment of aplastic anaemia with lower-dose anti-thymocyte globulin produces similar response rates and survival as per standard dose anti-thymocyte globulin schedules.

PubMed

Scott, A; Morris, K; Butler, J; Mills, A K; Kennedy, G A

2016-10-01

Aplastic anaemia (AA) is a rare acquired bone marrow failure syndrome resulting from the immune-mediated destruction of haemopoietic stem cells. For adults in whom first-line haemopoietic progenitor cell transplantation is not feasible, combination anti-thymocyte globulin (ATGAM) plus cyclosporine A is standard therapy; however, there are minimal data available regarding the optimal ATGAM dosage in terms of efficacy and survival. Our institutions have historically used different dosing protocols of ATGAM in the treatment of AA. We aimed to review the outcome of AA patients treated with these protocols and compare them to the published literature. We conducted a retrospective study of 31 adults who received first-line ATGAM for AA and compared response rates and survival between cohorts who received standard (40 mg/kg/day D1-4) versus lower-dose (15 mg/kg/day D1-5) ATGAM schedules. There were similar rates of response (64 vs 71%, P = 1.0), relapse (33 vs 33%, P = 1.0), transformation (14 vs 24%, P = 0.66) or infection (43 vs 47%, P = 1.0), respectively, between standard and lower-dose cohorts. At a median follow up of 24 months, there was no statistical difference between standard and lower-dose cohorts in either event-free (42.2 vs 64.7%, P = 0.91) or overall survival (73.1 vs 88.2%, P = 0.75). Our experience suggests that lower-dose ATGAM at 15 mg/kg/day D1-5 as treatment of AA produces similar responses and outcomes as per standard-dose ATGAM schedules. Prospective trials comparing ATGAM dose schedules in AA are warranted. © 2016 Royal Australasian College of Physicians.

Growth hormone regimens in Australia: analysis of the first 3 years of treatment for idiopathic growth hormone deficiency and idiopathic short stature.

PubMed

Hughes, Ian P; Harris, Mark; Choong, Catherine S; Ambler, Geoff; Cutfield, Wayne; Hofman, Paul; Cowell, Chris T; Werther, George; Cotterill, Andrew; Davies, Peter S W

2012-07-01

To investigate response to growth hormone (GH) in the first, second and third years of treatment for all idiopathic GH-deficient (GHD) and idiopathic short stature (ISS) patients in Australia. Eligibility for subsidized GH treatment in Australia is determined on auxological criteria for the indication of Short Stature and Slow Growth (SSSG), which includes ISS (SSSG-ISS). The biochemical GHD (BGHD, peak GH < 10 mU/l) and SSSG indications are treated similarly: starting dose of 4·5 mg/m(2)/week with provision for incremental dosing. Some ISS patients were specifically diagnosed with familial short stature (SSSG-FSS). Responses for each year of treatment for BGHD, SSSG-ISS and SSSG-FSS cohorts were compared in relation to influencing variables and with international benchmarks. The effect of incremental dosing was assessed. Australian BGHD, SSSG-ISS and SSSG-FSS patients who had completed 1, 2, or 3 years of treatment and were currently receiving GH. Growth hormone dose, change in height-standard deviation score (ΔSDS) and growth velocity (GV). First-year response was 2-3 times greater than that in subsequent years: ΔSDS(1st year) = 0·92, 0·50 and 0·46 for BGHD, SSSG-ISS and SSSG-FSS, respectively. Responses were similar to international reports and inversely related to age at commencement of GH. First-year GV-for-age for BGHD patients was similar to international standards for idiopathic GHD. However, girls had an inferior response to boys when treatment commenced at <6 years of age. First-year GV-for-age for SSSG-ISS/FSS patients was less than ISS standards. Dose increments attenuated the first- to second-year decline in response to BGHD but marginally improved the responses for SSSG-ISS/FSS. The Australian auxology-based GH programme produces comparable responses to international programmes. A lower starting dose is offset by the initiation of treatment at younger ages. Incremental dosing does not appear optimal. A first-year dose of 6·4-6·9 mg/m(2)/week for GHD and 8·9 mg/m(2)/week for ISS with early commencement of GH treatment may be most efficacious. © 2012 Blackwell Publishing Ltd.

Dosimetric characteristics of a PIN diode for radiotherapy application.

PubMed

Kumar, R; Sharma, S D; Philomina, A; Topkar, A

2014-08-01

The PIN diode developed by Bhabha Atomic Research Centre (BARC) was modified for its use as a dosimeter in radiation therapy. For this purpose the diode was mounted on a printed circuit board (PCB) and provided with necessary connections so that its response against irradiation can be recorded by a standard radiotherapy electrometer. The dosimetric characteristics of the diode were studied in Co-60 gamma rays as well as high energy X-rays. The measured sensitivity of this PIN diode is 4 nC/cGy which is about ten times higher than some commercial diode dosimeters. The leakage current from the diode is 0.04 nA. The response of the PIN diode is linear in the range of 20-1000 cGy which covers the full range of radiation dose encountered in radiotherapy treatments. The non-linearity of the diode response is 3.5% at 20 cGy and it is less than 1.5% at higher dose values. Its repeatability is within 0.5%. The angular response variation is about 5.6% within 6608 with respect to normal beam incidence. The response of the PIN diode at 6 and 18 MV X-rays varies within 2% with respect to its response at Co-60 gamma rays. The source to surface distance (SSD) dependence of the PIN diode was studied for Co-60 beam. It was found that the response of the diode decreases almost linearly relative to given dose for beams with constant collimator setting but increasing SSD (decreasing dose-rate). Within this study the diode response varied by about 2.5% between the maximum and minimum SSD. The dose-rate dependence of the PIN diode for 6 and 15 MV-rays was studied. The variation in response of diode for both energies in the studied dose range is less than 1%. The field size dependence of the PIN diode response is within 1% with respect to the response of ionisation chamber. These studies indicate that the characteristics of the PIN diode are suitable for use in radiotherapy dosimetry.

Modern dosimetric tools for 60Co irradiation at high containment laboratories

PubMed Central

Twardoski, Barri; Feldmann, Heinz; Bloom, Marshall E.; Ward, Joe

2011-01-01

Purpose To evaluate an innovative photo-fluorescent film as a routine dosimetric tool during 60Co irradiations at a high containment biological research laboratory, and to investigate whether manufacturer-provided chamber exposure rates can be used to accurately administer a prescribed dose to biological specimens. Materials and methods Photo-fluorescent, lithium fluoride film dosimeters and National Institutes of Standards and Technology (NIST) transfer dosimeters were co-located in a self-shielded 60Co irradiator and exposed to γ-radiation with doses ranging from 5–85 kGy. Film dose-response relationships were developed for varying temperatures simulating conditions present when irradiating infectious biological specimens. Dose measurement results from NIST transfer dosimeters were compared to doses predicted using manufacturer-provided irradiator chamber exposure rates. Results The film dosimeter exhibited a photo-fluorescent response signal that was consistent and nearly linear in relationship to γ-radiation exposure over a wide dose range. The dosimeter response also showed negligible effects from dose fractionization and humidity. Significant disparities existed between manufacturer-provided chamber exposure rates and actual doses administered. Conclusion This study demonstrates the merit of utilizing dosimetric tools to validate the process of exposing dangerous and exotic biological agents to γ-radiation at high containment laboratories. The film dosimeter used in this study can be utilized to eliminate potential for improperly administering γ-radiation doses. PMID:21961968

Low- and high-dose laser irradiation effects on cell migration and destruction

NASA Astrophysics Data System (ADS)

Layton, Elivia; Gallagher, Kyra A.; Zukerman, Sara; Stevens, Brianna; Zhou, Feifan; Liu, Hong; Chen, Wei R.

2018-02-01

Metastases are the cause of more than 90 percent of cancer-related deaths. Current treatment methods, including chemotherapy, radiation, and surgery, fail to target the metastases effectively. One potential treatment for metastatic cancer is laser immunotherapy (LIT). LIT combines the use of a photothermal laser with an immunoadjuvant, Glycated Chitosan (GC). GC combined with single-walled carbon nanotubes (SWNTs) has proven to be a viable alternative to traditional cancer treatment methods, when under irradiation of laser with appropriate wavelength. In this study, the effects of low dose and high dose laser irradiation on metastatic pancreatic cancer cell migration were observed. It was found that low dose irradiation increased the migration rate, but the high dose irradiation significantly decreased the migration rate of the cancer cells. When using LIT, the goal is to kill tumor cells and to prompt the correct immune response. If the tumor were irradiated with a low dose, it would promote metastasis. If the dose of irradiation were too high, it would destroy the entire tumor and the immune response would not recognize the tumor. Therefore, the laser dose plays an important role in LIT, particularly when using SWNT as light absorbing agent. Our results from this study will delineate the optimal laser irradiation dose for destroying tumor cells and at the same time preserve and release tumor antigens as a precursor of antitumor immune response.

Radiation dose response simulation for biomechanical-based deformable image registration of head and neck cancer treatment

NASA Astrophysics Data System (ADS)

Al-Mayah, Adil; Moseley, Joanne; Hunter, Shannon; Brock, Kristy

2015-11-01

Biomechanical-based deformable image registration is conducted on the head and neck region. Patient specific 3D finite element models consisting of parotid glands (PG), submandibular glands (SG), tumor, vertebrae (VB), mandible, and external body are used to register pre-treatment MRI to post-treatment MR images to model the dose response using image data of five patients. The images are registered using combinations of vertebrae and mandible alignments, and surface projection of the external body as boundary conditions. In addition, the dose response is simulated by applying a new loading technique in the form of a dose-induced shrinkage using the dose-volume relationship. The dose-induced load is applied as dose-induced shrinkage of the tumor and four salivary glands. The Dice Similarity Coefficient (DSC) is calculated for the four salivary glands, and tumor to calculate the volume overlap of the structures after deformable registration. A substantial improvement in the registration is found by including the dose-induced shrinkage. The greatest registration improvement is found in the four glands where the average DSC increases from 0.53, 0.55, 0.32, and 0.37 to 0.68, 0.68, 0.51, and 0.49 in the left PG, right PG, left SG, and right SG, respectively by using bony alignment of vertebrae and mandible (M), body (B) surface projection and dose (D) (VB+M+B+D).

Adaptive, dose-finding phase 2 trial evaluating the safety and efficacy of ABT-089 in mild to moderate Alzheimer disease.

PubMed

Lenz, Robert A; Pritchett, Yili L; Berry, Scott M; Llano, Daniel A; Han, Shu; Berry, Donald A; Sadowsky, Carl H; Abi-Saab, Walid M; Saltarelli, Mario D

2015-01-01

ABT-089, an α4β2 neuronal nicotinic receptor partial agonist, was evaluated for efficacy and safety in mild to moderate Alzheimer disease patients receiving stable doses of acetylcholinesterase inhibitors. This phase 2 double-blind, placebo-controlled, proof-of-concept, and dose-finding study adaptively randomized patients to receive ABT-089 (5, 10, 15, 20, 30, or 35 mg once daily) or placebo for 12 weeks. The primary efficacy endpoint was the Alzheimer's Disease Assessment Scale, cognition subscale (ADAS-Cog) total score. A Bayesian response-adaptive randomization algorithm dynamically assigned allocation probabilities based on interim ADAS-Cog total scores. A normal dynamic linear model for dose-response relationships and a longitudinal model for predicting final ADAS-cog score were employed in the algorithm. Stopping criteria for futility or success were defined. The futility stopping criterion was met, terminating the study with 337 patients randomized. No dose-response relationship was observed and no dose demonstrated statistically significant improvement over placebo on ADAS-Cog or any secondary endpoint. ABT-089 was well tolerated at all dose levels. When administered as adjunctive therapy to acetylcholinesterase inhibitors, ABT-089 was not efficacious in mild to moderate Alzheimer disease. The adaptive study design enabled the examination of a broad dose range, enabled rapid determination of futility, and reduced patient exposure to nonefficacious doses of the investigational compound.

