85 results on '"Tan, Sophia"'
Search Results
2. Comparing frequency of booster vaccination to prevent severe COVID-19 by risk group in the United States
- Author
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Park, Hailey J., Gonsalves, Gregg S., Tan, Sophia T., Kelly, J. Daniel, Rutherford, George W., Wachter, Robert M., Schechter, Robert, Paltiel, A. David, and Lo, Nathan C.
- Published
- 2024
- Full Text
- View/download PDF
3. Enabling Open-Ended Questions in Team-Based Learning Using Automated Marking: Impact on Student Achievement, Learning and Engagement
- Author
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Tan, Sophia Huey Shan, Thibault, Guillaume, Chew, Anna Chia Yin, and Rajalingam, Preman
- Abstract
Background: Different types of assessments influence learning and learning behaviour. Multiple-choice questions (MCQs) reward partial knowledge and encourage surface learning, while open-ended questions (OEQs) promote deeper learning. Currently, MCQs is part of team-based learning (TBL) curriculum, and it is challenging to implement OEQs as immediate feedback is necessary. Objectives: We asked if MCQ and OEQs affect student achievement, student learning and student engagement differently in a TBL classroom. Methods: MCQs and OEQs test scores of N = 66 students were automatically captured in Learning Activity Management System (LAMS) and were compared using a switching replications quasi-experimental design with pre- and post-tests to answer the research questions. Student learning approaches and engagement in the team activities were assessed using the study process questionnaire and the structure of observed learning outcomes taxonomy respectively. Results and Conclusions: Students get significantly higher MCQ scores than OEQs for the same set of questions, but the reverse is true for application exercises (AEs), which focus on higher-level application. Most students significantly deepened their learning approaches before OEQs, while poorly prepared students were less engaged during OEQ discussions. Interestingly students subjected to OEQs took less time and scored higher in AE discussions, suggesting better focus on higher-level thinking. Implications: This project is significant as it bridges our understanding of the value of OEQs and TBL. Our approach is transferable to other courses, and thus it can improve the quality of teaching and learning in tertiary education.
- Published
- 2022
- Full Text
- View/download PDF
4. Stress biomarkers and child development in young children in Bangladesh
- Author
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Butzin-Dozier, Zachary, Mertens, Andrew N., Tan, Sophia T., Granger, Douglas A., Pitchik, Helen O., Il'yasova, Dora, Tofail, Fahmida, Rahman, Md. Ziaur, Spasojevic, Ivan, Shalev, Idan, Ali, Shahjahan, Karim, Mohammed Rabiul, Shahriar, Sunny, Famida, Syeda Luthfa, Shuman, Gabrielle, Shoab, Abul K., Akther, Salma, Hossen, Md. Saheen, Mutsuddi, Palash, Rahman, Mahbubur, Unicomb, Leanne, Das, Kishor K., Yan, Liying, Meyer, Ann, Stewart, Christine P., Hubbard, Alan E., Naved, Ruchira Tabassum, Parvin, Kausar, Mamun, Md. Mahfuz Al, Luby, Stephen P., Colford, John M., Jr., Fernald, Lia C.H., and Lin, Audrie
- Published
- 2024
- Full Text
- View/download PDF
5. Stacked binding of a PET ligand to Alzheimer’s tau paired helical filaments
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Merz, Gregory E., Chalkley, Matthew J., Tan, Sophia K., Tse, Eric, Lee, Joanne, Prusiner, Stanley B., Paras, Nick A., DeGrado, William F., and Southworth, Daniel R.
- Published
- 2023
- Full Text
- View/download PDF
6. Infectiousness of SARS-CoV-2 breakthrough infections and reinfections during the Omicron wave
- Author
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Tan, Sophia T., Kwan, Ada T., Rodríguez-Barraquer, Isabel, Singer, Benjamin J., Park, Hailey J., Lewnard, Joseph A., Sears, David, and Lo, Nathan C.
- Published
- 2023
- Full Text
- View/download PDF
7. Micronutrient Status During Pregnancy is Associated with Child Immune Status in Rural Bangladesh
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Jung, Da Kyung, Tan, Sophia T., Hemlock, Caitlin, Mertens, Andrew N., Stewart, Christine P., Rahman, Md Ziaur, Ali, Shahjahan, Raqib, Rubhana, Grembi, Jessica A., Karim, Mohammed Rabiul, Shahriar, Sunny, Roy, Anjan Kumar, Abdelrahman, Sarah, Shoab, Abul K., Famida, Syeda L., Hossen, Md Saheen, Mutsuddi, Palash, Akther, Salma, Rahman, Mahbubur, Unicomb, Leanne, Hester, Lisa, Granger, Douglas A., Erhardt, Juergen, Naved, Ruchira Tabassum, Al Mamun, Md Mahfuz, Parvin, Kausar, Colford, John M., Jr., Fernald, Lia C.H., Luby, Stephen P., Dhabhar, Firdaus S., and Lin, Audrie
- Published
- 2023
- Full Text
- View/download PDF
8. Elucidation of the molecular interactions that enable stable assembly and structural diversity in multicomponent immune receptors
- Author
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Fong, Lam-Kiu, Chalkley, Matthew J., Tan, Sophia K., Grabe, Michael, and DeGrado, William F.
- Published
- 2021
9. Computational Methods for Designing and Probing Intermolecular Interactions
- Author
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Tan, Sophia K
- Subjects
Biophysics ,biomolecular condensate ,de novo protein design ,integrin ,knowledge-based scoring - Abstract
This dissertation presents methods developed for two biological systems. In the first chapter, we describe computational methods for designing a de novo kinase reporter. Our reporter operates as a switch, undergoing a change in oligomeric state in response to kinase activation. We designed the reporter to induce liquid-liquid phase separation upon substrate phosphorylation, making it the first example of a de novo designed protein switch capable of forming biomolecular condensates. In the second chapter, we introduce a simple knowledge-based metric to assess the strengths of residue-residue interactions in a protein complex interface. This structural bioinformatics-based method precludes the need for modeling mutation-induced structural and energetic effects. We tested this method on an integrin interface for which current computational alanine scanning methods were not able to accurately rank hot spot residues according to the degree they destabilize the integrin complex. Encouragingly, we found that our metric could more accurately differentiate the subtle energetics of hot spot residues that regulate integrin interfacial stability. Together, these projects were developed to test the limits of current design methods and discover new design rules for protein binding.
- Published
- 2023
10. What can Venn diagrams teach us about doing data science better?
- Author
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Ho, Sung Yang, Tan, Sophia, Sze, Chun Chau, Wong, Limsoon, and Goh, Wilson Wen Bin
- Published
- 2021
- Full Text
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11. De novo design of peptides that bind specific conformers of α-synuclein.
