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Radiation impacts on toxicity of cobalt–chromium (CoCr) implant debris
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Common and divergent features of galactose-1-phosphate and fructose-1-phosphate toxicity in yeast
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Electron microscopy evidence of gadolinium toxicity being mediated through cytoplasmic membrane dysregulation
Past functional toxicogenomic studies have indicated that genes relevant to membrane lipid synthesis are important for tolerance to the lanthanides. Moreover, previously reported imaging of patient's brains following administration of gadolinium-based contrast agents shows gadolinium lining the vessels of the brain. Taken together, these findings suggest the disruption of cytoplasmic membrane integrity as a mechanism by which lanthanides induce cytotoxicity. In the presented work we used scanning transmission electron microscopy and spatially resolved elemental spectroscopy to image the morphology and composition of gadolinium, europium, and samarium precipitates that formed on the outside of yeast cell membranes. In no sample did we find that the lanthanide contaminant had crossed the cell membrane, even in experiments using yeast mutants with disrupted genes for sphingolipid synthesis—the primary lipids found in yeast cytoplasmic membranes. Rather, we have evidence that lanthanides are co-located with phosphorus outside the yeast cells. Finally, these results lead us to hypothesize that the lanthanides scavenge or otherwise form complexes with phosphorus from the sphingophospholipid head groups in the cellular membrane, thereby compromising the structure or function of the membrane, and gaining the ability to disrupt membrane function without entering the cell.
Impact of Surface Chemistry of Ultrasmall Superparamagnetic Iron Oxide Nanoparticles on Protein Corona Formation and Endothelial Cell Uptake, Toxicity, and Barrier Function
Ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) have been investigated for biomedical applications, including novel contrast agents, magnetic tracers for tumor imaging, targeted drug delivery vehicles, and magneto-mechanical actuators for hyperthermia and thrombolysis. Despite significant progress, recent clinical reports have raised concerns regarding USPION safety related to endothelial cell dysfunction; however, there is limited information on factors contributing to these clinical responses. The influence of USPION surface chemistry on nanoparticle interactions with proteins may impact endothelial cell function leading to adverse responses. Therefore, the goal of this study was to assess the effects of carboxyl-functionalized USPION (CU) or amine-functionalized USPION (AU) (approximately 30 nm diameter) on biological responses in human coronary artery endothelial cells. Increased protein adsorption was observed for AU compared with CU after exposure to serum proteins. Exposure to CU, but not AU, resulted in a concentration-dependent decrease in cell viability and perinuclear accumulation inside cytoplasmic vesicles. Internalization of CU was correlated with endothelial cell functional changes under non-cytotoxic conditions, as evidenced by a marked decreased expression of endothelial-specific adhesion proteins (eg, vascular endothelial-cadherin and platelet endothelial cell adhesion molecule-1) and increased endothelial permeability. Evaluation of downstream signaling indicated endothelial permeability is associated with actin cytoskeleton remodeling, possibly elicited by intracellular events involving reactive oxygen species, calcium ions, and the nanoparticle cellular uptake pathway. This study demonstrated that USPION surface chemistry significantly impacts protein adsorption and endothelial cell uptake, viability, and barrier function. This information will advance the current toxicological profile of USPION and improve development, safety assessment, and clinical outcomes of USPION-enabled medical products.
Target Organ Specific Activity of Drosophila MRP (ABCC1) Moderates Developmental Toxicity of Methylmercury
Abstract not provided
Correlation between Toluene Exposure and Toxicity Effects of Toluene on Drosophila Melanogaster Fecundity and Offspring Survivability
Toluene is a volatile organic compound that is a common indoor contaminant. According to the U.S. Department of Health and Human Services, chronic toluene exposure negatively affects organ systems, such as nervous and respiratory, and acts as a fetotoxic agent in the development of humans. Toluene exposure causes damage to human myelin sheaths, thus we propose that damage to the fly nervous system will be similar to that seen in humans exposed to toluene. Our ultimate goal is to determine the effects of toluene exposure on developmental and neuronal processes in D. melanogaster . In this first phase, we hypothesize that toluene‐exposed adults, at the interpolated Lethal Exposure (LE 50 ), will demonstrate decreased fecundity and that offspring from toluene‐exposed females will have decreased survivability from the egg to adult stage. We developed a continuous flow system that delivers known concentrations of gaseous toluene to populations of D. melanogaster . Ten to twenty adult female flies per trial were exposed for 24 hours to known concentrations of toluene. Surviving females were collected, counted and mated to non‐exposed adult males. The toluene‐exposed females were placed on a colored agar plate to lay eggs for 24 hours. Eggs were counted to determine fecundity (number of eggs produced by a single female fly). Survivability of eggs to later life stages, was measured by counting number of larvae, pupae, and adults divided by number eggs, larvae, and pupae respectively. The interpolated LE 50 of gaseous toluene was between 1000 