Bayesian multimodel inference for dose-response studies

USGS Publications Warehouse

Link, W.A.; Albers, P.H.

2007-01-01

Statistical inference in dose?response studies is model-based: The analyst posits a mathematical model of the relation between exposure and response, estimates parameters of the model, and reports conclusions conditional on the model. Such analyses rarely include any accounting for the uncertainties associated with model selection. The Bayesian inferential system provides a convenient framework for model selection and multimodel inference. In this paper we briefly describe the Bayesian paradigm and Bayesian multimodel inference. We then present a family of models for multinomial dose?response data and apply Bayesian multimodel inferential methods to the analysis of data on the reproductive success of American kestrels (Falco sparveriuss) exposed to various sublethal dietary concentrations of methylmercury.

Cancer risk above 1 Gy and the impact for space radiation protection

NASA Astrophysics Data System (ADS)

Schneider, Uwe; Walsh, Linda

2009-07-01

Analyses of the epidemiological data on the Japanese A-bomb survivors, who were exposed to γ-rays and neutrons, provide most current information on the dose-response of radiation-induced cancer. Since the dose span of main interest is usually between 0 and 1 Gy, for radiation protection purposes, the analysis of the A-bomb survivors is often focused on this range. However, estimates of cancer risk for doses larger than 1 Gy are becoming more important for long-term manned space missions. Therefore in this work, emphasis is placed on doses larger than 1 Gy with respect to radiation-induced solid cancer and leukemia mortality. The present analysis of the A-bomb survivors data was extended by including two extra high-dose categories and applying organ-averaged dose instead of the colon-weighted dose. In addition, since there are some recent indications for a high neutron dose contribution, the data were fitted separately for three different values for the relative biological effectiveness (RBE) of the neutrons (10, 35 and 100) and a variable RBE as a function of dose. The data were fitted using a linear and a linear-exponential dose-response relationship using a dose and dose-rate effectiveness factor (DDREF) of both one and two. The work presented here implies that the use of organ-averaged dose, a dose-dependent neutron RBE and the bending-over of the dose-response relationship for radiation-induced cancer could result in a reduction of radiation risk by around 50% above 1 Gy. This could impact radiation risk estimates for space crews on long-term mission above 500 days who might be exposed to doses above 1 Gy. The consequence of using a DDREF of one instead of two increases cancer risk by about 40% and would therefore balance the risk decrease described above.

The Effect of Ritalin on Response to Reward and Punishment in Children with ADHD.

ERIC Educational Resources Information Center

Arnett, Peter A.; And Others

1996-01-01

Groups of attention deficit hyperactivity disorder (ADHD) children taking a placebo, high dose, or low dose of Ritalin were compared in their responses to reward and punishment. Results suggest that Ritalin may improve the ability of ADHD children to withhold inappropriate responding by dampening their response to reward cues and, possibly, making…

DOSE-RESPONSE FOR UV-INDUCED IMMUNE SUPPRESSION IN PEOPLE OF COLOR: DIFFERENCES BASED ON ERYTHEMAL REACTIVITY RATHER THAN SKIN PIGMENTATION

EPA Science Inventory

Ultraviolet radiation (UVR) is known to suppress immune responses in human subjects. The purpose of this study was to develop dose responses across a broad range of skin pigmentation in order to facilitate risk assessment. UVR was administered using FS 20 bulbs. Skin pigmentation...

Mechanisms underlying cellular responses of cells from haemopoietic tissue to low dose/low LET radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Munira A Kadhim

2010-03-05

To accurately define the risks associated with human exposure to relevant environmental doses of low LET ionizing radiation, it is necessary to completely understand the biological effects at very low doses (i.e., less than 0.1 Gy), including the lowest possible dose, that of a single electron track traversal. At such low doses, a range of studies have shown responses in biological systems which are not related to the direct interaction of radiation tracks with DNA. The role of these “non-targeted” responses in critical tissues is poorly understood and little is known regarding the underlying mechanisms. Although critical for dosimetry andmore » risk assessment, the role of individual genetic susceptibility in radiation risk is not satisfactorily defined at present. The aim of the proposed grant is to critically evaluate radiation-induced genomic instability and bystander responses in key stem cell populations from haemopoietic tissue. Using stem cells from two mouse strains (CBA/H and C57BL/6J) known to differ in their susceptibility to radiation effects, we plan to carefully dissect the role of genetic predisposition on two non-targeted radiation responses in these models; the bystander effect and genomic instability, which we believe are closely related. We will specifically focus on the effects of low doses of low LET radiation, down to doses approaching a single electron traversal. Using conventional X-ray and γ-ray sources, novel dish separation and targeted irradiation approaches, we will be able to assess the role of genetic variation under various bystander conditions at doses down to a few electron tracks. Irradiations will be carried out using facilities in routine operation for bystander targeted studies. Mechanistic studies of instability and the bystander response in different cell lineages will focus initially on the role of cytokines which have been shown to be involved in bystander signaling and the initiation of instability. These studies also aim to uncover protein mediators of the bystander responses using advanced proteomic screening of factors released from irradiated, bystander and unstable cells. Integral to these studies will be an assessment of the role of genetic susceptibility in these responses, using CBA/H and C57BL/6J mice. The relevance of in vivo interactions between stem cells and the stem cell niche will be explored in the future by re-implantation techniques of previously irradiated cells. The above studies will provide fundamental mechanistic information relating genetic predisposition to important low dose phenomena, and will aid in the development of Department of Energy policy, as well as radiation risk policy for the public and the workplace. We believe the proposed studies accurately reflect the goals of the DOE low dose program.« less

Comparison of thermoluminescence response of different sized Ge-doped flat fibers as a dosimeter

NASA Astrophysics Data System (ADS)

Begum, Mahfuza; Mizanur Rahman, A. K. M.; Abdul-Rashid, H. A.; Yusoff, Z.; Mat-Sharif, K. A.; Zulkifli, M. I.; Muhamad-Yasin, S. Z.; Ung, N. M.; Kadir, A. B. A.; Amin, Y. M.; Bradley, D. A.

2015-11-01

Prime dosimetric properties, including dose-response, linearity with dose, energy response, fading and threshold doses were investigated for three different dimension Ge-doped flat fibers. The results of measurement were also compared with two of the more commonly used standard TLD media, TLD-100 (LiF:Mg,Ti-7.5%6LiF) and TLD-700 (7LiF:Mg,Ti-99.9%7LiF) chips. The flat cross-section samples (60×180) μm2, (100×350) μm2 and (200×750) μm2 were fabricated using the Modified Chemical Vapor Deposition (MCVD) process and pulled from the same "preform." In the study, all flat fiber samples provided good linear dose-response for the photon and electron beams generated using a medical linear accelerator (LINAC), for doses in the range 0.5-8 Gy. Among the samples, the smallest dimension flat fiber provided the best response, with a sensitivity of some 61% and 54%, respectively of that of the TLD-100 and TLD-700 chips. The energy responses of the samples were studied for various photon (6 MV, 10 MV) and electron (6 MeV, 9 MeV) beam energies. TL fading of around 20% was observed over a period of thirty (30) days. These favorable TL characteristics point towards promising development of Ge-doped flat fibers for use in radiotherapy dosimetry.

Hormetic Response by Silver Nanoparticles on In Vitro Multiplication of Sugarcane (Saccharum spp. Cv. Mex 69-290) Using a Temporary Immersion System

PubMed Central

Chavez-Santoscoy, Rocío A.; Lecona-Guzmán, Carlos A.; Bogdanchikova, Nina; Salinas-Ruíz, Josafhat; Gómez-Merino, Fernando Carlos; Pestryakov, Alexey

2017-01-01

Background: Hormesis is considered a dose–response phenomenon characterized by growth stimulation at low doses and inhibition at high doses. The hormetic response by silver nanoparticles (AgNPs) on in vitro multiplication of sugarcane was evaluated using a temporary immersion system. Methods: Sugarcane shoots were used as explants cultured in Murashige and Skoog medium with AgNPs at concentrations of 0, 25, 50, 100, and 200 mg/L. Shoot multiplication rate and length were used to determine hormetic response. Total content of phenolic compounds of sugarcane, mineral nutrition, and reactive oxygen species (ROS) was determined. Results: Results were presented as a dose–response curve. Stimulation phase growth was observed at 50 mg/L AgNPs, whereas inhibition phase was detected at 200 mg/L AgNPs. Mineral nutrient analysis showed changes in macronutrient and micronutrient contents due to the effect of AgNPs. Moreover, AgNPs induced ROS production and increased total phenolic content, with a dose-dependent effect. Conclusion: Results suggested that the production of ROS and mineral nutrition are key mechanisms of AgNP-induced hormesis and that phenolic accumulation was obtained as a response of the plant to stress produced by high doses of AgNPs. Therefore, small doses of AgNPs in the culture medium could be an efficient strategy for commercial micropropagation. PMID:29238274

Plane of nutrition during the preweaned period and Mannheimia haemolytica dose influence metabolic responses in post-weaned Holstein calves challenged with bovine herpesvirus-1 and Mannheimia haemolytica

USDA-ARS?s Scientific Manuscript database

To determine whether previous plane of milk replacer nutrition (PON) and M. haemolytica (MH) dose influences metabolic responses to a combined viral-bacterial respiratory challenge, Holstein calves (1 day of age; n=30) were assigned to treatments in a 2 x 3 factorial with preweaned PON and dose of M...

Plane of nutrition during the preweaned period and Mannheimia haemolytica dose influences inflammatory responses to a combined bovine herpesvirus-1 and Mannheimia haemolytica challenge in post-weaned Holstein calves

USDA-ARS?s Scientific Manuscript database

To determine whether previous plane of milk replacer nutrition (PON) and M. haemolytica (MH) dose influences inflammatory responses to a combined viral-bacterial respiratory challenge, Holstein calves (1 day of age; n=30) were assigned to treatments in a 2 x 3 factorial with preweaned PON and dose o...

Persistence of memory B-cell and T-cell responses to the quadrivalent HPV vaccine in HIV-infected children.

PubMed

Weinberg, Adriana; Huang, Sharon; Moscicki, Anna-Barbara; Saah, Afred; Levin, Myron J

2018-04-24

To determine the magnitude and persistence of quadrivalent human papillomavirus (HPV)16 and HPV18 B-cell and T-cell memory after three or four doses of quadrivalent HPV vaccine (QHPV) in HIV-infected children. Seventy-four HIV-infected children immunized with four doses and 23 with three doses of QHPV had HPV16 and HPV18 IgG B-cell and IFNγ and IL2 T-cell ELISPOT performed at 2, 3.5 and 4-5 years after the last dose. HPV16 and HPV18 T-cell responses were similar in both treatment groups, with higher responses to HPV16 vs. HPV18. These HPV T-cell responses correlated with HIV disease characteristics at the study visits. Global T-cell function declined over time as measured by nonspecific mitogenic stimulation. B-cell memory was similar across treatment groups and HPV genotypes. There was a decline in HPV-specific B-cell memory over time that reached statistical significance for HPV16 in the four-dose group. B-cell and T-cell memory did not significantly differ after either three or four doses of QHPV in HIV-infected children. The clinical consequences of decreasing global T-cell function and HPV B-cell memory over time in HIV-infected children requires further investigation.

Development of a Bayesian response-adaptive trial design for the Dexamethasone for Excessive Menstruation study.

