147 results on '"Lai JR"'
Search Results
2. Multisite external validation of blood test for colorectal neoplasia screening in a majority average-risk screening cohort of 449 subjects.
- Author
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Friedland, Shai, primary, Watson, Drew, additional, Rex, Douglas K., additional, Nimgaonkar, Ashish, additional, Zhang, Zhen, additional, Atkins, Alex, additional, Hsieh, Ben, additional, Lai, Jr-Ming, additional, Su, Stephen, additional, Wu, Jen-chia, additional, Shao, Hung-Jen, additional, Tesoriero, Jessica, additional, Hannah, Lindsey, additional, McGowan, John, additional, Mishkin, Daniel S, additional, Gupta, Ekta, additional, Gupta, Samir, additional, Sninsky, John J., additional, and Mei, Rui, additional
- Published
- 2024
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3. Weak Annihilation Topologies and Final State Interactions in D -> PP Decays
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Lai, Jr-Hau and Yang, Kwei-Chou
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High Energy Physics - Phenomenology ,High Energy Physics - Experiment - Abstract
We study two-body D -> PP decays, assuming that each decay process go through the bare amplitude followed by elastic SU(3) rescattering, where the bare amplitude consists of (i) the color-allowed and color-suppressed factorization amplitudes and (ii) the short-distance weak annihilation amplitudes. We have performed the \chi^2 fit on 14 branching ratios of D -> PP decays in the formalism of the above mentioned model. The final state interactions can be well accounted for by the short-distance annihilation topologies and SU(3) rescatterings. The two SU(3) rescattering phase differences are \delta \equiv \delta_{27}-\delta_{8} \simeq -46^\circ and \sigma \equiv \delta_{27}-\delta_{1} \simeq -21^\circ, where \delta_{27}, \delta_{8} and \delta_{1}are the rescattering phases of final states corresponding to the representations 27, 8 and 1, respectively. We find that the D^0 -> K^0 \bar{K}^0 decay occurs mainly due to the nonzero short-distance weak annihilation effects, originating from SU(3) symmetry-breaking corrections to the distribution amplitudes of the final-state kaons, but receives tiny effects from other modes via SU(3) rescattering. Our results are in remarkable accordance with the current data., Comment: 27 pages; v3: some formulas corrected, the statement corrected in footnote 3 where the solution with "positive" a_1^K is stressed, to appear in Phys. Rev. D
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- 2005
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4. Novel Circulating Tumor Cell Assay for Detection of Colorectal Adenomas and Cancer
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Tsai, Wen-Sy, You, Jeng-Fu, Hung, Hsin-Yuan, Hsieh, Pao-Shiu, Hsieh, Ben, Lenz, Heinz-Josef, Idos, Gregory, Friedland, Shai, Yi-Jiun Pan, Jennifer, Shao, Hung-Jen, Wu, Jen-chia, Lai, Jr-Ming, Chang, Shih-En, Mei, Rui, Watson, Drew, Javey, Manana, and Nimgaonkar, Ashish
- Published
- 2019
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5. Clinical performance of a multimodal screening blood test for advanced adenomas and CRC in an average-risk cohort of 1,038 participants.
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Friedland, Shai, primary, Watson, Drew, additional, Rex, Douglas K., additional, Nimgaonkar, Ashish, additional, Zhang, Zhen, additional, Atkins, Alex, additional, Hsieh, Ben, additional, Lai, Jr-Ming, additional, Su, Stephen, additional, Wu, Jen-chia, additional, Shao, Hung-Jen, additional, Tesoriero, Jessica, additional, Hannah, Lindsey, additional, McGowan, John, additional, Gupta, Samir, additional, Sninsky, John J., additional, and Mei, Rui, additional
- Published
- 2023
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6. Evaluation of differential contribution of a circulating epithelial cell signal component in a multimodal colorectal neoplasia assay.
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Friedland, Shai, primary, Watson, Drew, additional, Zhang, Zhen, additional, Pan, Jennifer Y., additional, Chen, Yu, additional, Nimgaonkar, Ashish, additional, Gulzar, Zulfiqar, additional, Atkins, Alex, additional, Taussing, David, additional, Hsieh, Ben, additional, Lai, Jr-Ming, additional, Su, Stephen, additional, Wu, Jen-chia, additional, Shao, Hung-Jen, additional, Sninsky, John, additional, and Mei, Rui, additional
- Published
- 2022
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7. 789: PERFORMANCE OF A NONINVASIVE BLOOD-BASED MULTI-MODAL TEST FOR AN AVERAGE RISK SCREENING POPULATION ENRICHED WITH CASE-CONTROL FOR CRC AND AA
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Friedland, Shai, primary, Watson, Drew, additional, Pan, Jennifer Y., additional, Chen, Yu, additional, Gupta, Samir, additional, Nimgaonkar, Ashish, additional, Gulzar, Zulfiqar, additional, Atkins, Alexander, additional, Taussig, David, additional, Hsieh, Huangpin B., additional, Lai, Jr-Ming, additional, Su, Stephen, additional, Tesoriero, Jessica L., additional, Wu, Jen-chia, additional, Shao, Hung-Jen, additional, Hannah, Lindsey, additional, McGowan, John D., additional, Sninsky, John J., additional, and Mei, Rui, additional
- Published
- 2022
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8. Multifunctional magnetic plasmonic nanoparticles for applications of magnetic/photo-thermal hyperthermia and surface enhanced Raman spectroscopy
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Lai, Jr-Jie, Lai, Wan-Ru, Chen, Chuh-Yean, Chen, Shih-Wei, and Chiang, Chen-Li
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- 2013
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9. 685 A SENSITIVE AND QUANTITATIVE NON-INVASIVE MULTIMODAL BLOOD TEST THAT DETECTS CANCER AND RECAPITULATES ADENOMA PROGNOSIS AVAILABLE FROM COLONOSCOPY
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Friedland, Shai, primary, Pan, Jennifer Y., additional, Watson, Drew, additional, Chen, Yu, additional, Nimgaonkar, Ashish, additional, Gulzar, Zulfiqar, additional, Gupta, Pratyush, additional, Atkins, Alexander, additional, Lai, Jr-Ming, additional, Hsieh, Huangpin B., additional, Su, Stephen, additional, Gupta, Samir, additional, Sninsky, John J., additional, and Mei, Rui, additional
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- 2021
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10. Development and clinical validation of a blood test for early detection of colorectal adenomas and cancer.
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Friedland, Shai, primary, Pan, Jennifer Y., additional, Watson, Drew, additional, Chen, Yu, additional, Nimgaonkar, Ashish, additional, Gulzar, Zulfiqar, additional, Gupta, Pratyush, additional, Atkins, Alex, additional, Lai, Jr-Ming, additional, Hsieh, Ben, additional, Su, Stephen, additional, Ciu, Iris, additional, Setthasap, Ploy, additional, Sninsky, John, additional, and Mei, Rui, additional
- Published
- 2021
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11. Controlling the size of magnetic nanoparticles using pluronic block copolymer surfactants
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Lai, Jr-iuan, Shafi, Kurikka V.P.M., Ulman, Abraham, Ong, N.P., Loos, Katja, Lee, Wei-Li, Lee, Yongjae, and Vogt, Thomas
- Subjects
Transmission electron microscopes -- Usage ,Ferric oxide -- Magnetic properties ,Block copolymers -- Magnetic properties ,Chemicals, plastics and rubber industries - Abstract
The study successfully controlled the size of magnetic nanoparticles by adjusting the surfactant/solvent ratio. Gamma-Fe2O3 nanoparticles of 5.6 and 12.7 and Fe(super 0) nanoparticles of 22.3 nm in diameter were prepared, all having spherical shape and uniform size as confirmed by TEM.
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- 2005
12. A sensitive and quantitative multimodal blood test for the detection of colorectal adenomas and cancer: Correlation with size and number of polyps.