and 1500 ppm after 24‐hour exposure. Fecundity of toluene‐exposed females decreased by approximately 50% when compared to airexposed females. The survivability of offspring of air‐exposed flies from egg to larval stages was 84% higher than published studies. We observed that larval eclosure from eggs laid by toluene‐exposed females was 35–50% higher on days 1 and 2 when compared to larval eclosure from eggs of air‐exposed exposed females. On days 3–6 the eclosure rate was relatively similar. These data showed toluene's effects on fecundity and survivability were measurable, however, additional replicates are in progress to fully assess the life table characteristics of offspring of toluene‐exposed female flies. Further studies will focus on toluene's effect on nervous and reproductive organs of fruit flies, along with a study on the mutagenic effects of toluene on fly DNA. Support or Funding Information U.S. DOE, Hispanic‐Serving Institutions, STEM Articulation Grant P031C110128 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
WE-D-BRE-02: BEST IN PHYSICS (THERAPY) - Radiogenomic Modeling of Normal Tissue Toxicities in Prostate Cancer Patients Receiving Hypofractionated Radiotherapy
Purpose: It has been realized that inter-patient radiation sensitivity variability is a multifactorial process involving dosimetric, clinical, and genetic factors. Therefore, we explore a new framework to integrate physical, clinical, and biological data denoted as radiogenomic modeling. In demonstrating the feasibility of this work, we investigate the association of genetic variants (copy number variations [CNVs] and single nucleotide polymorphisms [SNPs]) with radiation induced rectal bleeding (RB) and erectile dysfunction (ED) while taking into account dosimetric and clinical variables in prostate cancer patients treated with curative irradiation. Methods: A cohort of 62 prostate cancer patients who underwent hypofractionated radiotherapy (66 Gy in 22 fractions) was retrospectively genotyped for CNV and SNP rs25489 in the xrcc1 DNA repair gene. Dosevolume metrics were extracted from treatment plans of 54 patients who had complete dosimetric profiles. Treatment outcomes were considered to be a Result of functional mapping of radiogenomic input variables according to a logit transformation. Model orders were estimated using resampling by leave-one out cross-validation (LOO-CV). Radiogenomic model performance was evaluated using area under the ROC curve (AUC) and LOO-CV. For continuous univariate dosimetric and clinical variables, Spearmans rank coefficients were calculated and p-values reported accordingly. In the case of binary variables, Chi-squared statistics and contingency table calculations were used. Results: Ten patients were found to have three copies of xrcc1 CNV (RB: χ2=14.6 [p<0.001] and ED: χ2=4.88[p=0.0272]) and twelve had heterozygous rs25489 SNP (RB: χ2=0.278[p=0.599] and ED: χ2=0.112[p=0.732]). LOO-CV identified penile bulb D60 as the only significant QUANTEC predictor (rs=0.312 [p=0.0145]) for ED. Radiogenomic modeling yielded statistically significant, cross-validated NTCP models for RB (rs=0.243[p=0.0443], AUC=0.665) and ED (rs=0.276[p=0.0217], AUC=0.754). Conclusion: The radiogenomic modeling approach presented herein has been shown to identify NTCP models which have increased predictive power. Furthermore, CNVs appears to be useful genetic variants when added to dosimetric NTCP models. This work was partially supported by CIHR grant MOP-114910.
WE-EF-210-06: Ultrasound 2D Strain Measurement of Radiation-Induced Toxicity: Phantom and Ex Vivo Experiments
Purpose: Radiation-induced fibrosis is a common long-term complication affecting many patients following cancer radiotherapy. Standard clinical assessment of subcutaneous fibrosis is subjective and often limited to visual inspection and palpation. Ultrasound strain imaging describes the compressibility (elasticity) of biological tissues. This study’s purpose is to develop a quantitative ultrasound strain imaging that can consistently and accurately characterize radiation-induce fibrosis. Methods: In this study, we propose a 2D strain imaging method based on deformable image registration. A combined affine and B-spline transformation model is used to calculate the displacement of tissue between pre-stress and post-stress B-mode image sequences. The 2D displacement is estimated through a hybrid image similarity measure metric, which is a combination of the normalized mutual information (NMI) and normalized sum-of-squared-differences (NSSD). And 2D strain is obtained from the gradient of the local displacement. We conducted phantom experiments under various compressions and compared the performance of our proposed method with the standard cross-correlation (CC)- based method using the signal-to-noise (SNR) and contrast-to-noise (CNS) ratios. In addition, we conducted ex-vivo beef muscle experiment to further validate the proposed method. Results: For phantom study, the SNR and CNS values of the proposed method were significantly higher than those calculated from the CC-based method under different strains. The SNR and CNR increased by a factor of 1.9 and 2.7 comparing to the CC-based method. For the ex-vivo experiment, the CC-based method failed to work due to large deformation (6.7%), while our proposed method could accurately detect the stiffness change. Conclusion: We have developed a 2D strain imaging technique based on the deformable image registration, validated its accuracy and feasibility with phantom and ex-vivo data. This 2D ultrasound strain imaging technology may be valuable as physicians try to eliminate radiation-induce fibrosis and improve the therapeutic ratio of cancer radiotherapy. This research is supported in part by DOD PCRP Award W81XWH-13-1-0269, and National Cancer Institute (NCI) Grant CA114313.