PubMed

Holm Hansen, Christian; Warner, Pamela; Parker, Richard A; Walker, Brian R; Critchley, Hilary Od; Weir, Christopher J

2017-12-01

It is often unclear what specific adaptive trial design features lead to an efficient design which is also feasible to implement. This article describes the preparatory simulation study for a Bayesian response-adaptive dose-finding trial design. Dexamethasone for Excessive Menstruation aims to assess the efficacy of Dexamethasone in reducing excessive menstrual bleeding and to determine the best dose for further study. To maximise learning about the dose response, patients receive placebo or an active dose with randomisation probabilities adapting based on evidence from patients already recruited. The dose-response relationship is estimated using a flexible Bayesian Normal Dynamic Linear Model. Several competing design options were considered including: number of doses, proportion assigned to placebo, adaptation criterion, and number and timing of adaptations. We performed a fractional factorial study using SAS software to simulate virtual trial data for candidate adaptive designs under a variety of scenarios and to invoke WinBUGS for Bayesian model estimation. We analysed the simulated trial results using Normal linear models to estimate the effects of each design feature on empirical type I error and statistical power. Our readily-implemented approach using widely available statistical software identified a final design which performed robustly across a range of potential trial scenarios.

Concord Grape Juice Polyphenols and Cardiovascular Risk Factors: Dose-Response Relationships

PubMed Central

Blumberg, Jeffrey B.; Vita, Joseph A.; Chen, C. -Y. Oliver

2015-01-01

Pure fruit juices provide nutritional value with evidence suggesting some of their benefits on biomarkers of cardiovascular disease risk may be derived from their constituent polyphenols, particularly flavonoids. However, few data from clinical trials are available on the dose-response relationship of fruit juice flavonoids to these outcomes. Utilizing the results of clinical trials testing single doses, we have analyzed data from studies of 100% Concord grape juice by placing its flavonoid content in the context of results from randomized clinical trials of other polyphenol-rich foods and beverages describing the same outcomes but covering a broader range of intake. We selected established biomarkers determined by similar methods for measuring flow-mediated vasodilation (FMD), blood pressure, platelet aggregation, and the resistance of low density lipoprotein cholesterol (LDL) to oxidation. Despite differences among the clinical trials in the treatment, subjects, and duration, correlations were observed between the dose and FMD. Inverse dose-response relationships, albeit with lower correlation coefficients, were also noted for the other outcomes. These results suggest a clear relationship between consumption of even modest serving sizes of Concord grape juice, flavonoid intake, and effects on risk factors for cardiovascular disease. This approach to dose-response relationships may prove useful for testing other individual foods and beverages. PMID:26633488

Effect of two doses of carbamylated allergoid extract of dust mite on nasal reactivity.

PubMed

Scalone, G; Compalati, E; Bruno, M E; Mistrello, G

2013-11-01

Background and Objective. Single SLIT studies with native allergen extracts support a dose-response effect for clinical and immunological outcomes. Conversely for carbamylated allergoids this dose-response effects is less evident, likely because the threshold for efficacy is more easily reached through the enhanced bioavailability of the extract consequent to the selective chemical modification. Thus this pilot study investigates the dose-response effect on nasal specific reactivity and safety of two unusual doses of carbamylated allergoid in patients mono-sensitized to house dust mites. Methods. A prospective open randomized study involved 6-65 year-old Italian patients with clinically relevant sensitization to house dust mites and positive response to nasal provocation challenge. Monomeric carbamylated allergoid was delivered once daily at the dose of 1000 AU or 2000 AU from June to September 2009, during the lowest level of mites exposure. Primary outcomes were the change of the threshold of allergen concentration for a positive nasal provocation test (NPT) before and after the treatment and the product safety. Secondary outcome was the change  in the mean percentage fall of peak nasal inspiratory flow (PNIF) following nasal challenge. Results. Thirty-four patients were enrolled. Fifteen in group 1 and 14 in group 2 concluded the study. After 12 weeks all patients treated in group 1 and all but one in group 2 showed an increase in the threshold dose provoking a positive NPT. Those with no symptoms onset with the highest dose delivered were 80% in group 1 and 78.6% in group 2 (p=0.92). From first to second challenge, the mean percentage fall of PNIF  was reduced with no statistical difference between groups (p=0.95), and with no difference between the final mean percentage falls (p=0.65). No serious adverse reactions occurred and the frequency of events, all mild, was similar in the two groups. Conclusions. Twelve weeks of carbamylated sublingual allergoid delivered at 1000AU or 2000AU once daily appear equally safe and show comparable effect in increasing  the threshold of allergen concentration for a positive nasal provocation test, confirming the apparent absence of a dose response effect for the used doses.

Green tea polyphenol (−)-epigallocatechin-3-gallate triggered hepatotoxicity in mice: Responses of major antioxidant enzymes and the Nrf2 rescue pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Dongxu; Wang, Yijun; Wan, Xiaochun

(−)-Epigallocatechin-3-gallate (EGCG), a constituent of green tea, has been suggested to have numerous health-promoting effects. On the other hand, high-dose EGCG is able to evoke hepatotoxicity. In the present study, we elucidated the responses of hepatic major antioxidant enzymes and nuclear factor erythroid 2-related factor 2 (Nrf2) rescue pathway to high-dose levels of EGCG in Kunming mice. At a non-lethal toxic dose (75 mg/kg, i.p.), repeated EGCG treatments markedly decreased the levels of superoxide dismutase, catalase, and glutathione peroxidase. As a rescue response, the nuclear distribution of Nrf2 was significantly increased; a battery of Nrf2-target genes, including heme oxygenase 1more » (HO1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), and those involved in glutathione and thioredoxin systems, were all up-regulated. At the maximum tolerated dose (45 mg/kg, i.p.), repeated EGCG treatments did not disturb the major antioxidant defense. Among the above-mentioned genes, only HO1, NQO1, and GST genes were significantly but modestly up-regulated, suggesting a comprehensive and extensive activation of Nrf2-target genes principally occurs at toxic levels of EGCG. At a lethal dose (200 mg/kg, i.p.), a single EGCG treatment dramatically decreased not only the major antioxidant defense but also the Nrf2-target genes, demonstrating that toxic levels of EGCG are able to cause a biphasic response of Nrf2. Overall, the mechanism of EGCG-triggered hepatotoxicity involves suppression of major antioxidant enzymes, and the Nrf2 rescue pathway plays a vital role for counteracting EGCG toxicity. - Highlights: • EGCG at maximum tolerated dose does not disturb hepatic major antioxidant defense. • EGCG at maximum tolerated dose modestly upregulates hepatic Nrf2 target genes. • EGCG at toxic dose suppresses hepatic major antioxidant enzymes. • EGCG at non-lethal toxic dose pronouncedly activates hepatic Nrf2 rescue response. • EGCG at lethal dose substantially suppresses hepatic Nrf2 pathway.« less

Immune Response And Anamnestic Immune Response In Children After A 3-Dose Primary Hepatitis B Vaccination.

PubMed

Afzal, Muhammad Faheem; Sultan, Muhammad Ashraf; Saleemi, Ahmad Imran

2016-01-01

Diseases caused by Hepatitis B virus (HBV) have a worldwide distribution. Pakistan adopted the recommendations of World Health Organization (WHO) for routine universal infant vaccination against hepatitis B in 2002, currently being administered at 6, 10, and 14 weeks of age in a combination vaccine. This study was conducted to determine the immune response & anamnestic immune response in children, 9 months-10 years of age, after a 3dose primary Hepatitis B vaccination. This cross sectional study was conducted in the Department of Paediatrics, King Edward Medical University/Mayo Hospital, Lahore, Pakistan, from January to June, 2014. A total of 200 children of either sex between the ages of 9 months to 10 years, documented to have received 3 doses of hepatitis B vaccines according to Expanded Program of Immunization (6,10,14 weeks) schedule in infancy, were recruited by consecutive sampling. The level of serum antiHBsAb by ELIZA was measured. Children with antiHBs titers ≥10 mIU/mL were considered to be immune. Those with anti HBsAb levels <10 mIU/mL were offered a booster dose of infant recombinant hepatitis B vaccine. The second serum sample was obtained 21-28 days following the administration of the booster dose and the anamnestic immune response was measured. Data was analysed using SPSS 17 to determine the relation between time interval since last vaccination and antibody titer. Chi square test was applied. Of the 200 children, protective antibody response was found in 58%. Median serological response was 18.60 (range 2.82 - 65.15). Antibody levels were found to have a statistically significant ( pvalue 0.019) negative correlation with the time since last administration of vaccine. A booster dose of Hepatitis B vacci ne was administered to all nonresponders, with each registering a statistically significant (pvalue 0.00) anamnestic response. The vaccination schedule with short dosage interval was unable to provide protection to 42% of the study population. Introduction of birth dose of Hepatitis B vaccine to the existing schedule is recommended.

Investigation of EBT2 and EBT3 films for proton dosimetry in the 4-20 MeV energy range.

PubMed

Reinhardt, S; Würl, M; Greubel, C; Humble, N; Wilkens, J J; Hillbrand, M; Mairani, A; Assmann, W; Parodi, K

2015-03-01

Radiochromic films such as Gafchromic EBT2 or EBT3 films are widely used for dose determination in radiation therapy because they offer a superior spatial resolution compared to any other digital dosimetric 2D detector array. The possibility to detect steep dose gradients is not only attractive for intensity-modulated radiation therapy with photons but also for intensity-modulated proton therapy. Their characteristic dose rate-independent response makes radiochromic films also attractive for dose determination in cell irradiation experiments using laser-driven ion accelerators, which are currently being investigated as future medical ion accelerators. However, when using these films in ion beams, the energy-dependent dose response in the vicinity of the Bragg peak has to be considered. In this work, the response of these films for low-energy protons is investigated. To allow for reproducible and background-free irradiation conditions, the films were exposed to mono-energetic protons from an electrostatic accelerator, in the 4-20 MeV energy range. For comparison, irradiation with clinical photons was also performed. It turned out that in general, EBT2 and EBT3 films show a comparable performance. For example, dose-response curves for photons and protons with energies as low as 11 MeV show almost no differences. However, corrections are required for proton energies below 11 MeV. Care has to be taken when correction factors are related to an average LET from depth-dose measurements, because only the dose-averaged LET yields similar results as obtained in mono-energetic measurements.

Sex differences in the subjective effects of oral Δ9-THC in cannabis users.

PubMed

Fogel, Jessica S; Kelly, Thomas H; Westgate, Philip M; Lile, Joshua A

2017-01-01

Previous studies suggest that there are sex differences in endocannabinoid function and the response to exogenous cannabinoids, though data from clinical studies comparing acute cannabinoid effects in men and women under controlled laboratory conditions are limited. To further explore these potential differences, data from 30 cannabis users (N=18 M, 12 F) who completed previous Δ 9 -tetrahydrocannabinol (Δ 9 -THC) discrimination studies were combined for this retrospective analysis. In each study, subjects learned to discriminate between oral Δ 9 -THC and placebo and then received a range of Δ 9 -THC doses (0, 5, 15 and a "high" dose of either 25 or 30mg). Responses on a drug-discrimination task, subjective effects questionnaire, psychomotor performance tasks, and physiological measures were assessed. Δ 9 -THC dose-dependently increased drug-appropriate responding, ratings on "positive" Visual Analog Scale (VAS) items (e.g., good effects, like drug, take again), and items related to intoxication (e.g., high, stoned). Δ 9 -THC also dose-dependently impaired performance on psychomotor tasks and elevated heart rate. Sex differences on VAS items emerged as a function of dose. Women exhibited significantly greater subjective responses to oral drug administration than men at the 5mg Δ 9 -THC dose, whereas men were more sensitive to the subjective effects of the 15mg dose of Δ 9 -THC than women. These results demonstrate dose-dependent separation in the subjective response to oral Δ 9 -THC administration by sex, which might contribute to the differential development of problematic cannabis use. Copyright © 2015 Elsevier Inc. All rights reserved.

Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: A dose escalation and pharmacologic study1

PubMed Central

Phuphanich, Surasak; Baker, Sharyn D.; Grossman, Stuart A.; Carson, Kathryn A.; Gilbert, Mark R.; Fisher, Joy D.; Carducci, Michael A.