- Author
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Wallace, Hailey M., Yang, Hyunjun, Tan, Sophia, Pan, Henry S., Yang, Rose, Xu, Junyi, Jo, Hyunil, Condello, Carlo, Polizzi, Nicholas F., and DeGrado, William F.
- Published
- 2024
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12. Transformative pedagogy and visual Literacy: reframing art and design student perspectives on sustainability with illustrated infographics.
- Author
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Winstanley, Lisa, Thompson, Jesse John, and Tan, Sophia Huey Shan
- Subjects
STUDENT attitudes ,DESIGN students ,VISUAL education ,ART students ,VISUAL literacy ,PRAGMATICS - Abstract
This study explores the integration of key Transformative Learning Theory (TLT) principles into design education to foster Visual Literacy (VL) and promote awareness of environmental issues among undergraduate students. Through thematic analysis of 22 illustrated infographics, ideation sketches and supporting textual data created by art and design students, the study examines patterns and insights related to perspective transformation, critical reflection, and visual writing skills. Findings reveal pedagogical efficacy when prompting students to explore counter-narratives to the prevailing negative zeitgeist, resulting in perspective transformation and critical reflection of the design process. In turn, this perspective shift and critical reflection fostered the development of students' abilities to convey complex ideas visually, thus broadening their visual vocabulary to advocate for positive change. Three main categories were considered: Critical Reflection, Perspective Transformation, and Visual Writing Skills, and six sub-categories were identified: Implicit Reflection, Paradigm Shift, Alternative Narratives, Rhetorical Concepts, Intentional Visual-Verbal Communication, and Emotional Visual Language. Implications for scholars include insights into curriculum development and the promotion of ethical and sustainable design practices, while pragmatic applications for faculty offer actionable recommendations for enhancing teaching practices. The study underscores the importance of ethical considerations, diverse perspectives, and real-world applications in nurturing students' growth as innovative, ethical and sustainable designers. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
13. Influence of gender modality on the delivery of breast cancer care from diagnosis to treatment: a systematic review.
- Author
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Ramadan, Retaj, Tan, Sophia, Lowik, A.J., and Isaac, Kathryn V.
- Published
- 2024
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14. De novo design of drug-binding proteins with predictable binding energy and specificity.
- Author
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Lei Lu, Xuxu Gou, Tan, Sophia K., Mann, Samuel I., Hyunjun Yang, Xiaofang Zhong, Gazgalis, Dimitrios, Valdiviezo, Jesús, Hyunil Jo, Yibing Wu, Diolaiti, Morgan E., Ashworth, Alan, Polizzi, Nicholas F., and DeGrado, William F.
- Published
- 2024
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15. Same, same, but different
- Author
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Tan, Sophia, Yin, Ho Yan, Pei, Tan Chin, Lew, Magdeleine, and Sockalingam, Nachamma
- Published
- 2021
16. Predicting the Public Health Impact of Bivalent Vaccines and Nirmatrelvir-Ritonavir Against Coronavirus Disease 2019.
- Author
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Park, Hailey J, Tan, Sophia T, León, Tomás M, Jain, Seema, Schechter, Robert, and Lo, Nathan C
- Subjects
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COVID-19 , *PUBLIC health , *HEALTH policy , *COVID-19 pandemic , *ACUTE diseases , *ORAL vaccines - Abstract
Background Uptake of coronavirus disease 2019 (COVID-19) bivalent vaccines and the oral medication nirmatrelvir-ritonavir (Paxlovid) has remained low across the United States. Assessing the public health impact of increasing uptake of these interventions in key risk groups can guide further public health resources and policy and determine what proportion of severe COVID-19 is avertable with these interventions. Methods This modeling study used person-level data from the California Department of Public Health on COVID-19 cases, hospitalizations, deaths, and vaccine administration from 23 July 2022 to 23 January 2023. We used a quasi-Poisson regression model calibrated to recent historical data to predict future COVID-19 outcomes and modeled the impact of increasing uptake (up to 70% coverage) of bivalent COVID-19 vaccines and nirmatrelvir-ritonavir during acute illness in different risk groups. Risk groups were defined by age (≥50, ≥65, ≥75 years) and vaccination status (everyone, primary series only, previously vaccinated). We predicted the number of averted COVID-19 cases, hospitalizations, and deaths and number needed to treat (NNT). Results The model predicted that increased uptake of bivalent COVID-19 boosters and nirmatrelvir-ritonavir (up to 70% coverage) in all eligible persons could avert an estimated 15.7% (95% uncertainty interval [UI], 11.2%–20.7%; NNT: 17 310) and 23.5% (95% UI, 13.1%–30.0%; NNT: 67) of total COVID-19–related deaths, respectively. In the high-risk group of persons ≥65 years old alone, increased uptake of bivalent boosters and nirmatrelvir-ritonavir could avert an estimated 11.9% (95% UI, 8.4%–15.1%; NNT: 2757) and 22.8% (95% UI, 12.7%–29.2%; NNT: 50) of total COVID-19–related deaths, respectively. Conclusions These findings suggest that prioritizing uptake of bivalent boosters and nirmatrelvir-ritonavir among older age groups (≥65 years) would be most effective (based on NNT) but would not address the entire burden of severe COVID-19. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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17. Are you meeting your disclosure obligations? Regulatory requirements for NSW retirement village operators
- Author
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Tan, Sophia
- Subjects
Disclosure laws -- Interpretation and construction ,Retirement communities -- Laws, regulations and rules ,Nursing homes -- Laws, regulations and rules ,Government regulation ,Business, international ,New South Wales. Retirement Villages Act 1999 - Abstract
The retirement village industry plays an important role in providing for the housing needs of seniors and retirement villages are becoming increasingly popular for their low maintenance lifestyle and ability [...]
- Published
- 2022
18. Singapore's Educational Reforms: The Case for Un-Standardizing Curriculum and Reducing Testing
- Author
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Tan, Sophia HueyShan
- Abstract
Is there validity to the claim that national standardized curriculum and testing will bring about the necessary education reform in the United States? To answer this question, the author has looked at and learned from Singapore, a country that has traditionally excelled and outperformed U.S. students in the international comparative studies. This commentary seeks to address the notion that if we could set high nation-wide standards, it will improve the quality of education that students get, close the achievement gap, and make the U.S. a more competitive player in the 21st century. Through examining the past and present educational reforms in Singapore, this commentary will expose the hidden costs associated with obtaining and sustaining high academic achievement in standardized curriculum and assessment. (Contains 2 tables.)
