Cell Therapy for Critical Limb Ischemia

Name: Work Video:
Duration: 3 min 30 s
Rajesh Gupta; Douglas W. Losordo
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1441, 1759, 1829, 2179, 2202, 2227, 2386, 2798, 2863, 2996, 3072, 3157], 'have': [140, 844, 1018, 1060, 1098, 1110, 1336, 1363, 1818, 1911, 2067], 'particularly': [142], 'poor': [143, 1443, 1602], 'prognosis,': [144], 'high': [146, 610], 'rates': [147, 740], 'amputation': [150, 613, 683, 710, 720, 739, 886, 2860, 2934, 3012], 'mortality.': [152], 'Despite': [153], 'improvements': [154, 166, 1387, 1547, 1795, 4029], 'medical': [156, 201], 'therapy': [157, 202, 424, 512, 877, 1315, 1333, 1569, 1908, 2001, 2116, 2221, 3010, 4203, 4281], 'atherosclerosis': [159, 1138], 'associated': [161, 1543, 4118], 'comorbidities': [162, 2205], 'as': [163, 165, 409, 469, 1027, 1188, 1345, 1604, 1774, 1798, 1800, 1836, 1853, 2175, 2210, 3174, 3625, 3827], 'well': [164, 1132, 1799], 'interventional': [168], 'surgical': [170], 'techniques': [171], 'improve': [173], 'perfusion,': [175], 'CLI': [176, 192, 559, 733, 851, 1426, 1652, 1709, 1733, 1910], 'continues': [177], 'carry': [179], 'risk': [182, 1104, 1122, 1135, 2861, 2935, 3117], 'amputation.2,3': [185], 'A': [186, 835, 3375, 3461, 3533, 3579, 3667, 3707, 3860, 3919, 4055, 4068, 4227, 4230, 4278, 4314], 'significant': [187, 1373, 1386, 1681, 1794], 'portion': [188], 'considered': [194, 403, 794], '"no': [195], 'option"': [196], 'revascularization,': [198], 'no': [200, 1372, 1903], 'has': [203, 357, 853, 1647], 'been': [204, 845, 1648, 2068], 'shown': [205, 966, 979, 1346], 'be': [207, 402, 465, 478, 833, 1163, 1317, 1721, 2207], 'capable': [208, 285], 'reducing': [210], 'need': [212, 856], 'amputation.': [214, 797], 'Therefore,': [215, 1173], 'novel': [216, 3668], 'therapies': [217, 371, 3226], 'needed': [219], 'treat': [221], 'this': [222, 495, 528, 765, 945, 1237, 1282, 1665, 1736, 1748, 1784, 1857, 1896, 2278], 'disorder.Articles': [223], 'see': [224], 'p': [225], '15': [226], '26In': [228], 'late': [230], '1990s,': [231], 'there': [232, 1355, 1384, 1679, 1859], 'was': [233, 250, 264, 572, 805, 888, 891, 974, 1082, 1600, 1738], 'paradigm': [235], 'shift': [236], 'our': [238, 521, 2100], 'understanding': [239, 522], 'mechanisms': [242], 'neovascularization': [244, 296, 3148], 'adult': [246], 'mammals.': [247], 'Previously,': [248], 'it': [249, 947, 1129, 1146], 'thought': [251], 'that': [252, 325, 400, 774, 802, 932, 952, 981, 1052, 1134, 1153, 1358, 1451, 1474, 1503, 1537, 1596, 1678, 1698, 1715, 2046, 2066], 'angiogenesis': [253, 2065, 2796, 2988, 3220, 3289, 3504, 3510], '(ie,': [254, 306], 'sprouting': [256, 3866], 'new': [258, 273, 349], 'vessels': [259, 274, 310], 'from': [260, 1055, 1067, 1351, 2031, 2036, 2201, 2401, 3156, 3971, 4024, 4237], 'previously': [261], 'existing': [262, 650], 'vasculature)': [263], 'only': [266, 892], 'means': [267], 'available': [268], 'formation': [271, 308, 3383, 3869], 'adults.': [276], 'discovery': [278], 'bone': [280, 507, 1927, 1954, 1982, 2604, 3067, 3151], 'marrow-derived': [281, 2605], 'circulating': [282, 2603, 3110], 'progenitor': [283, 318, 331, 369, 381, 1080, 2130, 2566, 2636, 2682, 2720, 2755, 3112, 3199, 4114], 'cells': [284, 292, 382, 1054, 1066, 1081, 1169, 1524, 