臺灣博碩士論文加值系統

常壓游離質譜法(AIMS)因其樣品前處理簡易、操作方便的特性，已經被廣泛引入生物醫學領域之應用。以紙片為取樣基材的常壓游離法能快速由樣品中游離得到待測物訊號，且具有取樣快速和易於保存樣品的特性。
醫院與醫學檢驗中心常以血液中的代謝物檢測判斷病患的生理狀況。本論文中，我們採用即時直接分析游離法（DART）搭配離子阱質譜儀（ion trap MS），以濾紙作為承載血清樣品的基材，即能從微量的人類血清中偵測到膽固醇（cholesterol）脫水後的[M-H2O+H]+訊號。並加入同位素內標準品輔助，可定量樣品中的膽固醇濃度。以此紙片基質取樣搭配即時直接分析游離質譜法（pDART-MS）得到的膽固醇濃度，與商業化的酵素反應螢光檢測組（fluorometric-enzymatic assay）和傳統定量用之液相層析質譜儀（LC-MS）測量同一樣品所得濃度比較，在統計上並無顯著差異。同時，我們以此法測量二十一位參與超級馬拉松的參賽者於賽前、賽後、賽後一天所得的血清樣品。此常壓游離法僅需簡易的樣品前處理，且只需費時約一分鐘，即可得到一個血清樣品的膽固醇濃度。
此外，我們也嘗試將紙片常壓游離法應用於癌症診斷。以乳癌為例，在醫院的常規檢查中，醫師通常以皮下針取患部組織，並將組織沾黏於濾紙上，作為後續病理學檢驗之樣本。我們以該含有組織的紙片樣品，於紙片電噴灑游離法下進行代謝物質分布的快速檢測，判斷該組織為癌症/非癌症。為了降低來自複雜基質的化學干擾，我們於紙片電噴灑游離源後方裝設場不對稱離子遷移譜（FAIMS-PSI-MS）。我們對磷脂質類代謝物所在的質荷比（m/z）600-900的範圍進行統計分析，結果顯示此法所獲得的組織樣品之非定標性代謝物質掃描，具有區別癌症與健康組織的潛能，能於診療過程中，協助醫師定位腫瘤組織之位置。
常壓游離法因其快速、易於操作的特性，能對複雜的生物樣品進行高效率、直接的定量或定性分析。本論文中，描述兩種紙片為基材的生物樣品檢測法，證明常壓游離法於生物醫學領域、臨床檢驗的適用性。

Ambient ionization mass spectrometry (AIMS) techniques have been widely introduced to the field of biomedical analysis due to their simplicity in sample pretreatment and low cost of operation. The advantages of paper-based ambient ionization contains fast extraction of analytes from the raw sample, featuring in its high sampling efficiency and convenience of preserving sample.
Blood test for endogenous small metabolites to determine physiological and biochemical states is routine for laboratory analysis. In this thesis we demonstrate that by combining a commercial direct analysis in real time (DART) ion source with an ion trap mass spectrometer in positive mode, native cholesterol in its dehydration form ([M-H2O+H+], m/z 369) is readily detected from few hundred nanoliters of human serum loaded onto a chromatography paper. Deuterium-labeled cholesterol was used as the internal standard to obtain the absolute quantity of the endogenous cholesterol. The amount of the cholesterol measured by this paper-loaded DART mass spectrometry (pDART-MS) is statistically comparable with that obtained by using commercially available fluorometric-enzymatic assay and LC/MS. Furthermore, serums from twenty-one participants at three different time points in an ultra-marathon were collected to obtain their cholesterol levels. The test requires only minimal sample preparations, and the concentrations of cholesterol in each sample were acquired within a minute.
Furthermore, we also explored the possibility of utilizing paper-based AIMS to cancer diagnosis. In the case of breast cancer, breast tissue is extracted with a hypodermic needle, and wiped onto filter papers for the following pathology diagnosis in hospital. We used this routine paper-based tissue sample incorporating with AIMS for a rapid metabolite profiling to discriminate cancerous/noncancerous tissues. To reduce the chemical noise in the complex matrix without additional sample pretreatment, we interfaced field asymmetric waveform ion mobility spectrometry with paper spray ionization mass spectrometry (FAIMS-PSI-MS). Statistical analysis of MS spectral profiles in the mass range of m/z 600-900, in which the phospholipid species were dominant, was performed. Relative signal intensity of 28 species showed significant difference in cancerous and noncancerous breast tissue with p value <0.05 in t-test. These markers were used to discriminate the 43 tissue samples from patients, potentially assist to locate the tumor during clinical treatment.
AIMS is characteristic for its speed and ease of use together that allows a rapid, direct, and quantitative analysis of complex biological samples. The two approaches of paper-based analysis of biological samples demonstrate that AIMS has the ability to perform clinical applications.

