Novel circulating- and imaging-based biomarkers to enhance the mechanistic understanding of human drug-induced liver injury
Liver safety biomarkers in current clinical practice are recognized to have certain shortcomings including their representation of general cell death and thus lacking in indicating the specific underlying mechanisms of injury. An informative panel of circulating- and imaging-based biomarkers, will allow a more complete understanding of the processes involved in the complex and multi-cellular disease of drug-induced liver injury; potentially preceding and therefore enabling prediction of disease progression as well as directing appropriate, existing or novel, therapeutic strategies. Several putative liver safety biomarkers are under investigation as discussed throughout this review, informing on a multitude of hepatocellular mechanisms including: early cell death (miR-122), necrosis (HMGB1, K18), apoptosis, (K18), inflammation (HMGB1), mitochondrial damage (GLDH, mtDNA), liver dysfunction (MRI, MSOT) and regeneration (CSF1). These biomarkers also hold translational value to provide important read across between in vitro-in vivo and clin ical test systems. However, gaps in our knowledge remain requiring further focussed research and the ulti mate qualification of key exploratory biomarkers.
Relevance for patients: this novel multi-modal approach of assessing drug-induced liver injury could potentially enable better patient stratification and enhance treatment strategies. Ultimately, this could reduce unnecessary treatment, also decreasing hospital bed occupancy, whilst ensuring early and accurate identifi cation of patients needing intervention.
[1] Lee WM, Senior JR. Recognizing drug-induced liver injury: Current problems, possible solutions. Toxicol Pathol 2005; 33: 155-164.
[2] Shapiro MA, Lewis JH. Causality assessment of drug-induced hepatotoxicity: Promises and pitfalls. Clin Liver Dis 2007; 11:
[3] Kleiner DE, Chalasani NP, Lee WM, Fontana RJ, Bonkovsky HL, Watkins PB, Hayashi PH, Davern TJ, Navarro V, Reddy R, Talwalkar JA, Stolz A, Gu J, Barnhart H, Hoofnagle JH, Drug-Induced Liver Injury N. Hepatic histological findings in suspected drug-induced liver injury: Systematic evaluation and clinical associations. Hepatology 2014; 59: 661-670.
[4] Ward J, Kanchagar C, Veksler-Lublinsky I, Lee RC, McGill MR, Jaeschke H, Curry SC, Ambros VR. Circulating microrna pro files in human patients with acetaminophen hepatotoxicity or ischemic hepatitis. Proc Natl Acad Sci U S A 2014; 111: 12169- 12174.
[5] Bateman DN, Carroll R, Pettie J, Yamamoto T, Elamin ME, Peart L, Dow M, Coyle J, Cranfield KR, Hook C, Sandilands EA, Veiraiah A, Webb D, Gray A, Dargan PI, Wood DM, Thomas SH, Dear JW, Eddleston M. Effect of the uk's revised paracetamol poisoning management guidelines on admissions, adverse reactions and costs of treatment. Br J Clin Pharmacol 2014; 78: 610-618.
[6] Albano E, Rundgren M, Harvison PJ, Nelson SD, Moldeus P. Mechanisms of n-acetyl-p-benzoquinone imine cytotoxicity. Mol Pharmacol 1985; 28: 306-311.
[7] Bray GP. Liver failure induced by paracetamol. BMJ 1993; 306: 157-158.
[8] Manyike PT, Kharasch ED, Kalhorn TF, Slattery JT. Contribu tion of cyp2e1 and cyp3a to acetaminophen reactive metabolite formation. Clin Pharmacol Ther 2000; 67: 275-282.
[9] Lee SST, Buters JTM, Pineau T, Fernandez-Salguero P, Gonza lez FJ. Role of cyp2e1 in the hepatotoxicity of acetaminophen. Journal of Biological Chemistry 1996; 271: 12063-12067.
[10] Zaher H, Buters JT, Ward JM, Bruno MK, Lucas AM, Stern ST, Cohen SD, Gonzalez FJ. Protection against acetaminophen tox icity in cyp1a2 and cyp2e1 double-null mice. Toxicol Appl Pharmacol 1998; 152: 193-199.
