Abstract

Two-photon fluorescence lifetime imaging microscopy (2P-FLIM) of autofluorescent metabolic coenzymes has been widely used to investigate energetic perturbations in living cells and tissues in a label-free manner with subcellular resolution. While the currently used state-of-the-art instruments are highly sensitive to local molecular changes associated with these metabolic processes, they are inherently slow and limit the study of dynamic metabolic environments. Here, a sustained video-rate 2P-FLIM imaging system is demonstrated for time-lapse lifetime imaging of reduced nicotinamide adenine dinucleotide, an autofluorescent metabolic coenzyme involved in both aerobic and anaerobic processes. This system is sufficiently sensitive to differences in metabolic activity between aggressive and nonaggressive cancer cell lines and is demonstrated for both wide field-of-view autofluorescence imaging as well as sustained video-rate image acquisition of metabolic dynamics following induction of apoptosis. The unique capabilities of this imaging platform provide a powerful technological advance to further explore rapid metabolic dynamics in living cells.

© 2018 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

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    [Crossref]

2018 (2)

Z. Liu, D. Pouli, C. A. Alonzo, A. Varone, S. Karaliota, K. P. Quinn, K. Münger, K. P. Karalis, and I. Georgakoudi, “Mapping metabolic changes by noninvasive, multiparametric, high-resolution imaging using endogenous contrast,” Sci. Adv. 4, eaap9302 (2018).
[Crossref]

J. Ryu, U. Kang, J. Kim, H. Kim, J. H. Kang, H. Kim, D. K. Sohn, J.-H. Jeong, H. Yoo, and B. Gweon, “Real-time visualization of two-photon fluorescence lifetime imaging microscopy using a wavelength-tunable femtosecond pulsed laser,” Biomed. Opt. Express 9, 3449–3663 (2018).
[Crossref]

2017 (3)

A. J. Bower, M. Marjanovic, Y. Zhao, J. Li, E. J. Chaney, and S. A. Boppart, “Label‐free in vivo cellular‐level detection and imaging of apoptosis,” J. Biophoton. 10, 143–150 (2017).
[Crossref]

M. Eibl, S. Karpf, D. Weng, H. Hakert, T. Pfeiffer, J. P. Kolb, and R. Huber, “Single pulse two photon fluorescence lifetime imaging (SP-FLIM) with MHz pixel rate,” Biomed. Opt. Express 8, 3132–3142 (2017).
[Crossref]

A. J. Bower, B. Chidester, J. Li, Y. Zhao, M. Marjanovic, E. J. Chaney, M. N. Do, and S. A. Boppart, “A quantitative framework for the analysis of multimodal optical microscopy images,” Quant. Imaging Med. Surg. 7, 24–37 (2017).
[Crossref]

2016 (1)

A. J. Bower, Z. Arp, Y. Zhao, J. Li, E. J. Chaney, M. Marjanovic, A. Hughes‐Earle, and S. A. Boppart, “Longitudinal in vivo tracking of adverse effects following topical steroid treatment,” Exp. Dermatol. 25, 362–367 (2016).
[Crossref]

2015 (2)

2014 (1)

2013 (2)

A. J. Walsh, R. S. Cook, H. C. Manning, D. J. Hicks, A. Lafontant, C. L. Arteaga, and M. C. Skala, “Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer,” Cancer Res. 73, 6164–6174 (2013).
[Crossref]

A. V. Miller, M. A. Hicks, W. Nakajima, A. C. Richardson, J. J. Windle, and H. Harada, “Paclitaxel-induced apoptosis Is BAK-dependent, but BAX and BIM-independent in breast tumor,” PLoS ONE 8, e60685 (2013).
[Crossref]

2012 (1)

L. Marcu, “Fluorescence lifetime techniques in medical applications,” Ann. Biomed. Eng. 40, 304–331 (2012).
[Crossref]

2011 (3)

S. Vesuna, R. Torres, and M. J. Levene, “Multiphoton fluorescence, second harmonic generation, and fluorescence lifetime imaging of whole cleared mouse organs,” J. Biomed. Opt. 16, 106009 (2011).
[Crossref]

J.-S. Yu, H.-W. Guo, H.-W. Wang, C.-H. Wang, and Y.-H. Wei, “Increase of reduced nicotinamide adenine dinucleotide fluorescence lifetime precedes mitochondrial dysfunction in staurosporine-induced apoptosis of HeLa cells,” J. Biomed. Opt. 16, 036008 (2011).
[Crossref]

A. M. D. Lee, H. Wang, Y. Yu, S. Tang, J. Zhao, H. Lui, D. McLean, and H. Zeng, “In vivo video rate multiphoton microscopy imaging of human skin,” Opt. Lett. 36, 2865–2867 (2011).
[Crossref]

2008 (1)

H.-W. Wang, V. Ghukasyan, C.-T. Chen, Y.-H. Wei, H.-W. Guo, J.-S. Yu, and F.-J. Kao, “Differentiation of apoptosis from necrosis by dynamic changes of reduced nicotinamide adenine dinucleotide fluorescence lifetime in live cells,” J. Biomed. Opt. 13, 054011 (2008).
[Crossref]

2007 (3)

T. Philippe and U. Michael, “User‐friendly semiautomated assembly of accurate image mosaics in microscopy,” Microsc. Res. Tech. 70, 135–146 (2007).
[Crossref]

N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
[Crossref]