謝誌 i
摘要 iii
Abstract v
圖目錄 x
表目錄 xii
Chapter 1. Clinical Application of Ambient Ionization Mass Spectrometry 1
1-1 Introduction 1
1-2 Desorption electrospray ionization (DESI) 5
1-2-1 Introduction of DESI-MS 5
1-2-2 Clinical applications of DESI-MS 7
1-3 Nanospray desorption electrospray ionization (nanoDESI) and liquid microjunction surface sampling probe (LMJ-SSP) 8
1-3-1 Introduction of NanoDESI and LMJ-SSP 8
1-3-2 Clinical applications of NanoDESI and LMJ-SSP 9
1-4 Direct Analysis in Real Time (DART) 11
1-4-1 Introduction of DART 11
1-4-2 Clinical applications of DART 11
1-5 Rapid evaporative ionization mass spectrometry (REIMS) 13
1-5-1 Introduction of REIMS 13
1-5-2 Clinical applications of REIMS 14
1-6 Touch spray ionization (TSI) and probe-ESI (PESI) 16
1-6-1 Introduction of TSI- and PESI-MS 16
1-6-2 Clinical applications of TSI- and PESI-MS 19
1-7 Paper spray ionization (PSI) 20
1-7-1 Introduction of PSI-MS 20
1-7-2 Clinical applications of PSI-MS 25
1-8 Two-step ESI droplet-assisted desorption ionization and its clinical applications 26
1-9 Conclusion 29
Chapter 2. Paper-based Serum Cholesterol Quantification Using DART-MS 33
2-1 Introduction 33
2-2 Materials and Methods 38
2-2-1 Materials and Reagents 38
2-2-2 Samples Preparations 39
2-2-3 DART Mass Spectrometry Analysis 40
2-2-4 Fluorometric-enzymatic Assay 42
2-2-5 Liquid Chromatography Mass Spectrometry for Quantification 43
2-3 Result and Discussion 45
2-4 Conclusion 58
Chapter 3. Breast Cancer Tissue Analysis Using ESI-MS 61
3-1 Introduction 61
3-2 Materials and Methods 65
3-2-1 Materials and Reagents 65
3-2-2 Sample Preparation 65
3-2-3 Mass Spectrometry and Ion Source 66
3-2-4 Field Asymmetric Waveform Ion Mobility Spectrometry (FAIMS) 67
3-3 Results and Discussion 68
3-4 Conclusion 82
Appendix A: Human Serum Cholesterol Quantification Using Reactive PSI-MS 85
Appendix B: Table of Abbreviation 91
References 93

1. Wagner, M.; Tonoli, D.; Varesio, E.; Hopfgartner, G. “The use of mass spectrometry to analyze dried blood spots” Mass Spectrom. Rev. 2016, 35, 361-438.
2. Hsu, C. C.; Dorrestein, P. C. “Visualizing life with ambient mass spectrometry” Curr. Opin. Biotechnol. 2015, 31, 24-34.
3. Lebedev, A. T. “Ambient ionization mass spectrometry” Russian Chemical Reviews 2015, 84, 665-692.
4. Huang, M. Z.; Cheng, S. C.; Cho, Y. T.; Shiea, J. “Ambient ionization mass spectrometry: a tutorial” Anal. Chim. Acta 2011, 702, 1-15.
5. Takats, Z.; Wiseman, J. M.; Gologan, B.; Cooks, R. G. “Mass spectrometry sampling under ambient conditions with desorption electrospray ionization” Science 2004, 306, 471-473.
6. Cody, R. B.; Laramee, J. A.; Durst, H. D. “Versatile new ion source for the analysis of materials in open air under ambient conditions” Anal. Chem. 2005, 77, 2297-2302.
7. Ifa, D. R.; Eberlin, L. S. “Ambient Ionization Mass Spectrometry for Cancer Diagnosis and Surgical Margin Evaluation” Clin. Chem. 2016, 62, 111-123.
8. Shariatgorji, M.; Strittmatter, N.; Nilsson, A.; Kallback, P.; Alvarsson, A.; Zhang, X.; Vallianatou, T.; Svenningsson, P.; Goodwin, R. J.; Andren, P. E. “Simultaneous imaging of multiple neurotransmitters and neuroactive substances in the brain by desorption electrospray ionization mass spectrometry” Neuroimage 2016, 136, 129-138.
9. Roach, P. J.; Laskin, J.; Laskin, A. “Nanospray desorption electrospray ionization: an ambient method for liquid-extraction surface sampling in mass spectrometry” Analyst 2010, 135, 2233-2236.
10. Manikandan, M.; Kazibwe, Z.; Hasan, N.; Deenadayalan, A.; Gopal, J.; Pradeep, T.; Chun, S. “Biological Desorption Electrospray Ionization Mass Spectrometry (DESI MS) - unequivocal role of crucial ionization factors, solvent system and substrates” Trac-Trends in Analytical Chemistry 2016, 78, 109-119.
11. Wu, C.; Ifa, D. R.; Manicke, N. E.; Cooks, R. G. “Rapid, direct analysis of cholesterol by charge labeling in reactive desorption electrospray ionization” Anal. Chem. 2009, 81, 7618-7624.
12. Heaton, K.; Solazzo, C.; Collins, M. J.; Thomas-Oates, J.; Bergstrom, E. T. “Towards the application of desorption electrospray ionisation mass spectrometry (DESI-MS) to the analysis of ancient proteins from artefacts” Journal of Archaeological Science 2009, 36, 2145-2154.
13. Weston, D. J. “Ambient ionization mass spectrometry: current understanding of mechanistic theory; analytical performance and application areas” Analyst 2010, 135, 661-668.
14. Chughtai, K.; Heeren, R. M. “Mass spectrometric imaging for biomedical tissue analysis” Chem. Rev. 2010, 110, 3237-3277.
15. Eberlin, L. S.; Tibshirani, R. J.; Zhang, J.; Longacre, T. A.; Berry, G. J.; Bingham, D. B.; Norton, J. A.; Zare, R. N.; Poultsides, G. A. “Molecular assessment of surgical-resection margins of gastric cancer by mass-spectrometric imaging” Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 2436-2441.
16. Liu, J.; Gingras, J.; Ganley, K. P.; Vismeh, R.; Teffera, Y.; Zhao, Z. “Whole-body tissue distribution study of drugs in neonate mice using desorption electrospray ionization mass spectrometry imaging” Rapid Commun. Mass Spectrom. 2014, 28, 185-190.