2005-01-01

We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 μM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme–inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants. PMID:15831235

Immune responses in Eimeria acervulina infected one-day-old broilers compared to amount of Eimeria in the duodenum, measured by real-time PCR.

PubMed

Swinkels, W J C; Post, J; Cornelissen, J B; Engel, B; Boersma, W J A; Rebel, J M J

2006-06-15

T-cell responses are supposed to be the major immune reactions in broilers infected with Eimeria. The nature of such T-cell responses is influenced by the species of Eimeria involved, age of the host, amount of parasites and the preceding infection history. In young chicks the intestine is still developing in length while the lymphocyte populations in the gut develop and differentiate. In chicks infected at young age the immune response may be different in quality as compared to responses in adults. We investigated the (T-cell) immune responses of young broilers to a primary Eimeria acervulina infection in relation to the number of parasites used for infection. In our experiment we infected one-day-old broilers with a low (5 x 10(2) oocysts) and a high (5 x 10(4) oocysts) dose of E. acervulina. We used a newly developed species specific real-time PCR to quantify total amount of parasites in the duodenum as the number of oocysts in faeces may not be representative for the exposure of the gut immune system. We characterized T-cell subsets in the duodenum by means of FACS-analyses, lymphocyte proliferation assays with spleen lymphocytes and the mRNA profiles of different cytokines (TGF-beta2, -4, IFN-gamma, IL-2, -6, -8 and -18) in the duodenum by means of real-time PCR. From day 5 p.i. broilers with a high dose of E. acervulina had a significantly lower body weight than the control group. No increase in CD4(+) cells, but a strong increase in CD8(+) cells was observed at days 7 and 9 p.i. in the duodenum of broilers infected with a high dose E. acervulina. IL-8 mRNA responses were observed after infection with low and with high infection doses, but no IFN-gamma and TGF-beta mRNA responses were found in the duodenum. The specific proliferative T-cell responses to a low infectious dose were not significantly different as compared to the control group. In conclusion, based on the kinetics of observed responses a primary infection with a high dose of E. acervulina in one-day-old broilers seems to generate an immune response that shows a peak at the time of oocyst excretion, whereas the immune response to a low dose is less explicit.

High- to low-dose extrapolation: critical determinants involved in the dose response of carcinogenic substances.

PubMed

Swenberg, J A; Richardson, F C; Boucheron, J A; Deal, F H; Belinsky, S A; Charbonneau, M; Short, B G

1987-12-01

Recent investigations on mechanism of carcinogenesis have demonstrated important quantitative relationships between the induction of neoplasia, the molecular dose of promutagenic DNA adducts and their efficiency for causing base-pair mismatch, and the extent of cell proliferation in target organ. These factors are involved in the multistage process of carcinogenesis, including initiation, promotion, and progression. The molecular dose of DNA adducts can exhibit supralinear, linear, or sublinear relationships to external dose due to differences in absorption, biotransformation, and DNA repair at high versus low doses. In contrast, increased cell proliferation is a common phenomena that is associated with exposures to relatively high doses of toxic chemicals. As such, it enhances the carcinogenic response at high doses, but has little effect at low doses. Since data on cell proliferation can be obtained for any exposure scenario and molecular dosimetry studies are beginning to emerge on selected chemical carcinogens, methods are needed so that these critical factors can be utilized in extrapolation from high to low doses and across species. The use of such information may provide a scientific basis for quantitative risk assessment.

High- to low-dose extrapolation: critical determinants involved in the dose response of carcinogenic substances.

PubMed Central

Swenberg, J A; Richardson, F C; Boucheron, J A; Deal, F H; Belinsky, S A; Charbonneau, M; Short, B G

1987-01-01

Recent investigations on mechanism of carcinogenesis have demonstrated important quantitative relationships between the induction of neoplasia, the molecular dose of promutagenic DNA adducts and their efficiency for causing base-pair mismatch, and the extent of cell proliferation in target organ. These factors are involved in the multistage process of carcinogenesis, including initiation, promotion, and progression. The molecular dose of DNA adducts can exhibit supralinear, linear, or sublinear relationships to external dose due to differences in absorption, biotransformation, and DNA repair at high versus low doses. In contrast, increased cell proliferation is a common phenomena that is associated with exposures to relatively high doses of toxic chemicals. As such, it enhances the carcinogenic response at high doses, but has little effect at low doses. Since data on cell proliferation can be obtained for any exposure scenario and molecular dosimetry studies are beginning to emerge on selected chemical carcinogens, methods are needed so that these critical factors can be utilized in extrapolation from high to low doses and across species. The use of such information may provide a scientific basis for quantitative risk assessment. PMID:3447904

Less than 3 doses of the HPV vaccine – Review of efficacy against virological and disease end points

PubMed Central

Basu, Partha; Bhatla, Neerja; Ngoma, Twalib; Sankaranarayanan, Rengaswamy

2016-01-01

ABSTRACT World Health Organization (WHO) recommended 2 doses of the Human Papillomavirus (HPV) vaccine for girls below 15 y on the basis of the immune-bridging studies demonstrating non-inferior immune response of 2 doses in the adolescent girls compared to 3 doses in the young adult women in whom the efficacy against disease is established. The biological nature of the antigens (virus-like particles) constituting the HPV vaccine is responsible for the vigorous antibody response that may make the third dose redundant. The protection offered by 2 doses has been demonstrated in non-randomized clinical trials to be comparable to that offered by 3 doses against incident and persistent infections of vaccine targeted HPV types. However, results emerging from the ecological and nested case-control studies embedded in the population based screening programs of different countries indicate reduced efficacy of 2 doses against virological and disease end points. Some recent studies observed the protective effect of single dose of the vaccine against incident and persistent infections of the vaccine targeted HPV types to be similar to 3 doses in spite of immunological inferiority. The sample size, duration of follow-ups and number of events were limited in these studies. Longer follow ups of the less than 3 doses cohorts in the ongoing studies as well as appropriately designed and ethically justifiable randomized studies are needed to establish the protection offered by the alternative schedules at least beyond 10 y of vaccination. PMID:26933961

Bayesian dose-response analysis for epidemiological studies with complex uncertainty in dose estimation.

PubMed

Kwon, Deukwoo; Hoffman, F Owen; Moroz, Brian E; Simon, Steven L

2016-02-10

Most conventional risk analysis methods rely on a single best estimate of exposure per person, which does not allow for adjustment for exposure-related uncertainty. Here, we propose a Bayesian model averaging method to properly quantify the relationship between radiation dose and disease outcomes by accounting for shared and unshared uncertainty in estimated dose. Our Bayesian risk analysis method utilizes multiple realizations of sets (vectors) of doses generated by a two-dimensional Monte Carlo simulation method that properly separates shared and unshared errors in dose estimation. The exposure model used in this work is taken from a study of the risk of thyroid nodules among a cohort of 2376 subjects who were exposed to fallout from nuclear testing in Kazakhstan. We assessed the performance of our method through an extensive series of simulations and comparisons against conventional regression risk analysis methods. When the estimated doses contain relatively small amounts of uncertainty, the Bayesian method using multiple a priori plausible draws of dose vectors gave similar results to the conventional regression-based methods of dose-response analysis. However, when large and complex mixtures of shared and unshared uncertainties are present, the Bayesian method using multiple dose vectors had significantly lower relative bias than conventional regression-based risk analysis methods and better coverage, that is, a markedly increased capability to include the true risk coefficient within the 95% credible interval of the Bayesian-based risk estimate. An evaluation of the dose-response using our method is presented for an epidemiological study of thyroid disease following radiation exposure. Copyright © 2015 John Wiley & Sons, Ltd.

Non-induction of radioadaptive response in zebrafish embryos by neutrons

PubMed Central

Ng, Candy Y.P.; Kong, Eva Y.; Kobayashi, Alisa; Suya, Noriyoshi; Uchihori, Yukio; Cheng, Shuk Han; Konishi, Teruaki; Yu, Kwan Ngok

2016-01-01

In vivo neutron-induced radioadaptive response (RAR) was studied using zebrafish (Danio rerio) embryos. The Neutron exposure Accelerator System for Biological Effect Experiments (NASBEE) facility at the National Institute of Radiological Sciences (NIRS), Japan, was employed to provide 2-MeV neutrons. Neutron doses of 0.6, 1, 25, 50 and 100 mGy were chosen as priming doses. An X-ray dose of 2 Gy was chosen as the challenging dose. Zebrafish embryos were dechorionated at 4 h post fertilization (hpf), irradiated with a chosen neutron dose at 5 hpf and the X-ray dose at 10 hpf. The responses of embryos were assessed at 25 hpf through the number of apoptotic signals. None of the neutron doses studied could induce RAR. Non-induction of RAR in embryos having received 0.6- and 1-mGy neutron doses was attributed to neutron-induced hormesis, which maintained the number of damaged cells at below the threshold for RAR induction. On the other hand, non-induction of RAR in embryos having received 25-, 50- and 100-mGy neutron doses was explained by gamma-ray hormesis, which mitigated neutron-induced damages through triggering high-fidelity DNA repair and removal of aberrant cells through apoptosis. Separate experimental results were obtained to verify that high-energy photons could disable RAR. Specifically, 5- or 10-mGy X-rays disabled the RAR induced by a priming dose of 0.88 mGy of alpha particles delivered to 5-hpf zebrafish embryos against a challenging dose of 2 Gy of X-rays delivered to the embryos at 10 hpf. PMID:26850927

Dose rate effect of pulsed electron beam on micronucleus frequency in human peripheral blood lymphocytes.

PubMed

Acharya, Santhosh; Sanjeev, Ganesh; Bhat, Nagesh N; Narayana, Yerol

2010-03-01

The micronucleus assay in human peripheral blood lymphocytes is a sensitive indicator of radiation damage and could serve as a biological dosimeter in evaluating suspected overexposure to ionising radiation. Micronucleus (MN) frequency as a measure of chromosomal damage has also extensively been employed to quantify the effects of radiation dose rate on biological systems. Here we studied the effects of 8 MeV pulsed electron beam emitted by Microtron electron accelerator on MN induction at dose rates between 35 Gy min-1 and 352.5 Gy min-1. These dose rates were achieved by varying the pulse repetition rate (PRR). Fricke dosimeter was employed to measure the absorbed dose at different PRR and to ensure uniform dose distribution of the electron beam. To study the dose rate effect, blood samples were irradiated to an absorbed dose of (4.7+/-0.2) Gy at different rates and cytogenetic damage was quantified using the micronucleus assay. The obtained MN frequency showed no dose rate dependence within the studied dose rate range. Our earlier dose effect study using 8 MeV electrons revealed that the response of MN was linear-quadratic. Therefore, in the event of an accident, dose estimation can be made using linear-quadratic dose response parameters, without adding dose rate as a correction factor.

Developing Software for Pharmacodynamics and Bioassay Studies

DTIC Science & Technology

The objective of the project is to develop a software system to process general pharmacologic, toxicological, or other biomedical research data that...exhibit a non-monotonic dose-response relationship - for which the current parametric models fail. The software will analyze dose-response

IS THE DOSE-RESPONSE LINEAR OR NONLINEAR FOR GENOTOXIC EFFECTS?

EPA Science Inventory

IS THE DOSE-RESPONSE LINEAR OR NONLINEAR FOR GENOTOXIC EFFECTS?
Preston, RJ. Environmental Carcinogenesis Division, NHEERL, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

For considerations of cancer risk assessment from exposure to environmenta...

A Framework for "Fit for Purpose" Dose Response Assessment

EPA Science Inventory

The NRC report Science and Decisions: Advancing Risk Assessment made several recommendations to improve chemical risk assessment, with a focus on in-depth chronic dose-response assessments conducted by the U.S. Environmental Protection Agency. The recommendations addressed two ...