[11] Howie D, Adriaenssens PI, Prescott LF. Paracetamol metabo lism following overdosage: Application of high performance liquid chromatography. J Pharm Pharmacol 1977; 29: 235-237.
[12] Tujios S, Fontana RJ. Mechanisms of drug-induced liver injury: From bedside to bench. Nat Rev Gastroenterol Hepatol 2011; 8: 202-211.
[13] Nelson SD. Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin Liver Dis 1990; 10: 267-278.
[14] Yang X, Greenhaw J, Ali A, Shi Q, Roberts DW, Hinson JA, Muskhelishvili L, Beger R, Pence LM, Ando Y, Sun J, Davis K, Salminen WF. Changes in mouse liver protein glutathionylation after acetaminophen exposure. J Pharmacol Exp Ther 2012; 340: 360-368.
[15] Moore M, Thor H, Moore G, Nelson S, Moldeus P, Orrenius S. The toxicity of acetaminophen and n-acetyl-p-benzoquinone imine in isolated hepatocytes is associated with thiol depletion and increased cytosolic ca2+. J Biol Chem 1985; 260: 13035- 13040.
[16] Senior JR. Alanine aminotransferase: A clinical and regulatory tool for detecting liver injury-past, present, and future. Clin Pharmacol Ther 2012; 92: 332-339.
[17] Temple R. Hy's law: Predicting serious hepatotoxicity. Phar macoepidemiol Drug Saf 2006; 15: 241-243.
[18] Watkins PB, Zimmerman HJ, Knapp MJ, Gracon SI, Lewis KW. Hepatotoxic effects of tacrine administration in patients with alzheimer's disease. JAMA 1994; 271: 992-998.
[19] Harrill AH, Roach J, Fier I, Eaddy JS, Kurtz CL, Antoine DJ, Spencer DM, Kishimoto TK, Pisetsky DS, Park BK, WatkinsPB. The effects of heparins on the liver: Application of mecha nistic serum biomarkers in a randomized study in healthy vol unteers. Clin Pharmacol Ther 2012; 92: 214-220.
[20] Starkey Lewis PJ, Dear J, Platt V, Simpson KJ, Craig DG, An toine DJ, French NS, Dhaun N, Webb DJ, Costello EM, Ne optolemos JP, Moggs J, Goldring CE, Park BK. Circulating mi crornas as potential markers of human drug-induced liver injury. Hepatology 2011; 54: 1767-1776.
[21] Clarke JI, Dear JW, Antoine DJ. Recent advances in biomarkers and therapeutic interventions for hepatic drug safety-false dawn or new horizon? Expert Opin Drug Saf 2016: 1-10.
[22] Ozer J, Ratner M, Shaw M, Bailey W, Schomaker S. The cur rent state of serum biomarkers of hepatotoxicity. Toxicology 2008; 245: 194-205.
[23] Antoine DJ, Harrill AH, Watkins PB, Park BK. Safety bi omarkers for drug-induced liver injury - current status and fu ture perspectives. Toxicol Res 2014; 3: 75-85.
[24] Weiler S, Merz M, Kullak-Ublick GA. Drug-induced liver inju ry: The dawn of biomarkers? F1000Prime Rep 2015; 7: 34.
[25] Watkins PB, Seligman PJ, Pears JS, Avigan MI, Senior JR. Us ing controlled clinical trials to learn more about acute drug-induced liver injury. Hepatology 2008; 48: 1680-1689.
[26] McGill MR, Staggs VS, Sharpe MR, Lee WM, Jaeschke H. Serum mitochondrial biomarkers and damage-associated mo lecular patterns are higher in acetaminophen overdose patients with poor outcome. Hepatology 2014; 60: 1336-1345.
[27] McGill MR, Jaeschke H. Mechanistic biomarkers in aceta minophen-induced hepatotoxicity and acute liver failure: From preclinical models to patients. Expert Opin Drug Metab Toxicol 2014; 10: 1005-1017.
[28] Vliegenthart AD, Antoine DJ, Dear JW. Target biomarker pro file for the clinical management of paracetamol overdose. Br J Clin Pharmacol 2015; 80: 351-362.
[29] Dear JW, Antoine DJ. Stratification of paracetamol overdose patients using new toxicity biomarkers: Current candidates and future challenges. Expert Rev Clin Pharmacol 2014; 7: 181-189.