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Friedland, Shai, primary, Pan, Jennifer Y., additional, Watson, Drew, additional, Chen, Yu, additional, Nimgaonkar, Ashish, additional, Gulzar, Zulfiqar, additional, Gupta, Pratyush, additional, Lucas, Julian, additional, Atkins, Alex, additional, Lai, Jr-Ming, additional, Hsieh, Ben, additional, Su, Stephen, additional, Lim, Austin, additional, Ciu, Iris, additional, Setthasap, Ploy, additional, Sninsky, John J., additional, and Mei, Rui, additional
- Published
- 2020
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13. 575 A HIGHLY SENSITIVE AND QUANTITATIVE MULTIMODAL BLOOD TEST FOR THE DETECTION OF COLORECTAL ADENOMAS AND CANCER
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Friedland, Shai, primary, Watson, Drew, additional, Pan, Jennifer Y., additional, Chen, Yu, additional, Nimgaonkar, Ashish, additional, Gulzar, Zulfiqar, additional, Gupta, Pratyush, additional, Lucas, Julian, additional, Atkins, Alexander, additional, Lai, Jr-Ming, additional, Hsieh, Huangpin B., additional, Su, Stephen, additional, Lim, Austin, additional, Chu, Iris, additional, Setthasap, Ploy, additional, Sninsky, John, additional, and Mei, Rui, additional
- Published
- 2020
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14. Circulating tumor cell count from a blood sample for colorectal cancer (CRC) prevention: A 627-patient prospective study.
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Tsai, Wen-Sy, primary, Watson, Drew, additional, Chang, Ying, additional, Hsieh, Ben, additional, Shao, Hung-Jen, additional, Wu, Jen-chia, additional, Lai, Jr-Ming, additional, Chang, Shih-En, additional, Javey, Mana, additional, Mei, Rui, additional, and Nimgaonkar, Ashish, additional
- Published
- 2019
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15. Abstract 2223: Analytical validation of a novel circulating tumor cell platform (CMx) for early detection of cancer
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Shao, Hung-Jen, primary, Hsieh, Huangpin B., additional, Tsai, Wen-Sy, additional, Wu, Jen-chia, additional, Lai, Jr-Ming, additional, Chang, Shih-En, additional, Javey, Mana, additional, Segurado, Oscar, additional, Amin, Mahul B., additional, Nimgaonkar, Ashish, additional, and Mei, Rui, additional
- Published
- 2018
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16. Therapy selection and monitoring of early and late stage non small cell lung cancer (NSCLC) using a novel circulating tumor cells (CTCs) PD-L1 blood test.
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Chen, Yen-Lin, primary, Huang, Wen-Jie, additional, Patterson, Bruce Kendrick, additional, Chargin, Amanda, additional, Hsieh, Chia-Hsin, additional, Hsieh, Ruey Kuen, additional, Amin, Mahul, additional, Segurado, Oscar, additional, Shao, Hung-Jen, additional, Lin, Feng-Ming, additional, Chang, Shih-En, additional, Wu, Jen-chia, additional, Lai, Jr-Ming, additional, Hsieh, Ben, additional, Javey, Mana, additional, and Mei, Rui, additional
- Published
- 2018
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17. A novel circulating tumor cell blood test for early detection of colorectal, prostate, and breast cancers: Results from 709 samples.
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Nimgaonkar, Ashish, primary, Segurado, Oscar, additional, Tsai, Wen-Sy, additional, Pang, SEE-TONG, additional, Hou, Ming-Feng, additional, Chang, Ying, additional, Watson, Drew, additional, Chang, Ying-Hsu, additional, Lin, Po-Hung, additional, Wu, Jen-chia, additional, Shao, Hung-Jen, additional, Lai, Jr-Ming, additional, Lin, Feng-Ming, additional, Lu, Si-Hong, additional, Chang, Shih-En, additional, Hsieh, Ben, additional, Javey, Mana, additional, and Mei, Rui, additional
- Published
- 2018
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18. MP40-20 NOVEL CIRCULATING TUMOR CELLS BLOOD ASSAY FOR THE CLARIFICATION OF 4-10 NG/ML PSA RESULTS ASSESSED IN A PROSPECTIVE CLINICAL STUDY
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Pang, See-Tong, primary, Chang, Ying-Hsu, additional, Lin, Po-Hung, additional, Chang, Ying-Chih, additional, Watson, Drew, additional, Segurado, Oscar, additional, Lu, Si-Hong, additional, Wu, Jen-chia, additional, Shao, Hung-Jen, additional, Lai, Jr-Ming, additional, Chang, Shih-En, additional, Hsieh, Ben, additional, Jarvey, Mana, additional, Amin, Mahul, additional, and Mei, Rui, additional
- Published
- 2018
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19. Prospective clinical study of a prostate cancer (PCa) rule-out blood test for PSA gray zone patients using a sensitive circulating tumor cell assay.
- Author
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Pang, SEE-TONG, primary, Chang, Ying-Hsu, additional, Lin, Po-Hung, additional, Chang, Ying, additional, Watson, Drew, additional, Segurado, Oscar, additional, Lu, Si-Hong, additional, Wu, Jen-chia, additional, Lai, Jr-Ming, additional, Shao, Hung-Jen, additional, Chang, Shih-En, additional, Hsieh, Ben, additional, Javey, Mana, additional, and Mei, Rui, additional
- Published
- 2018
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20. Prospective clinical study of circulating tumor cells for colorectal cancer screening.
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Tsai, Wen-Sy, primary, Nimgaonkar, Ashish, additional, Segurado, Oscar, additional, Chang, Ying, additional, Hsieh, Ben, additional, Shao, Hung-Jen, additional, Wu, Jen-chia, additional, Lai, Jr-Ming, additional, Javey, Mana, additional, Watson, Drew, additional, and Mei, Rui, additional
- Published
- 2018
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21. Circulating Tumor Cell Count Correlates with Colorectal Neoplasm Progression and Is a Prognostic Marker for Distant Metastasis in Non-Metastatic Patients
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Tsai, Wen-Sy, primary, Chen, Jinn-Shiun, additional, Shao, Hung-Jen, additional, Wu, Jen-Chia, additional, Lai, Jr-Ming, additional, Lu, Si-Hong, additional, Hung, Tsung-Fu, additional, Chiu, Yen-Chi, additional, You, Jeng-Fu, additional, Hsieh, Pao-Shiu, additional, Yeh, Chien-Yuh, additional, Hung, Hsin-Yuan, additional, Chiang, Sum-Fu, additional, Lin, Geng-Ping, additional, Tang, Reiping, additional, and Chang, Ying-Chih, additional
- Published
- 2016
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22. Sensitive and Specific Biomimetic Lipid Coated Microfluidics to Isolate Viable Circulating Tumor Cells and Microemboli for Cancer Detection
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Chen, Jia-Yang, primary, Tsai, Wen-Sy, additional, Shao, Hung-Jen, additional, Wu, Jen-Chia, additional, Lai, Jr-Ming, additional, Lu, Si-Hong, additional, Hung, Tsung-Fu, additional, Yang, Chih-Tsung, additional, Wu, Liang-Chun, additional, Chen, Jinn-Shiun, additional, Lee, Wen-Hwa, additional, and Chang, Ying-Chih, additional
- Published
- 2016
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23. Efficient elusion of viable adhesive cells from a microfluidic system by air foam
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Lai, Jr-Ming, primary, Shao, Hung-Jen, additional, Wu, Jen-Chia, additional, Lu, Si-Hong, additional, and Chang, Ying-Chih, additional
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- 2014
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24. Construction of orthogonal synchronized bi-directional field to enhance heating efficiency of magnetic nanoparticles
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Chen, Shih-Wei, primary, Lai, Jr-Jie, additional, Chiang, Chen-Li, additional, and Chen, Cheng-Lung, additional
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- 2012
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25. Numerical investigation of the effect of a transducer pulse on the microfluidic control of a piezoelectric printhead
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Lai, Jr-Ming, primary
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- 2010
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26. Influence of liquid hydrophobicity and nozzle passage curvature on microfluidic dynamics in a drop ejection process
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Lai, Jr-Ming, primary, Huang, Chang-Yan, additional, Chen, Chih-Hao, additional, Linliu, Kung, additional, and Lin, Jenn-Der, additional
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- 2009
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27. Effects of dye adsorption on the electron transport properties in ZnO-nanowire dye-sensitized solar cells
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Wu, Jih-Jen, primary, Chen, Guan-Ren, additional, Yang, Hung-Hsien, additional, Ku, Chen-Hao, additional, and Lai, Jr-Yuan, additional
- Published
- 2007
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28. Weak annihilation topologies and final state interactions inD→PPdecays
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Lai, Jr-Hau, primary and Yang, Kwei-Chou, additional
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- 2005
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29. Controlling the Size of Magnetic Nanoparticles Using Pluronic Block Copolymer Surfactants
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Lai, Jr-iuan, primary, Shafi, Kurikka V. P. M., additional, Ulman, Abraham, additional, Loos, Katja, additional, Lee, Yongjae, additional, Vogt, Thomas, additional, Lee, Wei-Li, additional, and Ong, N. P., additional
- Published
- 2004
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30. Three-Dimensional Anatomic Analysis of Retrosigmoid Approach With Thin-Section Computed Tomographic Image.