Comparison of skin responses from macroscopic and microscopic UV challenges

NASA Astrophysics Data System (ADS)

Seo, InSeok; Bargo, Paulo R.; Chu, Melissa; Ruvolo, Eduardo; Kollias, Nikiforos

2011-03-01

The minimal erythema dose induced by solar-simulated radiation is a useful measure of UV sensitivity of skin. Most skin phototests have been conducted by projecting a flat field of UV radiation onto the skin in an area greater than 15 cm × 15 cm with an increment of radiation doses. In this study, we investigated the responses of human skin to solar-simulated radiation of different field sizes. Twelve human subjects of skin phototype I-IV were exposed to solar-simulated radiation (SSR) on their upper inner arm or on their lower back with a series of doses in increments of 20% in order to determine the threshold dose to induce a minimal perceptible erythema response (MED). Each dose was delivered with a liquid light guide (8 mm diameter on the back or 6 mm on the upper inner arm) and with quartz optical fibers of 200 μm diameter. The resulting skin responses were evaluated visually and investigated with a reflectance confocal microscope and imaging. The erythema response to the microscopic challenge was always diffuse with no clear boundaries extending to several times the exposed site diameter at doses greater than 2 MED. The skin returned to normal appearance from the microscopic challenge after two weeks of exposure while change in appearance for the larger areas persisted for several weeks to months. This new modality of testing provides the possibility to study skin at the microscopic level with a rapid recovery following challenge.

A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa

PubMed Central

Kang, Sang Bum; Marchelletta, Ronald R; Penrose, Harrison; Docherty, Michael J; McCole, Declan F

2015-01-01

Linaclotide, a synthetic guanylyl cyclase C (GC-C) agonist, and the prostone analog, Lubiprostone, are approved to manage chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Lubiprostone also protects intestinal mucosal barrier function in ischemia. GC-C signaling regulates local fluid balance and other components of intestinal mucosal homeostasis including epithelial barrier function. The aim of this study was to compare if select dosing regimens differentially affect linaclotide and lubiprostone modulation of ion transport and barrier properties of normal human colonic mucosa. Normal sigmoid colon biopsies from healthy subjects were mounted in Ussing chambers. Tissues were treated with linaclotide, lubiprostone, or vehicle to determine effects on short-circuit current (Isc). Subsequent Isc responses to the cAMP agonist, forskolin, and the calcium agonist, carbachol, were also measured to assess if either drug caused desensitization. Barrier properties were assessed by measuring transepithelial electrical resistance. Isc responses to linaclotide and lubiprostone were significantly higher than vehicle control when administered bilaterally or to the mucosal side only. Single versus cumulative concentrations of linaclotide showed differences in efficacy while cumulative but not single dosing caused desensitization to forskolin. Lubiprostone reduced forskolin responses under all conditions. Linaclotide and lubiprostone exerted a positive effect on TER that was dependent on the dosing regimen. Linaclotide and lubiprostone increase ion transport responses across normal human colon but linaclotide displays increased sensitivity to the dosing regimen used. These findings may have implications for dosing protocols of these agents in patients with constipation. PMID:26038704

A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa.

PubMed

Kang, Sang Bum; Marchelletta, Ronald R; Penrose, Harrison; Docherty, Michael J; McCole, Declan F

2015-03-01

Linaclotide, a synthetic guanylyl cyclase C (GC-C) agonist, and the prostone analog, Lubiprostone, are approved to manage chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Lubiprostone also protects intestinal mucosal barrier function in ischemia. GC-C signaling regulates local fluid balance and other components of intestinal mucosal homeostasis including epithelial barrier function. The aim of this study was to compare if select dosing regimens differentially affect linaclotide and lubiprostone modulation of ion transport and barrier properties of normal human colonic mucosa. Normal sigmoid colon biopsies from healthy subjects were mounted in Ussing chambers. Tissues were treated with linaclotide, lubiprostone, or vehicle to determine effects on short-circuit current (I sc). Subsequent I sc responses to the cAMP agonist, forskolin, and the calcium agonist, carbachol, were also measured to assess if either drug caused desensitization. Barrier properties were assessed by measuring transepithelial electrical resistance. I sc responses to linaclotide and lubiprostone were significantly higher than vehicle control when administered bilaterally or to the mucosal side only. Single versus cumulative concentrations of linaclotide showed differences in efficacy while cumulative but not single dosing caused desensitization to forskolin. Lubiprostone reduced forskolin responses under all conditions. Linaclotide and lubiprostone exerted a positive effect on TER that was dependent on the dosing regimen. Linaclotide and lubiprostone increase ion transport responses across normal human colon but linaclotide displays increased sensitivity to the dosing regimen used. These findings may have implications for dosing protocols of these agents in patients with constipation.

Statistical methods for clinical verification of dose response parameters related to esophageal stricture and AVM obliteration from radiotherapy

NASA Astrophysics Data System (ADS)

Mavroidis, Panayiotis; Lind, Bengt K.; Theodorou, Kyriaki; Laurell, Göran; Fernberg, Jan-Olof; Lefkopoulos, Dimitrios; Kappas, Constantin; Brahme, Anders

2004-08-01

The purpose of this work is to provide some statistical methods for evaluating the predictive strength of radiobiological models and the validity of dose-response parameters for tumour control and normal tissue complications. This is accomplished by associating the expected complication rates, which are calculated using different models, with the clinical follow-up records. These methods are applied to 77 patients who received radiation treatment for head and neck cancer and 85 patients who were treated for arteriovenous malformation (AVM). The three-dimensional dose distribution delivered to esophagus and AVM nidus and the clinical follow-up results were available for each patient. Dose-response parameters derived by a maximum likelihood fitting were used as a reference to evaluate their compatibility with the examined treatment methodologies. The impact of the parameter uncertainties on the dose-response curves is demonstrated. The clinical utilization of the radiobiological parameters is illustrated. The radiobiological models (relative seriality and linear Poisson) and the reference parameters are validated to prove their suitability in reproducing the treatment outcome pattern of the patient material studied (through the probability of finding a worse fit, area under the ROC curve and khgr2 test). The analysis was carried out for the upper 5 cm of the esophagus (proximal esophagus) where all the strictures are formed, and the total volume of AVM. The estimated confidence intervals of the dose-response curves appear to have a significant supporting role on their clinical implementation and use.

Dose-response model of Rocky Mountain spotted fever (RMSF) for human.

PubMed

Tamrakar, Sushil B; Haas, Charles N

2011-10-01

Rickettsia rickettsii is the causative agent of Rocky Mountain spotted fever (RMSF) and is the prototype bacterium in the spotted fever group of rickettsiae, which is found in North, Central, and South America. The bacterium is gram negative and an obligate intracellular pathogen. The disease is transmitted to humans and vertebrate host through tick bites; however, some cases of aerosol transmission also have been reported. The disease can be difficult to diagnose in the early stages, and without prompt and appropriate treatment, it can be fatal. This article develops dose-response models of different routes of exposure for RMSF in primates and humans. The beta-Poisson model provided the best fit to the dose-response data of aerosol-exposed rhesus monkeys, and intradermally inoculated humans (morbidity as end point of response). The average 50% infectious dose among (ID₅₀) exposed human population, N₅₀, is 23 organisms with 95% confidence limits of 1 to 89 organisms. Similarly, ID₁₀ and ID₂₀ are 2.2 and 5.0, respectively. Moreover, the data of aerosol-exposed rhesus monkeys and intradermally inoculated humans could be pooled. This indicates that the dose-response models fitted to different data sets are not significantly different and can be described by the same relationship. © 2011 Society for Risk Analysis.

Non-Monotonic Dose Responses in Studies of Endocrine Disrupting Chemicals: Bisphenol A as a Case Study

PubMed Central

Vandenberg, Laura N.

2014-01-01

Non-monotonic dose response curves (NMDRCs) have been demonstrated for natural hormones and endocrine disrupting chemicals (EDCs) in a variety of biological systems including cultured cells, whole organ cultures, laboratory animals and human populations. The mechanisms responsible for these NMDRCs are well known, typically related to the interactions between the ligand (hormone or EDC) and a hormone receptor. Although there are hundreds of examples of NMDRCs in the EDC literature, there are claims that they are not ‘common enough’ to influence the use of high-to-low dose extrapolations in risk assessments. Here, we chose bisphenol A (BPA), a well-studied EDC, to assess the frequency of non-monotonic responses. Our results indicate that NMDRCs are common in the BPA literature, occurring in greater than 20% of all experiments and in at least one endpoint in more than 30% of all studies we examined. We also analyzed the types of endpoints that produce NMDRCs in vitro and factors related to study design that influence the ability to detect these kinds of responses. Taken together, these results provide strong evidence for NMDRCs in the EDC literature, specifically for BPA, and question the current risk assessment practice where ‘safe’ low doses are predicted from high dose exposures. PMID:24910584

Non-monotonic dose responses in studies of endocrine disrupting chemicals: bisphenol a as a case study.

PubMed

Vandenberg, Laura N

2014-05-01

Non-monotonic dose response curves (NMDRCs) have been demonstrated for natural hormones and endocrine disrupting chemicals (EDCs) in a variety of biological systems including cultured cells, whole organ cultures, laboratory animals and human populations. The mechanisms responsible for these NMDRCs are well known, typically related to the interactions between the ligand (hormone or EDC) and a hormone receptor. Although there are hundreds of examples of NMDRCs in the EDC literature, there are claims that they are not 'common enough' to influence the use of high-to-low dose extrapolations in risk assessments. Here, we chose bisphenol A (BPA), a well-studied EDC, to assess the frequency of non-monotonic responses. Our results indicate that NMDRCs are common in the BPA literature, occurring in greater than 20% of all experiments and in at least one endpoint in more than 30% of all studies we examined. We also analyzed the types of endpoints that produce NMDRCs in vitro and factors related to study design that influence the ability to detect these kinds of responses. Taken together, these results provide strong evidence for NMDRCs in the EDC literature, specifically for BPA, and question the current risk assessment practice where 'safe' low doses are predicted from high dose exposures.

Characterization of OSL dosimeters for use in dose assessment in Computed Tomography procedures.