[30] Chen Y, Verfaillie CM. Micrornas: The fine modulators of liver development and function. Liver Int 2014; 34: 976-990.
[31] Lewis AP, Jopling CL. Regulation and biological function of the liver-specific mir-122. Biochem Soc Trans 2010; 38: 1553- 1557.
[32] Vliegenthart AD, Starkey Lewis P, Tucker CS, Del Pozo J, Rid er S, Antoine DJ, Dubost V, Westphal M, Moulin P, Bailey MA, Moggs JG, Goldring CE, Park BK, Dear JW. Retro-orbital blood acquisition facilitates circulating microrna measurement in zebrafish with paracetamol hepatotoxicity. Zebrafish 2014; 11: 219-226.
[33] Dear JW, Antoine DJ, Starkey-Lewis P, Goldring CE, Park BK. Early detection of paracetamol toxicity using circulating liver microrna and markers of cell necrosis. Br J Clin Pharmacol 2014; 77: 904-905.
[34] Arrese M, Eguchi A, Feldstein AE. Circulating micrornas: Emerging biomarkers of liver disease. Semin Liver Dis 2015; 35: 43-54.
[35] Holman NS, Mosedale M, Wolf KK, LeCluyse EL, Watkins PB. Subtoxic alterations in hepatocyte-derived exosomes: An early step in drug-induced liver injury? Toxicol Sci 2016; 151: 365-375.
[36] Church RJ, Otieno M, McDuffie JE, Singh B, Sonee M, Hall L, Watkins PB, Ellinger-Ziegelbauer H, Harrill AH. Beyond mir-122: Identification of microrna alterations in blood during a time course of hepatobiliary injury and biliary hyperplasia in rats. Toxicol Sci 2016; 150: 3-14.
[37] Vliegenthart AD, Shaffer JM, Clarke JI, Peeters LE, Caporali A, Bateman DN, Wood DM, Dargan PI, Craig DG, Moore JK, Thompson AI, Henderson NC, Webb DJ, Sharkey J, Antoine DJ, Park BK, Bailey MA, Lader E, Simpson KJ, Dear JW. Com prehensive microrna profiling in acetaminophen toxicity identi fies novel circulating biomarkers for human liver and kidney injury. Sci Rep 2015; 5: 15501.
[38] Lu B, Wang H, Andersson U, Tracey KJ. Regulation of hmgb1 release by inflammasomes. Prot Cell 2013; 4: 163-167.
[39] Lea JD, Clarke JI, McGuire N, Antoine DJ. Redox-dependent hmgb1 isoforms as pivotal co-ordinators of drug-induced liver injury: Mechanistic biomarkers and therapeutic targets. Antiox id Redox Signal 2016; 24: 652-665.
[40] Andersson U, Antoine DJ, Tracey KJ. The functions of hmgb1 depend on molecular localization and post-translational modifi cations. J Intern Med 2014; 276: 420-424.
[41] Sutrias-Grau M, Bianchi ME, Bernues J. High mobility group protein 1 interacts specifically with the core domain of human tata box-binding protein and interferes with transcription factor iib within the pre-initiation complex. J Biol Chem 1999; 274: 1628-1634.
[42] Antoine DJ, Williams DP, Kipar A, Jenkins RE, Regan SL, Sathish JG, Kitteringham NR, Park BK. High-mobility group box-1 protein and keratin-18, circulating serum proteins in formative of acetaminophen-induced necrosis and apoptosis in vivo. Toxicol Sci 2009; 112: 521-531.
[43] Antoine DJ, Williams DP, Kipar A, Laverty H, Park BK. Diet restriction inhibits apoptosis and hmgb1 oxidation and promotes inflammatory cell recruitment during acetaminophen hepato toxicity. Mol Med 2010; 16: 479-490.
[44] Antoine DJ, Jenkins RE, Dear JW, Williams DP, McGill MR, Sharpe MR, Craig DG, Simpson KJ, Jaeschke H, Park BK. Molecular forms of hmgb1 and keratin-18 as mechanistic bi omarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity. J Hepatol 2012; 56: 1070-1079.