17. Eberlin, L. S.; Ifa, D. R.; Wu, C.; Cooks, R. G. “Three-dimensional vizualization of mouse brain by lipid analysis using ambient ionization mass spectrometry” Angew. Chem. Int. Ed. Engl. 2010, 49, 873-876.
18. Campbell, D. I.; Ferreira, C. R.; Eberlin, L. S.; Cooks, R. G. “Improved spatial resolution in the imaging of biological tissue using desorption electrospray ionization” Anal. Bioanal. Chem. 2012, 404, 389-398.
19. Wiseman, J. M.; Evans, C. A.; Bowen, C. L.; Kennedy, J. H. “Direct analysis of dried blood spots utilizing desorption electrospray ionization (DESI) mass spectrometry” The Analyst 2010, 135, 720.
20. Chen, H.; Cotte-Rodriguez, I.; Cooks, R. G. “cis-Diol functional group recognition by reactive desorption electrospray ionization (DESI)” Chem. Commun. (Camb.) 2006, 597-599.
21. Lostun, D.; Perez, C. J.; Licence, P.; Barrett, D. A.; Ifa, D. R. “Reactive DESI-MS imaging of biological tissues with dicationic ion-pairing compounds” Anal. Chem. 2015, 87, 3286-3293.
22. Calligaris, D.; Caragacianu, D.; Liu, X.; Norton, I.; Thompson, C. J.; Richardson, A. L.; Golshan, M.; Easterling, M. L.; Santagata, S.; Dillon, D. A.; Jolesz, F. A.; Agar, N. Y. “Application of desorption electrospray ionization mass spectrometry imaging in breast cancer margin analysis” Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 15184-15189.
23. Kerian, K. S.; Jarmusch, A. K.; Pirro, V.; Koch, M. O.; Masterson, T. A.; Cheng, L.; Cooks, R. G. “Differentiation of prostate cancer from normal tissue in radical prostatectomy specimens by desorption electrospray ionization and touch spray ionization mass spectrometry” Analyst 2015, 140, 1090-1098.
24. Santagata, S.; Eberlin, L. S.; Norton, I.; Calligaris, D.; Feldman, D. R.; Ide, J. L.; Liu, X.; Wiley, J. S.; Vestal, M. L.; Ramkissoon, S. H.; Orringer, D. A.; Gill, K. K.; Dunn, I. F.; Dias-Santagata, D.; Ligon, K. L.; Jolesz, F. A.; Golby, A. J.; Cooks, R. G.; Agar, N. Y. “Intraoperative mass spectrometry mapping of an onco-metabolite to guide brain tumor surgery” Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 11121-11126.
25. Eberlin, L. S.; Norton, I.; Dill, A. L.; Golby, A. J.; Ligon, K. L.; Santagata, S.; Cooks, R. G.; Agar, N. Y. “Classifying human brain tumors by lipid imaging with mass spectrometry” Cancer Res. 2012, 72, 645-654.
26. Laskin, J.; Heath, B. S.; Roach, P. J.; Cazares, L.; Semmes, O. J. “Tissue imaging using nanospray desorption electrospray ionization mass spectrometry” Anal. Chem. 2012, 84, 141-148.
27. Van Berkel, G. J.; Kertesz, V.; Koeplinger, K. A.; Vavrek, M.; Kong, A. N. “Liquid microjunction surface sampling probe electrospray mass spectrometry for detection of drugs and metabolites in thin tissue sections” J. Mass Spectrom. 2008, 43, 500-508.
28. Rao, W.; Pan, N.; Yang, Z. “High Resolution Tissue Imaging Using the Single-probe Mass Spectrometry under Ambient Conditions” J. Am. Soc. Mass Spectrom. 2015, 26, 986-993.
29. Van Berkel, G. J.; Kertesz, V. “Continuous-flow liquid microjunction surface sampling probe connected on-line with high-performance liquid chromatography/mass spectrometry for spatially resolved analysis of small molecules and proteins” Rapid Commun. Mass Spectrom. 2013, 27, 1329-1334.
30. Hsu, C. C.; White, N. M.; Hayashi, M.; Lin, E. C.; Poon, T.; Banerjee, I.; Chen, J.; Pfaff, S. L.; Macagno, E. R.; Dorrestein, P. C. “Microscopy ambient ionization top-down mass spectrometry reveals developmental patterning” Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 14855-14860.
31. Hsu, C. C.; Chou, P. T.; Zare, R. N. “Imaging of Proteins in Tissue Samples Using Nanospray Desorption Electrospray Ionization Mass Spectrometry” Anal. Chem. 2015, 87, 11171-11175.
32. Dutkiewicz, E. P.; Hsieh, K. T.; Wang, Y. S.; Chiu, H. Y.; Urban, P. L. “Hydrogel Micropatch and Mass Spectrometry-Assisted Screening for Psoriasis-Related Skin Metabolites” Clin. Chem. 2016, 62, 1120-1128.
33. Gross, J. H. “Direct analysis in real time--a critical review on DART-MS” Anal. Bioanal. Chem. 2014, 406, 63-80.
34. Andrade, F. J.; Shelley, J. T.; Wetzel, W. C.; Webb, M. R.; Gamez, G.; Ray, S. J.; Hieftje, G. M. “Atmospheric pressure chemical ionization source. 1. Ionization of compounds in the gas phase” Anal. Chem. 2008, 80, 2646-2653.
35. Jones, C. M.; Fernandez, F. M. “Transmission mode direct analysis in real time mass spectrometry for fast untargeted metabolic fingerprinting” Rapid Commun. Mass Spectrom. 2013, 27, 1311-1318.
36. Song, Y. Q.; Liao, J.; Zha, C.; Wang, B.; Liu, C. C. “A novel approach to determine the tyrosine concentration in human plasma by DART-MS/MS” Analytical Methods 2015, 7, 1600-1605.