Molecular Insights into Microbial b-Glucuronidase Inhibition to Abrogate CPT-11 Toxicity
Abstract not provided
The genomic landscape of rapid repeated evolutionary adaptation to toxic pollution in wild fish
Not Available
CDC-TMVI Dashboard: Contamination Distribution Centered Toxics Mobility Vulnerability Index
Visualizes census-tract-level vulnerability across 27 geospatial variables in four domains: built environment vulnerability, social vulnerability, health outcomes, and contamination sources
EMC3 regulates trafficking and pulmonary toxicity of the SFTPC I73T mutation associated with interstitial lung disease
The most common mutation in surfactant protein C gene (SFTPC), SFTPC I73T , causes interstitial lung disease with few therapeutic options. We previously demonstrated that EMC3, an important component of the multiprotein endoplasmic reticulum membrane complex (EMC), is required for surfactant homeostasis in alveolar type 2 epithelial (AT2) cells at birth. In the present study, we investigated the role of EMC3 in the control of SFTPC I73T metabolism and its associated alveolar dysfunction. Using a knock-in mouse model phenocopying the I73T mutation, we demonstrated that conditional deletion of Emc3 in AT2 cells rescued alveolar remodeling/simplification defects in neonatal and adult mice. Proteomic analysis revealed that Emc3 depletion reversed the disruption of vesicle trafficking pathways and rescued the mitochondrial dysfunction associated with I73T mutation. Affinity mass spectrometry analysis identified potential EMC3 interacting proteins in lung AT2 cells, including Valosin Containing Protein (VCP) and its interactors. Treatment of Sftpc I73T knock-in mice and SFTPC I73T expressing iAT2 cells derived from SFTPC I73T patient-specific iPSCs with the specific VCP inhibitor CB5083 restored alveolar structure and SFTPC I73T trafficking respectively. Taken together, the present work identifies the EMC complex and VCP in the metabolism of the disease-associated SFTPC I73T mutant, providing novel therapeutical targets for SFTPC I73T -associated interstitial lung disease.
Mechanism of imidazolium ionic liquids toxicity in Saccharomyces cerevisiae and rational engineering of a tolerant, xylose-fermenting strain
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Comprehensive characterization of toxicity of fermentative metabolites on microbial growth
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Flux balance analysis of the ammonia-oxidizing bacterium Nitrosomonas europaea ATCC19718 unravels specific metabolic activities while degrading toxic compounds
The ammonia-oxidizing bacterium Nitrosomonas europaea has been widely recognized as an important player in the nitrogen cycle as well as one of the most abundant members in microbial communities for the treatment of industrial or sewage wastewater. Its natural metabolic versatility and extraordinary ability to degrade environmental pollutants (e.g., aromatic hydrocarbons such as benzene and toluene) enable it to thrive under various harsh environmental conditions. Constraint-based metabolic models constructed from genome sequences enable quantitative insight into the central and specialized metabolism within a target organism. These genome-scale models have been utilized to understand, optimize, and design new strategies for improved bioprocesses. Reduced modeling approaches have been used to elucidate Nitrosomonas europaea metabolism at a pathway level. However, genome-scale knowledge about the simultaneous oxidation of ammonia and pollutant metabolism of N . europaea remains limited. Here, we describe the reconstruction, manual curation, and validation of the genome-scale metabolic model for N . europaea , i GC535. This reconstruction is the most accurate metabolic model for a nitrifying organism to date, reaching an average prediction accuracy of over 90% under several growth conditions. The manually curated model can predict phenotypes under chemolithotrophic and chemolithoorganotrophic conditions while oxidating methane and wastewater pollutants. Calculated flux distributions under different trophic conditions show that several key pathways are affected by the type of carbon source available, including central carbon metabolism and energy production.
Structure of a Bimodular Botulinum Neurotoxin Complex Provides Insights into Its Oral Toxicity
Abstract not provided