1969, 2200, 2568, 2637, 2756, 3070, 3113, 3154, 3584, 3632, 3826, 4026], 'contributing': [287, 294], 'differentiation': [289], 'into': [290, 336], 'endothelial': [291, 1079, 2567, 2606, 2635, 2681, 2711, 3111, 3204, 3631, 4020], 'ischemic': [298, 337, 355, 376, 2686, 3160, 3284, 4331], 'tissue': [299, 1430, 3379], 'introduced': [300], 'concept': [302], 'postnatal': [304], 'vasculogenesis': [305], 'de': [311], 'novo': [312], 'using': [313, 538, 918], 'building': [315], 'blocks': [316], 'cells).4,5': [319], 'Preclinical': [320], 'studies': [321, 425, 502, 852, 1653, 1663, 1884, 1904, 2002, 2097, 2122, 2163], 'then': [322], 'provided': [323], 'evidence': [324, 1051, 1357, 1502], 'variety': [327, 2072], 'stem': [329, 2718, 3583, 3676, 3825], 'cell': [332, 423, 442, 448, 453, 490, 510, 1184, 1198, 1314, 1332, 1483, 1487, 1491, 1504, 1568, 1907, 1989, 1993, 2000, 2078, 2093, 2109, 2115, 2131, 2144, 2168, 2220, 2683, 2855, 3179, 3200, 3677, 4115], 'types,': [333], 'delivered': [334, 1525], 'locally': [335], 'tissue,': [338], 'could': [339, 1162], 'exert': [340], 'therapeutic': [341, 378, 2639, 3509, 4028], 'effects': [342, 2676], 'models': [344, 2033], 'ischemia.6–8': [346], 'Subsequently,': [347], 'approach': [350, 906], 'treatment': [353, 545, 1269, 1290, 1297, 1765], 'conditions': [356], 'emerged': [358], 'rapidly': [361], 'evolving,': [362], 'investigators': [364, 1306, 1370, 1472, 1535], 'advancing': [365], 'use': [367, 379], 'cell-based': [370, 3508, 3512], 'advanced': [375, 1458], 'conditions.9,10The': [377], 'poses': [383], 'certain': [384, 928], 'unique': [385, 1301], 'questions': [386], 'clinical': [388, 728, 767, 1194, 1262, 1461, 1644, 1705, 2044, 2089, 2105, 3594, 4120], 'trial': [389, 873, 1263, 3026, 3081], 'design.': [390, 864, 1264], 'For': [391, 652, 865], 'example,': [392, 653, 866, 937], 'addition': [394], 'usual': [397], 'experimental': [398], 'variables': [399], 'would': [401], 'pharmaceutical': [406, 2009], 'agent,': [407], 'such': [408], 'dose': [411, 459, 462, 1998, 2192], 'drug,': [414], 'patient': [416], 'population,': [417], 'end': [420, 955, 977, 1395, 1587, 1607, 1635, 1645, 1702, 1718, 1730, 1749, 1777], 'points,': [421, 1396], 'cardiovascular': [422, 1331, 1567, 2092, 2108, 4332], 'must': [426, 477, 753], 'consider': [427, 754], 'many': [428], 'additional': [429], 'variables,': [430], 'including': [431, 1397], 'source': [433], 'stem/progenitor': [435, 1144, 1168], 'cells,': [436, 441, 1343, 1946], 'method': [438], 'obtaining': [440], 'processing': [443], 'protocols,': [444], 'selection': [446, 759, 1603], 'subtypes,': [449], 'route': [451], 'delivery,': [454], 'whether': [456, 1309], 'single': [458, 1322, 1340, 1360, 1556, 2157, 2185], 'multiple': [461, 1538, 1572, 2048, 2159, 2204], 'regimen': [463], 'will': [464, 2081, 2137, 2165, 2206], 'tested.': [466], 'In': [467, 494, 944, 1074, 1236, 1411, 1514], 'addition,': [468, 1075, 1412, 1515], 'biological': [471, 3591], 'therapy,': [472], 'extensive': [473, 3385], 'quality': [474], 'control': [475, 581, 616, 788, 816, 1821], 'measures': [476], 'place': [480], 'ensure': [482], 'safety': [483, 2215], 'evaluate': [486, 503], 'impact': [488], 'phenotype': [491, 2132], 'on': [492, 792, 1788, 2432, 2677, 3011, 3633], 'efficacy.': [493], 