- Published
- 2010
19. Attenuation of Lipopolysaccharide-Induced Inflammatory Responses through Inhibition of the NF-κB Pathway and the Increased NRF2 Level by a Flavonol-Enriched n‑Butanol Fraction from Uvaria alba.
- Author
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Notarte, Kin Israel R., Quimque, Mark Tristan J., Macaranas, Imee T., Khan, Abbas, Pastrana, Adriel M., Villaflores, Oliver B., Arturo, Hans Christian P., Pilapil IV, Delfin Yñigo H., Tan, Sophia Morgan M., Wei, Dong-Qing, Wenzel-Storjohann, Arlette, Tasdemir, Deniz, Yen, Chia-Hung, Ji, Seon Yeong, Kim, Gi-Young, Choi, Yung Hyun, and Macabeo, Allan Patrick G.
- Published
- 2023
- Full Text
- View/download PDF
20. Teaching and Learning: Whose Computer Is It? December/January E-Mail.
- Author
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Zhao, Yong, Hueyshan Tan, Sophia, and Mishra, Punya
- Abstract
Notes that teachers see the computer as a tool to help them teach better, while students use computers to play games, chat, and design Web sites. Describes the after-school program Kids Learning In Computer Klubhouses (KLICK!) that operates clubhouses within local middle schools. Discusses what participants have accomplished for themselves, their teachers, their schools, and for their community. (RS)
- Published
- 2001
21. From Concept to Software: Developing a Framework for Understanding the Process of Software Design.
- Author
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Mishra, Punyashloke, Zhao, Yong, and Tan, Sophia
- Abstract
Discussion of technological innovation and the process of design focuses on the design of computer software. Offers a framework for understanding the design process by examining two computer programs: FliPS, a multimedia program for learning complex problems in chemistry; and Tiger, a Web-based program for managing and publishing electronic manuscripts. (Author/LRW)
- Published
- 1999
22. Enabling open‐ended questions in team‐based learning using automated marking: Impact on student achievement, learning and engagement.
- Author
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Tan, Sophia Huey Shan, Thibault, Guillaume, Chew, Anna Chia Yin, and Rajalingam, Preman
- Subjects
- *
ACADEMIC achievement evaluation , *ACADEMIC medical centers , *RESEARCH methodology , *CLASSIFICATION , *ARTIFICIAL intelligence , *INTERVIEWING , *LEARNING strategies , *SOFTWARE architecture , *COMPARATIVE studies , *CRONBACH'S alpha , *T-test (Statistics) , *AUTOMATION , *STUDENTS , *QUESTIONNAIRES , *DESCRIPTIVE statistics , *SCALE analysis (Psychology) , *REPLICATION (Experimental design) , *SOUND recordings , *RESEARCH funding - Abstract
Background: Different types of assessments influence learning and learning behaviour. Multiple‐choice questions (MCQs) reward partial knowledge and encourage surface learning, while open‐ended questions (OEQs) promote deeper learning. Currently, MCQs is part of team‐based learning (TBL) curriculum, and it is challenging to implement OEQs as immediate feedback is necessary. Objectives: We asked if MCQ and OEQs affect student achievement, student learning and student engagement differently in a TBL classroom. Methods: MCQs and OEQs test scores of N = 66 students were automatically captured in Learning Activity Management System (LAMS) and were compared using a switching replications quasi‐experimental design with pre‐ and post‐tests to answer the research questions. Student learning approaches and engagement in the team activities were assessed using the study process questionnaire and the structure of observed learning outcomes taxonomy respectively. Results and Conclusions: Students get significantly higher MCQ scores than OEQs for the same set of questions, but the reverse is true for application exercises (AEs), which focus on higher‐level application. Most students significantly deepened their learning approaches before OEQs, while poorly prepared students were less engaged during OEQ discussions. Interestingly students subjected to OEQs took less time and scored higher in AE discussions, suggesting better focus on higher‐level thinking. Implications: This project is significant as it bridges our understanding of the value of OEQs and TBL. Our approach is transferable to other courses, and thus it can improve the quality of teaching and learning in tertiary education. Lay Description: What is already known about this topic?: Multiple‐choice questions (MCQs) do not promote deep learning as much as open‐ended questions (OEQ) do.Team‐based learning (TBL) requires MCQs because of the need for immediate feedback.Automated marking can make it more efficient to provide immediate feedback on OEQs as required by the TBL approach. What this paper adds?: OEQs changed student‐learning approaches in the TBL context.OEQs changed the quality of team discussions during the team‐readiness assessment.Test (tRAT) and application exercise phases.Students were concerned about the validity of automated grading. Implications for practitioners: Consider using OEQs in TBL context for deepening student learning.Consider how to defuse students' scepticism of new technology.Consider forming teams with a mix of deep and surface learners. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
23. Teaching and Learning: Whose Computer Is It?
- Author
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Zhao, Yong, Tan, Sophia Hueyshan, and Mishra, Punya
- Published
- 2000
24. COVID-19 Vaccination and Estimated Public Health Impact in California.
- Author
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Tan, Sophia T., Park, Hailey J., Rodríguez-Barraque, Isabel, Rutherford, George W., Bibbins-Domingo, Kirsten, Schechter, Robert, and Lo, Nathan C.
- Published
- 2022
- Full Text
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25. Telomere length is associated with growth in children in rural Bangladesh.
- Author
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Lin, Audrie, Mertens, Andrew N., Arnold, Benjamin F., Tan, Sophia, Jue Lin, Stewart, Christine P., Hubbard, Alan E., Ali, Shahjahan, Benjamin-Chung, Jade, Shoab, Abul K., Rahman, Md Ziaur, Famida, Syeda L., Hossen, Md Saheen, Mutsuddi, Palash, Akther, Salma, Rahman, Mahbubur, Unicomb, Leanne, Naved, Ruchira Tabassum, Al Mamun, Md Mahfuz, and Parvin, Kausar
- Published
- 2021
- Full Text
- View/download PDF
26. Elucidation of the molecular interactions that enable stable assembly and structural diversity in multicomponent immune receptors.
- Author
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Lam-Kiu Fong, Chalkley, Matthew J., Tan, Sophia K., Grabe, Michael, and DeGrado, William F.