37. Zhang, L.; Yong, W.; Liu, J.; Wang, S.; Chen, Q.; Guo, T.; Zhang, J.; Tan, T.; Su, H.; Dong, Y. “Determination of Dicyandiamide in Powdered Milk Using Direct Analysis in Real Time Quadrupole Time-of-Flight Tandem Mass Spectrometry” J. Am. Soc. Mass Spectrom. 2015, 26, 1414-1422.
38. Wang, Y.; Li, C.; Huang, L.; Liu, L.; Guo, Y.; Ma, L.; Liu, S. “Rapid identification of traditional Chinese herbal medicine by direct analysis in real time (DART) mass spectrometry” Anal. Chim. Acta 2014, 845, 70-76.
39. Zhou, M.; McDonald, J. F.; Fernandez, F. M. “Optimization of a direct analysis in real time/time-of-flight mass spectrometry method for rapid serum metabolomic fingerprinting” J. Am. Soc. Mass Spectrom. 2010, 21, 68-75.
40. Schafer, K. C.; Denes, J.; Albrecht, K.; Szaniszlo, T.; Balog, J.; Skoumal, R.; Katona, M.; Toth, M.; Balogh, L.; Takats, Z. “In vivo, in situ tissue analysis using rapid evaporative ionization mass spectrometry” Angew. Chem. Int. Ed. Engl. 2009, 48, 8240-8242.
41. Balog, J.; Sasi-Szabo, L.; Kinross, J.; Lewis, M. R.; Muirhead, L. J.; Veselkov, K.; Mirnezami, R.; Dezso, B.; Damjanovich, L.; Darzi, A.; Nicholson, J. K.; Takats, Z. “Intraoperative tissue identification using rapid evaporative ionization mass spectrometry” Sci. Transl. Med. 2013, 5, 194ra193.
42. Strittmatter, N.; Lovrics, A.; Sessler, J.; McKenzie, J. S.; Bodai, Z.; Doria, M. L.; Kucsma, N.; Szakacs, G.; Takats, Z. “Shotgun Lipidomic Profiling of the NCI60 Cell Line Panel Using Rapid Evaporative Ionization Mass Spectrometry” Anal. Chem. 2016, 88, 7507-7514.
43. Golf, O.; Strittmatter, N.; Karancsi, T.; Pringle, S. D.; Speller, A. V.; Mroz, A.; Kinross, J. M.; Abbassi-Ghadi, N.; Jones, E. A.; Takats, Z. “Rapid evaporative ionization mass spectrometry imaging platform for direct mapping from bulk tissue and bacterial growth media” Anal. Chem. 2015, 87, 2527-2534.
44. Balog, J.; Szaniszlo, T.; Schaefer, K. C.; Denes, J.; Lopata, A.; Godorhazy, L.; Szalay, D.; Balogh, L.; Sasi-Szabo, L.; Toth, M.; Takats, Z. “Identification of biological tissues by rapid evaporative ionization mass spectrometry” Anal. Chem. 2010, 82, 7343-7350.
45. Balog, J.; Kumar, S.; Alexander, J.; Golf, O.; Huang, J.; Wiggins, T.; Abbassi-Ghadi, N.; Enyedi, A.; Kacska, S.; Kinross, J.; Hanna, G. B.; Nicholson, J. K.; Takats, Z. “In vivo endoscopic tissue identification by rapid evaporative ionization mass spectrometry (REIMS)” Angew. Chem. Int. Ed. Engl. 2015, 54, 11059-11062.
46. Takats, Z.; Denes, J.; Kinross, J. “Identifying the margin: a new method to distinguish between cancerous and noncancerous tissue during surgery” Future Oncol. 2012, 8, 113-116.
47. Hicks, A. M.; DeLong, C. J.; Thomas, M. J.; Samuel, M.; Cui, Z. “Unique molecular signatures of glycerophospholipid species in different rat tissues analyzed by tandem mass spectrometry” Biochim. Biophys. Acta 2006, 1761, 1022-1029.
48. Hiraoka, K.; Nishidate, K.; Mori, K.; Asakawa, D.; Suzuki, S. “Development of probe electrospray using a solid needle” Rapid Commun. Mass Spectrom. 2007, 21, 3139-3144.
49. Mandal, M. K.; Saha, S.; Yoshimura, K.; Shida, Y.; Takeda, S.; Nonami, H.; Hiraoka, K. “Biomolecular analysis and cancer diagnostics by negative mode probe electrospray ionization” Analyst 2013, 138, 1682-1688.
50. Mandal, M. K.; Chen, L. C.; Hiraoka, K. “Sequential and exhaustive ionization of analytes with different surface activity by probe electrospray ionization” J. Am. Soc. Mass Spectrom. 2011, 22, 1493-1500.
51. Jeng, J.; Lin, C. H.; Shiea, J. “Electrospray from nanostructured tungsten oxide surfaces with ultralow sample volume” Anal. Chem. 2005, 77, 8170-8173.
52. Kebarle, P. “A brief overview of the present status of the mechanisms involved in electrospray mass spectrometry” J Mass Spectrom 2000, 35, 804-817.
53. Zhou, S. L.; Cook, K. D. “A mechanistic study of electrospray mass spectrometry: Charge gradients within electrospray droplets and their influence on ion response” Journal of the American Society for Mass Spectrometry 2001, 12, 206-214.
54. Cech, N. B.; Enke, C. G. “Effect of affinity for droplet surfaces on the fraction of analyte molecules charged during electrospray droplet fission” Anal Chem 2001, 73, 4632-4639.
55. Kerian, K. S.; Jarmusch, A. K.; Cooks, R. G. “Touch spray mass spectrometry for in situ analysis of complex samples” Analyst 2014, 139, 2714-2720.