[45] Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein hmgb1 by necrotic cells triggers inflammation. Nature 2002; 418: 191-195.
[46] Yang H, Antoine DJ, Andersson U, Tracey KJ. The many faces of hmgb1: Molecular structure-functional activity in inflamma tion, apoptosis, and chemotaxis. J Leukoc Biol 2013; 93: 865-873.
[47] Huebener P, Pradere JP, Hernandez C, Gwak GY, Caviglia JM, Mu X, Loike JD, Jenkins RE, Antoine DJ, Schwabe RF. The hmgb1/rage axis triggers neutrophil-mediated injury amplifica tion following necrosis. J Clin Invest 2015; 125: 539-550.
[48] Antoine DJ, Jenkins RE, Dear JW, Williams DP, McGill MR,Sharpe MR, Craig DG, Simpson KJ, Jaeschke H, Park BK. Molecular forms of hmgb1 and keratin-18 as mechanistic bi omarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity. J Hepatol 2012; 56: 1070- 1079.
[49] Lundback P, Lea JD, Sowinska A, Ottosson L, Furst CM, Steen J, Aulin C, Clarke JI, Kipar A, Klevenvall L, Yang H, Palmblad K, Park BK, Tracey KJ, Blom AM, Andersson U, Antoine DJ, Erlandsson Harris H. A novel high mobility group box 1 neu tralizing chimeric antibody attenuates drug-induced liver injury and postinjury inflammation in mice. Hepatology 2016; 64: 1699-1710.
[50] Jaeschke H, Williams CD, Ramachandran A, Bajt ML. Aceta minophen hepatotoxicity and repair: The role of sterile inflam mation and innate immunity. Liver Int 2012; 32: 8-20.
[51] Ge X, Antoine DJ, Lu Y, Arriazu E, Leung TM, Klepper AL, Branch AD, Fiel MI, Nieto N. High mobility group box-1 (hmgb1) participates in the pathogenesis of alcoholic liver dis ease (ald). J Biol Chem 2014; 289: 22672-22691.
[52] Ku NO, Strnad P, Zhong BH, Tao GZ, Omary MB. Keratins let liver live: Mutations predispose to liver disease and crosslinking generates mallory-denk bodies. Hepatology 2007; 46: 1639- 1649.
[53] Antoine DJ, Dear JW, Lewis PS, Platt V, Coyle J, Masson M, Thanacoody RH, Gray AJ, Webb DJ, Moggs JG, Bateman DN, Goldring CE, Park BK. Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital. Hepatology 2013; 58: 777-787.
[54] Cummings J, Ranson M, Butt F, Moore D, Dive C. Qualifica tion of m30 and m65 elisas as surrogate biomarkers of cell death: Long term antigen stability in cancer patient plasma. Cancer Chemother Pharmacol 2007; 60: 921-924.
[55] Woolbright BL, Dorko K, Antoine DJ, Clarke JI, Gholami P, Li F, Kumer SC, Schmitt TM, Forster J, Fan F, Jenkins RE, Park BK, Hagenbuch B, Olyaee M, Jaeschke H. Bile acid-induced necrosis in primary human hepatocytes and in patients with ob structive cholestasis. Toxicol Appl Pharmacol 2015; 283: 168-177.
[56] Woolbright BL, Antoine DJ, Jenkins RE, Bajt ML, Park BK, Jaeschke H. Plasma biomarkers of liver injury and inflamma tion demonstrate a lack of apoptosis during obstructive choles tasis in mice. Toxicol Appl Pharmacol 2013; 273: 524-531.
[57] Calogero S, Grassi F, Aguzzi A, Voigtlander T, Ferrier P, Ferrari S, Bianchi ME. The lack of chromosomal protein hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice. Nat Genet 1999; 22: 276-280.
[58] Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A, Rubartelli A, Agresti A, Bianchi ME. Monocytic cells hyper acetylate chromatin protein hmgb1 to redirect it towards secre tion. EMBO J 2003; 22: 5551-5560.
[59] Ostapowicz G, Fontana RJ, Schiodt FV, Larson A, Davern TJ, Han SH, McCashland TM, Shakil AO, Hay JE, Hynan L, Crip pin JS, Blei AT, Samuel G, Reisch J, Lee WM. Results of a prospective study of acute liver failure at 17 tertiary care centers in the united states. Ann Intern Med 2002; 137: 947- 954.
