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126 results on '"Carlson, Erin E."'

1. Evaluation of expanded 2-aminobenzothiazole library as inhibitors of a model histidine kinase and virulence suppressors in Pseudomonas aeruginosa

Author

Fihn, Conrad A., Lembke, Hannah K., Gaulin, Jeffrey, Bouchard, Patricia, Villarreal, Alex R., Penningroth, Mitchell R., Crone, Kathryn K., Vogt, Grace A., Gilbertsen, Adam J., Ayotte, Yann, Coutinho de Oliveira, Luciana, Serrano-Wu, Michael H., Drouin, Nathalie, Hung, Deborah T., Hunter, Ryan C., and Carlson, Erin E.

Published
2024
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7. Data from Breast Cancer Polygenic-Risk Score Influence on Risk-Reducing Endocrine Therapy Use: Genetic Risk Estimate (GENRE) Trial 1-Year and 2-Year Follow-Up

Author

Stan, Daniela L., primary, Kim, Julian O., primary, Schaid, Daniel J., primary, Carlson, Erin E., primary, Kim, Christina A., primary, Sinnwell, Jason P., primary, Couch, Fergus J., primary, Vachon, Celine M., primary, Cooke, Andrew L., primary, Goldenberg, Benjamin A., primary, and Pruthi, Sandhya, primary

Published
2024
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8. Supplemental Figure 1 from Breast Cancer Polygenic-Risk Score Influence on Risk-Reducing Endocrine Therapy Use: Genetic Risk Estimate (GENRE) Trial 1-Year and 2-Year Follow-Up

Author

Stan, Daniela L., primary, Kim, Julian O., primary, Schaid, Daniel J., primary, Carlson, Erin E., primary, Kim, Christina A., primary, Sinnwell, Jason P., primary, Couch, Fergus J., primary, Vachon, Celine M., primary, Cooke, Andrew L., primary, Goldenberg, Benjamin A., primary, and Pruthi, Sandhya, primary

Published
2024
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9. Supplemental Materials and Methods 1 from Breast Cancer Polygenic-Risk Score Influence on Risk-Reducing Endocrine Therapy Use: Genetic Risk Estimate (GENRE) Trial 1-Year and 2-Year Follow-Up

Author

Stan, Daniela L., primary, Kim, Julian O., primary, Schaid, Daniel J., primary, Carlson, Erin E., primary, Kim, Christina A., primary, Sinnwell, Jason P., primary, Couch, Fergus J., primary, Vachon, Celine M., primary, Cooke, Andrew L., primary, Goldenberg, Benjamin A., primary, and Pruthi, Sandhya, primary

Published
2024
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10. Breast Cancer Polygenic-Risk Score Influence on Risk-Reducing Endocrine Therapy Use: Genetic Risk Estimate (GENRE) Trial 1-Year and 2-Year Follow-Up

Author

Stan, Daniela L., primary, Kim, Julian O., additional, Schaid, Daniel J., additional, Carlson, Erin E., additional, Kim, Christina A., additional, Sinnwell, Jason P., additional, Couch, Fergus J., additional, Vachon, Celine M., additional, Cooke, Andrew L., additional, Goldenberg, Benjamin A., additional, and Pruthi, Sandhya, additional

Published
2023
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14. Evaluation of Expanded 2-Aminobenzothiazole Library for Inhibition of Pseudomonas aeruginosa Virulence Phenotypes

Author

Fihn, Conrad, primary, Lembke, Hannah, additional, Gaulin, Jeffrey, additional, Bouchard, Patricia, additional, Penningroth, Mitchell R, additional, Crone, Kathryn, additional, Vogt, Grace, additional, Gilbertsen, Adam, additional, Ayotte, Yann, additional, CouthinodeOliveira, Luciana, additional, Serrano-Wu, Michael, additional, Drouin, Nathalie, additional, Hung, Deborah, additional, Hunter, Ryan C, additional, and Carlson, Erin E, additional

Published
2023
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15. Evaluation of Expanded 2-Aminobenzothiazole Library for Inhibition ofPseudomonas aeruginosaVirulence Phenotypes

Author

Fihn, Conrad A., Lembke, Hannah K., Gaulin, Jeffrey, Bouchard, Patricia, Penningroth, Mitchell R., Crone, Kathryn K., Vogt, Grace A., Gilbertsen, Adam J., Ayotte, Yann, de Oliveira, Luciana Couthino, Serrano-Wu, Michael H., Drouin, Nathalie, Hung, Deborah T., Hunter, Ryan C., and Carlson, Erin E.