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. USA 104, 19494–19499 (2007).
[Crossref]

2006 (1)

A. E. Carpenter, T. R. Jones, M. R. Lamprecht, C. Clarke, I. H. Kang, O. Friman, D. A. Guertin, J. H. Chang, R. A. Lindquist, J. Moffat, P. Golland, and D. M. Sabatini, “CellProfiler: image analysis software for identifying and quantifying cell phenotypes,” Genome Biol. 7, R100 (2006).
[Crossref]

2005 (2)

R. Gerl and D. L. Vaux, “Apoptosis in the development and treatment of cancer,” Carcinogenesis 26, 263–270 (2005).
[Crossref]

J. R. Unruh, G. Gokulrangan, G. S. Wilson, and C. K. Johnson, “Fluorescence properties of fluorescein, tetramethylrhodamine and Texas Red linked to a DNA aptamer,” Photochem. Photobiol. 81, 682–690 (2005).
[Crossref]

2004 (3)

R. A. Gatenby and R. J. Gillies, “Why do cancers have high aerobic glycolysis?” Nat. Rev. Cancer 4, 891–899 (2004).
[Crossref]

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time‐correlated single‐photon counting,” Microsc. Res. Tech. 63, 58–66 (2004).
[Crossref]

S. Wang, E. A. Konorev, S. Kotamraju, J. Joseph, S. Kalivendi, and B. Kalyanaraman, “Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms,” J. Biol. Chem. 279, 25535–25543 (2004).
[Crossref]

2003 (1)

L.-Y. Xue, S.-M. Chiu, and N. L. Oleinick, “Staurosporine-induced death of MCF-7 human breast cancer cells: a distinction between caspase-3-dependent steps of apoptosis and the critical lethal lesions,” Exp. Cell Res. 283, 135–145 (2003).
[Crossref]

2002 (2)

L. M. Mooney, K. A. Al-Sakkaf, B. L. Brown, and P. R. M. Dobson, “Apoptotic mechanisms in T47D and MCF-7 human breast cancer cells,” Br. J. Cancer 87, 909–917 (2002).
[Crossref]

H. C. Gerritsen, M. A. H. Asselbergs, A. V. Agronskaia, and W. G. J. H. M. Van Sark, “Fluorescence lifetime imaging in scanning microscopes: acquisition speed, photon economy and lifetime resolution,” J. Microsc. 206, 218–224 (2002).
[Crossref]

1999 (1)

D. Magde, G. E. Rojas, and P. G. Seybold, “Solvent dependence of the fluorescence lifetimes of xanthene dyes,” Photochem. Photobiol. 70, 737–744 (1999).
[Crossref]

1996 (1)

G. J. Brakenhoff, M. Müller, and R. I. Ghauharali, “Analysis of efficiency of two‐photon versus single‐photon absorption for fluorescence generation in biological objects,” J. Microsc. 183, 140–144 (1996).
[Crossref]

1995 (1)

C. Thompson, “Apoptosis in the pathogenesis and treatment of disease,” Science 267, 1456–1462 (1995).
[Crossref]

1992 (1)

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. USA 89, 1271–1275 (1992).
[Crossref]

Agronskaia, A. V.

H. C. Gerritsen, M. A. H. Asselbergs, A. V. Agronskaia, and W. G. J. H. M. Van Sark, “Fluorescence lifetime imaging in scanning microscopes: acquisition speed, photon economy and lifetime resolution,” J. Microsc. 206, 218–224 (2002).
[Crossref]

Alonzo, C. A.

Z. Liu, D. Pouli, C. A. Alonzo, A. Varone, S. Karaliota, K. P. Quinn, K. Münger, K. P. Karalis, and I. Georgakoudi, “Mapping metabolic changes by noninvasive, multiparametric, high-resolution imaging using endogenous contrast,” Sci. Adv. 4, eaap9302 (2018).
[Crossref]

Al-Sakkaf, K. A.

L. M. Mooney, K. A. Al-Sakkaf, B. L. Brown, and P. R. M. Dobson, “Apoptotic mechanisms in T47D and MCF-7 human breast cancer cells,” Br. J. Cancer 87, 909–917 (2002).
[Crossref]

Ameloot, M.

N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
[Crossref]

Arp, Z.

A. J. Bower, Z. Arp, Y. Zhao, J. Li, E. J. Chaney, M. Marjanovic, A. Hughes‐Earle, and S. A. Boppart, “Longitudinal in vivo tracking of adverse effects following topical steroid treatment,” Exp. Dermatol. 25, 362–367 (2016).
[Crossref]

Arteaga, C. L.

A. J. Walsh, R. S. Cook, H. C. Manning, D. J. Hicks, A. Lafontant, C. L. Arteaga, and M. C. Skala, “Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer,” Cancer Res. 73, 6164–6174 (2013).
[Crossref]

Asselbergs, M. A. H.

H. C. Gerritsen, M. A. H. Asselbergs, A. V. Agronskaia, and W. G. J. H. M. Van Sark, “Fluorescence lifetime imaging in scanning microscopes: acquisition speed, photon economy and lifetime resolution,” J. Microsc. 206, 218–224 (2002).
[Crossref]

Basaric, N.

