@article{green_wall_weeks_mattingly_marsden_planchart_2023, title={Developmental cadmium exposure disrupts zebrafish vestibular calcium channels interfering with otolith formation and inner ear function}, volume={96}, ISSN={["1872-9711"]}, DOI={10.1016/j.neuro.2023.04.006}, abstractNote={Dizziness or balance problems are estimated to affect approximately 3.3 million children aged three to 17 years. These disorders develop from a breakdown in the balance control system and can be caused by anything that affects the inner ear or the brain, including exposure to environmental toxicants. One potential environmental toxicant linked to balance disorders is cadmium, an extremely toxic metal that occurs naturally in the earth’s crust and is released as a byproduct of industrial processes. Cadmium is associated with balance and vestibular dysfunction in adults exposed occupationally, but little is known about the developmental effects of low-concentration cadmium exposure. Our findings indicate that zebrafish exposed to 10–60 parts per billion (ppb) cadmium from four hours post-fertilization (hpf) to seven days post-fertilization (dpf) exhibit abnormal behaviors, including pronounced increases in auditory sensitivity and circling behavior, both of which are linked to reductions in otolith growth and are rescued by the addition of calcium to the media. Pharmacological intervention shows that agonist-induced activation of the P2X calcium ion channel in the presence of cadmium restores otolith size. In conclusion, cadmium-induced ototoxicity is linked to vestibular-based behavioral abnormalities and auditory sensitivity following developmental exposure, and calcium ion channel function is associated with these defects.}, journal={NEUROTOXICOLOGY}, author={Green, Adrian J. and Wall, Alex R. and Weeks, Ryan D. and Mattingly, Carolyn J. and Marsden, Kurt C. and Planchart, Antonio}, year={2023}, month={May}, pages={129–139} }
 @article{gonzalez_small_green_akhtari_motsinger-reif_quintanilha_havener_reif_mcleod_wiltshire_2023, title={MKX-AS1 Gene Expression Associated with Variation in Drug Response to Oxaliplatin and Clinical Outcomes in Colorectal Cancer Patients}, volume={16}, ISSN={["1424-8247"]}, url={https://doi.org/10.3390/ph16050757}, DOI={10.3390/ph16050757}, abstractNote={Oxaliplatin (OXAL) is a commonly used chemotherapy for treating colorectal cancer (CRC). A recent genome wide association study (GWAS) showed that a genetic variant (rs11006706) in the lncRNA gene MKX-AS1 and partnered sense gene MKX could impact the response of genetically varied cell lines to OXAL treatment. This study found that the expression levels of MKX-AS1 and MKX in lymphocytes (LCLs) and CRC cell lines differed between the rs11006706 genotypes, indicating that this gene pair could play a role in OXAL response. Further analysis of patient survival data from the Cancer Genome Atlas (TCGA) and other sources showed that patients with high MKX-AS1 expression status had significantly worse overall survival (HR = 3.2; 95%CI = (1.17-9); p = 0.024) compared to cases with low MKX-AS1 expression status. Alternatively, high MKX expression status had significantly better overall survival (HR = 0.22; 95%CI = (0.07-0.7); p = 0.01) compared to cases with low MKX expression status. These results suggest an association between MKX-AS1 and MKX expression status that could be useful as a prognostic marker of response to OXAL and potential patient outcomes in CRC.}, number={5}, journal={PHARMACEUTICALS}, author={Gonzalez, Ricardo D. and Small, George W. and Green, Adrian J. and Akhtari, Farida S. and Motsinger-Reif, Alison A. and Quintanilha, Julia C. F. and Havener, Tammy M. and Reif, David M. and McLeod, Howard L. and Wiltshire, Tim}, year={2023}, month={May} }
 @article{small_akhtari_green_havener_sikes_quintanhila_gonzalez_reif_motsinger-reif_mcleod_et al._2023, title={Pharmacogenomic Analyses Implicate B Cell Developmental Status and MKL1 as Determinants of Sensitivity toward Anti-CD20 Monoclonal Antibody Therapy}, volume={12}, ISSN={["2073-4409"]}, url={https://doi.org/10.3390/cells12121574}, DOI={10.3390/cells12121574}, abstractNote={Monoclonal antibody (mAb) therapy directed against CD20 is an important tool in the treatment of B cell disorders. However, variable patient response and acquired resistance remain important clinical challenges. To identify genetic factors that may influence sensitivity to treatment, the cytotoxic activity of three CD20 mAbs: rituximab; ofatumumab; and obinutuzumab, were screened in high-throughput assays using 680 ethnically diverse lymphoblastoid cell lines (LCLs) followed by a pharmacogenomic assessment. GWAS analysis identified several novel gene candidates. The most significant SNP, rs58600101, in the gene MKL1 displayed ethnic stratification, with the variant being significantly more prevalent in the African cohort and resulting in reduced transcript levels as measured by qPCR. Functional validation of MKL1 by shRNA-mediated