PubMed

Giansante, Louise; Santos, Josilene C; Umisedo, Nancy K; Terini, Ricardo A; Costa, Paulo R

2018-03-01

This study describes the characterization of an Al 2 O 3 :C OSLD (Landauer's Luxel™ tape) for dose evaluation in Computed Tomography. The irradiations were conducted using both a constant potential X-ray equipment and a 64-slice clinical CT scanner, and the readouts were performed using a Risø TL/OSL reader. The following aspects were studied: batch homogeneity, energy response, linearity of dose response, reproducibility, reusability, and effect of uncertainties with the normalization of OSL signals per their response to beta radiation. A group of 330 dosimeters from the 452 irradiated with the same dose presented OSL signals within the interval of 4.7% from the average. The dosimeters presented energy-dependent response in good agreement with results found in the literature. The air kerma response of the OSL signal showed a linear trend for both the constant potential X-ray device and the clinical CT scanner, with differences in their slopes of approximately 10%. Reproducibility, reusability, and effect of beta normalization were analyzed by separating 72 dosimeters in 3 groups. The results obtained in this study together with those of previous works indicate that this type of dosimeter is adequate for dose evaluation in CT clinical applications. Copyright © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Inhalation Anthrax: Dose Response and Risk Analysis

PubMed Central

Thran, Brandolyn; Morse, Stephen S.; Hugh-Jones, Martin; Massulik, Stacey

2008-01-01

The notion that inhalation of a single Bacillus anthracis spore is fatal has become entrenched nearly to the point of urban legend, in part because of incomplete articulation of the scientific basis for microbial risk assessment, particularly dose-response assessment. Risk analysis (ie, risk assessment, risk communication, risk management) necessitates transparency: distinguishing scientific facts, hypotheses, judgments, biases in interpretations, and potential misinformation. The difficulty in achieving transparency for biothreat risk is magnified by misinformation and poor characterization of both dose-response relationships and the driving mechanisms that cause susceptibility or resistance to disease progression. Regrettably, this entrenchment unnecessarily restricts preparedness planning to a single response scenario: decontaminate until no spores are detectable in air, water, or on surfaces—essentially forcing a zero-tolerance policy inconsistent with the biology of anthrax. We present evidence about inhalation anthrax dose-response relationships, including reports from multiple studies documenting exposures insufficient to cause inhalation anthrax in laboratory animals and humans. The emphasis of the article is clarification about what is known from objective scientific evidence for doses of anthrax spores associated with survival and mortality. From this knowledge base, we discuss the need for future applications of more formal risk analysis processes to guide development of alternative non-zero criteria or standards based on science to inform preparedness planning and other risk management activities. PMID:18582166

Fundamental Flaws of Hormesis for Public Health Decisions

PubMed Central

Thayer, Kristina A.; Melnick, Ronald; Burns, Kathy; Davis, Devra; Huff, James

2005-01-01

Hormesis (defined operationally as low-dose stimulation, high-dose inhibition) is often used to promote the notion that while high-level exposures to toxic chemicals could be detrimental to human health, low-level exposures would be beneficial. Some proponents claim hormesis is an adaptive, generalizable phenomenon and argue that the default assumption for risk assessments should be that toxic chemicals induce stimulatory (i.e., “beneficial”) effects at low exposures. In many cases, nonmonotonic dose–response curves are called hormetic responses even in the absence of any mechanistic characterization of that response. Use of the term “hormesis,” with its associated descriptors, distracts from the broader and more important questions regarding the frequency and interpretation of nonmonotonic dose responses in biological systems. A better understanding of the biological basis and consequences of nonmonotonic dose–response curves is warranted for evaluating human health risks. The assumption that hormesis is generally adaptive is an oversimplification of complex biological processes. Even if certain low-dose effects were sometimes considered beneficial, this should not influence regulatory decisions to allow increased environmental exposures to toxic and carcinogenic agents, given factors such as interindividual differences in susceptibility and multiplicity in exposures. In this commentary we evaluate the hormesis hypothesis and potential adverse consequences of incorporating low-dose beneficial effects into public health decisions. PMID:16203233

Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia

PubMed Central

Despotovic, Jenny M.; Mortier, Nicole A.; Flanagan, Jonathan M.; He, Jin; Smeltzer, Matthew P.; Kimble, Amy C.; Aygun, Banu; Wu, Song; Howard, Thad; Sparreboom, Alex

2011-01-01

Hydroxyurea therapy has proven laboratory and clinical efficacies for children with sickle cell anemia (SCA). When administered at maximum tolerated dose (MTD), hydroxyurea increases fetal hemoglobin (HbF) to levels ranging from 10% to 40%. However, interpatient variability of percentage of HbF (%HbF) response is high, MTD itself is variable, and accurate predictors of hydroxyurea responses do not currently exist. HUSTLE (NCT00305175) was designed to provide first-dose pharmacokinetics (PK) data for children with SCA initiating hydroxyurea therapy, to investigate pharmacodynamics (PD) parameters, including HbF response and MTD after standardized dose escalation, and to evaluate pharmacogenetics influences on PK and PD parameters. For 87 children with first-dose PK studies, substantial interpatient variability was observed, plus a novel oral absorption phenotype (rapid or slow) that influenced serum hydroxyurea levels and total hydroxyurea exposure. PD responses in 174 subjects were robust and similar to previous cohorts; %HbF at MTD was best predicted by 5 variables, including baseline %HbF, whereas MTD was best predicted by 5 variables, including serum creatinine. Pharmacogenetics analysis showed single nucleotide polymorphisms influencing baseline %HbF, including 5 within BCL11A, but none influencing MTD %HbF or dose. Accurate prediction of hydroxyurea treatment responses for SCA remains a worthy but elusive goal. PMID:21876119

EPA and EFSA approaches for Benchmark Dose modeling

EPA Science Inventory

Benchmark dose (BMD) modeling has become the preferred approach in the analysis of toxicological dose-response data for the purpose of deriving human health toxicity values. The software packages most often used are Benchmark Dose Software (BMDS, developed by EPA) and PROAST (de...

NOTE: Investigating the potential of polymer gel dosimetry for interventional radiology: first results

NASA Astrophysics Data System (ADS)

Antoniou, P. E.; Bousbouras, P.; Sandaltzopoulos, R.; Kaldoudi, E.

2008-04-01

Complex interventional radiology (IR) procedures contribute an increasing percentage of the overall medical radiation exposure of the population making accurate dosimetry a challenge. Magnetic resonance (MR) based polymer gel dosimetry has been widely employed in complex dosimetric problems in radiotherapy. The aim of this note is to investigate the feasibility of normoxic gel dosimetry in IR. Dose response, energy dependence and dose rate dependence were investigated in irradiation set-ups relevant to IR for a particular normoxic gel, based on methacrylic acid (MAA) as the monomer and including tetrakis-hydroxy-methyl-phosphonium chloride (THPC) as antioxidant. The gel presents a linear dose response beyond a 25 cGy threshold. No significant energy dependence was observed in the useful range of interventional radiology (80-110 kVp). A linear correlation between the gel response and dose rate was observed in the range of dose rates relevant to IR (5-8 cGy min-1). These results demonstrate a reduction of gel sensitivity at very low dose rate levels. A possible explanation of this effect is suggested.

Tissue responses to low protracted doses of high LET radiations or photons: Early and late damage relevant to radio-protective countermeasures

NASA Astrophysics Data System (ADS)

Ainsworth, E. J.; Afzal, S. M. J.; Crouse, D. A.; Hanson, W. R.; Fry, R. J. M.

Early and late murine tissue responses to single or fractionated low doses of heavy charged particles, fission-spectrum neutrons or gamma rays are considered. Damage to the hematopoietic system is emphasized, but results on acute lethality, host response to challenge with transplanted leukemia cells and life-shortening are presented. Low dose rates per fraction were used in some neutron experiments. Split-dose lethality studies (LD 50/30) with fission neutrons indicated greater accumulation of injury during a 9 fraction course (over 17 days) than was the case for γ-radiation. When total doses of 96 or 247 cGy of neutrons or γ rays were given as a single dose or in 9 fractions, a significant sparing effect on femur CFU-S depression was observed for both radiation qualities during the first 11 days, but there was not an earlier return to normal with dose fractionation. During the 9 fraction sequence, a significant sparing effect of low dose rate on CFU-S depression was observed in both neutron and γ-irradiated mice. CFU-S content at the end of the fractionation sequence did not correlate with measured LD 50/30. Sustained depression of femur and spleen CFU-S and a significant thrombocytopenia were observed when a total neutron dose of 240 cGy was given in 72 fractions over 24 weeks at low dose rates. The temporal aspects of CFU-S repopulation were different after a single versus fractionated neutron doses. The sustained reduction in the size of the CFU-S population was accompanied by an increase in the fraction in DNA synthesis. The proliferation characteristics and effects of age were different for radial CFU-S population closely associated with bone, compared with the axial population that can be readily aspirated from the femur. In aged irradiated animals, the CFU-S proliferation/redistribution response to typhoid vaccine showed both an age and radiation effect. After high single doses of neutrons or γ rays, a significant age- and radiation-related deficiency in host defense mechanisms was detected by a shorter mean survival time following challenge with transplantable leukemia cells. Comparison of dose-response curves for life shortening after irradiation with fission-spectrum neutrons or high energy silicon particles indicated high initial slopes for both radiation qualities at low doses, but for higher doses of silicon, the effect per Gy decreased to a value similar to that for γ rays. The two component life-shortening curve for silicon particles has implications for the potential efficacy of radioprotectants. Recent studies on protection against early and late effects by aminothiols, prostaglandins, and other compounds are discussed.

Radiation and breast cancer: a review of current evidence

PubMed Central

Ronckers, Cécile M; Erdmann, Christine A; Land, Charles E

2005-01-01

This paper summarizes current knowledge on ionizing radiation-associated breast cancer in the context of established breast cancer risk factors, the radiation dose–response relationship, and modifiers of dose response, taking into account epidemiological studies and animal experiments. Available epidemiological data support a linear dose–response relationship down to doses as low as about 100 mSv. However, the magnitude of risk per unit dose depends strongly on when radiation exposure occurs: exposure before the age of 20 years carries the greatest risk. Other characteristics that may influence the magnitude of dose-specific risk include attained age (that is, age at observation for risk), age at first full-term birth, parity, and possibly a history of benign breast disease, exposure to radiation while pregnant, and genetic factors. PMID:15642178

Bladder pain in an LL-37 interstitial cystitis and painful bladder syndrome model.

PubMed

Jia, Wanjian; Schults, Austin J; Jensen, Mark Martin; Ye, Xiangyang; Alt, Jeremiah A; Prestwich, Glenn D; Oottamasathien, Siam

2017-01-01

Our goal was to evaluate the pain response in an LL-37 induced murine model for interstitial cystitis/painful bladder syndrome (IC/PBS). In particular, we sought to characterize the dose dependence, time-course, and relationship of LL-37 induced bladder inflammation and pain. The IC/PBS model was induced in C57Bl/6 mice by instilling 50 μL of LL-37, an immunomodulatory human cathelicidin (anti-microbial peptide), in the bladder for 1 hr. Pain responses were measured using von Frey filaments (0.04 gm to 4.0 gm) before and after LL-37 instillation. Inflammation was evaluated using tissue myeloperoxidase (MPO) assay, gross inspection, and microscopic histologic examination. The dose response experiment demonstrated a graded pain response, with higher concentrations of LL-37 challenge yielding higher pain responses across all stimuli tested. Statistical significance was seen when comparing 1.0 gm von Frey filament results at 320 μM (68 ± 8% response) vs. 0 μM (38 ± 6% response). Interestingly, pain responses did not attenuate across time but increased significantly after 5 (p=0.0012) and 7 days (p=0.0096). Comparison with MPO data suggested that pain responses could be independent of inflammation. We demonstrated within our LL-37 induced IC/PBS model pain occurs in a dose-dependent fashion, pain responses persist beyond the initial point of insult, and our dose response and time course experiments demonstrated that pain was independent of inflammation.

Exposures involving perturbations of the EM field have non-linear effects on radiation response and can alter the expression of radiation induced bystander effects

NASA Astrophysics Data System (ADS)

Mothersill, Carmel; Seymour, Colin

2012-07-01

Our recent data suggest there is a physical component to the bystander signal induced by radiation exposure and that alternative medicine techniques such as Reiki and acupuncture or exposures to weak EM fields alter the response of cells to direct irradiation and either altered bystander signal production or altered the response of cells receiving bystander signals. Our proposed mechanism to explain these findings is that perturbation of electromagnetic (EM) fields is central to the induction of low radiation dose responses especially non-targeted bystander effects. In this presentation we review the alternative medicine data and other data sets from our laboratory which test our hypothesis that perturbation of bio-fields will modulate radiation response in the low dose region. The other data sets include exposure to MRI, shielding using lead and or Faraday cages, the use of physical barriers to bystander signal transmission and the use of membrane channel blockers. The data taken together strongly suggest that EM field perturbation can modulate low dose response and that in fact the EM field rather than the targeted deposition of ionizing energy in the DNA may be the key determinant of dose response in a cell or organism The results also lead us to suspect that at least when chemical transmission is blocked, bystander signals can be transmitted by other means. Our recent experiments suggest light signals and volatiles are not likely. We conclude that alternative medicine and other techniques involving electromagnetic perturbations can modify the response of cells to low doses of ionizing radiation and can induce bystander effects similar to those seen in medium transfer experiments. In addition to the obvious implications for mechanistic studies of low dose effects, this could perhaps provide a novel target to exploit in space radiation protection and in optimizing therapeutic gain during radiotherapy.