56. Jarmusch, A. K.; Pirro, V.; Kerian, K. S.; Cooks, R. G. “Detection of strep throat causing bacterium directly from medical swabs by touch spray-mass spectrometry” Analyst 2014, 139, 4785-4789.
57. Saha, S.; Mandal, M. K.; Hiraoka, K. “Direct detection of trace level illicit drugs in human body fluids by probe electrospray ionization mass spectrometry (PESI-MS)” Anal Methods-Uk 2013, 5, 4731-4738.
58. Yoshimura, K.; Mandal, M. K.; Hara, M.; Fujii, H.; Chen, L. C.; Tanabe, K.; Hiraoka, K.; Takeda, S. “Real-time diagnosis of chemically induced hepatocellular carcinoma using a novel mass spectrometry-based technique” Anal. Biochem. 2013, 441, 32-37.
59. Liu, J.; Cooks, R. G.; Ouyang, Z. “Biological tissue diagnostics using needle biopsy and spray ionization mass spectrometry” Anal. Chem. 2011, 83, 9221-9225.
60. Guthrie, R.; Susi, A. “A Simple Phenylalanine Method for Detecting Phenylketonuria in Large Populations of Newborn Infants” Pediatrics 1963, 32, 338-343.
61. Barfield, M.; Spooner, N.; Lad, R.; Parry, S.; Fowles, S. “Application of dried blood spots combined with HPLC-MS/MS for the quantification of acetaminophen in toxicokinetic studies” J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2008, 870, 32-37.
62. Alfazil, A. A.; Anderson, R. A. “Stability of benzodiazepines and cocaine in blood spots stored on filter paper” J. Anal. Toxicol. 2008, 32, 511-515.
63. Li, W.; Tse, F. L. “Dried blood spot sampling in combination with LC-MS/MS for quantitative analysis of small molecules” Biomed. Chromatogr. 2010, 24, 49-65.
64. Hopfgartner, G.; Bourgogne, E. “Quantitative high-throughput analysis of drugs in biological matrices by mass spectrometry” Mass Spectrom. Rev. 2003, 22, 195-214.
65. Edelbroek, P. M.; van der Heijden, J.; Stolk, L. M. “Dried blood spot methods in therapeutic drug monitoring: methods, assays, and pitfalls” Ther. Drug Monit. 2009, 31, 327-336.
66. Wang, H.; Liu, J.; Cooks, R. G.; Ouyang, Z. “Paper spray for direct analysis of complex mixtures using mass spectrometry” Angew. Chem. Int. Ed. Engl. 2010, 49, 877-880.
67. Yang, Q.; Manicke, N. E.; Wang, H.; Petucci, C.; Cooks, R. G.; Ouyang, Z. “Direct and quantitative analysis of underivatized acylcarnitines in serum and whole blood using paper spray mass spectrometry” Anal. Bioanal. Chem. 2012, 404, 1389-1397.
68. Liu, J.; Wang, H.; Manicke, N. E.; Lin, J. M.; Cooks, R. G.; Ouyang, Z. “Development, characterization, and application of paper spray ionization” Anal. Chem. 2010, 82, 2463-2471.
69. Ren, Y.; Chiang, S.; Zhang, W.; Wang, X.; Lin, Z.; Ouyang, Z. “Paper-capillary spray for direct mass spectrometry analysis of biofluid samples” Anal. Bioanal. Chem. 2016, 408, 1385-1390.
70. Wang, Q.; Zheng, Y.; Zhang, X.; Han, X.; Wang, T.; Zhang, Z. “A silica coated paper substrate: development and its application in paper spray mass spectrometry for rapid analysis of pesticides in milk” Analyst 2015, 140, 8048-8056.
71. Lai, P. H.; Chen, P. C.; Liao, Y. W.; Liu, J. T.; Chen, C. C.; Lin, C. H. “Comparison of gampi paper and nanofibers to chromatography paper used in paper spray-mass spectrometry” Int. J. Mass spectrom. 2015, 375, 14-17.
72. Ren, Y.; Wang, H.; Liu, J.; Zhang, Z.; McLuckey, M. N.; Ouyang, Z. “Analysis of Biological Samples Using Paper Spray Mass Spectrometry: An Investigation of Impacts by the Substrates, Solvents and Elution Methods” Chromatographia 2013, 76, 1339-1346.
73. Zheng, Y. J.; Zhang, X. L.; Yang, H. J.; Liu, X. N.; Zhang, X. R.; Wang, Q.; Zhang, Z. P. “Facile preparation of paper substrates coated with different materials and their applications in paper spray mass spectrometry” Analytical Methods 2015, 7, 5381-5386.
74. Ji, J.; Nie, L.; Liao, L.; Du, R.; Liu, B.; Yang, P. “Ambient ionization based on mesoporous graphene coated paper for therapeutic drug monitoring” J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2016, 1015-1016, 142-149.
75. Zheng, Y.; Wang, Q.; Wang, X.; Chen, Y.; Wang, X.; Zhang, X.; Bai, Z.; Han, X.; Zhang, Z. “Development and Application of Zirconia Coated Paper Substrate for High Sensitivity Analysis of Therapeutic Drugs in Dried Blood Spots” Anal. Chem. 2016, 88, 7005-7013.
76. Manicke, N. E.; Yang, Q. A.; Wang, H.; Oradu, S.; Ouyang, Z.; Cooks, R. G. “Assessment of paper spray ionization for quantitation of pharmaceuticals in blood spots” International Journal of Mass Spectrometry 2011, 300, 123-129.