knockdown of MKL1 resulted in a more resistant phenotype. Gene expression analysis identified the developmentally associated TGFB1I1 as the most significant gene associated with sensitivity. qPCR among a panel of sensitive and resistant LCLs revealed immunoglobulin class-switching as well as differences in the expression of B cell activation markers. Flow cytometry showed heterogeneity within some cell lines relative to surface Ig isotype with a shift to more IgG+ cells among the resistant lines. Pretreatment with prednisolone could partly reverse the resistant phenotype. Results suggest that the efficacy of anti-CD20 mAb therapy may be influenced by B cell developmental status as well as polymorphism in the MKL1 gene. A clinical benefit may be achieved by pretreatment with corticosteroids such as prednisolone followed by mAb therapy.}, number={12}, journal={CELLS}, author={Small, George W. and Akhtari, Farida S. and Green, Adrian J. and Havener, Tammy M. and Sikes, Michael and Quintanhila, Julia and Gonzalez, Ricardo D. and Reif, David M. and Motsinger-Reif, Alison A. and McLeod, Howard L. and et al.}, year={2023}, month={Jun} }
 @article{gonzalez_small_green_akhtari_havener_quintanilha_cipriani_reif_mcleod_motsinger-reif_et al._2023, title={RYK Gene Expression Associated with Drug Response Variation of Temozolomide and Clinical Outcomes in Glioma Patients}, volume={16}, ISSN={["1424-8247"]}, url={https://doi.org/10.3390/ph16050726}, DOI={10.3390/ph16050726}, abstractNote={Temozolomide (TMZ) chemotherapy is an important tool in the treatment of glioma brain tumors. However, variable patient response and chemo-resistance remain exceptionally challenging. Our previous genome-wide association study (GWAS) identified a suggestively significant association of SNP rs4470517 in the RYK (receptor-like kinase) gene with TMZ drug response. Functional validation of RYK using lymphocytes and glioma cell lines resulted in gene expression analysis indicating differences in expression status between genotypes of the cell lines and TMZ dose response. We conducted univariate and multivariate Cox regression analyses using publicly available TCGA and GEO datasets to investigate the impact of RYK gene expression status on glioma patient overall (OS) and progression-free survival (PFS). Our results indicated that in IDH mutant gliomas, RYK expression and tumor grade were significant predictors of survival. In IDH wildtype glioblastomas (GBM), MGMT status was the only significant predictor. Despite this result, we revealed a potential benefit of RYK expression in IDH wildtype GBM patients. We found that a combination of RYK expression and MGMT status could serve as an additional biomarker for improved survival. Overall, our findings suggest that RYK expression may serve as an important prognostic or predictor of TMZ response and survival for glioma patients.}, number={5}, journal={PHARMACEUTICALS}, author={Gonzalez, Ricardo D. and Small, George W. and Green, Adrian J. and Akhtari, Farida S. and Havener, Tammy M. and Quintanilha, Julia C. F. and Cipriani, Amber B. and Reif, David M. and McLeod, Howard L. and Motsinger-Reif, Alison A. and et al.}, year={2023}, month={May} }
 @article{weeks_banack_howell_thunga_green_cox_planchart_metcalf_2023, title={The Effects of Long-term, Low-dose & beta;-N-methylamino-l-alanine (BMAA) Exposures in Adult SODG93R Transgenic Zebrafish}, volume={8}, ISSN={["1476-3524"]}, DOI={10.1007/s12640-023-00658-z}, journal={NEUROTOXICITY RESEARCH}, author={Weeks, Ryan D. and Banack, Sandra A. and Howell, Shaunacee and Thunga, Preethi and Green, Adrian J. and Cox, Paul A. and Planchart, Antonio and Metcalf, James S.}, year={2023}, month={Aug} }
 @article{weeks_banack_howell_thunga_metcalf_green_cox_planchart_2023, title={The Effects of Long-term, Low-dose beta-N-methylamino-L-alanine (BMAA) Exposures in Adult SODG93R (Aug, 10.1007/s12640-023-00658-z, 2023)}, volume={8}, ISSN={["1476-3524"]}, DOI={10.1007/s12640-023-00664-1}, journal={NEUROTOXICITY RESEARCH}, author={Weeks, Ryan D. and Banack, Sandra A. and Howell, Shaunacee and Thunga, Preethi and Metcalf, James S. and Green, Adrian J. and Cox, Paul A. and Planchart, Antonio}, year={2023}, month={Aug} }
 @article{polkoff_gupta_green_murphy_chung_gleason_simpson_walker_collins_piedrahita_2022, title={LGR5 is a conserved marker of hair follicle stem cells in multiple species and is present early and throughout follicle morphogenesis}, volume={12}, ISSN={["2045-2322"]}, DOI={10.1038/s41598-022-13056-w}, abstractNote={Abstract Hair follicle stem cells are key for driving growth and homeostasis of the hair follicle niche, have remarkable regenerative capacity throughout hair cycling, and display fate plasticity during cutaneous wound healing. Due to the need for a transgenic reporter, essentially all observations related to LGR5-expressing hair follicle stem cells have been generated using transgenic mice, which have significant differences in anatomy and physiology from the human. Using a transgenic pig model, a widely accepted model for human skin and human skin repair, we demonstrate that LGR5 is a marker of hair follicle stem cells across species in homeostasis and development. We also report the strong similarities and important differences in expression patterns, gene expression profiles, and developmental processes between species. This information is important for understanding the fundamental differences and similarities across species, and ultimately improving human hair follicle regeneration, cutaneous wound healing, and skin cancer treatment.