- Subjects
MOLECULAR interactions ,DENSITY functional theory ,SOCIAL interaction ,PROTON transfer reactions - Abstract
Multicomponent immune receptors are essential complexes in which distinct ligand-recognition and signaling subunits are held together by interactions between acidic and basic residues of their transmembrane helices. A 2:1 acidic-to-basic motif in the transmembrane domains of the subunits is necessary and sufficient to assemble these receptor complexes. Here, we study a prototype for these receptors, a DAP12-NKG2C 2:1 heterotrimeric complex, in which the two DAP12 subunits each contribute a single transmembrane Asp residue, and the NKG2C subunit contributes a Lys to form the complex. DAP12 can also associate with 20 other subunits using a similar motif. Here, we use molecular-dynamics simulations to understand the basis for the high affinity and diversity of interactions in this group of receptors. Simulations of the transmembrane helices with differing protonation states of the Asp-Asp-Lys triad identified a structurally stable interaction in which a singly-protonated Asp-Asp pair forms a hydrogen-bonded carboxyl-carboxylate clamp that clasps onto a charged Lys side chain. This polar motif was also supported by density functional theory and a Protein Data Bank-wide search. In contrast, the helices are dynamic at sites distal to the stable carboxyl-carboxylate clamp motif. Such a locally stable but globally dynamic structure is well suited to accommodate the sequence and structural variations in the transmembrane helices of multicomponent receptors, which mix and match subunits to create combinatorial functional diversity from a limited number of subunits. It also supports a signaling mechanism based on multisubunit clustering rather than propagation of rigid conformational changes through the membrane. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
27. Acyl Transfer Catalytic Activity in De Novo Designed Protein with N‑Terminus of α‑Helix As Oxyanion-Binding Site.
- Author
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Naudin, Elise A., McEwen, Alastair G., Tan, Sophia K., Poussin-Courmontagne, Pierre, Schmitt, Jean-Louis, Birck, Catherine, DeGrado, William F., and Torbeev, Vladimir
- Published
- 2021
- Full Text
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28. Smorgasburg is Brooklyn's food fest you never knew you needed
- Author
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Tan, Sophia
- Subjects
News, opinion and commentary ,Sports and fitness - Abstract
Byline: Sophia Tan New York's hippest and most photogenic weekly food festival, Smorgasburg, is the place to be on your weekend adventures into town. If you're looking to try out [...]
- Published
- 2017
29. Modulating Integrin αIIbβ3 Activity through Mutagenesis of Allosterically Regulated Intersubunit Contacts.
- Author
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Tan, Sophia K., Fong, Karen P., Polizzi, Nicholas F., Sternisha, Alex, Slusky, Joanna S. G., Yoon, Kyungchul, DeGrado, William F., and Bennett, Joel S.
- Published
- 2019
- Full Text
- View/download PDF
30. Use of Big Data and Information and Communications Technology in Disasters: An Integrative Review.
- Author
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Freeman, Jeffrey D., Blacker, Brigette, Hatt, Grace, Tan, Sophia, Ratcliff, Jeremy, Woolf, Thomas B., Tower, Craig, and Barnett, Daniel J.
- Published
- 2019
- Full Text
- View/download PDF
31. Computation-Guided Design of a Stimulus-Responsive Multienzyme Supramolecular Assembly.
- Author
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Yang, Lu, Dolan, Elliott M., Tan, Sophia K., Lin, Tianyun, Sontag, Eduardo D., and Khare, Sagar D.
- Published
- 2017
- Full Text
- View/download PDF
32. The effect of nasal irrigation formulation on the antimicrobial activity of nasal secretions.
- Author
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Woods, Charmaine M., Tan, Sophia, Ullah, Shahid, Frauenfelder, Claire, Ooi, Eng H., and Carney, A. Simon
- Subjects
- *
NASAL irrigation , *EXCIPIENTS , *ANTI-infective agents , *PARANASAL sinus diseases , *SECRETION - Abstract
Background: Saline-based irrigation solutions are evidence-based rhinological treatments; however, the formulation of these solutions could theoretically alter the function of innate antimicrobial peptides. The aim of this study was to determine if the antimicrobial activity of normal human nasal secretions in vivo is altered by commercially available large volume irrigation solutions. Methods: Minimally manipulated sinonasal secretionswere collected from patients with chronic rhinosinusitis (CRS; n = 10) and normal healthy volunteers (n = 20). In a subset of control patients (n = 10) secretions were collected prior to, and at 1 hour, 6 hours, and 24 hours after nasal irrigation with 4 commercial irrigation solutions. Lysozyme and lactoferrin levels were analyzed and the antimicrobial activity of secretions determined using a radial diffusion assay. Results: The antimicrobial activity of nasal secretions was reduced in CRS patients compared to healthy volunteers (p < 0.01), but there was no significant difference in antimicrobial peptide concentrations. Isotonic nasal irrigation reduced lysozyme and lactoferrin levels, which returned to baseline levels by 6 hours; in addition to a sustained decrease in antimicrobial activity before returning to baseline at 24 hours. Low-salt solution stimulated peptide secretion by approximately 40% at 6 hours and 24 hours, but produced a transient decrease in antimicrobial activity, returning to baseline levels by 6 hours. Hypertonic solution initially decreased lysozyme and lactoferrin levels but maintained baseline levels of antimicrobial activity and increased peptide secretion by approximately 30% at 24 hours. Conclusion: The formulation of nasal irrigation solutions significantly affects the measured levels and functionality of sinonasal antimicrobial peptides. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
33. Virtual Combinatorial Library Screening of Quinadoline B Derivatives against SARS-CoV-2 RNA-Dependent RNA Polymerase.
- Author
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Brogi, Simone, Quimque, Mark Tristan, Notarte, Kin Israel, Africa, Jeremiah Gabriel, Hernandez, Jenina Beatriz, Tan, Sophia Morgan, Calderone, Vincenzo, and Macabeo, Allan Patrick
- Subjects
RNA replicase ,DIGITAL libraries ,SARS-CoV-2 ,MOLECULAR dynamics ,CHEMICAL libraries - Abstract
The unprecedented global health threat of SARS-CoV-2 has sparked a continued interest in discovering novel anti-COVID-19 agents. To this end, we present here a computer-based protocol for identifying potential compounds targeting RNA-dependent RNA polymerase (RdRp). Starting from our previous study wherein, using a virtual screening campaign, we identified a fumiquinazolinone alkaloid quinadoline B (Q3), an antiviral fungal metabolite with significant activity against SARS-CoV-2 RdRp, we applied in silico combinatorial methodologies for generating and screening a library of anti-SARS-CoV-2 candidates with strong in silico affinity for RdRp. For this study, the quinadoline pharmacophore was subjected to structural iteration, obtaining a Q3-focused library of over 900,000 unique structures. This chemical library was explored to identify binders of RdRp with greater affinity with respect to the starting compound Q3. Coupling this approach with the evaluation of physchem profile, we found 26 compounds with significant affinities for the RdRp binding site. Moreover, top-ranked compounds were submitted to molecular dynamics to evaluate the stability of the systems during a selected time, and to deeply investigate the binding mode of the most promising derivatives. Among the generated structures, five compounds, obtained by inserting nucleotide-like scaffolds (1, 2, and 5), heterocyclic thiazolyl benzamide moiety (compound 3), and a peptide residue (compound 4), exhibited enhanced binding affinity for SARS-CoV-2 RdRp, deserving further investigation as possible antiviral agents. Remarkably, the presented in silico procedure provides a useful computational procedure for hit-to-lead optimization, having implications in anti-SARS-CoV-2 drug discovery and in general in the drug optimization process. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