Subjects
Article
Abstract

Bacterial resistance to antibiotics is a rapidly increasing threat to human health. New strategies to combat resistant organisms are desperately needed. One potential avenue is targeting two-component systems, which are the main bacterial signal transduction pathways used to regulate development, metabolism, virulence, and antibiotic resistance. These systems consist of a homodimeric membrane-bound sensor histidine kinase, and a cognate effector, the response regulator. The high sequence conservation in the catalytic and adenosine triphosphate-binding (CA) domain of histidine kinases and their essential role in bacterial signal transduction could enable broad-spectrum antibacterial activity. Through this signal transduction, histidine kinases regulate multiple virulence mechanisms including toxin production, immune evasion, and antibiotic resistance. Targeting virulence, as opposed to development of bactericidal compounds, could reduce evolutionary pressure for acquired resistance. Additionally, compounds targeting the CA domain have the potential to impair multiple two-component systems that regulate virulence in one or more pathogens. We conducted structure-activity relationship studies of 2-aminobenzothiazole-based inhibitors designed to target the CA domain of histidine kinases. We found these compounds have anti-virulence activities inPseudomonas aeruginosa,reducing motility phenotypes and toxin production associated with the pathogenic functions of this bacterium.Abstract Figure

Published
2023
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16. Supplementary Figure S2 from Selective Estrogen Receptor Modulators and Pharmacogenomic Variation in ZNF423 Regulation of BRCA1 Expression: Individualized Breast Cancer Prevention

Author

Ingle, James N., primary, Liu, Mohan, primary, Wickerham, D. Lawrence, primary, Schaid, Daniel J., primary, Wang, Liewei, primary, Mushiroda, Taisei, primary, Kubo, Michiaki, primary, Costantino, Joseph P., primary, Vogel, Victor G., primary, Paik, Soonmyung, primary, Goetz, Matthew P., primary, Ames, Matthew M., primary, Jenkins, Gregory D., primary, Batzler, Anthony, primary, Carlson, Erin E., primary, Flockhart, David A., primary, Wolmark, Norman, primary, Nakamura, Yusuke, primary, and Weinshilboum, Richard M., primary

Published
2023
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17. Data from Selective Estrogen Receptor Modulators and Pharmacogenomic Variation in ZNF423 Regulation of BRCA1 Expression: Individualized Breast Cancer Prevention

Author

Ingle, James N., primary, Liu, Mohan, primary, Wickerham, D. Lawrence, primary, Schaid, Daniel J., primary, Wang, Liewei, primary, Mushiroda, Taisei, primary, Kubo, Michiaki, primary, Costantino, Joseph P., primary, Vogel, Victor G., primary, Paik, Soonmyung, primary, Goetz, Matthew P., primary, Ames, Matthew M., primary, Jenkins, Gregory D., primary, Batzler, Anthony, primary, Carlson, Erin E., primary, Flockhart, David A., primary, Wolmark, Norman, primary, Nakamura, Yusuke, primary, and Weinshilboum, Richard M., primary

Published
2023
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18. Supplementary Material from Selective Estrogen Receptor Modulators and Pharmacogenomic Variation in ZNF423 Regulation of BRCA1 Expression: Individualized Breast Cancer Prevention

Author

Ingle, James N., primary, Liu, Mohan, primary, Wickerham, D. Lawrence, primary, Schaid, Daniel J., primary, Wang, Liewei, primary, Mushiroda, Taisei, primary, Kubo, Michiaki, primary, Costantino, Joseph P., primary, Vogel, Victor G., primary, Paik, Soonmyung, primary, Goetz, Matthew P., primary, Ames, Matthew M., primary, Jenkins, Gregory D., primary, Batzler, Anthony, primary, Carlson, Erin E., primary, Flockhart, David A., primary, Wolmark, Norman, primary, Nakamura, Yusuke, primary, and Weinshilboum, Richard M., primary

Published
2023
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19. Supplementary Figure S2 from Genetic Polymorphisms in the Long Noncoding RNA MIR2052HG Offer a Pharmacogenomic Basis for the Response of Breast Cancer Patients to Aromatase Inhibitor Therapy