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Xiangliang Liu, Kailiang Cheng Jr., Li Li, Bin Zhang, Shihui Guan, Li Chen Jr., Yu Chen Jr., Youqiong Li, Lina Yi, Huayang Wang, and Ying Lai Jr.
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- 2015
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31. Sensitive and Specific Biomimetic Lipid Coated Microfluidics to Isolate Viable Circulating Tumor Cells and Microemboli for Cancer Detection
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Tsung-Fu Hung, Jia-Yang Chen, Liang-Chun Wu, Wen-Sy Tsai, Jr-Ming Lai, Wen-Hwa Lee, Hung-Jen Shao, Chih-Tsung Yang, Si-Hong Lu, Jen-chia Wu, Jinn-Shiun Chen, Ying-Chih Chang, Chen, Jia-Yang, Tsai, Wen-Sy, Shao, Hung-Jen, Wu, Jen-Chia, Lai, Jr-Ming, Lu, Si-Hong, Hung, Tsung-Fu, Yang, Chih-Tsung, Wu, Liang-Chun, Chen, Jinn-Shiun, Lee, Wen-Hwa, and Chang, Ying-Chih
- Subjects
0301 basic medicine ,Male ,Pathology ,Colorectal cancer ,Physiology ,Microfluidics ,lcsh:Medicine ,02 engineering and technology ,Biochemistry ,Metastasis ,Circulating tumor cell ,Fluorescence Microscopy ,Lab-On-A-Chip Devices ,Medicine and Health Sciences ,lcsh:Science ,Early Detection of Cancer ,Whole blood ,Flow Rate ,Microscopy ,Multidisciplinary ,biology ,Physics ,Light Microscopy ,Classical Mechanics ,Hematology ,Middle Aged ,021001 nanoscience & nanotechnology ,Neoplastic Cells, Circulating ,Lipids ,Foam ,Body Fluids ,Multidisciplinary Sciences ,Blood ,Oncology ,Physical Sciences ,Engineering and Technology ,Female ,Fluidics ,Antibody ,Anatomy ,0210 nano-technology ,Colorectal Neoplasms ,Research Article ,Adult ,medicine.medical_specialty ,Materials by Structure ,Materials Science ,Fluid Mechanics ,Research and Analysis Methods ,Continuum Mechanics ,Antibodies ,03 medical and health sciences ,Antigen ,Antigens, Neoplasm ,medicine ,Cancer Detection and Diagnosis ,Humans ,Colorectal Cancer ,metastatic prostate-cancer ,lcsh:R ,colorectal-cancer ,Cancer ,Cancers and Neoplasms ,Biology and Life Sciences ,Fluid Dynamics ,medicine.disease ,HCT116 Cells ,030104 developmental biology ,biology.protein ,Cancer research ,lcsh:Q ,Ex vivo - Abstract
Here we presented a simple and effective membrane mimetic microfluidic device with antibody conjugated supported lipid bilayer (SLB) "smart coating" to capture viable circulating tumor cells (CTCs) and circulating tumor microemboli (CTM) directly from whole blood of all stage clinical cancer patients. The non-covalently bound SLB was able to promote dynamic clustering of lipid-tethered antibodies to CTC antigens and minimized non-specific blood cells retention through its non-fouling nature. A gentle flow further flushed away loosely-bound blood cells to achieve high purity of CTCs, and a stream of air foam injected disintegrate the SLB assemblies to release intact and viable CTCs from the chip. Human blood spiked cancer cell line test showed the similar to 95% overall efficiency to recover both CTCs and CTMs. Live/dead assay showed that at least 86% of recovered cells maintain viability. By using 2 mL of peripheral blood, the CTCs and CTMs counts of 63 healthy and colorectal cancer donors were positively correlated with the cancer progression. In summary, a simple and effective strategy utilizing biomimetic principle was developed to retrieve viable CTCs for enumeration, molecular analysis, as well as ex vivo culture over weeks. Due to the high sensitivity and specificity, it is the first time to show the high detection rates and quantity of CTCs in non-metastatic cancer patients. This work offers the values in both early cancer detection and prognosis of CTC and provides an accurate non-invasive strategy for routine clinical investigation on CTCs. Refereed/Peer-reviewed
- Published
- 2016
32. Broadly protective bispecific antibodies that simultaneously target influenza virus hemagglutinin and neuraminidase.
- Author
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Ramos KE, Okba NMA, Tan J, Bandawane P, Meade PS, Loganathan M, Francis B, Shulenin S, Holtsberg FW, Aman MJ, McMahon M, Krammer F, and Lai JR
- Subjects
- Animals, Humans, Mice, Orthomyxoviridae Infections prevention & control, Orthomyxoviridae Infections immunology, Antibodies, Neutralizing immunology, Antibodies, Monoclonal immunology, Influenza, Human immunology, Influenza, Human prevention & control, Influenza, Human virology, Mice, Inbred BALB C, Influenza A Virus, H1N1 Subtype immunology, Influenza A Virus, H1N1 Subtype drug effects, Neuraminidase immunology, Hemagglutinin Glycoproteins, Influenza Virus immunology, Antibodies, Bispecific immunology, Antibodies, Bispecific pharmacology, Antibodies, Viral immunology
- Abstract
Monoclonal antibodies (mAbs) are an attractive therapeutic platform for the prevention and treatment of influenza virus infection. There are two major glycoproteins on the influenza virion surface: hemagglutinin (HA), which is responsible for viral attachment and entry, and neuraminidase (NA), which mediates viral egress by enzymatically cleaving sialic acid to release budding particles from the host cell surface. Broadly neutralizing antibodies (bNAbs) that target the conserved HA central stalk region, such as CR9114, can inhibit both viral entry and egress. More recently, broadly binding mAbs that engage and inhibit the NA active site, such as 1G01, have been described to prevent viral egress. Here, we engineered bispecific antibodies (bsAbs) that combine the variable domains of CR9114 and 1G01 into a single molecule and evaluated if simultaneous targeting of two different glycoproteins improved antiviral properties in vitro and in vivo . Several CR9114/1G01 bsAbs were generated with various configurations of the two sets of the variable domains ("bsAb formats"). We found that combinations employing the addition of a single-chain variable fragment in the hinge region of an IgG scaffold had the best properties in terms of expression, stability, and binding. Further characterization of selected bsAbs showed potent neutralizing and egress-inhibiting activity. One such bsAb ("hSC_CR9114_1G01") provided higher levels of prophylactic protection from mortality and morbidity upon challenge with H1N1 than either of the parental mAbs at low dosing (1 mg/kg). These results highlight the potential use of bsAbs that simultaneously target HA and NA as new influenza immunotherapeutics., Importance: Infection by the influenza virus remains a global health burden. The approaches utilized here to augment the activity of broadly protective influenza virus antibodies may lead to a new class of immunotherapies with enhanced activity., Competing Interests: The Icahn School of Medicine at Mount Sinai has filed patent applications regarding influenza virus vaccines and therapeutics which list F.K. as an inventor. The Krammer laboratory has received support for influenza virus research in the past from GSK and is currently receiving support from Dynavax. F.K. is currently consulting for GSK, Third Rock Ventures, Gritstone, and Avimex.
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- 2024
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33. Design and characterization of protective pan-ebolavirus and pan-filovirus bispecific antibodies.