}, number={1}, journal={SCIENTIFIC REPORTS}, author={Polkoff, Kathryn M. and Gupta, Nithin K. and Green, Adrian J. and Murphy, Yanet and Chung, Jaewook and Gleason, Katherine L. and Simpson, Sean G. and Walker, Derek M. and Collins, Bruce and Piedrahita, Jorge A.}, year={2022}, month={Jun} }
 @article{gilchrist_alexander_green_sanders_hooker_reif_2021, title={Development of a Pandemic Awareness STEM Outreach Curriculum: Utilizing a Computational Thinking Taxonomy Framework}, volume={11}, ISSN={["2227-7102"]}, url={https://doi.org/10.3390/educsci11030109}, DOI={10.3390/educsci11030109}, abstractNote={Computational thinking is an essential skill in the modern global workforce. The current public health crisis has highlighted the need for students and educators to have a deeper understanding of epidemiology. While existing STEM curricula has addressed these topics in the past, current events present an opportunity for new curricula that can be designed to present epidemiology, the science of public health, as a modern topic for students that embeds the problem-solving and mathematics skills of computational thinking practices authentically. Using the Computational Thinking Taxonomy within the informal education setting of a STEM outreach program, a curriculum was developed to introduce middle school students to epidemiological concepts while developing their problem-solving skills, a subset of their computational thinking and mathematical thinking practices, in a contextually rich environment. The informal education setting at a Research I Institution provides avenues to connect diverse learners to visually engaging computational thinking and data science curricula to understand emerging teaching and learning approaches. This paper documents the theory and design approach used by researchers and practitioners to create a Pandemic Awareness STEM Curriculum and future implications for teaching and learning computational thinking practices through engaging with data science.}, number={3}, journal={EDUCATION SCIENCES}, author={Gilchrist, Pamela O. and Alexander, Alonzo B. and Green, Adrian J. and Sanders, Frieda E. and Hooker, Ashley Q. and Reif, David M.}, year={2021}, month={Mar} }
 @article{green_anchang_akhtari_reif_motsinger-reif_2021, title={Extending the lymphoblastoid cell line model for drug combination pharmacogenomics}, volume={22}, ISSN={["1744-8042"]}, url={https://doi.org/10.2217/pgs-2020-0160}, DOI={10.2217/pgs-2020-0160}, abstractNote={Combination drug therapies have become an integral part of precision oncology, and while evidence of clinical effectiveness continues to grow, the underlying mechanisms supporting synergy are poorly understood. Immortalized human lymphoblastoid cell lines (LCLs) have been proven as a particularly useful, scalable and low-cost model in pharmacogenetics research, and are suitable for elucidating the molecular mechanisms of synergistic combination therapies. In this review, we cover the advantages of LCLs in synergy pharmacogenomics and consider recent studies providing initial evidence of the utility of LCLs in synergy research. We also discuss several opportunities for LCL-based systems to address gaps in the research through the expansion of testing regimens, assessment of new drug classes and higher-order combinations, and utilization of integrated omics technologies.}, number={9}, journal={PHARMACOGENOMICS}, publisher={Future Medicine Ltd}, author={Green, Adrian J. and Anchang, Benedict and Akhtari, Farida S. and Reif, David M. and Motsinger-Reif, Alison}, year={2021}, month={May} }
 @article{akhtari_green_small_havener_house_roell_reif_mcleod_wiltshire_motsinger-reif_2021, title={High-throughput screening and genome-wide analyses of 44 anticancer drugs in the 1000 Genomes cell lines reveals an association of the NQO1 gene with the response of multiple anticancer drugs}, volume={17}, ISSN={["1553-7404"]}, url={https://doi.org/10.1371/journal.pgen.1009732}, DOI={10.1371/journal.pgen.1009732}, abstractNote={Cancer patients exhibit a broad range of inter-individual variability in response and toxicity to widely used anticancer drugs, and genetic variation is a major contributor to this variability. To identify new genes that influence the response of 44 FDA-approved anticancer drug treatments widely used to treat various types of cancer, we conducted high-throughput screening and genome-wide