Ongoing Response in BRAF V600E-Mutant Melanoma After Cessation of Intermittent Vemurafenib Therapy: A Case Report.

PubMed

Dooley, Andrew J; Gupta, Avinash; Middleton, Mark R

2016-08-01

The selective BRAF inhibitors vemurafenib and dabrafenib yield high response rates and improved overall survival in patients with BRAF V600E-mutant metastatic melanoma. Treatment traditionally continues until disease progression or the development of unacceptable toxicity. Acquired drug resistance and toxicity are key challenges with the use of these drugs. Resistance to vemurafenib usually develops within 6-8 months. Management of drug toxicity typically involves stopping vemurafenib until resolution, before restarting at a lower dose, or permanently ceasing vemurafenib therapy. We have recently considered whether intermittent dosing could be used as an alternative to dose reduction/termination in the management of vemurafenib toxicity. One patient treated with intermittent vemurafenib was an 89-year-old woman with metastatic melanoma, who initially showed a good response to continuous dosing. Recurrent toxicity meant that the continuous vemurafenib dosage was repeatedly ceased before restarting at a lower dose. Ten months after vemurafenib was first begun, an intermittent dosing regimen was introduced in an attempt to control toxicity. This continued for 2 months, before cessation due to continued unacceptable toxicity. A further 24 months later, the patient remains fit and well in complete clinical remission, with no recurrence of her previous melanoma and no new primary malignancies. To the best of our knowledge, a continued response after the cessation of selective BRAF inhibitors has never before been described in melanoma. Induction of an immune response and/or epigenetic changes could explain continued disease response after cessation of vemurafenib therapy. Care should be taken when extrapolating the findings from the continued response after vemurafenib cessation to other tumour types. We recommend the collection and analysis of data to investigate the clinical responses seen after cessation of vemurafenib due to intolerable toxicities, which could help further explain vemurafenib's mechanism of action.

Temporal changes in physiology and haematology in response to high- and micro-doses of recombinant human erythropoietin.

PubMed

Clark, Brad; Woolford, Sarah M; Eastwood, Annette; Sharpe, Ken; Barnes, Peter G; Gore, Christopher J

2017-10-01

There is evidence to suggest athletes have adopted recombinant human erythropoietin (rHuEPO) dosing regimens that diminish the likelihood of being caught by direct detection techniques. However, the temporal response in physiology, performance, and Athlete Biological Passport (ABP) parameters to such regimens is not clearly understood. Participants were assigned to a high-dose only group (HIGH, n = 8, six rHuEPO doses of 250 IU/kg over two weeks), a combined high micro-dose group (COMB, n = 8, high-dose plus nine rHuEPO micro-doses over a further three weeks), or one of two placebo control groups who received saline in the same pattern as the HIGH (HIGH-PLACEBO, n = 4) or COMB (COMB-PLACEBO, n = 4) groups. Temporal changes in physiology and performance were tracked by graded exercise test (GXT) and haemoglobin mass assessment at baseline, after high dose, after micro-dose (COMB and COMB-PLACEBO only) and after a four-week washout. Venous blood samples were collected throughout the baseline, rHuEPO administration, and washout periods to determine the haematological and ABP response to each dosing regimen. Physiological adaptations induced by a two-week rHuEPO high-dose were maintained by rHuEPO micro-dosing for at least three weeks. However, all participants administered rHuEPO registered at least one suspicious ABP value during the administration or washout periods. These results indicate there is sufficient sensitivity in the ABP to detect use of high rHuEPO doping regimens in athletic populations and they provide important empirical examples for use by anti-doping experts. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Influence of vector dose on factor IX-specific T and B cell responses in muscle-directed gene therapy.

PubMed

Herzog, Roland W; Fields, Paul A; Arruda, Valder R; Brubaker, Jeff O; Armstrong, Elina; McClintock, Darryl; Bellinger, Dwight A; Couto, Linda B; Nichols, Timothy C; High, Katherine A

2002-07-20

Intramuscular injection of an adeno-associated virus (AAV) vector has resulted in vector dose-dependent, stable expression of canine factor IX (cF.IX) in hemophilia B dogs with an F.IX missense mutation (Herzog et al., Nat. Med. 1999;5:56-63). The use of a species-specific transgene allowed us to study risks and characteristics of antibody formation against the therapeutic transgene product. We analyzed seven dogs that had been injected at a single time point at multiple intramuscular sites with varying vector doses (dose per kilogram, dose per animal, dose per site). Comparison of individual animals suggests an increased likelihood of inhibitory anti-cF.IX (inhibitor) development with increased vector doses, with dose per site showing the strongest correlation with the risk of inhibitor formation. In six of seven animals, such immune responses were either absent or transient, and therefore did not prevent sustained systemic expression of cF.IX. Transient inhibitory/neutralizing anti-cF.IX responses occurred at vector doses of 2 x 10(12)/site, whereas a 6-fold higher dose resulted in a longer lasting, higher titer inhibitor. Anti-cF.IX was efficiently blocked in an eighth animal that was injected with a high vector dose per site, but in addition received transient immune suppression. Inhibitor formation was characterized by synthesis of two IgG subclasses and in vitro proliferation of lymphocytes to cF.IX antigen, indicating a helper T cell-dependent mechanism. Anti-cF.IX formation is likely influenced by the extent of local antigen presentation and may be avoided by limited vector doses or by transient immune modulation.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Berrington de Gonzalez, Amy, E-mail: berringtona@mail.nih.gov; Gilbert, Ethel; Curtis, Rochelle

Rapid innovations in radiation therapy techniques have resulted in an urgent need for risk projection models for second cancer risks from high-dose radiation exposure, because direct observation of the late effects of newer treatments will require patient follow-up for a decade or more. However, the patterns of cancer risk after fractionated high-dose radiation are much less well understood than those after lower-dose exposures (0.1-5 Gy). In particular, there is uncertainty about the shape of the dose-response curve at high doses and about the magnitude of the second cancer risk per unit dose. We reviewed the available evidence from epidemiologic studiesmore » of second solid cancers in organs that received high-dose exposure (>5 Gy) from radiation therapy where dose-response curves were estimated from individual organ-specific doses. We included 28 eligible studies with 3434 second cancer patients across 11 second solid cancers. Overall, there was little evidence that the dose-response curve was nonlinear in the direction of a downturn in risk, even at organ doses of ≥60 Gy. Thyroid cancer was the only exception, with evidence of a downturn after 20 Gy. Generally the excess relative risk per Gray, taking account of age and sex, was 5 to 10 times lower than the risk from acute exposures of <2 Gy among the Japanese atomic bomb survivors. However, the magnitude of the reduction in risk varied according to the second cancer. The results of our review provide insights into radiation carcinogenesis from fractionated high-dose exposures and are generally consistent with current theoretical models. The results can be used to refine the development of second solid cancer risk projection models for novel radiation therapy techniques.« less

Incidence of salivary gland tumors among atomic bomb survivors, 1950-1987. Evaluation of radiation-related risk

DOE Office of Scientific and Technical Information (OSTI.GOV)

Land, C.E.; Saku, Takashi; Tokuoka, Shoji

1996-07-01

A wide-ranging seach for benign and malignant tumors of the major and minor salivary glands among members of the Life Span Study sample of the Radiation Effects Research Foundation identified 41 malignant and 94 benign incident tumors, including 14 malignant and 12 benign tumors of the minor salivary gland, plus 10 major gland tumors of unknown behavior. Dose-response analyses found statistically significant increases in risk with increasing A-bomb dose for both cancer and benign tumors. Estimated relative risks at 1 Sv weighted tissue kerma (RR{sub 1}Sv, with 90% confidence interval in parentheses) were 4.5 (2.5-8.5) for cancer and 1.7 (1.1-2.7)more » for benign tumors. When analyzed by histological subtype within these two broad groups, it appeared that most of the dose response for malignant tumors was provided by an exceptionally strong dose response for mucoepidermoid carcinoma [11 exposed cases with dose estimates, RR{sub 1Sv} - 9.3 (3.5-30.6)], and most or all of that for benign tumors corresponded to Warthin`s tumor [12 cases, RR{sub 1Sv} = 4.1 (1.6-11.3)]. There was a marginal dose response for malignant tumors other than mucoepidermoid carcinoma [RR{sub 1Sv} = 2.4 (0.99-5.7)] but no significant trend for benign tumors other than Warthin`s tumor [RR{sub 1Sv} = 1.3 (0.9-2.2)]. Re-examination of the original data from published studies of other irradiated populations may shed new light on the remarkable type specificity of the salivary tumor dose response observed in the present study. 33 refs., 3 figs., 7 tabs.« less

Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study.

PubMed

Gutzmer, R; Rivoltini, L; Levchenko, E; Testori, A; Utikal, J; Ascierto, P A; Demidov, L; Grob, J J; Ridolfi, R; Schadendorf, D; Queirolo, P; Santoro, A; Loquai, C; Dreno, B; Hauschild, A; Schultz, E; Lesimple, T P; Vanhoutte, N; Salaun, B; Gillet, M; Jarnjak, S; De Sousa Alves, P M; Louahed, J; Brichard, V G; Lehmann, F F

2016-01-01

The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays. 66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected. The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose. NCT01149343, Results.

Determination of minimal erythema dose and anomalous reactions to UVA radiation by skin phototype.

PubMed

Pérez Ferriols, A; Aguilera, J; Aguilera, P; de Argila, D; Barnadas, M A; de Cabo, X; Carrrascosa, J M; de Gálvez Aranda, M V; Gardeazábal, J; Giménez-Arnau, A; Lecha, M; Lorente, J; Martínez-Lozano, J A; Rodríguez Granados, M T; Sola, Y; Utrillas, M P

2014-10-01

Phototesting is a technique that assesses the skin's sensitivity to UV radiation by determining the smallest dose of radiation capable of inducing erythema (minimal erythema dose [MED]) and anomalous responses to UV-A radiation. No phototesting protocol guidelines have been published to date. This was a multicenter prospective cohort study in which 232 healthy volunteers were recruited at 9 hospitals. Phototests were carried out with solar simulators or fluorescent broadband UV-B lamps. Each individual received a total of 5 or 6 incremental doses of erythemal radiation and 4 doses of UV-A radiation. The results were read at 24hours. At hospitals where solar simulators were used, the mean (SD) MED values were 23 (8), 28 (4), 35 (4), and 51 (6) mJ/cm(2) for skin phototypes i to iv, respectively. At hospitals where broadband UV-B lamps were used, these values were 28 (5), 32 (3), and 34 (5) mJ/cm(2) for phototypes ii to iv, respectively. MED values lower than 7, 19, 27, and 38 mJ/cm(2) obtained with solar simulators were considered to indicate a pathologic response for phototypes I to IV, respectively. MED values lower than 18, 24, and 24mJ/cm(2) obtained with broadband UV-B lamps were considered to indicate a pathologic response for phototypes ii to iv, respectively. No anomalous responses were observed at UV-A radiation doses of up to 20J/cm(2). Results were homogeneous across centers, making it possible to standardize diagnostic phototesting for the various skin phototypes and establish threshold doses that define anomalous responses to UV radiation. Copyright © 2014 Elsevier España, S.L.U. y AEDV. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Richter, Christian; Pawelke, Joerg; Karsch, Leonhard

Purpose: The aim of this article is to investigate the energy dependence of the radiochromic film type, Gafchromic EBT-1, when scanned with a flatbed scanner for film readout. Methods: Dose response curves were determined for 12 different beam qualities ranging from a 10 kVp x-ray beam to a 15 MVp x-ray beam and include also two high energy electron beam qualities (6 and 18 MeV). The dose responses measured as net optical density (netOD) for the different beam qualities were normalized to the response of a reference beam quality (6 MVp). Results: A strong systematic energy dependence of the filmmore » response was found. The lower the effective beam energy, the less sensitive the EBT-1 films get. The maximum decrease in dose for the same film response between the 25 kVp and 6 MVp beam qualities was 44%. Additionally, a difference in energy dependence for different doses was discovered, meaning that higher doses show a smaller dependency on energy than lower doses. The maximum decrease in the normalized netOD was found to be 25% for a dose of 0.5 Gy relative to the normalized netOD for 10 Gy. Moreover, a scaling procedure is introduced, allowing the correction of the energy dependence for the investigated beam qualities and also for comparable x-ray beam qualities within the energy range studied. Conclusions: A strong energy dependence for EBT-1 radiochromic films was found. The films were readout with a flatbed scanner. If the effective beam energy is known, the energy dependence can be corrected with the introduced scaling procedure. Further investigation of the influence of the spectral band of the readout device on energy dependence is needed to understand the reason for the different energy dependences found in this and previous works.« less

Inhibition of Mutated, Activated BRAF in Metastatic Melanoma

PubMed Central

Flaherty, Keith T.; Puzanov, Igor; Kim, Kevin B.; Ribas, Antoni; McArthur, Grant A.; Sosman, Jeffrey A.; O'Dwyer, Peter J.; Lee, Richard J.; Grippo, Joseph F.; Nolop, Keith; Chapman, Paul B.