34. Simulation for a Shingled Magnetic Recording Disk.
- Author
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Tan, Sophia, Xi, Weiya, Ching, Zhi Yong, Jin, Chao, and Lim, Chun Teck
- Subjects
- *
SIMULATION methods & models , *MAGNETIC recording media , *INFORMATION technology , *DATA analysis , *INFORMATION resources management , *DATA mapping - Abstract
Shingled magnetic recording (SMR) is a new technology based on partially overlapping, or shingling, adjacent tracks, which is capable of increasing the density of a disk drive up to 10 \Tbit/in^2. To write data on overlapping tracks may erase data being written previously. Therefore, without any data translation layer to redirect updates to different locations to avoid unintended data erasures, the SMR disk cannot be used as a conventional disk to perform unrestricted reads/writes directly. Various data translation/mapping strategies have been proposed to allow the disk to perform unrestricted reads/writes. However, these strategies have tradeoffs in terms of system performance and cost, such as disk space utilization. Nevertheless, system performance varies for different applications and under different workload conditions. [ABSTRACT FROM PUBLISHER]
- Published
- 2013
- Full Text
- View/download PDF
35. Serological responses following influenza A H1N1 2009 infection in adults.
- Author
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Tan, Sophia, Gordon, David L., Honda-Okubo, Yoshikazu, Petrovsky, Nikolai, Phillips, Peter, Huddleston, Sandra, and Sadlon, Tania A.
- Subjects
SEROLOGY ,H1N1 influenza ,IMMUNE response ,BLOOD agglutination ,SEASONAL influenza ,VIRAL variation ,IMMUNOGLOBULINS - Abstract
Objective: The aim of this study was to determine the humoral immune response to influenza A H1N1 2009 and cross reactivity against seasonal H1N1 and H3N2 strains.Methods: Baseline and convalescent sera from 88 subjects with confirmed H1N1 2009 were screened for serological responses by HAI assay.Results: Protective antibody titres to H1N1 2009 were present in 87% post-infection, but varied with age, sex and pregnancy. Some cross reactivity with seasonal influenza strains was observed.Conclusions: Females and pregnant subjects had an attenuated immune response to H1N1 2009 in comparison to the rest of the study population. Antibodies from the serum of H1N1 2009 infected subjects cross reacted with seasonal H1N1 and H3N2 influenza viruses. [ABSTRACT FROM AUTHOR]- Published
- 2011
- Full Text
- View/download PDF
36. TECHNOLOGY.
- Author
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Zhao, Yong, Hueyshan Tan, Sophia, and Mishra, Punya
- Subjects
- *
COMPUTERS & children , *EDUCATION , *EDUCATIONAL technology , *COMPUTER assisted instruction - Abstract
Discusses the different approaches that teachers and students apply when using the computer. Cautious attitude of teachers when letting students use the computer; Disadvantages of making the computer a machine for the teacher; Goal of educational technology; Description of the Kids Learning In Computer Klubhouses after-school program for the middle school students.
- Published
- 2000
37. Macrolide, lincosamide and streptogramin resistance in E faecium
- Author
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Australian Society for Antimicrobials Conference, Barton, Mary Darvall, Peng, Hai Hong, and Tan,Sophia
- Published
- 2004
38. Streptogramin resistance in Enterococcus faecium isolates from chickens, pigs, humans and sewage
- Author
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Sydney 2004-09-26, Barton, Mary Darvall, Kutek, Lynda Anne, and Tan,Sophia
- Subjects
chickens ,pigs ,sewage ,Streptogramin resistance ,humans ,enterococcus faecium - Published
- 2004
39. SuFEx Chemistry Enables Covalent Assembly of a 280-kDa 18-Subunit Pore-Forming Complex.
- Author
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Schnaider L, Tan S, Singh PR, Capuano F, Scott AJ, Hambley R, Lu L, Yang H, Wallace EJ, Jo H, and DeGrado WF
- Abstract
Proximity-enhanced chemical cross-linking is an invaluable tool for probing protein-protein interactions and enhancing the potency of potential peptide and protein drugs. Here, we extend this approach to covalently stabilize large macromolecular assemblies. We used SuFEx chemistry to covalently stabilize an 18-subunit pore-forming complex, CsgG:CsgF, consisting of nine CsgG membrane protein subunits that noncovalently associate with nine CsgF peptides. Derivatives of the CsgG:CsgF pore have been used for DNA sequencing, which places high demands on the structural stability and homogeneity of the complex. To increase the robustness of the pore, we designed and synthesized derivatives of CsgF-bearing sulfonyl fluorides, which react with CsgG in very high yield to form a covalently stabilized CsgG:CsgF complex. The resulting pores formed highly homogeneous channels when added to artificial membranes. The high yield and rapid reaction rate of the SuFEx reaction prompted molecular dynamics simulations, which revealed that the SO
2 F groups in the initially formed complex are poised for nucleophilic reaction with a targeted Tyr. These results demonstrate the utility of SuFEx chemistry to structurally stabilize very large (here, 280 kDa) assemblies.- Published
- 2024
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40. Dynamics of indirect protection against SARS-CoV-2 infection through vaccine and infection-acquired immunity.