- Author
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Wirchnianski AS, Nyakatura EK, Herbert AS, Kuehne AI, Abbasi SA, Florez C, Storm N, McKay LGA, Dailey L, Kuang E, Abelson DM, Wec AZ, Chakraborti S, Holtsberg FW, Shulenin S, Bornholdt ZA, Aman MJ, Honko AN, Griffiths A, Dye JM, Chandran K, and Lai JR
- Subjects
- Animals, Mice, Humans, Filoviridae immunology, Antibodies, Neutralizing immunology, Antibodies, Neutralizing therapeutic use, Antibodies, Monoclonal immunology, Female, Mice, Inbred BALB C, Filoviridae Infections immunology, Filoviridae Infections therapy, Filoviridae Infections prevention & control, Antibodies, Bispecific immunology, Antibodies, Bispecific pharmacology, Antibodies, Bispecific therapeutic use, Ebolavirus immunology, Hemorrhagic Fever, Ebola immunology, Hemorrhagic Fever, Ebola prevention & control, Hemorrhagic Fever, Ebola virology, Antibodies, Viral immunology
- Abstract
Monoclonal antibodies (mAbs) are an important class of antiviral therapeutics. MAbs are highly selective, well tolerated, and have long in vivo half-life as well as the capacity to induce immune-mediated virus clearance. Their activities can be further enhanced by integration of their variable fragments (Fvs) into bispecific antibodies (bsAbs), affording simultaneous targeting of multiple epitopes to improve potency and breadth and/or to mitigate against viral escape by a single mutation. Here, we explore a bsAb strategy for generation of pan-ebolavirus and pan-filovirus immunotherapeutics. Filoviruses, including Ebola virus (EBOV), Sudan virus (SUDV), and Marburg virus (MARV), cause severe hemorrhagic fever. Although there are two FDA-approved mAb therapies for EBOV infection, these do not extend to other filoviruses. Here, we combine Fvs from broad ebolavirus mAbs to generate novel pan-ebolavirus bsAbs that are potently neutralizing, confer protection in mice, and are resistant to viral escape. Moreover, we combine Fvs from pan-ebolavirus mAbs with those of protective MARV mAbs to generate pan-filovirus protective bsAbs. These results provide guidelines for broad antiviral bsAb design and generate new immunotherapeutic candidates., Competing Interests: K.C. owns shares in Integrum Scientific LLC and Eitr Biologics, Inc, and has consulted for Axon Advisors, LLC. J.R.L. is a paid consultant for Celdara Medical, LLC., (Copyright: © 2024 Wirchnianski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2024
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34. Generation and Study of Antibodies against Two Triangular Trimers Derived from Aβ.
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Kreutzer AG, Malonis RJ, Parrocha CMT, Tong K, Guaglianone G, Nguyen JT, Diab MN, Lai JR, and Nowick JS
- Abstract
Monoclonal antibodies (mAbs) that target the P-amyloid peptide (Aβ) are important Alzheimer's disease research tools and are now being used as Alzheimer's disease therapies. Conformation-specific mAbs that target oligomeric and fibrillar Aβ assemblies are of particular interest, as these assemblies are associated with Alzheimer's disease pathogenesis and progression. This paper reports the generation of rabbit mAbs against two different triangular trimers derived from Aβ. These antibodies are the first mAbs generated against Aβ oligomer mimics in which the high-resolution structures of the oligomers are known. We describe the isolation of the mAbs using single B-cell sorting of peripheral blood mononuclear cells (PBMCs) from immunized rabbits, the selectivity of the mAbs for the triangular trimers, the immunoreactivity of the mAbs with aggregated Aβ
42 , and the immunoreactivity of the mAbs in brain tissue from the 5xFAD Alzheimer's disease mouse model. The characterization of these mAbs against structurally defined trimers derived from Aβ enhances understanding of antibody-amyloid recognition and may benefit the development of diagnostics and immunotherapies in Alzheimer's disease., Competing Interests: CONFLICT OF INTEREST STATEMENT The Regents of the University of California has been assigned a United States patent for compounds reported in this paper in which A.G.K. and J.S.N. are inventors.- Published
- 2024
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35. Chikungunya virus cell-to-cell transmission is mediated by intercellular extensions in vitro and in vivo.
- Author
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Yin P, Davenport BJ, Wan JJ, Kim AS, Diamond MS, Ware BC, Tong K, Couderc T, Lecuit M, Lai JR, Morrison TE, and Kielian M
- Subjects
- Humans, Animals, Mice, HeLa Cells, Antibodies, Neutralizing, Coculture Techniques, Chikungunya virus, Chikungunya Fever
- Abstract
Chikungunya virus (CHIKV) has recently emerged to cause millions of human infections worldwide. Infection can induce the formation of long intercellular extensions that project from infected cells and form stable non-continuous membrane bridges with neighbouring cells. The mechanistic role of these intercellular extensions in CHIKV infection was unclear. Here we developed a co-culture system and flow cytometry methods to quantitatively evaluate transmission of CHIKV from infected to uninfected cells in the presence of neutralizing antibody. Endocytosis and endosomal acidification were critical for virus cell-to-cell transmission, while the CHIKV receptor MXRA8 was not. By using distinct antibodies to block formation of extensions and by evaluation of transmission in HeLa cells that did not form extensions, we showed that intercellular extensions mediate CHIKV cell-to-cell transmission. In vivo, pre-treatment of mice with a neutralizing antibody blocked infection by direct virus inoculation, while adoptive transfer of infected cells produced antibody-resistant host infection. Together our data suggest a model in which the contact sites of intercellular extensions on target cells shield CHIKV from neutralizing antibodies and promote efficient intercellular virus transmission both in vitro and in vivo., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2023
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36. Probing differences among Aβ oligomers with two triangular trimers derived from Aβ.
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Kreutzer AG, Guaglianone G, Yoo S, Parrocha CMT, Ruttenberg SM, Malonis RJ, Tong K, Lin YF, Nguyen JT, Howitz WJ, Diab MN, Hamza IL, Lai JR, Wysocki VH, and Nowick JS
- Subjects
- Humans, Protein Conformation, Crystallography, X-Ray, Cell Membrane metabolism, Peptide Fragments chemistry, Amyloid beta-Peptides metabolism, Alzheimer Disease
- Abstract
The assembly of the β-amyloid peptide (Aβ) to form oligomers and fibrils is closely associated with the pathogenesis and progression of Alzheimer's disease. Aβ is a shape-shifting peptide capable of adopting many conformations and folds within the multitude of oligomers and fibrils the peptide forms. These properties have precluded detailed structural elucidation and biological characterization of homogeneous, well-defined Aβ oligomers. In this paper, we compare the structural, biophysical, and biological characteristics of two different covalently stabilized isomorphic trimers derived from the central and C -terminal regions Aβ. X-ray crystallography reveals the structures of the trimers and shows that each trimer forms a ball-shaped dodecamer. Solution-phase and cell-based studies demonstrate that the two trimers exhibit markedly different assembly and biological properties. One trimer forms small soluble oligomers that enter cells through endocytosis and activate capase-3/7-mediated apoptosis, while the other trimer forms large insoluble aggregates that accumulate on the outer plasma membrane and elicit cellular toxicity through an apoptosis-independent mechanism. The two trimers also exhibit different effects on the aggregation, toxicity, and cellular interaction of full-length Aβ, with one trimer showing a greater propensity to interact with Aβ than the other. The studies described in this paper indicate that the two trimers share structural, biophysical, and biological characteristics with oligomers of full-length Aβ. The varying structural, assembly, and biological characteristics of the two trimers provide a working model for how different Aβ trimers can assemble and lead to different biological effects, which may help shed light on the differences among Aβ oligomers.
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- 2023
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37. Silver-catalysed three-component reactions of alkynyl aryl ketones, element selenium, and boronic acids leading to 3-organoselenylchromones.
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Lai JR, Yin FD, Guo QS, Yuan F, Nian BF, Zhang M, Wu ZB, Zhang HB, and Tang E
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- Boronic Acids, Cyclization, Silver, Ketones, Selenium
- Abstract
An Ag-catalysed three-component reaction of alkynyl aryl ketones bearing an ortho -methoxy group, element selenium, and arylboronic acid, providing a facile route to selenofunctionalized chromone products has been developed. This protocol features high efficiency and high regioselectivity, and the use of selenium powder as the selenium source. Mechanistic experiments indicated that the combined oxidative effect of (bis(trifluoroacetoxy)iodo)benzene and oxygen in the air pushes the catalytic redox cycle of the Ag catalyst and the phenylselenium trifluoroacetate formed in situ is the key intermediate of the PIFA-mediated 6- endo -electrophilic cyclization and selenofunctionalization reaction of alkynyl aryl ketones.
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- 2022
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38. A Powassan virus domain III nanoparticle immunogen elicits neutralizing and protective antibodies in mice.
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Malonis RJ, Georgiev GI, Haslwanter D, VanBlargan LA, Fallon G, Vergnolle O, Cahill SM, Harris R, Cowburn D, Chandran K, Diamond MS, and Lai JR
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- Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Epitopes, Mice, Encephalitis Viruses, Tick-Borne, Nanoparticles
- Abstract
Powassan virus (POWV) is an emerging tick borne flavivirus (TBFV) that causes severe neuroinvasive disease. Currently, there are no approved treatments or vaccines to combat POWV infection. Here, we generated and characterized a nanoparticle immunogen displaying domain III (EDIII) of the POWV E glycoprotein. Immunization with POWV EDIII presented on nanoparticles resulted in significantly higher serum neutralizing titers against POWV than immunization with monomeric POWV EDIII. Furthermore, passive transfer of EDIII-reactive sera protected against POWV challenge in vivo. We isolated and characterized a panel of EDIII-specific monoclonal antibodies (mAbs) and identified several that potently inhibit POWV infection and engage distinct epitopes within the lateral ridge and C-C' loop of the EDIII. By creating a subunit-based nanoparticle immunogen with vaccine potential that elicits antibodies with protective activity against POWV infection, our findings enhance our understanding of the molecular determinants of antibody-mediated neutralization of TBFVs., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: J.R.L. is a paid consultant for Celdara Medical, LLC. M.S.D. is a consultant for Inbios, Vir Biotechnology, and Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. K.C. is a member of the scientific advisory boards of Integrum Scientific, LLC and Biovaxys Technology Corp.