N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
[Crossref]

Becker, W.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time‐correlated single‐photon counting,” Microsc. Res. Tech. 63, 58–66 (2004).
[Crossref]

Benndorf, K.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time‐correlated single‐photon counting,” Microsc. Res. Tech. 63, 58–66 (2004).
[Crossref]

Bergmann, A.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time‐correlated single‐photon counting,” Microsc. Res. Tech. 63, 58–66 (2004).
[Crossref]

Biskup, C.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time‐correlated single‐photon counting,” Microsc. Res. Tech. 63, 58–66 (2004).
[Crossref]

Boens, N.

N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
[Crossref]

Boppart, M. D.

Boppart, S. A.

A. J. Bower, B. Chidester, J. Li, Y. Zhao, M. Marjanovic, E. J. Chaney, M. N. Do, and S. A. Boppart, “A quantitative framework for the analysis of multimodal optical microscopy images,” Quant. Imaging Med. Surg. 7, 24–37 (2017).
[Crossref]

A. J. Bower, M. Marjanovic, Y. Zhao, J. Li, E. J. Chaney, and S. A. Boppart, “Label‐free in vivo cellular‐level detection and imaging of apoptosis,” J. Biophoton. 10, 143–150 (2017).
[Crossref]

A. J. Bower, Z. Arp, Y. Zhao, J. Li, E. J. Chaney, M. Marjanovic, A. Hughes‐Earle, and S. A. Boppart, “Longitudinal in vivo tracking of adverse effects following topical steroid treatment,” Exp. Dermatol. 25, 362–367 (2016).
[Crossref]

Y. Zhao, M. Marjanovic, E. J. Chaney, B. W. Graf, Z. Mahmassani, M. D. Boppart, and S. A. Boppart, “Longitudinal label-free tracking of cell death dynamics in living engineered human skin tissue with a multimodal microscope,” Biomed. Opt. Express 5, 3699–3716 (2014).
[Crossref]

Bower, A. J.

A. J. Bower, M. Marjanovic, Y. Zhao, J. Li, E. J. Chaney, and S. A. Boppart, “Label‐free in vivo cellular‐level detection and imaging of apoptosis,” J. Biophoton. 10, 143–150 (2017).
[Crossref]

A. J. Bower, B. Chidester, J. Li, Y. Zhao, M. Marjanovic, E. J. Chaney, M. N. Do, and S. A. Boppart, “A quantitative framework for the analysis of multimodal optical microscopy images,” Quant. Imaging Med. Surg. 7, 24–37 (2017).
[Crossref]

A. J. Bower, Z. Arp, Y. Zhao, J. Li, E. J. Chaney, M. Marjanovic, A. Hughes‐Earle, and S. A. Boppart, “Longitudinal in vivo tracking of adverse effects following topical steroid treatment,” Exp. Dermatol. 25, 362–367 (2016).
[Crossref]

Brakenhoff, G. J.

G. J. Brakenhoff, M. Müller, and R. I. Ghauharali, “Analysis of efficiency of two‐photon versus single‐photon absorption for fluorescence generation in biological objects,” J. Microsc. 183, 140–144 (1996).
[Crossref]

Brown, B. L.

L. M. Mooney, K. A. Al-Sakkaf, B. L. Brown, and P. R. M. Dobson, “Apoptotic mechanisms in T47D and MCF-7 human breast cancer cells,” Br. J. Cancer 87, 909–917 (2002).
[Crossref]

Carpenter, A. E.

A. E. Carpenter, T. R. Jones, M. R. Lamprecht, C. Clarke, I. H. Kang, O. Friman, D. A. Guertin, J. H. Chang, R. A. Lindquist, J. Moffat, P. Golland, and D. M. Sabatini, “CellProfiler: image analysis software for identifying and quantifying cell phenotypes,” Genome Biol. 7, R100 (2006).
[Crossref]

Chaney, E. J.

A. J. Bower, B. Chidester, J. Li, Y. Zhao, M. Marjanovic, E. J. Chaney, M. N. Do, and S. A. Boppart, “A quantitative framework for the analysis of multimodal optical microscopy images,” Quant. Imaging Med. Surg. 7, 24–37 (2017).
[Crossref]