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Tan ST, Rodríguez-Barraquer I, Kwan AT, Blumberg S, Hutchinson J, Leidner D, Lewnard JA, Sears D, and Lo NC
- Abstract
Early investigation revealed that COVID-19 vaccines confer indirect protection to fully susceptible and unvaccinated persons, defined as a reduced risk of SARS-CoV-2 infection among social contacts of vaccinated individuals. However, indirect protection from infection-acquired immunity and its comparative strength and durability to vaccine-derived indirect protection in the current epidemiologic context of high levels of vaccination, prior infection, and novel variants are not well characterized. Here, we show that both infection-acquired and vaccine-derived immunity independently yield indirect protection to close social contacts with key differences in their strength and waning. Analyzing anonymized data from a system-wide SARS-CoV-2 surveillance program of 177,319 residents across 35 California state prisons from December 2021 to December 2022, we find that vaccine-derived indirect protection against Omicron SARS-CoV-2 infection is strongest within three months post-vaccination [30% (95% confidence interval: 20-38%)], whereas infection-acquired immunity provides 39% (25-51%) indirect protection to roommates for 6 months after SARS-CoV-2 infection, with moderate indirect protection persisting for over one year. Variant-targeted vaccines (bivalent formulation including Omicron subvariants BA.4/BA.5) confer strong indirect protection for at least three months [51% (18-70%)]. These results have important implications for understanding the long-term transmission dynamics of SARS-CoV-2 and can guide vaccine policy and public health measures, especially in high-risk environments such as prisons.
- Published
- 2024
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- View/download PDF
41. Optimization of a Novel DEL Hit That Binds in the Cbl-b SH2 Domain and Blocks Substrate Binding.
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Liang J, Lambrecht MJ, Arenzana TL, Aubert-Nicol S, Bao L, Broccatelli F, Cai J, Eidenschenk C, Everett C, Garner T, Gruber F, Haghshenas P, Huestis MP, Hsu PL, Kou P, Jakalian A, Larouche-Gauthier R, Leclerc JP, Leung DH, Martin A, Murray J, Prangley M, Rutz S, Kakiuchi-Kiyota S, Satz AL, Skelton NJ, Steffek M, Stoffler D, Sudhamsu J, Tan S, Wang J, Wang S, Wang Q, Wendorff TJ, Wichert M, Yadav A, Yu C, and Wang X
- Abstract
We were attracted to the therapeutic potential of inhibiting Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), a RING E3 ligase that plays a critical role in regulating the activation of T cells. However, given that only protein-protein interactions were involved, it was unclear whether inhibition by a small molecule would be a viable approach. After screening an ∼6 billion member DNA-encoded library (DEL) using activated Cbl-b, we identified compound 1 as a hit for which the cis -isomer ( 2 ) was confirmed by biochemical and surface plasmon resonance (SPR) assays. Our hit optimization effort was greatly accelerated when we obtained a cocrystal structure of 2 with Cbl-b, which demonstrated induced binding at the substrate binding site, namely, the Src homology-2 (SH2) domain. This was quite noteworthy given that there are few reports of small molecule inhibitors that bind to SH2 domains and block protein-protein interactions. Structure- and property-guided optimization led to compound 27 , which demonstrated measurable cell activity, albeit only at high concentrations., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)
- Published
- 2024
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42. De novo design of drug-binding proteins with predictable binding energy and specificity.
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Lu L, Gou X, Tan SK, Mann SI, Yang H, Zhong X, Gazgalis D, Valdiviezo J, Jo H, Wu Y, Diolaiti ME, Ashworth A, Polizzi NF, and DeGrado WF
- Subjects
- Humans, Binding Sites, Ligands, Molecular Dynamics Simulation, Protein Binding, Poly(ADP-ribose) Polymerase Inhibitors chemistry, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Proteins chemistry, Proteins genetics, Protein Engineering methods, Pharmacophore
- Abstract
The de novo design of small molecule-binding proteins has seen exciting recent progress; however, high-affinity binding and tunable specificity typically require laborious screening and optimization after computational design. We developed a computational procedure to design a protein that recognizes a common pharmacophore in a series of poly(ADP-ribose) polymerase-1 inhibitors. One of three designed proteins bound different inhibitors with affinities ranging from <5 nM to low micromolar. X-ray crystal structures confirmed the accuracy of the designed protein-drug interactions. Molecular dynamics simulations informed the role of water in binding. Binding free energy calculations performed directly on the designed models were in excellent agreement with the experimentally measured affinities. We conclude that de novo design of high-affinity small molecule-binding proteins with tuned interaction energies is feasible entirely from computation.
- Published
- 2024
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43. De novo design of drug-binding proteins with predictable binding energy and specificity.
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Lu L, Gou X, Tan SK, Mann SI, Yang H, Zhong X, Gazgalis D, Valdiviezo J, Jo H, Wu Y, Diolaiti ME, Ashworth A, Polizzi NF, and DeGrado WF
- Abstract
The de novo design of small-molecule-binding proteins has seen exciting recent progress; however, the ability to achieve exquisite affinity for binding small molecules while tuning specificity has not yet been demonstrated directly from computation. Here, we develop a computational procedure that results in the highest affinity binders to date with predetermined relative affinities, targeting a series of PARP1 inhibitors. Two of four designed proteins bound with affinities ranging from < 5 nM to low μM, in a predictable manner. X-ray crystal structures confirmed the accuracy of the designed protein-drug interactions. Molecular dynamics simulations informed the role of water in binding. Binding free-energy calculations performed directly on the designed models are in excellent agreement with the experimentally measured affinities, suggesting that the de novo design of small-molecule-binding proteins with tuned interaction energies is now feasible entirely from computation. We expect these methods to open many opportunities in biomedicine, including rapid sensor development, antidote design, and drug delivery vehicles., Competing Interests: Competing financial interests A.A. is a co-founder of Tango Therapeutics, Azkarra Therapeutics, Ovibio Corporation and Kytarro, a member of the board of Cytomx and Cambridge Science Corporation, a member of the scientific advisory board of Genentech, GLAdiator, Circle, Bluestar, Earli, Ambagon, Phoenix Molecular Designs, Yingli, ProRavel, Oric, Hap10 and Trial Library, a consultant for SPARC, ProLynx, Novartis and GSK, receives research support from SPARC, and holds patents on the use of PARP inhibitors held jointly with AstraZeneca from which he has benefited financially (and may do so in the future).
- Published
- 2023
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44. De novo Design of Peptides that Bind Specific Conformers of α-Synuclein.
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Wallace HM, Yang H, Tan S, Pan HS, Yang R, Xu J, Jo H, Condello C, Polizzi NF, and DeGrado WF
- Abstract
Insoluble amyloids rich in cross-β fibrils are observed in a number of neurodegenerative diseases. Depending on the clinicopathology, the amyloids can adopt distinct supramolecular assemblies, termed conformational strains. However, rapid methods to study amyloid in a conformationally specific manner are lacking. We introduce a novel computational method for de novo design of peptides that tile the surface of α-synuclein fibrils in a conformationally specific manner. Our method begins by identifying surfaces that are unique to the conformational strain of interest, which becomes a "target backbone" for the design of a peptide binder. Next, we interrogate structures in the PDB database with high geometric complementarity to the target. Then, we identify secondary structural motifs that interact with this target backbone in a favorable, highly occurring geometry. This method produces monomeric helical motifs with a favorable geometry for interaction with the strands of the underlying amyloid. Each motif is then symmetrically replicated to form a monolayer that tiles the amyloid surface. Finally, amino acid sequences of the peptide binders are computed to provide a sequence with high geometric and physicochemical complementarity to the target amyloid. This method was applied to a conformational strain of α-synuclein fibrils, resulting in a peptide with high specificity for the target relative to other amyloids formed by α-synuclein, tau, or Aβ40. This designed peptide also markedly slowed the formation of α-synuclein amyloids. Overall, this method offers a new tool for examining conformational strains of amyloid proteins.