[60] Singer JB, Lewitzky S, Leroy E, Yang F, Zhao X, Klickstein L, Wright TM, Meyer J, Paulding CA. A genome-wide study iden tifies hla alleles associated with lumiracoxib-related liver injury. Nat Genet 2010; 42: 711-714.
[61] Metushi IG, Hayes MA, Uetrecht J. Treatment of pd-1(-/-) mice with amodiaquine and anti-ctla4 leads to liver injury similar to idiosyncratic liver injury in patients. Hepatology 2015; 61: 1332-1342.
[62] Kim SH, Naisbitt DJ. Update on advances in research on idio syncratic drug-induced liver injury. Allergy Asthma Immunol Res 2016; 8: 3-11.
[63] Antoine DJ, Williams DP, Kipar A, Jenkins RE, Regan SL, Sathish JG, Kitteringham NR, Park BK. High-mobility group box-1 protein and keratin-18, circulating serum proteins in formative of acetaminophen-induced necrosis and apoptosis in vivo. Toxicol Sci 2009; 112: 521-531.
[64] Caulin C, Salvesen GS, Oshima RG. Caspase cleavage of kera tin 18 and reorganization of intermediate filaments during epi thelial cell apoptosis. J Cell Biol 1997; 138: 1379-1394.
[65] Bell CW, Jiang W, Reich CF, 3rd, Pisetsky DS. The extracellu lar release of hmgb1 during apoptotic cell death. Am J Physiol Cell Physiol 2006; 291: C1318-1325.
[66] Kang R, Livesey KM, Zeh HJ, 3rd, Lotze MT, Tang D. Meta bolic regulation by hmgb1-mediated autophagy and mitophagy. Autophagy 2011; 7: 1256-1258.
[67] Tang D, Kang R, Livesey KM, Kroemer G, Billiar TR, Van Houten B, Zeh HJ, 3rd, Lotze MT. High-mobility group box 1 is essential for mitochondrial quality control. Cell Metab 2011; 13: 701-711.
[68] Tang D, Kang R, Cheh CW, Livesey KM, Liang X, Schapiro NE, Benschop R, Sparvero LJ, Amoscato AA, Tracey KJ, Zeh HJ, Lotze MT. Hmgb1 release and redox regulates autophagy and apoptosis in cancer cells. Oncogene 2010; 29: 5299-5310.
[69] McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest 2012; 122: 1574-1583.
[70] Prima V, Cao M, Svetlov SI. Ass and sult2a1 are novel and sensitive biomarkers of acute hepatic injury-a comparative study in animal models. J Liver 2013;2
[71] McGill MR, Li F, Sharpe MR, Williams CD, Curry SC, Ma X, Jaeschke H. Circulating acylcarnitines as biomarkers of mito chondrial dysfunction after acetaminophen overdose in mice and humans. Arch Toxicol 2014; 88: 391-401.
[72] Feldman BF. Cerebrospinal fluid; in Kaneko J (ed): Clinical biochemistry of domestic animals. San Diego, Academic Press, 1989, pp 835-865.
[73] Stonard MD. Assessment of nephrotoxicity; in Evans GO (ed): Animal clinical chemistry. London, Taylor & Francis, 1996, pp 87-89.
[74] Schomaker S, Warner R, Bock J, Johnson K, Potter D, Van Winkle J, Aubrecht J. Assessment of emerging biomarkers of liver injury in human subjects. Toxicol Sci 2013;132:276-283.
[75] Antoine DJ, Mercer AE, Williams DP, Park BK. Mecha-nism-based bioanalysis and biomarkers for hepatic chemical stress. Xenobiotica 2009; 39: 565-577.
[76] Nakahira K, Kyung SY, Rogers AJ, Gazourian L, Youn S, Mas saro AF, Quintana C, Osorio JC, Wang Z, Zhao Y, Lawler LA, Christie JD, Meyer NJ, Mc Causland FR, Waikar SS, Waxman AB, Chung RT, Bueno R, Rosas IO, Fredenburgh LE, Baron RM, Christiani DC, Hunninghake GM, Choi AM. Circulating mitochondrial DNA in patients in the icu as a marker of mortal ity: Derivation and validation. PLoS Med 2013; 10:e1001577; discussion e1001577.