A. J. Bower, M. Marjanovic, Y. Zhao, J. Li, E. J. Chaney, and S. A. Boppart, “Label‐free in vivo cellular‐level detection and imaging of apoptosis,” J. Biophoton. 10, 143–150 (2017).
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A. J. Bower, Z. Arp, Y. Zhao, J. Li, E. J. Chaney, M. Marjanovic, A. Hughes‐Earle, and S. A. Boppart, “Longitudinal in vivo tracking of adverse effects following topical steroid treatment,” Exp. Dermatol. 25, 362–367 (2016).
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Y. Zhao, M. Marjanovic, E. J. Chaney, B. W. Graf, Z. Mahmassani, M. D. Boppart, and S. A. Boppart, “Longitudinal label-free tracking of cell death dynamics in living engineered human skin tissue with a multimodal microscope,” Biomed. Opt. Express 5, 3699–3716 (2014).
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A. E. Carpenter, T. R. Jones, M. R. Lamprecht, C. Clarke, I. H. Kang, O. Friman, D. A. Guertin, J. H. Chang, R. A. Lindquist, J. Moffat, P. Golland, and D. M. Sabatini, “CellProfiler: image analysis software for identifying and quantifying cell phenotypes,” Genome Biol. 7, R100 (2006).
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H.-W. Wang, V. Ghukasyan, C.-T. Chen, Y.-H. Wei, H.-W. Guo, J.-S. Yu, and F.-J. Kao, “Differentiation of apoptosis from necrosis by dynamic changes of reduced nicotinamide adenine dinucleotide fluorescence lifetime in live cells,” J. Biomed. Opt. 13, 054011 (2008).
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A. J. Bower, B. Chidester, J. Li, Y. Zhao, M. Marjanovic, E. J. Chaney, M. N. Do, and S. A. Boppart, “A quantitative framework for the analysis of multimodal optical microscopy images,” Quant. Imaging Med. Surg. 7, 24–37 (2017).
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A. J. Bower, B. Chidester, J. Li, Y. Zhao, M. Marjanovic, E. J. Chaney, M. N. Do, and S. A. Boppart, “A quantitative framework for the analysis of multimodal optical microscopy images,” Quant. Imaging Med. Surg. 7, 24–37 (2017).
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A. E. Carpenter, T. R. Jones, M. R. Lamprecht, C. Clarke, I. H. Kang, O. Friman, D. A. Guertin, J. H. Chang, R. A. Lindquist, J. Moffat, P. Golland, and D. M. Sabatini, “CellProfiler: image analysis software for identifying and quantifying cell phenotypes,” Genome Biol. 7, R100 (2006).
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Z. Liu, D. Pouli, C. A. Alonzo, A. Varone, S. Karaliota, K. P. Quinn, K. Münger, K. P. Karalis, and I. Georgakoudi, “Mapping metabolic changes by noninvasive, multiparametric, high-resolution imaging using endogenous contrast,” Sci. Adv. 4, eaap9302 (2018).
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G. J. Brakenhoff, M. Müller, and R. I. Ghauharali, “Analysis of efficiency of two‐photon versus single‐photon absorption for fluorescence generation in biological objects,” J. Microsc. 183, 140–144 (1996).
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Ghukasyan, V.

H.-W. Wang, V. Ghukasyan, C.-T. Chen, Y.-H. Wei, H.-W. Guo, J.-S. Yu, and F.-J. Kao, “Differentiation of apoptosis from necrosis by dynamic changes of reduced nicotinamide adenine dinucleotide fluorescence lifetime in live cells,” J. Biomed. Opt. 13, 054011 (2008).
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Gillies, R. J.

R. A. Gatenby and R. J. Gillies, “Why do cancers have high aerobic glycolysis?” Nat. Rev. Cancer 4, 891–899 (2004).
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J. R. Unruh, G. Gokulrangan, G. S. Wilson, and C. K. Johnson, “Fluorescence properties of fluorescein, tetramethylrhodamine and Texas Red linked to a DNA aptamer,” Photochem. Photobiol. 81, 682–690 (2005).
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A. E. Carpenter, T. R. Jones, M. R. Lamprecht, C. Clarke, I. H. Kang, O. Friman, D. A. Guertin, J. H. Chang, R. A. Lindquist, J. Moffat, P. Golland, and D. M. Sabatini, “CellProfiler: image analysis software for identifying and quantifying cell phenotypes,” Genome Biol. 7, R100 (2006).
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Gratton, E.

N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
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N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
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A. E. Carpenter, T. R. Jones, M. R. Lamprecht, C. Clarke, I. H. Kang, O. Friman, D. A. Guertin, J. H. Chang, R. A. Lindquist, J. Moffat, P. Golland, and D. M. Sabatini, “CellProfiler: image analysis software for identifying and quantifying cell phenotypes,” Genome Biol. 7, R100 (2006).
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H.-W. Wang, V. Ghukasyan, C.-T. Chen, Y.-H. Wei, H.-W. Guo, J.-S. Yu, and F.-J. Kao, “Differentiation of apoptosis from necrosis by dynamic changes of reduced nicotinamide adenine dinucleotide fluorescence lifetime in live cells,” J. Biomed. Opt. 13, 054011 (2008).
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Hakert, H.

Harada, H.

A. V. Miller, M. A. Hicks, W. Nakajima, A. C. Richardson, J. J. Windle, and H. Harada, “Paclitaxel-induced apoptosis Is BAK-dependent, but BAX and BIM-independent in breast tumor,” PLoS ONE 8, e60685 (2013).
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A. J. Walsh, R. S. Cook, H. C. Manning, D. J. Hicks, A. Lafontant, C. L. Arteaga, and M. C. Skala, “Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer,” Cancer Res. 73, 6164–6174 (2013).
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A. V. Miller, M. A. Hicks, W. Nakajima, A. C. Richardson, J. J. Windle, and H. Harada, “Paclitaxel-induced apoptosis Is BAK-dependent, but BAX and BIM-independent in breast tumor,” PLoS ONE 8, e60685 (2013).
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W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time‐correlated single‐photon counting,” Microsc. Res. Tech. 63, 58–66 (2004).
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N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
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Hughes-Earle, A.

A. J. Bower, Z. Arp, Y. Zhao, J. Li, E. J. Chaney, M. Marjanovic, A. Hughes‐Earle, and S. A. Boppart, “Longitudinal in vivo tracking of adverse effects following topical steroid treatment,” Exp. Dermatol. 25, 362–367 (2016).
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Jeong, J.-H.

Johnson, C. K.