77. Yang, Q.; Wang, H.; Maas, J. D.; Chappell, W. J.; Manicke, N. E.; Cooks, R. G.; Ouyang, Z. “Paper spray ionization devices for direct, biomedical analysis using mass spectrometry” Int. J. Mass spectrom. 2012, 312, 201-207.
78. Espy, R. D.; Muliadi, A. R.; Ouyang, Z.; Cooks, R. G. “Spray mechanism in paper spray ionization” International Journal of Mass Spectrometry 2012, 325, 167-171.
79. Tang, K.; Gomez, A. “Monodisperse Electrosprays of Low Electric Conductivity Liquids in the Cone-Jet Mode” J. Colloid Interface Sci. 1996, 184, 500-511.
80. Li, A.; Wang, H.; Ouyang, Z.; Cooks, R. G. “Paper spray ionization of polar analytes using non-polar solvents” Chem. Commun. (Camb.) 2011, 47, 2811-2813.
81. Klampfl, C. W.; Himmelsbach, M. “Direct ionization methods in mass spectrometry: An overview” Anal. Chim. Acta 2015, 890, 44-59.
82. Manicke, N. E.; Abu-Rabie, P.; Spooner, N.; Ouyang, Z.; Cooks, R. G. “Quantitative analysis of therapeutic drugs in dried blood spot samples by paper spray mass spectrometry: an avenue to therapeutic drug monitoring” J. Am. Soc. Mass Spectrom. 2011, 22, 1501-1507.
83. Vreken, P.; van Lint, A. E.; Bootsma, A. H.; Overmars, H.; Wanders, R. J.; van Gennip, A. H. “Quantitative plasma acylcarnitine analysis using electrospray tandem mass spectrometry for the diagnosis of organic acidaemias and fatty acid oxidation defects” J. Inherit. Metab. Dis. 1999, 22, 302-306.
84. Rashed, M. S.; Bucknall, M. P.; Little, D.; Awad, A.; Jacob, M.; Alamoudi, M.; Alwattar, M.; Ozand, P. T. “Screening blood spots for inborn errors of metabolism by electrospray tandem mass spectrometry with a microplate batch process and a computer algorithm for automated flagging of abnormal profiles” Clin. Chem. 1997, 43, 1129-1141.
85. Smith, E. H.; Matern, D. “Acylcarnitine analysis by tandem mass spectrometry” Curr Protoc Hum Genet 2010, Chapter 17, Unit 17 18 11-20.
86. Chen, H.; Venter, A.; Cooks, R. G. “Extractive electrospray ionization for direct analysis of undiluted urine, milk and other complex mixtures without sample preparation” Chem. Commun. (Camb.) 2006, 2042-2044.
87. Chen, H.; Yang, S.; Wortmann, A.; Zenobi, R. “Neutral desorption sampling of living objects for rapid analysis by extractive electrospray ionization mass spectrometry” Angew. Chem. Int. Ed. Engl. 2007, 46, 7591-7594.
88. Li, M.; Ding, J.; Gu, H.; Zhang, Y.; Pan, S.; Xu, N.; Chen, H.; Li, H. “Facilitated diffusion of acetonitrile revealed by quantitative breath analysis using extractive electrospray ionization mass spectrometry” Sci. Rep. 2013, 3, 1205.
89. Shiea, J.; Huang, M. Z.; Hsu, H. J.; Lee, C. Y.; Yuan, C. H.; Beech, I.; Sunner, J. “Electrospray-assisted laser desorption/ionization mass spectrometry for direct ambient analysis of solids” Rapid Commun. Mass Spectrom. 2005, 19, 3701-3704.
90. Nemes, P.; Vertes, A. “Laser ablation electrospray ionization for atmospheric pressure, in vivo, and imaging mass spectrometry” Anal. Chem. 2007, 79, 8098-8106.
91. Li, H.; Balan, P.; Vertes, A. “Molecular Imaging of Growth, Metabolism, and Antibiotic Inhibition in Bacterial Colonies by Laser Ablation Electrospray Ionization Mass Spectrometry” Angew. Chem. Int. Ed. Engl. 2016, 55, 15035-15039.
92. Shiea, C.; Huang, Y. L.; Liu, D. L.; Chou, C. C.; Chou, J. H.; Chen, P. Y.; Shiea, J.; Huang, M. Z. “Rapid screening of residual pesticides on fruits and vegetables using thermal desorption electrospray ionization mass spectrometry” Rapid Commun. Mass Spectrom. 2015, 29, 163-170.
93. Lee, C. W.; Su, H.; Wu, K. D.; Shiea, J.; Wu, D. C.; Chen, B. H.; Shin, S. J. “Rapid point-of-care identification of oral medications in gastric lavage content by ambient mass spectrometry in the emergency room” Rapid Commun. Mass Spectrom. 2016, 30, 1295-1303.
94. Lee, C. W.; Su, H.; Chen, P. Y.; Lin, S. J.; Shiea, J.; Shin, S. J.; Chen, B. H. “Rapid identification of pesticides in human oral fluid for emergency management by thermal desorption electrospray ionization/mass spectrometry” J. Mass Spectrom. 2016, 51, 97-104.
95. Feider, C. L.; Elizondo, N.; Eberlin, L. S. “Ambient Ionization and FAIMS Mass Spectrometry for Enhanced Imaging of Multiply Charged Molecular Ions in Biological Tissues” Anal Chem 2016.
96. Griffiths, R. L.; Creese, A. J.; Race, A. M.; Bunch, J.; Cooper, H. J. “LESA FAIMS Mass Spectrometry for the Spatial Profiling of Proteins from Tissue” Anal. Chem. 2016, 88, 6758-6766.