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- 2022
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39. Resurfaced ZIKV EDIII nanoparticle immunogens elicit neutralizing and protective responses in vivo.
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Georgiev GI, Malonis RJ, Wirchnianski AS, Wessel AW, Jung HS, Cahill SM, Nyakatura EK, Vergnolle O, Dowd KA, Cowburn D, Pierson TC, Diamond MS, and Lai JR
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- Antibodies, Neutralizing, Antibodies, Viral, Humans, Viral Envelope Proteins chemistry, Viral Envelope Proteins genetics, Dengue Virus chemistry, Nanoparticles, Zika Virus, Zika Virus Infection prevention & control
- Abstract
Zika virus (ZIKV) is a flavivirus that can cause severe disease, but there are no approved treatments or vaccines. A complication for flavivirus vaccine development is the potential of immunogens to enhance infection via antibody-dependent enhancement (ADE), a process mediated by poorly neutralizing and cross-reactive antibodies. Thus, there is a great need to develop immunogens that minimize the potential to elicit enhancing antibodies. Here we utilized structure-based protein engineering to develop "resurfaced" (rs) ZIKV immunogens based on E glycoprotein domain III (ZDIIIs), in which epitopes bound by variably neutralizing antibodies were masked by combinatorial mutagenesis. We identified one resurfaced ZDIII immunogen (rsZDIII-2.39) that elicited a protective but immune-focused response. Compared to wild type ZDIII, immunization with resurfaced rsZDIII-2.39 protein nanoparticles produced fewer numbers of ZIKV EDIII antigen-reactive B cells and elicited serum that had a lower magnitude of induced ADE against dengue virus serotype 1 (DENV1) Our findings enhance our understanding of the structural and functional determinants of antibody protection against ZIKV., Competing Interests: Declaration of interests A US Patent Application describing the rsZDIII clones has been submitted, with J.R.L., G.I.G., A.S.W., and E.K.N. as co-inventors. J.R.L. is a consultant for Celdara Medical, LLC. .M.S.D. is a consultant for Inbios, Vir Biotechnology, Senda Biosciences, and Carnival Corporation and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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40. Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients: A Randomized Clinical Trial.
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Ortigoza MB, Yoon H, Goldfeld KS, Troxel AB, Daily JP, Wu Y, Li Y, Wu D, Cobb GF, Baptiste G, O'Keeffe M, Corpuz MO, Ostrosky-Zeichner L, Amin A, Zacharioudakis IM, Jayaweera DT, Wu Y, Philley JV, Devine MS, Desruisseaux MS, Santin AD, Anjan S, Mathew R, Patel B, Nigo M, Upadhyay R, Kupferman T, Dentino AN, Nanchal R, Merlo CA, Hager DN, Chandran K, Lai JR, Rivera J, Bikash CR, Lasso G, Hilbert TP, Paroder M, Asencio AA, Liu M, Petkova E, Bragat A, Shaker R, McPherson DD, Sacco RL, Keller MJ, Grudzen CR, Hochman JS, Pirofski LA, Parameswaran L, Corcoran AT, Rohatgi A, Wronska MW, Wu X, Srinivasan R, Deng FM, Filardo TD, Pendse J, Blaser SB, Whyte O, Gallagher JM, Thomas OE, Ramos D, Sturm-Reganato CL, Fong CC, Daus IM, Payoen AG, Chiofolo JT, Friedman MT, Wu DW, Jacobson JL, Schneider JG, Sarwar UN, Wang HE, Huebinger RM, Dronavalli G, Bai Y, Grimes CZ, Eldin KW, Umana VE, Martin JG, Heath TR, Bello FO, Ransford DL, Laurent-Rolle M, Shenoi SV, Akide-Ndunge OB, Thapa B, Peterson JL, Knauf K, Patel SU, Cheney LL, Tormey CA, and Hendrickson JE
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- Adult, Aged, Double-Blind Method, Female, Hospitalization statistics & numerical data, Humans, Immunization, Passive, Male, Middle Aged, Respiration, Artificial statistics & numerical data, Treatment Outcome, United States, COVID-19 Serotherapy, Blood Component Transfusion, COVID-19 therapy, Critical Illness therapy
- Abstract
Importance: There is clinical equipoise for COVID-19 convalescent plasma (CCP) use in patients hospitalized with COVID-19., Objective: To determine the safety and efficacy of CCP compared with placebo in hospitalized patients with COVID-19 receiving noninvasive supplemental oxygen., Design, Setting, and Participants: CONTAIN COVID-19, a randomized, double-blind, placebo-controlled trial of CCP in hospitalized adults with COVID-19, was conducted at 21 US hospitals from April 17, 2020, to March 15, 2021. The trial enrolled 941 participants who were hospitalized for 3 or less days or presented 7 or less days after symptom onset and required noninvasive oxygen supplementation., Interventions: A unit of approximately 250 mL of CCP or equivalent volume of placebo (normal saline)., Main Outcomes and Measures: The primary outcome was participant scores on the 11-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement on day 14 after randomization; the secondary outcome was WHO scores determined on day 28. Subgroups were analyzed with respect to age, baseline WHO score, concomitant medications, symptom duration, CCP SARS-CoV-2 titer, baseline SARS-CoV-2 serostatus, and enrollment quarter. Outcomes were analyzed using a bayesian proportional cumulative odds model. Efficacy of CCP was defined as a cumulative adjusted odds ratio (cOR) less than 1 and a clinically meaningful effect as cOR less than 0.8., Results: Of 941 participants randomized (473 to placebo and 468 to CCP), 556 were men (59.1%); median age was 63 years (IQR, 52-73); 373 (39.6%) were Hispanic and 132 (14.0%) were non-Hispanic Black. The cOR for the primary outcome adjusted for site, baseline risk, WHO score, age, sex, and symptom duration was 0.94 (95% credible interval [CrI], 0.75-1.18) with posterior probability (P[cOR<1] = 72%); the cOR for the secondary adjusted outcome was 0.92 (95% CrI, 0.74-1.16; P[cOR<1] = 76%). Exploratory subgroup analyses suggested heterogeneity of treatment effect: at day 28, cORs were 0.72 (95% CrI, 0.46-1.13; P[cOR<1] = 93%) for participants enrolled in April-June 2020 and 0.65 (95% CrI, 0.41 to 1.02; P[cOR<1] = 97%) for those not receiving remdesivir and not receiving corticosteroids at randomization. Median CCP SARS-CoV-2 neutralizing titer used in April to June 2020 was 1:175 (IQR, 76-379). Any adverse events (excluding transfusion reactions) were reported for 39 (8.2%) placebo recipients and 44 (9.4%) CCP recipients (P = .57). Transfusion reactions occurred in 2 (0.4) placebo recipients and 8 (1.7) CCP recipients (P = .06)., Conclusions and Relevance: In this trial, CCP did not meet the prespecified primary and secondary outcomes for CCP efficacy. However, high-titer CCP may have benefited participants early in the pandemic when remdesivir and corticosteroids were not in use., Trial Registration: ClinicalTrials.gov Identifier: NCT04364737.
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- 2022
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41. Longitudinally monitored immune biomarkers predict the timing of COVID-19 outcomes.