Author

Ingle, James N., primary, Xie, Fang, primary, Ellis, Matthew J., primary, Goss, Paul E., primary, Shepherd, Lois E., primary, Chapman, Judith-Anne W., primary, Chen, Bingshu E., primary, Kubo, Michiaki, primary, Furukawa, Yoichi, primary, Momozawa, Yukihide, primary, Stearns, Vered, primary, Pritchard, Kathleen I., primary, Barman, Poulami, primary, Carlson, Erin E., primary, Goetz, Matthew P., primary, Weinshilboum, Richard M., primary, Kalari, Krishna R., primary, and Wang, Liewei, primary

Published
2023
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20. Supplementary Figure from Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer

Author

Fasching, Peter A., primary, Liu, Duan, primary, Scully, Steve, primary, Ingle, James N., primary, Lyra, Paulo C., primary, Rack, Brigitte, primary, Hein, Alexander, primary, Ekici, Arif B., primary, Reis, Andre, primary, Schneeweiss, Andreas, primary, Tesch, Hans, primary, Fehm, Tanja N., primary, Heinrich, Georg, primary, Beckmann, Matthias W., primary, Ruebner, Matthias, primary, Huebner, Hanna, primary, Lambrechts, Diether, primary, Madden, Ebony, primary, Shen, Jess, primary, Romm, Jane, primary, Doheny, Kim, primary, Jenkins, Gregory D., primary, Carlson, Erin E., primary, Li, Liang, primary, Fridley, Brooke L., primary, Cunningham, Julie M., primary, Janni, Wolfgang, primary, Monteiro, Alvaro N.A., primary, Schaid, Daniel J., primary, Häberle, Lothar, primary, Weinshilboum, Richard M., primary, and Wang, Liewei, primary

Published
2023
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21. Data from Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer

Author

Fasching, Peter A., primary, Liu, Duan, primary, Scully, Steve, primary, Ingle, James N., primary, Lyra, Paulo C., primary, Rack, Brigitte, primary, Hein, Alexander, primary, Ekici, Arif B., primary, Reis, Andre, primary, Schneeweiss, Andreas, primary, Tesch, Hans, primary, Fehm, Tanja N., primary, Heinrich, Georg, primary, Beckmann, Matthias W., primary, Ruebner, Matthias, primary, Huebner, Hanna, primary, Lambrechts, Diether, primary, Madden, Ebony, primary, Shen, Jess, primary, Romm, Jane, primary, Doheny, Kim, primary, Jenkins, Gregory D., primary, Carlson, Erin E., primary, Li, Liang, primary, Fridley, Brooke L., primary, Cunningham, Julie M., primary, Janni, Wolfgang, primary, Monteiro, Alvaro N.A., primary, Schaid, Daniel J., primary, Häberle, Lothar, primary, Weinshilboum, Richard M., primary, and Wang, Liewei, primary

Published
2023
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22. Supplementary Data from Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer

Author

Fasching, Peter A., primary, Liu, Duan, primary, Scully, Steve, primary, Ingle, James N., primary, Lyra, Paulo C., primary, Rack, Brigitte, primary, Hein, Alexander, primary, Ekici, Arif B., primary, Reis, Andre, primary, Schneeweiss, Andreas, primary, Tesch, Hans, primary, Fehm, Tanja N., primary, Heinrich, Georg, primary, Beckmann, Matthias W., primary, Ruebner, Matthias, primary, Huebner, Hanna, primary, Lambrechts, Diether, primary, Madden, Ebony, primary, Shen, Jess, primary, Romm, Jane, primary, Doheny, Kim, primary, Jenkins, Gregory D., primary, Carlson, Erin E., primary, Li, Liang, primary, Fridley, Brooke L., primary, Cunningham, Julie M., primary, Janni, Wolfgang, primary, Monteiro, Alvaro N.A., primary, Schaid, Daniel J., primary, Häberle, Lothar, primary, Weinshilboum, Richard M., primary, and Wang, Liewei, primary

Published
2023
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23. Data from Genetic Polymorphisms in the Long Noncoding RNA MIR2052HG Offer a Pharmacogenomic Basis for the Response of Breast Cancer Patients to Aromatase Inhibitor Therapy