J. R. Unruh, G. Gokulrangan, G. S. Wilson, and C. K. Johnson, “Fluorescence properties of fluorescein, tetramethylrhodamine and Texas Red linked to a DNA aptamer,” Photochem. Photobiol. 81, 682–690 (2005).
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Johnson, M. L.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. USA 89, 1271–1275 (1992).
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Jones, T. R.

A. E. Carpenter, T. R. Jones, M. R. Lamprecht, C. Clarke, I. H. Kang, O. Friman, D. A. Guertin, J. H. Chang, R. A. Lindquist, J. Moffat, P. Golland, and D. M. Sabatini, “CellProfiler: image analysis software for identifying and quantifying cell phenotypes,” Genome Biol. 7, R100 (2006).
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S. Wang, E. A. Konorev, S. Kotamraju, J. Joseph, S. Kalivendi, and B. Kalyanaraman, “Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms,” J. Biol. Chem. 279, 25535–25543 (2004).
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S. Wang, E. A. Konorev, S. Kotamraju, J. Joseph, S. Kalivendi, and B. Kalyanaraman, “Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms,” J. Biol. Chem. 279, 25535–25543 (2004).
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Kalyanaraman, B.

S. Wang, E. A. Konorev, S. Kotamraju, J. Joseph, S. Kalivendi, and B. Kalyanaraman, “Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms,” J. Biol. Chem. 279, 25535–25543 (2004).
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A. E. Carpenter, T. R. Jones, M. R. Lamprecht, C. Clarke, I. H. Kang, O. Friman, D. A. Guertin, J. H. Chang, R. A. Lindquist, J. Moffat, P. Golland, and D. M. Sabatini, “CellProfiler: image analysis software for identifying and quantifying cell phenotypes,” Genome Biol. 7, R100 (2006).
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Kang, J. H.

Kang, U.

Kao, F.-J.

H.-W. Wang, V. Ghukasyan, C.-T. Chen, Y.-H. Wei, H.-W. Guo, J.-S. Yu, and F.-J. Kao, “Differentiation of apoptosis from necrosis by dynamic changes of reduced nicotinamide adenine dinucleotide fluorescence lifetime in live cells,” J. Biomed. Opt. 13, 054011 (2008).
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Z. Liu, D. Pouli, C. A. Alonzo, A. Varone, S. Karaliota, K. P. Quinn, K. Münger, K. P. Karalis, and I. Georgakoudi, “Mapping metabolic changes by noninvasive, multiparametric, high-resolution imaging using endogenous contrast,” Sci. Adv. 4, eaap9302 (2018).
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Karalis, K. P.

Z. Liu, D. Pouli, C. A. Alonzo, A. Varone, S. Karaliota, K. P. Quinn, K. Münger, K. P. Karalis, and I. Georgakoudi, “Mapping metabolic changes by noninvasive, multiparametric, high-resolution imaging using endogenous contrast,” Sci. Adv. 4, eaap9302 (2018).
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Kim, H.

Kim, J.

Kolb, J. P.

König, K.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time‐correlated single‐photon counting,” Microsc. Res. Tech. 63, 58–66 (2004).
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Konorev, E. A.

S. Wang, E. A. Konorev, S. Kotamraju, J. Joseph, S. Kalivendi, and B. Kalyanaraman, “Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms,” J. Biol. Chem. 279, 25535–25543 (2004).
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Kotamraju, S.

S. Wang, E. A. Konorev, S. Kotamraju, J. Joseph, S. Kalivendi, and B. Kalyanaraman, “Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms,” J. Biol. Chem. 279, 25535–25543 (2004).
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N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
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A. J. Walsh, R. S. Cook, H. C. Manning, D. J. Hicks, A. Lafontant, C. L. Arteaga, and M. C. Skala, “Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer,” Cancer Res. 73, 6164–6174 (2013).
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N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
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A. E. Carpenter, T. R. Jones, M. R. Lamprecht, C. Clarke, I. H. Kang, O. Friman, D. A. Guertin, J. H. Chang, R. A. Lindquist, J. Moffat, P. Golland, and D. M. Sabatini, “CellProfiler: image analysis software for identifying and quantifying cell phenotypes,” Genome Biol. 7, R100 (2006).
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Lefèvre, J.-P.

N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
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Li, J.

A. J. Bower, B. Chidester, J. Li, Y. Zhao, M. Marjanovic, E. J. Chaney, M. N. Do, and S. A. Boppart, “A quantitative framework for the analysis of multimodal optical microscopy images,” Quant. Imaging Med. Surg. 7, 24–37 (2017).
[Crossref]

A. J. Bower, M. Marjanovic, Y. Zhao, J. Li, E. J. Chaney, and S. A. Boppart, “Label‐free in vivo cellular‐level detection and imaging of apoptosis,” J. Biophoton. 10, 143–150 (2017).
[Crossref]

A. J. Bower, Z. Arp, Y. Zhao, J. Li, E. J. Chaney, M. Marjanovic, A. Hughes‐Earle, and S. A. Boppart, “Longitudinal in vivo tracking of adverse effects following topical steroid treatment,” Exp. Dermatol. 25, 362–367 (2016).
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Lindquist, R. A.

A. E. Carpenter, T. R. Jones, M. R. Lamprecht, C. Clarke, I. H. Kang, O. Friman, D. A. Guertin, J. H. Chang, R. A. Lindquist, J. Moffat, P. Golland, and D. M. Sabatini, “CellProfiler: image analysis software for identifying and quantifying cell phenotypes,” Genome Biol. 7, R100 (2006).
[Crossref]

Liu, Z.