- Published
- 2023
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45. Stress Biomarkers and Child Development in Young Children in Bangladesh.
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Butzin-Dozier Z, Mertens AN, Tan ST, Granger DA, Pitchik HO, Il'yasova D, Tofail F, Rahman MZ, Spasojevic I, Shalev I, Ali S, Karim MR, Shahriar S, Famida SL, Shuman G, Shoab AK, Akther S, Hossen MS, Mutsuddi P, Rahman M, Unicomb L, Das KK, Yan L, Meyer A, Stewart CP, Hubbard A, Tabassum Naved R, Parvin K, Mamun MMA, Luby SP, Colford JM Jr, Fernald LCH, and Lin A
- Abstract
Background: Hundreds of millions of children in low- and middle-income countries are exposed to chronic stressors, such as poverty, poor sanitation and hygiene, and sub-optimal nutrition. These stressors can have physiological consequences for children and may ultimately have detrimental effects on child development. This study explores associations between biological measures of chronic stress in early life and developmental outcomes in a large cohort of young children living in rural Bangladesh., Methods: We assessed physiologic measures of stress in the first two years of life using measures of the hypothalamic-pituitary-adrenal (HPA) axis (salivary cortisol and glucocorticoid receptor gene methylation), the sympathetic-adrenal-medullary (SAM) system (salivary alpha-amylase, heart rate, and blood pressure), and oxidative status (F2-isoprostanes). We assessed child development in the first two years of life with the MacArthur-Bates Communicative Development Inventories (CDI), the WHO gross motor milestones, and the Extended Ages and Stages Questionnaire (EASQ). We compared development outcomes of children at the 75th and 25th percentiles of stress biomarker distributions while adjusting for potential confounders (hereafter referred to as contrasts) using generalized additive models, which are statistical models where the outcome is predicted by a potentially non-linear function of predictor variables., Results: We analyzed data from 684 children (49% female) at both 14 and 28 months of age; we included an additional 765 children at 28 months of age. We observed 135 primary contrasts of the differences in child development outcomes at the 75
th and 25th percentiles of stress biomarkers, where we detected significant relationships in 5 out of 30 contrasts (17%) of HPA axis activity, 1 out of 30 contrasts (3%) of SAM activity, and 3 out of 75 contrasts (4%) of oxidative status. These findings revealed that measures of HPA axis activity were associated with poor development outcomes. We did not find consistent evidence that markers of SAM system activity or oxidative status were associated with developmental status., Conclusions: Our observations reveal associations between the physiological evidence of stress in the HPA axis with developmental status in early childhood. These findings add to the existing evidence exploring the developmental consequences of early life stress.- Published
- 2023
- Full Text
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46. Predicting the public health impact of bivalent vaccines and nirmatrelvir-ritonavir against COVID-19.
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Park HJ, Tan ST, León TM, Jain S, Schechter R, and Lo NC
- Abstract
Background: Uptake of COVID-19 bivalent vaccines and oral medication nirmatrelvir-ritonavir (Paxlovid) has remained low across the United States. Assessing the public health impact of increasing uptake of these interventions in key risk groups can guide further public health resources and policy., Methods: This modeling study used person-level data from the California Department of Public Health on COVID-19 cases, hospitalizations, deaths, and vaccine administration from July 23, 2022 to January 23, 2023. We modeled the impact of additional uptake of bivalent COVID-19 vaccines and nirmatrelvir-ritonavir during acute illness in different risk groups defined by age (50+, 65+, 75+ years) and vaccination status (everyone, primary series only, previously vaccinated). We predicted the number of averted COVID-19 cases, hospitalizations, and deaths and number needed to treat (NNT)., Results: For both bivalent vaccines and nirmatrelvir-ritonavir, the most efficient strategy (based on NNT) for averting severe COVID-19 was targeting the 75+ years group. We predicted that perfect coverage of bivalent boosters in the 75+ years group would avert 3,920 hospitalizations (95%UI: 2,491-4,882; 7.8% total averted; NNT 387) and 1,074 deaths (95%UI: 774-1,355; 16.2% total averted; NNT 1,410). Perfect uptake of nirmatrelvir-ritonavir in the 75+ years group would avert 5,644 hospitalizations (95%UI: 3,947-6,826; 11.2% total averted; NNT 11) and 1,669 deaths (95%UI: 1,053-2,038; 25.2% total averted; NNT 35)., Conclusions: These findings suggest prioritizing uptake of bivalent boosters and nirmatrelvir-ritonavir among the oldest age groups would be efficient and have substantial public health impact in reducing the burden of severe COVID-19, but would not address the entire burden of severe COVID-19.
- Published
- 2023
- Full Text
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47. Polyphenolic Natural Products Active In Silico Against SARS-CoV-2 Spike Receptor Binding Domains and Non-structural Proteins - A Review.
- Author
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Quimque MT, Notarte KI, Adviento XA, Cabunoc MH, de Leon VN, Delos Reyes FSL, Lugtu EJ, Manzano JA, Monton SN, Muñoz JE, Ong KD, Pilapil DY, Roque V, Tan SM, Lim JA, and Macabeo AP
- Subjects
- Humans, SARS-CoV-2, Spike Glycoprotein, Coronavirus, COVID-19, Biological Products
- Abstract
The ongoing Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has been proven to be more severe than the previous coronavirus outbreaks due to the virus' high transmissibility. With the emergence of new variants, this global phenomenon took a more dramatic turn, with many countries recently experiencing higher surges of confirmed cases and deaths. On top of this, the inadequacy of effective treatment options for COVID-19 aggravated the problem. As a way to address the unavailability of target-specific viral therapeutics, computational strategies have been employed to hasten and systematize the search. The objective of this review is to provide initial data highlighting the utility of polyphenols as potential prophylaxis or treatment for COVID-19. In particular, presented here are virtually screened polyphenolic compounds which showed potential as either antagonists to viral entry and host cell recognition through binding with various receptor-binding regions of SARS-CoV-2 spike protein or as inhibitors of viral replication and post-translational modifications through binding with essential SARS-CoV-2 non-structural proteins., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2023