[77] Simmons JD, Lee YL, Mulekar S, Kuck JL, Brevard SB, Gon zalez RP, Gillespie MN, Richards WO. Elevated levels of plas ma mitochondrial DNA damps are linked to clinical outcome in severely injured human subjects. Ann Surg 2013; 258: 591-596; discussion 596-598.
[78] Bhattacharyya S, Yan K, Pence L, Simpson PM, Gill P, Letzig LG, Beger RD, Sullivan JE, Kearns GL, Reed MD, Marshall JD, Van Den Anker JN, James LP. Targeted liquid chromatog raphy-mass spectrometry analysis of serum acylcarnitines in acetaminophen toxicity in children. Biomark Med 2014; 8: 147-159.
[79] Moggs J, Moulin P, Pognan F, Brees D, Leonard M, Busch S, Cordier A, Heard DJ, Kammuller M, Merz M, Bouchard P, Chibout SD. Investigative safety science as a competitive ad vantage for pharma. Expert Opin Drug Metab Toxicol 2012; 8: 1071-1082.
[80] Chundru S, Kalb B, Arif-Tiwari H, Sharma P, Costello J, Martin DR. Mri of diffuse liver disease: Characteristics of acute and chronic diseases. Diagn Interv Radiol 2014; 20: 200-208.
[81] Lee SS, Park SH. Radiologic evaluation of nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20: 7392-7402
[82] Martin DR, Lauenstein T, Kalb B, Lurie C, Kitajima H, Sharma P, Salman K, Moreira R, Farris AB, 3rd, Spivey J, Martinez E, Hanish S, Adsay V. Liver mri and histological correlates in chronic liver disease on multiphase gadolinium-enhanced 3d gradient echo imaging. J Magn Reson Imaging 2012; 36: 422-429.
[83] Venkatesh SK, Yin M, Ehman RL. Magnetic resonance elas tography of liver: Technique, analysis, and clinical applications. J Magn Reson Imaging 2013; 37: 544-555.
[84] Cruite I, Schroeder M, Merkle EM, Sirlin CB. Gadoxetate diso dium-enhanced mri of the liver: Part 2, protocol optimization and lesion appearance in the cirrhotic liver. AJR Am J Roent genol 2010; 195: 29-41.
[85] Eakins R, Walsh J, Randle L, Jenkins RE, Schuppe-Koistinen I, Rowe C, Starkey Lewis P, Vasieva O, Prats N, Brillant N, Auli M, Bayliss M, Webb S, Rees JA, Kitteringham NR, Goldring CE, Park BK. Adaptation to acetaminophen exposure elicits major changes in expression and distribution of the hepatic pro teome. Sci Rep 2015; 5: 16423.
[86] Levesque E, Martin E, Dudau D, Lim C, Dhonneur G, Azoulay D. Current use and perspective of indocyanine green clearance in liver diseases. Anaesth Crit Care Pain Med 2016; 35: 49-57.
[87] Sakka SG. Assessing liver function. Curr Opin Crit Care 2007; 13: 207-214.
[88] Imamura H, Sano K, Sugawara Y, Kokudo N, Makuuchi M. Assessment of hepatic reserve for indication of hepatic resec tion: Decision tree incorporating indocyanine green test. J Hepatobiliary Pancreat Surg 2005; 12: 16-22.
[89] Wang X, Pang Y, Ku G, Xie X, Stoica G, Wang LV. Noninva sive laser-induced photoacoustic tomography for structural and functional in vivo imaging of the brain. Nat Biotechnol 2003; 21: 803-806.
[90] Zhang HF, Maslov K, Stoica G, Wang LV. Functional photoa coustic microscopy for high-resolution and noninvasive in vivo imaging. Nat Biotechnol 2006; 24: 848-851.
[91] Dima A, Burton NC, Ntziachristos V. Multispectral optoacous tic tomography at 64, 128, and 256 channels. J Biomed Opt 2014; 19: 36021.