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Lasso G, Khan S, Allen SA, Mariano M, Florez C, Orner EP, Quiroz JA, Quevedo G, Massimi A, Hegde A, Wirchnianski AS, Bortz RH 3rd, Malonis RJ, Georgiev GI, Tong K, Herrera NG, Morano NC, Garforth SJ, Malaviya A, Khokhar A, Laudermilch E, Dieterle ME, Fels JM, Haslwanter D, Jangra RK, Barnhill J, Almo SC, Chandran K, Lai JR, Kelly L, Daily JP, and Vergnolle O
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers blood, Computational Biology, Diagnosis, Computer-Assisted, Female, Humans, Male, Middle Aged, Prognosis, Spike Glycoprotein, Coronavirus immunology, Young Adult, Antibodies, Viral blood, COVID-19 diagnosis, COVID-19 epidemiology, COVID-19 immunology, COVID-19 therapy, SARS-CoV-2 immunology
- Abstract
The clinical outcome of SARS-CoV-2 infection varies widely between individuals. Machine learning models can support decision making in healthcare by assessing fatality risk in patients that do not yet show severe signs of COVID-19. Most predictive models rely on static demographic features and clinical values obtained upon hospitalization. However, time-dependent biomarkers associated with COVID-19 severity, such as antibody titers, can substantially contribute to the development of more accurate outcome models. Here we show that models trained on immune biomarkers, longitudinally monitored throughout hospitalization, predicted mortality and were more accurate than models based on demographic and clinical data upon hospital admission. Our best-performing predictive models were based on the temporal analysis of anti-SARS-CoV-2 Spike IgG titers, white blood cell (WBC), neutrophil and lymphocyte counts. These biomarkers, together with C-reactive protein and blood urea nitrogen levels, were found to correlate with severity of disease and mortality in a time-dependent manner. Shapley additive explanations of our model revealed the higher predictive value of day post-symptom onset (PSO) as hospitalization progresses and showed how immune biomarkers contribute to predict mortality. In sum, we demonstrate that the kinetics of immune biomarkers can inform clinical models to serve as a powerful monitoring tool for predicting fatality risk in hospitalized COVID-19 patients, underscoring the importance of contextualizing clinical parameters according to their time post-symptom onset., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interets: K.C. is a member of the scientific advisory board of Integrum Scientific, LLC. J.R.L is a consultant for Celdara Medical.
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- 2022
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42. A Combination of Receptor-Binding Domain and N-Terminal Domain Neutralizing Antibodies Limits the Generation of SARS-CoV-2 Spike Neutralization-Escape Mutants.
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Haslwanter D, Dieterle ME, Wec AZ, O'Brien CM, Sakharkar M, Florez C, Tong K, Rappazzo CG, Lasso G, Vergnolle O, Wirchnianski AS, Bortz RH 3rd, Laudermilch E, Fels JM, Mengotto A, Malonis RJ, Georgiev GI, Quiroz JA, Wrapp D, Wang N, Dye KE, Barnhill J, Dye JM, McLellan JS, Daily JP, Lai JR, Herbert AS, Walker LM, Chandran K, and Jangra RK
- Subjects
- Humans, Neutralization Tests, Antibodies, Neutralizing immunology, COVID-19 genetics, COVID-19 immunology, Mutation immunology, RNA-Binding Motifs immunology, SARS-CoV-2 genetics, SARS-CoV-2 immunology
- Abstract
Most known SARS-CoV-2 neutralizing antibodies (nAbs), including those approved by the FDA for emergency use, inhibit viral infection by targeting the receptor-binding domain (RBD) of the spike (S) protein. Variants of concern (VOC) carrying mutations in the RBD or other regions of S reduce the effectiveness of many nAbs and vaccines by evading neutralization. Therefore, therapies that are less susceptible to resistance are urgently needed. Here, we characterized the memory B-cell repertoire of COVID-19 convalescent donors and analyzed their RBD and non-RBD nAbs. We found that many of the non-RBD-targeting nAbs were specific to the N-terminal domain (NTD). Using neutralization assays with authentic SARS-CoV-2 and a recombinant vesicular stomatitis virus carrying SARS-CoV-2 S protein (rVSV-SARS2), we defined a panel of potent RBD and NTD nAbs. Next, we used a combination of neutralization-escape rVSV-SARS2 mutants and a yeast display library of RBD mutants to map their epitopes. The most potent RBD nAb competed with hACE2 binding and targeted an epitope that includes residue F490. The most potent NTD nAb epitope included Y145, K150, and W152. As seen with some of the natural VOC, the neutralization potencies of COVID-19 convalescent-phase sera were reduced by 4- to 16-fold against rVSV-SARS2 bearing Y145D, K150E, or W152R spike mutations. Moreover, we found that combining RBD and NTD nAbs did not enhance their neutralization potential. Notably, the same combination of RBD and NTD nAbs limited the development of neutralization-escape mutants in vitro , suggesting such a strategy may have higher efficacy and utility for mitigating the emergence of VOC. IMPORTANCE The U.S. FDA has issued emergency use authorizations (EUAs) for multiple investigational monoclonal antibody (MAb) therapies for the treatment of mild to moderate COVID-19. These MAb therapeutics are solely targeting the receptor-binding domain of the SARS-CoV-2 spike protein. However, the N-terminal domain of the spike protein also carries crucial neutralizing epitopes. Here, we show that key mutations in the N-terminal domain can reduce the neutralizing capacity of convalescent-phase COVID-19 sera. We report that a combination of two neutralizing antibodies targeting the receptor-binding and N-terminal domains may be beneficial to combat the emergence of virus variants.
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- 2021
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43. Monascin and Ankaflavin of Monascus purpureus Prevent Alcoholic Liver Disease through Regulating AMPK-Mediated Lipid Metabolism and Enhancing Both Anti-Inflammatory and Anti-Oxidative Systems.
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Lai JR, Hsu YW, Pan TM, and Lee CL
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- AMP-Activated Protein Kinases genetics, Animals, Central Nervous System Depressants toxicity, Ethanol toxicity, Lipid Metabolism, Liver Diseases, Alcoholic etiology, Liver Diseases, Alcoholic metabolism, Liver Diseases, Alcoholic pathology, Male, Mice, Mice, Inbred C57BL, AMP-Activated Protein Kinases metabolism, Anti-Inflammatory Agents pharmacology, Antioxidants pharmacology, Flavins pharmacology, Heterocyclic Compounds, 3-Ring pharmacology, Liver Diseases, Alcoholic drug therapy, Monascus chemistry
- Abstract
Alcohol metabolism causes an excessive accumulation of liver lipids and inflammation, resulting in liver damage. The yellow pigments monascin (MS) and ankaflavin (AK) of Monascus purpureus -fermented rice were proven to regulate ethanol-induced damage in HepG2 cells, but the complete anti-inflammatory and anti-fatty liver mechanisms in the animal model are still unclear. This study explored the roles of MS and AK in improving alcoholic liver injury. MS and AK were simultaneously fed to evaluate their effects and mechanisms in C57BL/6J mice fed the Lieber-DeCarli liquid alcohol diet for 6 weeks. The results indicated that MS and AK significantly reduced the serum aspartate aminotransferase and alanine aminotransferase activity, as well as the total liver cholesterol and triglyceride levels. The histopathological results indicated that MS and AK prevented lipid accumulation in the liver. MS and AK effectively enhanced the activity of antioxidant enzymes and reduced the degree of lipid peroxidation; AK was particularly effective and exhibited a superior preventive effect against alcoholic liver injury and fatty liver. In addition to inhibiting the phosphorylation of the MAPK family, MS and AK directly reduced TNF-α, IL-6, and IL-1β levels, thereby reducing NF-κB and its downstream iNOS and COX-2 expressions, as well as increasing PPAR-γ, Nrf-2, and HO-1 expressions to prevent liver damage. MS and AK also directly reduced TNF-α, IL-6, and IL-1β expression, thereby reducing the production of NF-κB and its downstream iNOS and COX-2, and increasing PPAR-γ, Nrf-2, and HO-1 expressions, preventing alcohol damage to the liver.
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- 2021
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44. Two Distinct Lysosomal Targeting Strategies Afford Trojan Horse Antibodies With Pan-Filovirus Activity.