- Full Text
- View/download PDF
48. Infectiousness of SARS-CoV-2 breakthrough infections and reinfections during the Omicron wave.
- Author
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Tan ST, Kwan AT, Rodríguez-Barraquer I, Singer BJ, Park HJ, Lewnard JA, Sears D, and Lo NC
- Abstract
SARS-CoV-2 breakthrough infections in vaccinated individuals and reinfections among previously infected individuals have become increasingly common. Such infections highlight a broader need to understand the contribution of vaccination, including booster doses, and natural immunity to the infectiousness of persons with SARS-CoV-2 infections, especially in high-risk populations with intense transmission such as prisons. Here, we show that both vaccine-derived and naturally acquired immunity independently reduce the infectiousness of persons with Omicron variant SARS-CoV-2 infections in a prison setting. Analyzing SARS-CoV-2 surveillance data from December 2021 to May 2022 across 35 California state prisons with a predominately male population, we estimate that unvaccinated Omicron cases had a 36% (95% confidence interval (CI): 31-42%) risk of transmitting infection to close contacts, as compared to 28% (25-31%) risk among vaccinated cases. In adjusted analyses, we estimated that any vaccination, prior infection alone, and both vaccination and prior infection reduced an index case's risk of transmitting infection by 22% (6-36%), 23% (3-39%) and 40% (20-55%), respectively. Receipt of booster doses and more recent vaccination further reduced infectiousness among vaccinated cases. These findings suggest that although vaccinated and/or previously infected individuals remain highly infectious upon SARS-CoV-2 infection in this prison setting, their infectiousness is reduced compared to individuals without any history of vaccination or infection, underscoring some benefit of vaccination to reduce but not eliminate transmission.
- Published
- 2022
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49. Extending chemical perturbations of the ubiquitin fitness landscape in a classroom setting reveals new constraints on sequence tolerance.
- Author
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Mavor D, Barlow KA, Asarnow D, Birman Y, Britain D, Chen W, Green EM, Kenner LR, Mensa B, Morinishi LS, Nelson CA, Poss EM, Suresh P, Tian R, Arhar T, Ary BE, Bauer DP, Bergman ID, Brunetti RM, Chio CM, Dai SA, Dickinson MS, Elledge SK, Helsell CVM, Hendel NL, Kang E, Kern N, Khoroshkin MS, Kirkemo LL, Lewis GR, Lou K, Marin WM, Maxwell AM, McTigue PF, Myers-Turnbull D, Nagy TL, Natale AM, Oltion K, Pourmal S, Reder GK, Rettko NJ, Rohweder PJ, Schwarz DMC, Tan SK, Thomas PV, Tibble RW, Town JP, Tsai MK, Ugur FS, Wassarman DR, Wolff AM, Wu TS, Bogdanoff D, Li J, Thorn KS, O'Conchúir S, Swaney DL, Chow ED, Madhani HD, Redding S, Bolon DN, Kortemme T, DeRisi JL, Kampmann M, and Fraser JS
- Abstract
Although the primary protein sequence of ubiquitin (Ub) is extremely stable over evolutionary time, it is highly tolerant to mutation during selection experiments performed in the laboratory. We have proposed that this discrepancy results from the difference between fitness under laboratory culture conditions and the selective pressures in changing environments over evolutionary timescales. Building on our previous work (Mavor et al., 2016), we used deep mutational scanning to determine how twelve new chemicals (3-Amino-1,2,4-triazole, 5-fluorocytosine, Amphotericin B, CaCl
2 , Cerulenin, Cobalt Acetate, Menadione, Nickel Chloride, p-Fluorophenylalanine, Rapamycin, Tamoxifen, and Tunicamycin) reveal novel mutational sensitivities of ubiquitin residues. Collectively, our experiments have identified eight new sensitizing conditions for Lys63 and uncovered a sensitizing condition for every position in Ub except Ser57 and Gln62. By determining the ubiquitin fitness landscape under different chemical constraints, our work helps to resolve the inconsistencies between deep mutational scanning experiments and sequence conservation over evolutionary timescales., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)- Published
- 2018
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50. Modulation of cancer cell survival pathways using multivalent liposomal therapeutic antibody constructs.
- Author
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Chiu GN, Edwards LA, Kapanen AI, Malinen MM, Dragowska WH, Warburton C, Chikh GG, Fang KY, Tan S, Sy J, Tucker C, Waterhouse DN, Klasa R, and Bally MB
- Subjects
- Animals, Antibodies, Monoclonal, Humanized, Antibodies, Monoclonal, Murine-Derived, Antibodies, Neoplasm, Antigens, CD20 immunology, Antigens, Neoplasm immunology, Blotting, Western, Breast Neoplasms immunology, Breast Neoplasms pathology, Cell Survival, DNA-Binding Proteins genetics, DNA-Binding Proteins physiology, Down-Regulation, Female, Flow Cytometry, Genes, erbB-2 genetics, Genes, erbB-2 immunology, Humans, Liposomes, Mice, Mice, Knockout, Phosphorylation, Proto-Oncogene Proteins c-akt metabolism, Receptor, ErbB-2 immunology, Rituximab, Signal Transduction, Transcription Factor RelA metabolism, Trastuzumab, Antibodies, Monoclonal administration & dosage, Antineoplastic Agents administration & dosage, Breast Neoplasms therapy
- Abstract
Various methods have been explored to enhance antibody-based cancer therapy. The use of multivalent antibodies or fragments against tumor antigens has generated a great deal of interest, as various cellular signals, including induction of apoptosis, inhibition of cell growth/survival, or internalization of the surface molecules, can be triggered or enhanced on extensive cross-linking of the target/antibody complex by the multivalent form of the antibody. The goal of the studies reported here was to develop multivalent antibody constructs via grafting of antibody molecules onto liposome membranes to enhance antibody activity. Using trastuzumab and rituximab as examples, up to a 25-fold increase in the antibody potency in cell viability assay was observed when the antibodies were presented in the multivalent liposome formulation. Key cell survival signaling molecules, such as phosphorylated Akt and phosphorylated p65 nuclear factor-kappaB, were down-regulated on treatment with multivalent liposomal trastuzumab and liposomal rituximab, respectively. Potent in vivo antitumor activity was shown for liposomal trastuzumab. The data presented here showed the potential of liposome technology to enhance the therapeutic effect of antibodies via a mechanism that modulates cell survival through clustering of the target/antibody complex.
- Published
- 2007
- Full Text
- View/download PDF
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