Author

Ingle, James N., primary, Xie, Fang, primary, Ellis, Matthew J., primary, Goss, Paul E., primary, Shepherd, Lois E., primary, Chapman, Judith-Anne W., primary, Chen, Bingshu E., primary, Kubo, Michiaki, primary, Furukawa, Yoichi, primary, Momozawa, Yukihide, primary, Stearns, Vered, primary, Pritchard, Kathleen I., primary, Barman, Poulami, primary, Carlson, Erin E., primary, Goetz, Matthew P., primary, Weinshilboum, Richard M., primary, Kalari, Krishna R., primary, and Wang, Liewei, primary

Published
2023
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24. Supplementary Material from Genetic Polymorphisms in the Long Noncoding RNA MIR2052HG Offer a Pharmacogenomic Basis for the Response of Breast Cancer Patients to Aromatase Inhibitor Therapy

Author

Ingle, James N., primary, Xie, Fang, primary, Ellis, Matthew J., primary, Goss, Paul E., primary, Shepherd, Lois E., primary, Chapman, Judith-Anne W., primary, Chen, Bingshu E., primary, Kubo, Michiaki, primary, Furukawa, Yoichi, primary, Momozawa, Yukihide, primary, Stearns, Vered, primary, Pritchard, Kathleen I., primary, Barman, Poulami, primary, Carlson, Erin E., primary, Goetz, Matthew P., primary, Weinshilboum, Richard M., primary, Kalari, Krishna R., primary, and Wang, Liewei, primary

Published
2023
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25. Supplementary Data Clean from Anastrozole has an Association between Degree of Estrogen Suppression and Outcomes in Early Breast Cancer and is a Ligand for Estrogen Receptor α

Author

Ingle, James N., primary, Cairns, Junmei, primary, Suman, Vera J., primary, Shepherd, Lois E., primary, Fasching, Peter A., primary, Hoskin, Tanya L., primary, Singh, Ravinder J., primary, Desta, Zeruesenay, primary, Kalari, Krishna R., primary, Ellis, Matthew J., primary, Goss, Paul E., primary, Chen, Bingshu E., primary, Volz, Bernhard, primary, Barman, Poulami, primary, Carlson, Erin E., primary, Haddad, Tufia, primary, Goetz, Matthew P., primary, Goodnature, Barbara, primary, Cuellar, Matthew E., primary, Walters, Michael A., primary, Correia, Cristina, primary, Kaufmann, Scott H., primary, Weinshilboum, Richard M., primary, and Wang, Liewei, primary

Published
2023
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34. Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Breast Cancer Patients

Author

Fasching, Peter. A., Liu, Duan, Scully, Steve, Ingle, James N., Lyra, Paulo C., Rack, Brigitte, Hein, Alexander, Ekici, Arif B., Reis, Andre, Schneeweiss, Andreas, Tesch, Hans, Fehm, Tanja N., Heinrich, Georg, Beckmann, Matthias W., Ruebner, Matthias, Huebner, Hanna, Lambrechts, Diether, Madden, Ebony, Shen, Jess, Romm, Jane, Doheny, Kim, Jenkins, Gregory D., Carlson, Erin E., Li, Liang, Fridley, Brooke L., Cunningham, Julie M., Janni, Wolfgang, Monteiro, Alvaro N.A., Schaid, Daniel J., Häberle, Lothar, Weinshilboum, Richard M., and Wang, Liewei

Subjects
Genotype, Genetic Loci, Intracellular Signaling Peptides and Proteins, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Leukopenia, Polymorphism, Single Nucleotide, Article, Genome-Wide Association Study
Abstract

PURPOSE: To identify molecular predictors of grade 3/4 neutropenic or leukopenic events (NLEs) after chemotherapy using a genome-wide association study (GWAS). PATIENTS AND METHODS: A GWAS was performed on patients in the phase III chemotherapy study SUCCESS-A (n = 3322). Genotyping was done using the Illumina HumanOmniExpress-12v1 array. Findings were functionally validated with cell culture models and the genotypes and gene expression of possible causative genes were correlated with clinical treatment response and prognostic outcomes. RESULTS: One locus on chromosome 16 (rs4784750; NLRC5; P = 1.56E-8) and another locus on chromosome 13 (rs16972207; TNFSF13B; P = 3.42E-8) were identified at a genome-wide significance level. Functional validation revealed that expression of these two genes is altered by genotype-dependent and chemotherapy-dependent activity of two transcription factors. Genotypes also showed an association with disease-free survival in patients with an NLE. CONCLUSIONS: Two loci in NLRC5 and TNFSF13B are associated with NLEs. The involvement of the major histocompatibility complex I regulator NLRC5 implies the possible involvement of immuno-oncological pathways.