Z. Liu, D. Pouli, C. A. Alonzo, A. Varone, S. Karaliota, K. P. Quinn, K. Münger, K. P. Karalis, and I. Georgakoudi, “Mapping metabolic changes by noninvasive, multiparametric, high-resolution imaging using endogenous contrast,” Sci. Adv. 4, eaap9302 (2018).
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Malak, H.

N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
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Manning, H. C.

A. J. Walsh, R. S. Cook, H. C. Manning, D. J. Hicks, A. Lafontant, C. L. Arteaga, and M. C. Skala, “Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer,” Cancer Res. 73, 6164–6174 (2013).
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L. Marcu, “Fluorescence lifetime techniques in medical applications,” Ann. Biomed. Eng. 40, 304–331 (2012).
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A. J. Bower, B. Chidester, J. Li, Y. Zhao, M. Marjanovic, E. J. Chaney, M. N. Do, and S. A. Boppart, “A quantitative framework for the analysis of multimodal optical microscopy images,” Quant. Imaging Med. Surg. 7, 24–37 (2017).
[Crossref]

A. J. Bower, M. Marjanovic, Y. Zhao, J. Li, E. J. Chaney, and S. A. Boppart, “Label‐free in vivo cellular‐level detection and imaging of apoptosis,” J. Biophoton. 10, 143–150 (2017).
[Crossref]

A. J. Bower, Z. Arp, Y. Zhao, J. Li, E. J. Chaney, M. Marjanovic, A. Hughes‐Earle, and S. A. Boppart, “Longitudinal in vivo tracking of adverse effects following topical steroid treatment,” Exp. Dermatol. 25, 362–367 (2016).
[Crossref]

Y. Zhao, M. Marjanovic, E. J. Chaney, B. W. Graf, Z. Mahmassani, M. D. Boppart, and S. A. Boppart, “Longitudinal label-free tracking of cell death dynamics in living engineered human skin tissue with a multimodal microscope,” Biomed. Opt. Express 5, 3699–3716 (2014).
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Michael, U.

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A. V. Miller, M. A. Hicks, W. Nakajima, A. C. Richardson, J. J. Windle, and H. Harada, “Paclitaxel-induced apoptosis Is BAK-dependent, but BAX and BIM-independent in breast tumor,” PLoS ONE 8, e60685 (2013).
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N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
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Moffat, J.

A. E. Carpenter, T. R. Jones, M. R. Lamprecht, C. Clarke, I. H. Kang, O. Friman, D. A. Guertin, J. H. Chang, R. A. Lindquist, J. Moffat, P. Golland, and D. M. Sabatini, “CellProfiler: image analysis software for identifying and quantifying cell phenotypes,” Genome Biol. 7, R100 (2006).
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Mooney, L. M.

L. M. Mooney, K. A. Al-Sakkaf, B. L. Brown, and P. R. M. Dobson, “Apoptotic mechanisms in T47D and MCF-7 human breast cancer cells,” Br. J. Cancer 87, 909–917 (2002).
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Muir, R. D.

Müller, M.

G. J. Brakenhoff, M. Müller, and R. I. Ghauharali, “Analysis of efficiency of two‐photon versus single‐photon absorption for fluorescence generation in biological objects,” J. Microsc. 183, 140–144 (1996).
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Z. Liu, D. Pouli, C. A. Alonzo, A. Varone, S. Karaliota, K. P. Quinn, K. Münger, K. P. Karalis, and I. Georgakoudi, “Mapping metabolic changes by noninvasive, multiparametric, high-resolution imaging using endogenous contrast,” Sci. Adv. 4, eaap9302 (2018).
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A. V. Miller, M. A. Hicks, W. Nakajima, A. C. Richardson, J. J. Windle, and H. Harada, “Paclitaxel-induced apoptosis Is BAK-dependent, but BAX and BIM-independent in breast tumor,” PLoS ONE 8, e60685 (2013).
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J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. USA 89, 1271–1275 (1992).
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L.-Y. Xue, S.-M. Chiu, and N. L. Oleinick, “Staurosporine-induced death of MCF-7 human breast cancer cells: a distinction between caspase-3-dependent steps of apoptosis and the critical lethal lesions,” Exp. Cell Res. 283, 135–145 (2003).
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N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
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Z. Liu, D. Pouli, C. A. Alonzo, A. Varone, S. Karaliota, K. P. Quinn, K. Münger, K. P. Karalis, and I. Georgakoudi, “Mapping metabolic changes by noninvasive, multiparametric, high-resolution imaging using endogenous contrast,” Sci. Adv. 4, eaap9302 (2018).
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Z. Liu, D. Pouli, C. A. Alonzo, A. Varone, S. Karaliota, K. P. Quinn, K. Münger, K. P. Karalis, and I. Georgakoudi, “Mapping metabolic changes by noninvasive, multiparametric, high-resolution imaging using endogenous contrast,” Sci. Adv. 4, eaap9302 (2018).
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M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. USA 104, 19494–19499 (2007).
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A. V. Miller, M. A. Hicks, W. Nakajima, A. C. Richardson, J. J. Windle, and H. Harada, “Paclitaxel-induced apoptosis Is BAK-dependent, but BAX and BIM-independent in breast tumor,” PLoS ONE 8, e60685 (2013).
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M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. USA 104, 19494–19499 (2007).
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D. Magde, G. E. Rojas, and P. G. Seybold, “Solvent dependence of the fluorescence lifetimes of xanthene dyes,” Photochem. Photobiol. 70, 737–744 (1999).
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N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
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D. Magde, G. E. Rojas, and P. G. Seybold, “Solvent dependence of the fluorescence lifetimes of xanthene dyes,” Photochem. Photobiol. 70, 737–744 (1999).
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N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
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N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
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N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
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J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. USA 89, 1271–1275 (1992).
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J. R. Unruh, G. Gokulrangan, G. S. Wilson, and C. K. Johnson, “Fluorescence properties of fluorescein, tetramethylrhodamine and Texas Red linked to a DNA aptamer,” Photochem. Photobiol. 81, 682–690 (2005).
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Wang, H.-W.