2013-01-01

Background The identification of somatic mutations in the gene encoding the serine–threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease. Methods We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition. Results A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Conclusions Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.) PMID:20818844

Treatment dose-response in amblyopia therapy: the Monitored Occlusion Treatment of Amblyopia Study (MOTAS).

PubMed

Stewart, Catherine E; Moseley, Merrick J; Stephens, David A; Fielder, Alistair R

2004-09-01

Amblyopia is the commonest visual disorder of childhood. Yet the contributions of the two principal treatments (spectacle wear and occlusion) to outcome are unknown. This study was undertaken to investigate the dose-response relationship of amblyopia therapy. The study comprised three distinct phases: baseline, in which repeat measures of visual function were undertaken to confirm the initial visual deficit; refractive adaptation: an 18-week period of spectacle wear with six weekly measurements of logarithm of the minimum angle of resolution (logMAR) visual acuity; occlusion: in which participants were prescribed 6 hours of "patching" per day. In the latter phase, occlusion was objectively monitored and logMAR visual acuity recorded at 2-week intervals until any observed gains had ceased. Data were obtained from 94 participants (mean age, 5.1 +/- 1.4 years) with amblyopia associated with strabismus (n = 34), anisometropia (n = 23), and both anisometropia and strabismus (n = 37). Eighty-six underwent refractive adaptation. Average concordance with patching was 48%. The relationship between logMAR visual acuity gain and total occlusion dose was monotonic and linear. Increasing dose rate beyond 2 h/d hastened the response but did not improve outcome. More than 80% of the improvement during occlusion occurred within 6 weeks. Treatment outcome was significantly better for children younger than 4 years (n = 17) than in those older than 6 years (n = 24; P = 0.0014). Continuous objective monitoring of the amount of patching therapy received has provided insight into the dose-response relationship of occlusion therapy for amblyopia. Patching is most effective within the first few weeks of treatment, even for those in receipt of a relatively small dose. Further studies are needed to elucidate the neural basis for the dose-response functions. Copyright Association for Research in Vision and Ophthalmology

WE-FG-202-09: Voxel-Level Analysis of Adverse Treatment Response in Pediatric Patients Treated for Ependymoma with Passive Scattering Proton Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peeler, C; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX; Mirkovic, D

2016-06-15

Purpose: We identified patients treated for ependymoma with passive scattering proton therapy who subsequently developed treatment-related imaging changes on MRI. We sought to determine if there is any spatial correlation between imaged response, dose, and LET. Methods: A group of 14 patients treated for ependymoma were identified as having post-treatment MR imaging changes observable as T2-FLAIR hyperintensity with or without enhancement on T1 post-contrast sequences. MR images were registered with treatment planning CT images and regions of treatment-related change contoured by a practicing radiation oncologist. The contoured regions were identified as response with voxels represented as 1 while voxels withinmore » the brain outside of the response region were represented as 0. An in-house Monte Carlo system was used to recalculate treatment plans to obtain dose and LET information. Voxels were binned according to LET values in 0.3 keV µm{sup −1} bins. Dose and corresponding response value (0 or 1) for each voxel for a given LET bin were then plotted and fit with the Lyman-Kutcher-Burman dose response model to determine TD{sub 50} and m parameters for each LET value. Response parameters from all patients were then collated, and linear fits of the data were performed. Results: The response parameters TD50 and m both show trends with LET. Outliers were observed due to low numbers of response voxels in some cases. TD{sub 50} values decreased with LET while m increased with LET. The former result would indicate that for higher LET values, the dose is more effective, which is consistent with relative biological effectiveness (RBE) models for proton therapy. Conclusion: A novel method of voxel-level analysis of image biomarker-based adverse patient treatment response in proton therapy according to dose and LET has been presented. Fitted TD{sub 50} values show a decreasing trend with LET supporting the typical models of proton RBE. Funding provided by NIH Program Project Grant 2U19CA021239-35.« less

Involvement of NMDA receptor mechanisms in jaw electromyographic activity and plasma extravasation induced by inflammatory irritant application to temporomandibular joint region of rats.

PubMed

Yu, X M; Sessle, B J; Haas, D A; Izzo, A; Vernon, H; Hu, J W

1996-11-01

The aim of this study was to examine the possible role of N-methyl-D-aspartate (NMDA) receptor mechanisms in responses induced by the small-fibre excitant and inflammatory irritant mustard oil injected into the temporomandibular joint (TMJ) region of rats. The effects of the non-competitive NMDA antagonist MK-801 were tested on the mustard oil-evoked increases in electromyographic (EMG) activity of the masseter and digastric muscles and Evans Blue plasma extravasation. Five minutes before the mustard oil injection, MK-801 or its vehicle was administered systemically (i.v.), into the third ventricle (i.c.v.), or locally into the TMJ region. Compared with control animals receiving vehicle, the rats receiving MK-801 at an i.v. dose of 0.5 mg/kg (n = 5) showed a significant reduction in the incidence and magnitude of EMG responses as well as in the plasma extravasation evoked by mustard oil; MK-801 at an i.v. dose of 0.1 mg/kg (n = 5) had no significant effect on plasma extravasation or on the incidence and magnitude of EMG responses but did significantly increase the latency of EMG responses. An i.c.v. dose of 0.1 mg/kg (n = 5) or 0.01 mg/kg (n = 5) had no significant effect on plasma extravasation or incidence of EMG responses but did significantly reduce the magnitudes of the masseter EMG response; the 0.01 mg/kg dose also significantly increased the latency of the digastric EMG response. The magnitudes of both the masseter and digastric EMG responses were also significantly reduced by MK-801 administered into the TMJ region at a dose of 0.1 mg/kg (n = 5) but not by 0.01 mg/kg (n = 5); neither dose significantly affected the incidence of EMG responses or the plasma extravasation. These data suggest that both central and peripheral NMDA receptor mechanisms may play an important role in EMG responses evoked by the small-fibre excitant and inflammatory irritant mustard oil, but that different neurochemical mechanisms may be involved in the plasma extravasation induced by mustard oil.

A phase I safety and immunogenicity dose escalation trial of plague vaccine, Flagellin/F1/V, in healthy adult volunteers (DMID 08-0066).

PubMed

Frey, Sharon E; Lottenbach, Kathleen; Graham, Irene; Anderson, Edwin; Bajwa, Kanwaldeep; May, Ryan C; Mizel, Steven B; Graff, Aaron; Belshe, Robert B

2017-12-04

Intentional aerosolization of Yersinia pestis may result in pneumonic plague which is highly fatal if not treated early. We conducted a phase 1 randomized, double blind (within each group), placebo controlled, dose escalation trial to evaluate a plague vaccine, Flagellin/F1/V, in healthy adults aged 8 through 45years. Vaccine was administered intramuscularly on Days 0 and 28 at a dose of 1, 3, 6 or 10mcg. Subjects were observed for 4h after vaccination for cytokine release syndrome. Reactogenicity and adverse events (AE) were collected for 14 and 28days, respectively, after each vaccination. Serious AE were collected for the entire study. ELISA antibody and cytokines were measured at multiple time points. Subject's participation lasted 13months. Sixty healthy subjects were enrolled; 52% males, 100% non-Hispanic, 91.7% white and mean age 30.8years. No severe reactogenicity events occurred; most AE were mild. No serious AE related to vaccine occurred. A dose response effect was observed to F1, V and flagellin. The peak ELISA IgG antibody titers (95% CI) after two 10mcg doses of vaccine were 260.0 (102.6-659.0) and 983.6 (317.3-3048.8), respectively, against F1 and V antigens. The 6mcg dose group provided similar titers. Titers were low for the placebo, 1mcg and 3mcg recipients. A positive antibody dose response was observed to F1, V and flagellin. Vaccine antigen specific serum IgE was not detected. There were no significant rises in serum or cellular cytokine responses and no significant IgG increase to flagellin after the second dose. The Flagellin/F1/V vaccine exhibited a dose dependent increase in immunogenicity and was well tolerated at all doses. Antibody specific responses to F1, V and flagellin increased as dose increased. Given the results from this trial, testing higher doses of the vaccine may be merited. Copyright © 2017. Published by Elsevier Ltd.

Meningococcal Serogroup B Bivalent rLP2086 Vaccine Elicits Broad and Robust Serum Bactericidal Responses in Healthy Adolescents

PubMed Central

Vesikari, Timo; Østergaard, Lars; Diez-Domingo, Javier; Wysocki, Jacek; Flodmark, Carl-Erik; Beeslaar, Johannes; Eiden, Joseph; Jiang, Qin; Jansen, Kathrin U.; Jones, Thomas R.; Harris, Shannon L.; O'Neill, Robert E.; York, Laura J.; Crowther, Graham; Perez, John L.

2016-01-01

Background Neisseria meningitidis serogroup B (MnB) is a leading cause of invasive meningococcal disease in adolescents and young adults. A recombinant factor H binding protein (fHBP) vaccine (Trumenba®; bivalent rLP2086) was recently approved in the United States in individuals aged 10–25 years. Immunogenicity and safety of 2- or 3-dose schedules of bivalent rLP2086 were assessed in adolescents. Methods Healthy adolescents (11 to <19 years) were randomized to 1 of 5 bivalent rLP2086 dosing regimens (0,1,6-month; 0,2,6-month; 0,2-month; 0,4-month; 0,6-month). Immunogenicity was assessed by serum bactericidal antibody assay using human complement (hSBA). Safety assessments included local and systemic reactions and adverse events. Results Bivalent rLP2086 was immunogenic when administered as 2 or 3 doses; the most robust hSBA responses occurred with 3 doses. The proportion of subjects with hSBA titers ≥1:8 after 3 doses ranged from 91.7% to 95.0%, 98.9% to 99.4%, 88.4% to 89.0%, and 86.1% to 88.5% for MnB test strains expressing vaccine­-heterologous fHBP variants A22, A56, B24, and B44, respectively. After 2 doses, responses ranged from 90.8% to 93.5%, 98.4% to 100%, 69.1% to 81.1%, and 70.1% to 77.5%. Geometric mean titers (GMTs) were highest among subjects receiving 3 doses and similar between the 2- and 3-dose regimens. After 2 doses, GMTs trended numerically higher among subjects with longer intervals between the first and second dose (6 months vs 2 and 4 months). Bivalent rLP2086 was well tolerated. Conclusions Bivalent rLP2086 was immunogenic and well tolerated when administered in 2 or 3 doses. Three doses yielded the most robust hSBA response rates against MnB strains expressing vaccine-heterologous subfamily B fHBPs. PMID:26407272