Published
2022

35. S29 Dilated Main Pancreatic Duct Without a Visible Pancreatic Mass: Long-Term Follow-Up and Predictors of Future Pancreatic Ductal Adenocarcinoma

Author

Chatterjee, Arjun, primary, Lakhmani, Varun, additional, Khasawneh, Hala A., additional, Horibe, Masayasu, additional, De la Fuente, Jaime, additional, Bamlet, William R., additional, Carlson, Erin E., additional, Oberg, Ann L., additional, Delgado, Adriana M., additional, Doering, Karen A., additional, Takahashi, Naoki, additional, Goenka, Ajit H., additional, Petersen, Gloria M., additional, and Majumder, Shounak, additional

Published
2022
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38. Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer

Author

Fasching, Peter A., primary, Liu, Duan, additional, Scully, Steve, additional, Ingle, James N., additional, Lyra, Paulo C., additional, Rack, Brigitte, additional, Hein, Alexander, additional, Ekici, Arif B., additional, Reis, Andre, additional, Schneeweiss, Andreas, additional, Tesch, Hans, additional, Fehm, Tanja N., additional, Heinrich, Georg, additional, Beckmann, Matthias W., additional, Ruebner, Matthias, additional, Huebner, Hanna, additional, Lambrechts, Diether, additional, Madden, Ebony, additional, Shen, Jess, additional, Romm, Jane, additional, Doheny, Kim, additional, Jenkins, Gregory D., additional, Carlson, Erin E., additional, Li, Liang, additional, Fridley, Brooke L., additional, Cunningham, Julie M., additional, Janni, Wolfgang, additional, Monteiro, Alvaro N.A., additional, Schaid, Daniel J., additional, Häberle, Lothar, additional, Weinshilboum, Richard M., additional, and Wang, Liewei, additional

Published
2022
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40. 639 THE REGARD STUDY: A PROSPECTIVE STUDY OF RISK OF PANCREATIC DUCTAL ADENOCARCINOMA IN GLYCEMICALLY DEFINED NEW-ONSET DIABETES ASCERTAINED BY ALGORITHM BASED PASSIVE SURVEILLANCE OF ELECTRONIC HEALTH RECORDS

Author

Chari, Suresh, Wu, Bechien U., Qian, Lu, Lustigova, Eva, Chen, Qiaoling, Van Den Eeden, Stephen K., Leimpeter, Amethyst D., Fisher, William E., Alexander, Ashley S., Wood, Amy, Valenta, John, Vege, Santhi Swaroop, Carlson, Erin E., Rabe, Kari G., Kenner, Barbara, Yosuf, Nadia, Lopez, Camden, Zhao, Ying-Qi, Matrisian, Lynn, Maitra, Anirban, Rinaudo, Jo Ann, and Feng, Ziding

Published
2024
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45. Challenges of Biological Complexity in the Study of Nanotoxicology

Author

Northwick, Andrew B. and Carlson, Erin E.

Abstract

The scale of nanoparticle use in consumer goods has grown exponentially over several decades owing to the unique properties of materials in this size range. At the same time, well-defined end of life cycle disposal strategies have not been developed for most materials, meaning that we are approaching the potential for a new ecological disaster with the release of millions of metric tons of nanoparticles into the waste stream. The field of nanotoxicology has grown to meet the challenge of investigating the potential hazards of these materials and has already identified toxicity mechanisms that affect multiple tropes of life. However, there are stipulations on how applicable many of these results are to real world applications. These limitations largely arise from the complex network of variables that must be considered during these investigations. Herein, we focus on the challenges posed by the transformations that nanoparticles undergo when they are introduced into a biological environment. For example, biomolecules, such as proteins, rapidly coat nanoparticles with a shell, called a corona, that can modulate the toxicity of the core materials and/or aid its internalization into cells. As such, unlike in the evaluation of small molecule toxicity, one cannot assume that they know the composition of the nanoparticle-biomolecule species at any given time. This additional layer of complication, as well as the noncovalent nature of the corona, have made it difficult to identify consistent toxicity trends. In this Perspective, we highlight current analysis strategies and the difficulties in studying nanotoxicity, recent advances to aid in these studies, and efforts to reduce nanotoxicity and outline remaining challenges.