97. Li, L.; Chen, T. C.; Ren, Y.; Hendricks, P. I.; Cooks, R. G.; Ouyang, Z. “Mini 12, miniature mass spectrometer for clinical and other applications--introduction and characterization” Anal. Chem. 2014, 86, 2909-2916.
98. Perkel, J. M. “Miniaturizing Mass Spectrometry” Science AAAS Custom Publishing Office 2014, 928-930.
99. Blick, K. E. “Current trends in automation of immunoassays” J Clin Ligand Assay 1999, 22, 6-12.
100. St-Louis, P. “Status of point-of-care testing: promise, realities, and possibilities” Clin Biochem 2000, 33, 427-440.
101. Annesley, T. M. “Ion Suppression in Mass Spectrometry” Clin. Chem. 2003, 49, 1041-1044.
102. Ganesana, M.; Lee, S. T.; Wang, Y.; Venton, B. J. “Analytical Techniques in Neuroscience: Recent Advances in Imaging, Separation, and Electrochemical Methods” Anal. Chem. 2017, 89, 314-341.
103. Jannetto, P. J.; Fitzgerald, R. L. “Effective Use of Mass Spectrometry in the Clinical Laboratory” Clin. Chem. 2016, 62, 92-98.
104. Peacock, P. M.; Zhang, W. J.; Trimpin, S. “Advances in Ionization for Mass Spectrometry” Anal. Chem. 2017, 89, 372-388.
105. Ferreira, C. R.; Yannell, K. E.; Jarmusch, A. K.; Pirro, V.; Ouyang, Z.; Cooks, R. G. “Ambient Ionization Mass Spectrometry for Point-of-Care Diagnostics and Other Clinical Measurements” Clin. Chem. 2016, 62, 99-110.
106. Li, L.-H.; Hsieh, H.-Y.; Hsu, C.-C. “Clinical Application of Ambient Ionization Mass Spectrometry” Mass Spectrom. 2017, 6, S0060-S0060.
107. Manicke, N. E.; Bills, B. J.; Zhang, C. “Analysis of biofluids by paper spray MS: advances and challenges” Bioanalysis 2016, 8, 589-606.
108. Ma, X.; Ouyang, Z. “Ambient ionization and miniature mass spectrometry system for chemical and biological analysis” Trends Analyt. Chem. 2016, 85, 10-19.
109. Wang, J. H.; Byun, J.; Pennathur, S. “Analytical approaches to metabolomics and applications to systems biology” Semin. Nephrol. 2010, 30, 500-511.
110. Zhang, A.; Sun, H.; Yan, G.; Wang, P.; Wang, X. “Metabolomics for Biomarker Discovery: Moving to the Clinic” Biomed Res. Int. 2015, 2015, 354671.
111. Monteiro, M. S.; Carvalho, M.; Bastos, M. L.; Guedes de Pinho, P. “Metabolomics analysis for biomarker discovery: advances and challenges” Curr. Med. Chem. 2013, 20, 257-271.
112. Song, Y.-q.; Liao, J.; Zha, C.; Wang, B.; Liu, C. C. “A novel approach to determine the tyrosine concentration in human plasma by DART-MS/MS” Anal. Methods 2015, 7, 1600-1605.
113. Gaissmaier, T.; Siebenhaar, M.; Todorova, V.; Hullen, V.; Hopf, C. “Therapeutic drug monitoring in dried blood spots using liquid microjunction surface sampling and high resolution mass spectrometry” Analyst 2016, 141, 892-901.
114. Chiu, Y. H.; Hou, S. K.; How, C. K.; Li, L. H.; Kao, W. F.; Yang, C. C.; Chou, S. L.; Shiau, Y. T.; Lam, C.; Chen, R. J. “Influence of a 100-km ultra-marathon on hepatitis B carrier runners” Int. J. Sports Med. 2013, 34, 841-845.
115. Amundson, D. M.; Zhou, M. “Fluorometric method for the enzymatic determination of cholesterol” J. Biochem. Biophys. Methods 1999, 38, 43-52.
116. Hu, J.; Zhang, Z.; Shen, W. J.; Azhar, S. “Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones” Nutr. Metab. (Lond.) 2010, 7, 47.
117. Felton, C. V.; Crook, D.; Davies, M. J.; Oliver, M. F. “Relation of plaque lipid composition and morphology to the stability of human aortic plaques” Arterioscler. Thromb. Vasc. Biol. 1997, 17, 1337-1345.
118. Bondjers, G.; Olofsson, S. O.; Fager, A.; Wiklund, O. “Atherosclerosis Basic Mechanisms” Acta Med. Scand. 1986, 220, 10-18.
119. Fielding, C. J.; Reaven, G. M.; Liu, G.; Fielding, P. E. “Increased free cholesterol in plasma low and very low density lipoproteins in non-insulin-dependent diabetes mellitus: its role in the inhibition of cholesteryl ester transfer” Proc. Natl. Acad. Sci. U. S. A. 1984, 81, 2512-2516.
120. Martin, M. G.; Pfrieger, F.; Dotti, C. G. “Cholesterol in brain disease: sometimes determinant and frequently implicated” EMBO Rep. 2014, 15, 1036-1052.
121. Stamler, J. “Is Relationship Between Serum Cholesterol and Risk of Premature Death From Coronary Heart Disease Continuous and Graded?” JAMA 1986, 256, 2823.
122. De Hoff, J. L.; Davidson, L. M.; Kritchevsky, D. “An enzymatic assay for determining free and total cholesterol in tissue” Clin. Chem. 1978, 24, 433-435.
123. Minami, Y.; Yokoi, S.; Setoyama, M.; Bando, N.; Takeda, S.; Kawai, Y.; Terao, J. “Combination of TLC blotting and gas chromatography-mass spectrometry for analysis of peroxidized cholesterol” Lipids 2007, 42, 1055-1063.