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H.-W. Wang, V. Ghukasyan, C.-T. Chen, Y.-H. Wei, H.-W. Guo, J.-S. Yu, and F.-J. Kao, “Differentiation of apoptosis from necrosis by dynamic changes of reduced nicotinamide adenine dinucleotide fluorescence lifetime in live cells,” J. Biomed. Opt. 13, 054011 (2008).
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J.-S. Yu, H.-W. Guo, H.-W. Wang, C.-H. Wang, and Y.-H. Wei, “Increase of reduced nicotinamide adenine dinucleotide fluorescence lifetime precedes mitochondrial dysfunction in staurosporine-induced apoptosis of HeLa cells,” J. Biomed. Opt. 16, 036008 (2011).
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J. R. Unruh, G. Gokulrangan, G. S. Wilson, and C. K. Johnson, “Fluorescence properties of fluorescein, tetramethylrhodamine and Texas Red linked to a DNA aptamer,” Photochem. Photobiol. 81, 682–690 (2005).
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L.-Y. Xue, S.-M. Chiu, and N. L. Oleinick, “Staurosporine-induced death of MCF-7 human breast cancer cells: a distinction between caspase-3-dependent steps of apoptosis and the critical lethal lesions,” Exp. Cell Res. 283, 135–145 (2003).
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H.-W. Wang, V. Ghukasyan, C.-T. Chen, Y.-H. Wei, H.-W. Guo, J.-S. Yu, and F.-J. Kao, “Differentiation of apoptosis from necrosis by dynamic changes of reduced nicotinamide adenine dinucleotide fluorescence lifetime in live cells,” J. Biomed. Opt. 13, 054011 (2008).
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A. J. Bower, M. Marjanovic, Y. Zhao, J. Li, E. J. Chaney, and S. A. Boppart, “Label‐free in vivo cellular‐level detection and imaging of apoptosis,” J. Biophoton. 10, 143–150 (2017).
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Anal. Chem. (1)

N. Boens, W. Qin, N. Basarić, J. Hofkens, M. Ameloot, J. Pouget, J.-P. Lefèvre, B. Valeur, E. Gratton, M. vandeVen, N. D. Silva, Y. Engelborghs, K. Willaert, A. Sillen, G. Rumbles, D. Phillips, A. J. W. G. Visser, A. van Hoek, J. R. Lakowicz, H. Malak, I. Gryczynski, A. G. Szabo, D. T. Krajcarski, N. Tamai, and A. Miura, “Fluorescence lifetime standards for time and frequency domain fluorescence spectroscopy,” Anal. Chem. 79, 2137–2149 (2007).
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Ann. Biomed. Eng. (1)

L. Marcu, “Fluorescence lifetime techniques in medical applications,” Ann. Biomed. Eng. 40, 304–331 (2012).
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Biomed. Opt. Express (4)

Br. J. Cancer (1)

L. M. Mooney, K. A. Al-Sakkaf, B. L. Brown, and P. R. M. Dobson, “Apoptotic mechanisms in T47D and MCF-7 human breast cancer cells,” Br. J. Cancer 87, 909–917 (2002).
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Cancer Res. (1)

A. J. Walsh, R. S. Cook, H. C. Manning, D. J. Hicks, A. Lafontant, C. L. Arteaga, and M. C. Skala, “Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer,” Cancer Res. 73, 6164–6174 (2013).
[Crossref]

Carcinogenesis (1)

R. Gerl and D. L. Vaux, “Apoptosis in the development and treatment of cancer,” Carcinogenesis 26, 263–270 (2005).
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Exp. Cell Res. (1)

L.-Y. Xue, S.-M. Chiu, and N. L. Oleinick, “Staurosporine-induced death of MCF-7 human breast cancer cells: a distinction between caspase-3-dependent steps of apoptosis and the critical lethal lesions,” Exp. Cell Res. 283, 135–145 (2003).
[Crossref]

Exp. Dermatol. (1)

A. J. Bower, Z. Arp, Y. Zhao, J. Li, E. J. Chaney, M. Marjanovic, A. Hughes‐Earle, and S. A. Boppart, “Longitudinal in vivo tracking of adverse effects following topical steroid treatment,” Exp. Dermatol. 25, 362–367 (2016).
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Genome Biol. (1)

A. E. Carpenter, T. R. Jones, M. R. Lamprecht, C. Clarke, I. H. Kang, O. Friman, D. A. Guertin, J. H. Chang, R. A. Lindquist, J. Moffat, P. Golland, and D. M. Sabatini, “CellProfiler: image analysis software for identifying and quantifying cell phenotypes,” Genome Biol. 7, R100 (2006).
[Crossref]