Published
2025
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46. Natural Products as Chemical Probes

Author

Carlson, Erin E.

Abstract

Natural products have evolved to encompass a broad spectrum of chemical and functional diversity. It is this diversity, along with their structural complexity, that enables nature’s small molecules to target a nearly limitless number of biological macromolecules and to often do so in a highly selective fashion. Because of these characteristics, natural products have seen great success as therapeutic agents. However, this vast pool of compounds holds much promise beyond the development of future drugs. These features also make them ideal tools for the study of biological systems. Recent examples of the use of natural products and their derivatives as chemical probes to explore biological phenomena and assemble biochemical pathways are presented here.

Published
2024
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47. k inact / K I Value Determination for Penicillin-Binding Proteins in Live Cells.

Author

Shirley JD, Gillingham JR, Nauta KM, Diwakar S, and Carlson EE

Subjects
Kinetics, beta-Lactams pharmacology, Microbial Sensitivity Tests, Boron Compounds, Penicillins, Penicillin-Binding Proteins metabolism, Penicillin-Binding Proteins genetics, Penicillin-Binding Proteins antagonists & inhibitors, Streptococcus pneumoniae drug effects, Streptococcus pneumoniae metabolism, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents chemistry
Abstract

Penicillin-binding proteins (PBPs) are an essential family of bacterial enzymes that are covalently inhibited by the β-lactam class of antibiotics. PBP inhibition disrupts peptidoglycan biosynthesis, which results in deficient growth and proliferation, and ultimately leads to lysis. IC 50 values are often employed as descriptors of enzyme inhibition and inhibitor selectivity, but can be misleading in the study of time-dependent, covalent inhibitors. Due to this disconnect, the second-order rate constant, k inact / K I , is a more appropriate metric of covalent-inhibitor potency. Despite being the gold standard measurement of potency, k inact / K I values are typically obtained from in vitro assays, which limits assay throughput if investigating an enzyme family with multiple homologues (such as the PBPs). Therefore, we developed a whole-cell k inact / K I assay to define inhibitor potency for the PBPs in Streptococcus pneumoniae using the fluorescent, activity-based probe, Bocillin-FL. Our results align with in vitro k inact / K I data and show a comparable relationship to previously established IC 50 values. These results support the validity of our in vivo k inact / K I method as a means of obtaining β-lactam potency for a suite of PBPs to enable structure-activity relationship studies.

Published
2024
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48. Breast Cancer Polygenic-Risk Score Influence on Risk-Reducing Endocrine Therapy Use: Genetic Risk Estimate (GENRE) Trial 1-Year and 2-Year Follow-Up.

Author

Stan DL, Kim JO, Schaid DJ, Carlson EE, Kim CA, Sinnwell JP, Couch FJ, Vachon CM, Cooke AL, Goldenberg BA, and Pruthi S

Subjects
Female, Humans, Quality of Life, Follow-Up Studies, Risk Assessment, Genetic Risk Score, Risk Factors, Genetic Predisposition to Disease, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Breast Neoplasms prevention & control
Abstract

Refinement of breast cancer risk estimates with a polygenic-risk score (PRS) may improve uptake of risk-reducing endocrine therapy (ET). A previous clinical trial assessed the influence of adding a PRS to traditional risk estimates on ET use. We stratified participants according to PRS-refined breast cancer risk and evaluated ET use and ET-related quality of life (QOL) at 1-year (previously reported) and 2-year follow-ups. Of 151 participants, 58 (38.4%) initiated ET, and 22 (14.6%) discontinued ET by 2 years; 42 (27.8%) and 36 (23.8%) participants were using ET at 1- and 2-year follow-ups, respectively. At the 2-year follow-up, 39% of participants with a lifetime breast cancer risk of 40.1% to 100.0%, 18% with a 20.1% to 40.0% risk, and 16% with a 0.0% to 20.0% risk were taking ET (overall P = 0.01). Moreover, 40% of participants whose breast cancer risk increased by 10% or greater with addition of the PRS to a traditional breast cancer-risk model were taking ET versus 0% whose risk decreased by 10% or greater (P = 0.004). QOL was similar for participants taking or not taking ET at 1- and 2-year follow-ups, although most who discontinued ET did so because of adverse effects. However, these QOL results may have been skewed by the long interval between QOL surveys and lack of baseline QOL data. PRS-informed breast cancer prevention counseling has a lasting, but waning, effect over time. Additional follow-up studies are needed to address the effect of PRS on ET adherence, ET-related QOL, supplemental breast cancer screening, and other risk-reducing behaviors., Prevention Relevance: Risk-reducing medications for breast cancer are considerably underused. Informing women at risk with precise and individualized risk assessment tools may substantially affect the incidence of breast cancer. In our study, a risk assessment tool (IBIS-polygenic-risk score) yielded promising results, with 39% of women at highest risk starting preventive medication., (©2023 American Association for Cancer Research.)