124. Tian, Q.; Failla, M. L.; Bohn, T.; Schwartz, S. J. “High-performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry determination of cholesterol uptake by Caco-2 cells” Rapid Commun. Mass Spectrom. 2006, 20, 3056-3060.
125. Al-Balaa, D.; Rajchl, A.; Gregrova, A.; Sevcik, R.; Cizkova, H. “DART mass spectrometry for rapid screening and quantitative determination of cholesterol in egg pasta” J. Mass Spectrom. 2014, 49, 911-917.
126. Leonard, P. J.; Shaper, A. G.; Jones, K. W. “Relationship between free and total cholesterol values in human serum” Am. J. Clin. Nutr. 1965, 17, 377-380.
127. Sperry, W. M. “The relationship between total and free cholesterol in human blood serum” J. Biol. Chem. 1936, 114, 125-133.
128. Lie, R. F.; Schmitz, J. M.; Pierre, K. J.; Gochman, N. “Cholesterol oxidase-based determination, by continuous-flow analysis, of total and free cholesterol in serum” Clin. Chem. 1976, 22, 1627-1630.
129. Chou, S. L.; Chou, M. Y.; Wang, Y. H.; Kuo, F. C.; Kao, W. F. “The impact of chronic carrier of hepatitis B virus on liver function in a 7-day ultramarathon race” J. Chin. Med. Assoc. 2016, 79, 179-184.
130. Kao, W. F.; Hou, S. K.; Chiu, Y. H.; Chou, S. L.; Kuo, F. C.; Wang, S. H.; Chen, J. J. “Effects of 100-km ultramarathon on acute kidney injury” Clin. J. Sport Med. 2015, 25, 49-54.
131. Li, L. H.; How, C. K.; Kao, W. F.; Chiu, Y. H.; Meng, C.; Hsu, C. C.; Tsay, Y. G. “The impact of hepatitis B carrier on cardiac troponin I in 100-km ultramarathon runners” J. Chin. Med. Assoc. 2017, 80, 347-352.
132. Wenk, M. R. “The emerging field of lipidomics” Nat. Rev. Drug Discov. 2005, 4, 594-610.
133. Adibhatla, R. M.; Hatcher, J. F.; Dempsey, R. J. “Lipids and lipidomics in brain injury and diseases” The AAPS Journal 2006, 8, E314-E321.
134. Zhou, X.; Mao, J.; Ai, J.; Deng, Y.; Roth, M. R.; Pound, C.; Henegar, J.; Welti, R.; Bigler, S. A. “Identification of plasma lipid biomarkers for prostate cancer by lipidomics and bioinformatics” PLoS One 2012, 7, e48889.
135. Hu, C.; van der Heijden, R.; Wang, M.; van der Greef, J.; Hankemeier, T.; Xu, G. “Analytical strategies in lipidomics and applications in disease biomarker discovery” J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2009, 877, 2836-2846.
136. Fahy, E.; Subramaniam, S.; Brown, H. A.; Glass, C. K.; Merrill, A. H., Jr.; Murphy, R. C.; Raetz, C. R.; Russell, D. W.; Seyama, Y.; Shaw, W.; Shimizu, T.; Spener, F.; van Meer, G.; VanNieuwenhze, M. S.; White, S. H.; Witztum, J. L.; Dennis, E. A. “A comprehensive classification system for lipids” J. Lipid Res. 2005, 46, 839-861.
137. DeSantis, C.; Ma, J.; Bryan, L.; Jemal, A. “Breast cancer statistics, 2013” CA Cancer J. Clin. 2014, 64, 52-62.
138. Siegel, R. L.; Miller, K. D.; Jemal, A. “Cancer statistics, 2016” CA Cancer J. Clin. 2016, 66, 7-30.
139. Eroles, P.; Bosch, A.; Perez-Fidalgo, J. A.; Lluch, A. “Molecular biology in breast cancer: intrinsic subtypes and signaling pathways” Cancer Treat. Rev. 2012, 38, 698-707.
140. Goldhirsch, A.; Wood, W. C.; Coates, A. S.; Gelber, R. D.; Thurlimann, B.; Senn, H. J.; Panel, m. “Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011” Ann. Oncol. 2011, 22, 1736-1747.
141. Veta, M.; Pluim, J. P.; van Diest, P. J.; Viergever, M. A. “Breast cancer histopathology image analysis: a review” IEEE Trans. Biomed. Eng. 2014, 61, 1400-1411.
142. Eberlin, L. S.; Ferreira, C. R.; Dill, A. L.; Ifa, D. R.; Cheng, L.; Cooks, R. G. “Nondestructive, histologically compatible tissue imaging by desorption electrospray ionization mass spectrometry” ChemBioChem 2011, 12, 2129-2132.
143. Espy, R. D.; Muliadi, A. R.; Ouyang, Z.; Cooks, R. G. “Spray mechanism in paper spray ionization” Int. J. Mass spectrom. 2012, 325-327, 167-171.
144. Pirro, V.; Jarmusch, A. K.; Alfaro, C. M.; Hattab, E. M.; Cohen-Gadol, A. A.; Cooks, R. G. “Utility of neurological smears for intrasurgical brain cancer diagnostics and tumour cell percentage by DESI-MS” Analyst 2017, 142, 449-454.
145. Tibshirani, R. “Regression Shrinkage and Selection via the Lasso” Journal of the Royal Statistical Society. Series B (Methodological) 1996, 58, 267-288.
146. Zhou, X.; Pei, J.; Huang, G. “Reactive paper spray mass spectrometry for in situ identification of quinones” Rapid Commun. Mass Spectrom. 2015, 29, 100-106.