J. Biol. Chem. (1)

S. Wang, E. A. Konorev, S. Kotamraju, J. Joseph, S. Kalivendi, and B. Kalyanaraman, “Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms,” J. Biol. Chem. 279, 25535–25543 (2004).
[Crossref]

J. Biomed. Opt. (3)

H.-W. Wang, V. Ghukasyan, C.-T. Chen, Y.-H. Wei, H.-W. Guo, J.-S. Yu, and F.-J. Kao, “Differentiation of apoptosis from necrosis by dynamic changes of reduced nicotinamide adenine dinucleotide fluorescence lifetime in live cells,” J. Biomed. Opt. 13, 054011 (2008).
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J.-S. Yu, H.-W. Guo, H.-W. Wang, C.-H. Wang, and Y.-H. Wei, “Increase of reduced nicotinamide adenine dinucleotide fluorescence lifetime precedes mitochondrial dysfunction in staurosporine-induced apoptosis of HeLa cells,” J. Biomed. Opt. 16, 036008 (2011).
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S. Vesuna, R. Torres, and M. J. Levene, “Multiphoton fluorescence, second harmonic generation, and fluorescence lifetime imaging of whole cleared mouse organs,” J. Biomed. Opt. 16, 106009 (2011).
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J. Biophoton. (1)

A. J. Bower, M. Marjanovic, Y. Zhao, J. Li, E. J. Chaney, and S. A. Boppart, “Label‐free in vivo cellular‐level detection and imaging of apoptosis,” J. Biophoton. 10, 143–150 (2017).
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J. Microsc. (2)

H. C. Gerritsen, M. A. H. Asselbergs, A. V. Agronskaia, and W. G. J. H. M. Van Sark, “Fluorescence lifetime imaging in scanning microscopes: acquisition speed, photon economy and lifetime resolution,” J. Microsc. 206, 218–224 (2002).
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Microsc. Res. Tech. (2)

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Nat. Rev. Cancer (1)

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Opt. Lett. (2)

Photochem. Photobiol. (2)

J. R. Unruh, G. Gokulrangan, G. S. Wilson, and C. K. Johnson, “Fluorescence properties of fluorescein, tetramethylrhodamine and Texas Red linked to a DNA aptamer,” Photochem. Photobiol. 81, 682–690 (2005).
[Crossref]

D. Magde, G. E. Rojas, and P. G. Seybold, “Solvent dependence of the fluorescence lifetimes of xanthene dyes,” Photochem. Photobiol. 70, 737–744 (1999).
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PLoS ONE (1)

A. V. Miller, M. A. Hicks, W. Nakajima, A. C. Richardson, J. J. Windle, and H. Harada, “Paclitaxel-induced apoptosis Is BAK-dependent, but BAX and BIM-independent in breast tumor,” PLoS ONE 8, e60685 (2013).
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Supplementary Material (1)

NameDescription
» Visualization 1       Label-free, cellular resolution metabolic tracking of metabolic dynamics during apoptotic cell death using a video-rate two-photon fluorescence lifetime imaging microscope.

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Figures (3)

Fig. 1.
Fig. 1. High-speed 2P-FLIM system design and characterization. (a) System schematic of 2P-FLIM microscope; (b) representative fluorescence decay curves from standard fluorescent dyes. Inset plot shows comparison between extracted lifetime values compared to literature values for rhodamine B [16], 5' carboxytetramethyl rhodamine [17], and fluorescein [18]. (c) 2P-FLIM image of SHG signal from a urea crystal giving a measure of the response function of the system. Scale bar is approximately 10 μm. Abbreviations: BS, beam splitter; PD, photodiode; M, mirror; RM, resonant mirror; GM, galvo mirror; TL, tube lens; DM, dichroic mirror; OL, objective lens; S, sample; PMT, photomultiplier tube.
Fig. 2.
Fig. 2. High-throughput NADH 2P-FLIM imaging. (a) Wide FOV mosaic of a rat testis specimen acquired in under 5 min; (b) zoomed region from (a) corresponding to red box. White arrows correspond to elastin fluorescence from the fibrous cap of the seminiferous tubules. (c) Lifetime histogram of the acquired mosaic. The large peak corresponds to the NADH fluorescence, while the lower lifetime shoulder (blue arrow) corresponds to the elastin fluorescence. (d), (e) High-speed NADH 2P-FLIM images of (d) MDA-MB-231 and (e) MCF-7 cells; (f) statistical analysis comparing cytoplasmic lifetime from the two cell lines. Bar chart values represent mean ± s.e.m. ( N = 17 for each group). Scale bar in (a) is 250 μm. Scale bar in (d), (e) is approximately 50 μm. * p < 0.01 .
Fig. 3.
Fig. 3. High-speed 2P-FLIM of apoptosis induction in MCF-7 cells. (a)–(c) NADH intensity and (d)–(f) NADH lifetime images of apoptosis induction at time points of (a), (d) 0 s, (b), (e) 20 s, and (c), (f) 70 s. (g) NADH fluorescence intensity and (h) lifetime dynamics in cells 1 and 2 as labeled in (c). (i), (j) Comparison of NADH intensity (i) and lifetime (j) values at 0 and 20 s. Bar chart values represent mean ± s.e.m. ( N = 16 ). Scale bar is approximately 50 μm. * p < 0.01 .

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