Published
2024
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49. Penicillin-binding protein redundancy in Bacillus subtilis enables growth during alkaline shock.

Author

Mitchell SL, Kearns DB, and Carlson EE

Subjects
Penicillin-Binding Proteins, Cell Wall metabolism, Cytoplasm metabolism, Bacillus subtilis metabolism, Bacterial Proteins metabolism
Abstract

Penicillin-binding proteins (PBPs) play critical roles in cell wall construction, cell shape maintenance, and bacterial replication. Bacteria maintain a diversity of PBPs, indicating that despite their apparent functional redundancy, there is differentiation across the PBP family. Apparently-redundant proteins can be important for enabling an organism to cope with environmental stressors. In this study, we evaluated the consequence of environmental pH on PBP enzymatic activity in Bacillus subtilis . Our data show that a subset of PBPs in B. subtilis change activity levels during alkaline shock and that one PBP isoform is rapidly modified to generate a smaller protein (i.e., PBP1a to PBP1b). Our results indicate that a subset of the PBPs are favored for growth under alkaline conditions, while others are readily dispensable. Indeed, we found that this phenomenon could also be observed in Streptococcus pneumoniae , implying that it may be generalizable across additional bacterial species and further emphasizing the evolutionary benefit of maintaining many, seemingly-redundant periplasmic enzymes.IMPORTANCEMicrobes adapt to ever-changing environments and thrive over a vast range of conditions. While bacterial genomes are relatively small, significant portions encode for "redundant" functions. Apparent redundancy is especially pervasive in bacterial proteins that reside outside of the inner membrane. While conditions within the cytoplasm are carefully controlled, those of the periplasmic space are largely determined by the cell's exterior environment. As a result, proteins within this environmentally exposed region must be capable of functioning under a vast array of conditions, and/or there must be several similar proteins that have evolved to function under a variety of conditions. This study examines the activity of a class of enzymes that is essential in cell wall construction to determine if individual proteins might be adapted for activity under particular growth conditions. Our results indicate that a subset of these proteins are preferred for growth under alkaline conditions, while others are readily dispensable., Competing Interests: The authors declare no conflict of interest.

Published
2024
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50. Evaluation of Expanded 2-Aminobenzothiazole Library for Inhibition of Pseudomonas aeruginosa Virulence Phenotypes.

Author

Fihn CA, Lembke HK, Gaulin J, Bouchard P, Villarreal AR, Penningroth MR, Crone KK, Vogt GA, Gilbertsen AJ, Ayotte Y, de Oliveira LC, Serrano-Wu MH, Drouin N, Hung DT, Hunter RC, and Carlson EE

Abstract

Bacterial resistance to antibiotics is a rapidly increasing threat to human health. New strategies to combat resistant organisms are desperately needed. One potential avenue is targeting two-component systems, which are the main bacterial signal transduction pathways used to regulate development, metabolism, virulence, and antibiotic resistance. These systems consist of a homodimeric membrane-bound sensor histidine kinase, and a cognate effector, the response regulator. The high sequence conservation in the catalytic and adenosine triphosphate-binding (CA) domain of histidine kinases and their essential role in bacterial signal transduction could enable broad-spectrum antibacterial activity. Through this signal transduction, histidine kinases regulate multiple virulence mechanisms including toxin production, immune evasion, and antibiotic resistance. Targeting virulence, as opposed to development of bactericidal compounds, could reduce evolutionary pressure for acquired resistance. Additionally, compounds targeting the CA domain have the potential to impair multiple two-component systems that regulate virulence in one or more pathogens. We conducted structure-activity relationship studies of 2-aminobenzothiazole-based inhibitors designed to target the CA domain of histidine kinases. We found these compounds have anti-virulence activities in Pseudomonas aeruginosa , reducing motility phenotypes and toxin production associated with the pathogenic functions of this bacterium.

Published
2024
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