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Wirchnianski AS, Wec AZ, Nyakatura EK, Herbert AS, Slough MM, Kuehne AI, Mittler E, Jangra RK, Teruya J, Dye JM, Lai JR, and Chandran K
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- Antibodies, Bispecific genetics, Broadly Neutralizing Antibodies genetics, Ebolavirus immunology, Ebolavirus pathogenicity, Epitopes, Hemorrhagic Fever, Ebola immunology, Hemorrhagic Fever, Ebola metabolism, Hemorrhagic Fever, Ebola virology, Host-Pathogen Interactions, Humans, Ligands, Lysosomes immunology, Lysosomes metabolism, Lysosomes virology, Niemann-Pick C1 Protein genetics, Niemann-Pick C1 Protein immunology, Niemann-Pick C1 Protein metabolism, Protein Engineering, Receptor, IGF Type 2 genetics, Receptor, IGF Type 2 metabolism, THP-1 Cells, Vesicular Transport Proteins genetics, Vesicular Transport Proteins metabolism, Viral Envelope Proteins genetics, Viral Envelope Proteins immunology, Viral Envelope Proteins metabolism, Antibodies, Bispecific pharmacology, Antiviral Agents pharmacology, Broadly Neutralizing Antibodies pharmacology, Ebolavirus drug effects, Hemorrhagic Fever, Ebola drug therapy, Lysosomes drug effects, Niemann-Pick C1 Protein antagonists & inhibitors, Viral Envelope Proteins antagonists & inhibitors, Virus Internalization drug effects
- Abstract
Multiple agents in the family Filoviridae (filoviruses) are associated with sporadic human outbreaks of highly lethal disease, while others, including several recently identified agents, possess strong zoonotic potential. Although viral glycoprotein (GP)-specific monoclonal antibodies have demonstrated therapeutic utility against filovirus disease, currently FDA-approved molecules lack antiviral breadth. The development of broadly neutralizing antibodies has been challenged by the high sequence divergence among filovirus GPs and the complex GP proteolytic cleavage cascade that accompanies filovirus entry. Despite this variability in the antigenic surface of GP, all filoviruses share a site of vulnerability-the binding site for the universal filovirus entry receptor, Niemann-Pick C1 (NPC1). Unfortunately, this site is shielded in extracellular GP and only uncovered by proteolytic cleavage by host proteases in late endosomes and lysosomes, which are generally inaccessible to antibodies. To overcome this obstacle, we previously developed a 'Trojan horse' therapeutic approach in which engineered bispecific antibodies (bsAbs) coopt viral particles to deliver GP:NPC1 interaction-blocking antibodies to their endo/lysosomal sites of action. This approach afforded broad protection against members of the genus Ebolavirus but could not neutralize more divergent filoviruses. Here, we describe next-generation Trojan horse bsAbs that target the endo/lysosomal GP:NPC1 interface with pan-filovirus breadth by exploiting the conserved and widely expressed host cation-independent mannose-6-phosphate receptor for intracellular delivery. Our work highlights a new avenue for the development of single therapeutics protecting against all known and newly emerging filoviruses., Competing Interests: KC is a member of the scientific advisory boards of Integrum Scientific, LLC, Biovaxys Technology Corp, and the Pandemic Security Initiative of Celdara Medical, LLC, and he has consulted for Axon Advisors, LLC. JL is a consultant for Celdara Medical, LLC. Author JT was employed by company Mapp Biopharmaceutical. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wirchnianski, Wec, Nyakatura, Herbert, Slough, Kuehne, Mittler, Jangra, Teruya, Dye, Lai and Chandran.)
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- 2021
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45. Monoclonal antibodies from humans with Mycobacterium tuberculosis exposure or latent infection recognize distinct arabinomannan epitopes.
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Ishida E, Corrigan DT, Malonis RJ, Hofmann D, Chen T, Amin AG, Chatterjee D, Joe M, Lowary TL, Lai JR, and Achkar JM
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- Humans, Antibodies, Bacterial blood, Antibodies, Monoclonal blood, Latent Infection physiopathology, Mycobacterium tuberculosis immunology, Tuberculosis physiopathology
- Abstract
The surface polysacharide arabinomannan (AM) and related glycolipid lipoarabinomannan (LAM) play critical roles in tuberculosis pathogenesis. Human antibody responses to AM/LAM are heterogenous and knowledge of reactivity to specific glycan epitopes at the monoclonal level is limited, especially in individuals who can control M. tuberculosis infection. We generated human IgG mAbs to AM/LAM from B cells of two asymptomatic individuals exposed to or latently infected with M. tuberculosis. Here, we show that two of these mAbs have high affinity to AM/LAM, are non-competing, and recognize different glycan epitopes distinct from other anti-AM/LAM mAbs reported. Both mAbs recognize virulent M. tuberculosis and nontuberculous mycobacteria with marked differences, can be used for the detection of urinary LAM, and can detect M. tuberculosis and LAM in infected lungs. These mAbs enhance our understanding of the spectrum of antibodies to AM/LAM epitopes in humans and are valuable for tuberculosis diagnostic and research applications., (© 2021. The Author(s).)
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- 2021
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46. Near-germline human monoclonal antibodies neutralize and protect against multiple arthritogenic alphaviruses.
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Malonis RJ, Earnest JT, Kim AS, Angeliadis M, Holtsberg FW, Aman MJ, Jangra RK, Chandran K, Daily JP, Diamond MS, Kielian M, and Lai JR
- Subjects
- Alphavirus immunology, Alphavirus pathogenicity, Animals, Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacology, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Arthritis etiology, Arthritis immunology, Arthritis virology, Broadly Neutralizing Antibodies isolation & purification, Broadly Neutralizing Antibodies pharmacology, Chikungunya Fever virology, Chikungunya virus immunology, Chikungunya virus pathogenicity, Cross Reactions, Epitopes immunology, Germ Cells immunology, Glycoproteins immunology, Humans, Male, Mice, Mice, Inbred C57BL, Alphavirus Infections immunology, Antibodies, Monoclonal isolation & purification, Broadly Neutralizing Antibodies immunology
- Abstract
Arthritogenic alphaviruses are globally distributed, mosquito-transmitted viruses that cause rheumatological disease in humans and include Chikungunya virus (CHIKV), Mayaro virus (MAYV), and others. Although serological evidence suggests that some antibody-mediated heterologous immunity may be afforded by alphavirus infection, the extent to which broadly neutralizing antibodies that protect against multiple arthritogenic alphaviruses are elicited during natural infection remains unknown. Here, we describe the isolation and characterization of MAYV-reactive alphavirus monoclonal antibodies (mAbs) from a CHIKV-convalescent donor. We characterized 33 human mAbs that cross-reacted with CHIKV and MAYV and engaged multiple epitopes on the E1 and E2 glycoproteins. We identified five mAbs that target distinct regions of the B domain of E2 and potently neutralize multiple alphaviruses with differential breadth of inhibition. These broadly neutralizing mAbs (bNAbs) contain few somatic mutations and inferred germline-revertants retained neutralizing capacity. Two bNAbs, DC2.M16 and DC2.M357, protected against both CHIKV- and MAYV-induced musculoskeletal disease in mice. These findings enhance our understanding of the cross-reactive and cross-protective antibody response to human alphavirus infections., Competing Interests: Competing interest statement: The antibodies described in this manuscript are the subject of a US Patent Application that lists R.J.M., M.K., and J.R.L. as coinventors. J.R.L. and K.C. are consultants for Celdara Medical. K.C. is a member of the Scientific Advisory Board of Integrum Scientific, LLC and Biovaxys Tecchnology Corp. M.S.D. is a consultant for Inbios, Vir Biotechnology, and Fortress Biotech and is on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory at Washington University School of Medicine has received sponsored unrelated research agreements from Vir Biotechnology and Emergent BioSolutions.
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- 2021
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47. Pan-protective anti-alphavirus human antibodies target a conserved E1 protein epitope.
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Kim AS, Kafai NM, Winkler ES, Gilliland TC Jr, Cottle EL, Earnest JT, Jethva PN, Kaplonek P, Shah AP, Fong RH, Davidson E, Malonis RJ, Quiroz JA, Williamson LE, Vang L, Mack M, Crowe JE Jr, Doranz BJ, Lai JR, Alter G, Gross ML, Klimstra WB, Fremont DH, and Diamond MS
- Subjects
- Alphavirus Infections immunology, Alphavirus Infections virology, Amino Acid Sequence, Animals, Antibodies, Monoclonal immunology, Chikungunya Fever immunology, Chikungunya Fever virology, Chikungunya virus immunology, Chlorocebus aethiops, Epitope Mapping, Epitopes chemistry, Humans, Male, Mice, Inbred C57BL, Models, Biological, Monocytes metabolism, Vero Cells, Viral Proteins chemistry, Virus Release, Mice, Alphavirus immunology, Antibodies, Viral immunology, Conserved Sequence immunology, Epitopes immunology, Viral Proteins immunology
- Abstract
Alphaviruses are emerging, mosquito-transmitted pathogens that cause musculoskeletal and neurological disease in humans. Although neutralizing antibodies that inhibit individual alphaviruses have been described, broadly reactive antibodies that protect against both arthritogenic and encephalitic alphaviruses have not been reported. Here, we identify DC2.112 and DC2.315, two pan-protective yet poorly neutralizing human monoclonal antibodies (mAbs) that avidly bind to viral antigen on the surface of cells infected with arthritogenic and encephalitic alphaviruses. These mAbs engage a conserved epitope in domain II of the E1 protein proximal to and within the fusion peptide. Treatment with DC2.112 or DC2.315 protects mice against infection by both arthritogenic (chikungunya and Mayaro) and encephalitic (Venezuelan, Eastern, and Western equine encephalitis) alphaviruses through multiple mechanisms, including inhibition of viral egress and monocyte-dependent Fc effector functions. These findings define a conserved epitope recognized by weakly neutralizing yet protective antibodies that could be targeted for pan-alphavirus immunotherapy and vaccine design., Competing Interests: Declaration of interests M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and Carnival Corporation and on the scientific advisory boards of Moderna and Immunome. The Diamond and Fremont laboratories received support from Emergent BioSolutions under a sponsored research agreement. The Diamond laboratory has unrelated research agreements from Moderna and Vir Biotechnology. D.H.F. is a founder of Courier Therapeutics. J.R.L. is a consultant for Celdara Medical. DC2.112 and DC2.315 are the subject of a US patent application with R.J.M., J.A.Q., and J.R.L. as co-inventors. R.H.F., E.D., and B.J.D. are employees of Integral Molecular, and B.J.D. is a shareholder of Integral Molecular. J.E.C. has served as a consultant for Lilly and Luna Biologics, is a member of the Scientific Advisory Boards of CompuVax and Meissa Vaccines, and is founder of IDBiologics. The Crowe laboratory has received unrelated sponsored research agreements from Astra Zeneca and IDBiologics. M.L.G. is an unpaid member of the scientific advisory boards of Protein Metrics and GenNext. G.A. is a founder of SeromYx Systems., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2021
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48. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Qualitative Immunoglobulin G Assays: The Value of Numeric Reporting.