[92] Scarfe L, Rak-Raszewska A, Geraci S, Darssan D, Sharkey J, Huang J, Burton NC, Mason D, Ranjzad P, Kenny S, Gretz N, Levy R, Kevin Park B, Garcia-Finana M, Woolf AS, Murray P, Wilm B. Measures of kidney function by minimally invasive techniques correlate with histological glomerular damage in scid mice with adriamycin-induced nephropathy. Sci Rep 2015; 5: 13601.
[93] Waldner MJ, Knieling F, Egger C, Morscher S, Claussen J, Vet ter M, Kielisch C, Fischer S, Pfeifer L, Hagel A, Goertz RS, Wildner D, Atreya R, Strobel D, Neurath MF. Multispectral optoacoustic tomography in crohn's disease: Noninvasive im aging of disease activity. Gastroenterology 2016; 151: 238-240.
[94] Lisotti A, Azzaroli F, Buonfiglioli F, Montagnani M, Cecinato P, Turco L, Calvanese C, Simoni P, Guardigli M, Arena R, Cucchetti A, Colecchia A, Festi D, Golfieri R, Mazzella G. In docyanine green retention test as a noninvasive marker of portal hypertension and esophageal varices in compensated liver cir rhosis. Hepatology 2014; 59: 643-650.
[95] Stutchfield BM, Antoine DJ, Mackinnon AC, Gow DJ, Bain CC, Hawley CA, Hughes MJ, Francis B, Wojtacha D, Man TY, Dear JW, Devey LR, Mowat AM, Pollard JW, Park BK, Jenkins SJ, Simpson KJ, Hume DA, Wigmore SJ, Forbes SJ. Csf1 restores innate immunity after liver injury in mice and serum levels in Distributed under creative commons license 4.0 dicate outcomes of patients with acute liver failure. Gastroen terol 2015; 149: 1896-1909.
[96] Sauter KA, Waddell LA, Lisowski ZM, Young R, Lefevre L, Davis GM, Clohisey SM, McCulloch M, Magowan E, Mabbott NA, Summers KM, Hume DA. Macrophage colony-stimulating factor (csf1) controls monocyte production and maturation and the steady-state size of the liver in pigs. Am J Physiol Gastroin test Liver Physiol 2016; 311: G533-547.
[97] Castro RE, Ferreira DM, Zhang X, Borralho PM, Sarver AL, Zeng Y, Steer CJ, Kren BT, Rodrigues CM. Identification of micrornas during rat liver regeneration after partial hepatectomy and modulation by ursodeoxycholic acid. Am J Physiol Gastro intest Liver Physiol 2010; 299: G887-897.
[98] Marquez RT, Wendlandt E, Galle CS, Keck K, McCaffrey AP. Microrna-21 is upregulated during the proliferative phase of liver regeneration, targets pellino-1, and inhibits nf-kappab sig naling. Am J Physiol Gastrointest Liver Physiol 2010; 298: G535-541.
[99] Park HK, Jo W, Choi HJ, Jang S, Ryu JE, Lee HJ, Lee H, Kim H, Yu ES, Son WC. Time-course changes in the expression lev els of mir-122, -155, and -21 as markers of liver cell damage, inflammation, and regeneration in acetaminophen-induced liver injury in rats. J Vet Sci 2016; 17: 45-51.
[100] Juskeviciute E, Dippold RP, Antony AN, Swarup A, Vadigepalli R, Hoek JB. Inhibition of mir-21 rescues liver regeneration after partial hepatectomy in ethanol-fed rats. Am J Physiol Gastroin test Liver Physiol 2016: ajpgi 00292 02016.
[101] Yan IK, Wang X, Asmann YW, Haga H, Patel T. Circulating extracellular rna markers of liver regeneration. PLoS One 2016; 11:e0155888.
[102] Mandrekar SJ, Dahlberg SE, Simon R. Improving clinical trial efficiency: Thinking outside the box. Am Soc Clin Oncol Educ Book 2015:e141-147.
[103] Pollock NR, Colby D, Rolland JP. A point-of-care paper-based fingerstick transaminase test: Toward low-cost "lab-on-a-chip" technology for the developing world. Clin Gastroenterol Hepa tol 2013; 11: 478-482.