association mapping using 680 lymphoblastoid cell lines from the 1000 Genomes Project. The drug treatments considered in this study represent nine drug classes widely used in the treatment of cancer in addition to the paclitaxel + epirubicin combination therapy commonly used for breast cancer patients. Our genome-wide association study (GWAS) found several significant and suggestive associations. We prioritized consistent associations for functional follow-up using gene-expression analyses. The NAD(P)H quinone dehydrogenase 1 (NQO1) gene was found to be associated with the dose-response of arsenic trioxide, erlotinib, trametinib, and a combination treatment of paclitaxel + epirubicin. NQO1 has previously been shown as a biomarker of epirubicin response, but our results reveal novel associations with these additional treatments. Baseline gene expression of NQO1 was positively correlated with response for 43 of the 44 treatments surveyed. By interrogating the functional mechanisms of this association, the results demonstrate differences in both baseline and drug-exposed induction.}, number={8}, journal={PLOS GENETICS}, publisher={Public Library of Science (PLoS)}, author={Akhtari, Farida S. and Green, Adrian J. and Small, George W. and Havener, Tammy M. and House, John S. and Roell, Kyle R. and Reif, David M. and McLeod, Howard L. and Wiltshire, Timothy and Motsinger-Reif, Alison A.}, editor={Vazquez, FranciscaEditor}, year={2021}, month={Aug} }
 @article{green_mohlenkamp_das_chaudhari_truong_tanguay_reif_2021, title={Leveraging high-throughput screening data, deep neural networks, and conditional generative adversarial networks to advance predictive toxicology}, volume={17}, ISSN={["1553-7358"]}, url={https://doi.org/10.1371/journal.pcbi.1009135}, DOI={10.1371/journal.pcbi.1009135}, abstractNote={There are currently 85,000 chemicals registered with the Environmental Protection Agency (EPA) under the Toxic Substances Control Act, but only a small fraction have measured toxicological data. To address this gap, high-throughput screening (HTS) and computational methods are vital. As part of one such HTS effort, embryonic zebrafish were used to examine a suite of morphological and mortality endpoints at six concentrations from over 1,000 unique chemicals found in the ToxCast library (phase 1 and 2). We hypothesized that by using a conditional generative adversarial network (cGAN) or deep neural networks (DNN), and leveraging this large set of toxicity data we could efficiently predict toxic outcomes of untested chemicals. Utilizing a novel method in this space, we converted the 3D structural information into a weighted set of points while retaining all information about the structure. In vivo toxicity and chemical data were used to train two neural network generators. The first was a DNN (Go-ZT) while the second utilized cGAN architecture (GAN-ZT) to train generators to produce toxicity data. Our results showed that Go-ZT significantly outperformed the cGAN, support vector machine, random forest and multilayer perceptron models in cross-validation, and when tested against an external test dataset. By combining both Go-ZT and GAN-ZT, our consensus model improved the SE, SP, PPV, and Kappa, to 71.4%, 95.9%, 71.4% and 0.673, respectively, resulting in an area under the receiver operating characteristic (AUROC) of 0.837. Considering their potential use as prescreening tools, these models could provide in vivo toxicity predictions and insight into the hundreds of thousands of untested chemicals to prioritize compounds for HT testing.}, number={7}, journal={PLOS COMPUTATIONAL BIOLOGY}, publisher={Public Library of Science (PLoS)}, author={Green, Adrian J. and Mohlenkamp, Martin J. and Das, Jhuma and Chaudhari, Meenal and Truong, Lisa and Tanguay, Robyn L. and Reif, David M.}, editor={Hatzimanikatis, VassilyEditor}, year={2021}, month={Jul} }
 @article{green_planchart_2018, title={The neurological toxicity of heavy metals: A fish perspective}, volume={208}, ISSN={1532-0456}, url={http://dx.doi.org/10.1016/j.cbpc.2017.11.008}, DOI={10.1016/j.cbpc.2017.11.008}, abstractNote={The causes of neurodegenerative diseases are complex with likely contributions from genetic susceptibility and environmental exposures over an organism's lifetime. In this review, we examine the role that aquatic models, especially zebrafish, have played in the elucidation of mechanisms of heavy metal toxicity and nervous system function over the last decade. Focus is applied to cadmium, lead, and mercury as significant contributors to central nervous system morbidity, and the application of numerous transgenic zebrafish expressing fluorescent reporters in specific neuronal populations or brain regions enabling high-resolution neurodevelopmental and neurotoxicology research.}, journal={Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology}, publisher={Elsevier BV}, author={Green, Adrian J. and Planchart, Antonio}, year={2018}, month={Jun}, pages={12–19} }