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Forest SK, Orner EP, Goldstein DY, Wirchnianski AS, Bortz RH, Laudermilch E, Florez C, Malonis RJ, Georgiev GI, Vergnolle O, Lo Y, Campbell ST, Barnhill J, Cadoff EM, Lai JR, Chandran K, Weiss LM, Fox AS, Prystowsky MB, and Wolgast LR
- Subjects
- COVID-19 diagnosis, COVID-19 epidemiology, COVID-19 Nucleic Acid Testing statistics & numerical data, COVID-19 Serological Testing statistics & numerical data, Cohort Studies, Humans, New York City epidemiology, Pandemics, Sensitivity and Specificity, Severity of Illness Index, Antibodies, Viral blood, COVID-19 immunology, COVID-19 Serological Testing methods, Immunoglobulin G blood, SARS-CoV-2 immunology
- Abstract
Context.—: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) testing is used for serosurveillance and will be important to evaluate vaccination status. Given the urgency to release coronavirus disease 2019 (COVID-19) serology tests, most manufacturers have developed qualitative tests., Objective.—: To evaluate clinical performance of 6 different SARS-CoV-2 IgG assays and their quantitative results to better elucidate the clinical role of serology testing in COVID-19., Design.—: Six SARS-CoV-2 IgG assays were tested using remnant specimens from 190 patients. Sensitivity and specificity were evaluated for each assay with the current manufacturer's cutoff and a lower cutoff. A numeric result analysis and discrepancy analysis were performed., Results.—: Specificity was higher than 93% for all assays, and sensitivity was higher than 80% for all assays (≥7 days post-polymerase chain reaction testing). Inpatients with more severe disease had higher numeric values compared with health care workers with mild or moderate disease. Several discrepant serology results were those just below the manufacturers' cutoff., Conclusions.—: Severe acute respiratory syndrome coronavirus 2 IgG antibody testing can aid in the diagnosis of COVID-19, especially with negative polymerase chain reaction. Quantitative COVID-19 IgG results are important to better understand the immunologic response and disease course of this novel virus and to assess immunity as part of future vaccination programs., Competing Interests: Chandran, Lai, Fox, Prystowsky, and Weiss are inventors on a patent application related to a COVID-19 diagnostic antibody test. Chandran is an inventor on a patent application related to a COVID-19 neutralization assay. Both applications are assigned to Albert Einstein College of Medicine. Chandran is a member of the scientific advisory board of Integrum Scientific, LLC. Chandran and Lai are members of the scientific advisory board of the Pandemic Security Initiative of Celdara Medical, LLC. The other authors (Forest, Orner, Goldstein, Wirchnianski, Bortz, Laudermilch, Florez, Malonis, Georgiev, Vergnolle, Lo, Campbell, Barnhill, Cadoff, Wolgast) have no relevant financial interest in the products or companies described in this article.
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- 2021
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49. Diverse contributions of avidity to the broad neutralization of Dengue virus by antibodies targeting the E dimer epitope.
- Author
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Remmel JL, Frei JC, Butler SE, Lai JR, and Ackerman ME
- Subjects
- Epitopes chemistry, Epitopes immunology, Hydrogen-Ion Concentration, Immunoglobulin G immunology, Immunoglobulin G metabolism, Neutralization Tests, Antibodies, Neutralizing metabolism, Antibodies, Viral metabolism, Antibody Affinity, Dengue Virus immunology, Epitopes metabolism
- Abstract
Antibodies (Abs) recognizing the Dengue virus (DENV) E dimer epitope (EDE) that potently neutralize all DENV serotypes are promising templates for vaccine design. As an important feature for some Abs is their bivalency, we sought to define the role avidity plays in neutralization by EDE Abs. We compared neutralization activity between bivalent IgGs and monovalent Ab fragments (Fabs) for two EDE Abs, A11 and C10. IgG forms of both Abs exhibited more potent neutralization activity than their counterpart Fabs, yet only for C10 was this enhanced activity associated with bivalent binding. A11 and C10 also exhibited differential binding profiles to DENV virus-like particles under acidic conditions mimicking the environment that triggers viral membrane fusion, suggesting that EDE Abs employ diverse neutralization mechanisms despite sharing an epitope. Delineating the full range of Ab binding modes and neutralization mechanisms against a single epitope may inform therapeutic approaches and refine vaccine design., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2021
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50. Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever.
- Author
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Fels JM, Maurer DP, Herbert AS, Wirchnianski AS, Vergnolle O, Cross RW, Abelson DM, Moyer CL, Mishra AK, Aguilan JT, Kuehne AI, Pauli NT, Bakken RR, Nyakatura EK, Hellert J, Quevedo G, Lobel L, Balinandi S, Lutwama JJ, Zeitlin L, Geisbert TW, Rey FA, Sidoli S, McLellan JS, Lai JR, Bornholdt ZA, Dye JM, Walker LM, and Chandran K
- Subjects
- Amino Acid Sequence, Animals, Antibodies, Monoclonal immunology, Antigens, Viral metabolism, Biophysical Phenomena, Chlorocebus aethiops, Epitope Mapping, Epitopes metabolism, Female, Hemorrhagic Fever Virus, Crimean-Congo immunology, Hemorrhagic Fever, Crimean prevention & control, Humans, Immunoglobulin G metabolism, Male, Mice, Neutralization Tests, Protein Binding, Protein Engineering, Recombinant Proteins immunology, Vero Cells, Viral Proteins chemistry, Antibodies, Neutralizing immunology, Hemorrhagic Fever, Crimean immunology, Survivors
- Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is a World Health Organization priority pathogen. CCHFV infections cause a highly lethal hemorrhagic fever for which specific treatments and vaccines are urgently needed. Here, we characterize the human immune response to natural CCHFV infection to identify potent neutralizing monoclonal antibodies (nAbs) targeting the viral glycoprotein. Competition experiments showed that these nAbs bind six distinct antigenic sites in the Gc subunit. These sites were further delineated through mutagenesis and mapped onto a prefusion model of Gc. Pairwise screening identified combinations of non-competing nAbs that afford synergistic neutralization. Further enhancements in neutralization breadth and potency were attained by physically linking variable domains of synergistic nAb pairs through bispecific antibody (bsAb) engineering. Although multiple nAbs protected mice from lethal CCHFV challenge in pre- or post-exposure prophylactic settings, only a single bsAb, DVD-121-801, afforded therapeutic protection. DVD-121-801 is a promising candidate suitable for clinical development as a CCHFV therapeutic., Competing Interests: Declaration of interests K.C. is a scientific advisory board member of Integrum Scientific and Biovaxys Technology Corporation. K.C., J.S.M., and J.R.L. are scientific advisory board members of the Pandemic Security Initiative of Celdara Medical. N.T.P. and L.M.W. are employees and shareholders of Adimab. D.P.M. is a shareholder of Adimab. Z.A.B., D.M.A., C.L.M., and L.Z. are shareholders and employees of Mapp Biopharmaceutical. Mapp Biopharmaceutical has filed a patent application related to this work., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
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