'issue': [496, 2085], 'Circulation:': [498], 'Interventions,': [500, 2416], '2': [501, 1670, 1861, 2096, 3415], 'efficacy': [505, 1195, 1701, 2037, 2217, 3177], 'marrow': [508, 1928, 1955, 1983, 3068, 3152, 3582, 4366], 'mononuclear': [509, 2854, 3069, 3153], '(BM-MNC)': [511], 'subjects': [514, 551, 557, 731, 776, 789, 1056, 1068, 1085, 1158, 1405], 'CLI,': [516, 882], 'both': [518], 'simultaneously': [519], 'advance': [520], 'underscore': [524, 1180], 'challenges': [526], 'field.Idei': [529], 'colleagues11': [531], 'report': [532, 1206, 2400], 'results': [534, 1208], 'their': [536, 1575, 1837, 2171], 'experience': [537, 849], 'intramuscular': [539, 1886, 2990], 'injection': [540, 1935], 'BM-MNCs': [542, 554, 1252, 1272, 1408, 1521, 1541, 1845, 1940, 1963], 'CLI.': [547], 'They': [548, 2111], 'studied': [549], '51': [550], 'treated': [552, 567, 775, 838, 1406, 1843, 2534], '46': [556], 'similar': [561, 584], 'baseline': [562, 1433], 'demographics': [563], 'who': [564, 1834], 'were': [565, 777, 790, 1241, 1276, 1385, 1418, 1542, 1786], 'not': [566, 573, 812, 821, 1435, 1612, 1739, 1817, 2018, 2022, 2281], 'BM-MNCs.': [569, 1299], 'This': [570, 1015, 1300, 1324, 1498, 1558, 1630], 'study': [571, 660, 692, 898, 909, 1033, 1257, 1499, 1576, 1581, 1737, 1785, 1827, 1871, 2150, 2810], 'randomized,': [574, 862, 1211], 'placebo': [575, 3024], 'controlled,': [576], 'blinded.': [578], 'Although': [579], 'group': [582, 1685], 'had': [583, 781, 1006, 1442, 1976], 'characteristics': [585], 'BM-MNC-treated': [588], 'subjects,': [589, 617], 'reported': [591], 'differences': [592, 1863], 'amputation-free': [594, 620, 628, 2993], 'survival': [595, 621, 629, 1725, 2932, 2994, 3014], 'striking.': [597], 'notable': [602], 'aspects': [603, 3592], 'findings': [606], 'extremely': [609], 'incidence': [611], 'among': [614, 1157], '0%': [619], 'PAD': [625, 736, 1005, 1071, 1087], '≈10%': [627], 'Buerger': [633, 665, 697, 999, 1058, 1091, 1095, 1160, 2876, 2911], 'disease.': [634, 1092, 2877, 2912, 3122, 3162], 'Even': [635], 'allowing': [636], 'small': [639], 'sample': [640], 'size,': [641], 'these': [642, 828, 993, 1009, 1171, 1440, 1467, 2095], 'numbers': [643], 'difficult': [645, 1899, 2005], 'reconcile': [647], 'literature.12': [651], 'Ohta': [654, 2898], 'et': [655, 687, 912, 987, 1036, 1048, 1353, 1673, 1869, 1882, 1921], 'al13': [656], 'performed': [657, 689], 'retrospective': [659, 691], '110': [662], 'mean': [669, 701], 'follow-up': [670, 702, 940, 984, 1349], '10.6': [672], 'years': [673, 705, 716], 'found': [675, 707, 1371], 'cumulative': [677], '43.6%': [678], 'combined': [679], 'minor': [680], 'rate,': [684], 'whereas': [685, 787, 1001, 1064, 1947], 'Cooper': [686, 2919], 'al14': [688], '111': [694], '15.6': [704], 'rate': [711, 721, 887], '11%': [713], '5': [715, 725], 'total': [719, 738, 1482, 1520, 1988], '25%': [723], 'years.14': [726], 'Recent': [727], 'trials': [729, 1329, 1565, 1706, 2045], 'atherosclerotic': [735, 1004, 1070, 1103, 1121, 2871], 'revealed': [737], 'range': [743], '50%': [745], '60%': [747], '1': [749, 1823, 1841, 4346], 'year.15': [750], 'Thus,': [751], 'one': [752, 1675], 'possibility': [756, 1152], 'bias': [760], 'when': [761], 'comparing': [762], 'outcomes': [763], 'nonrandomized': [766], 'trial.': [768, 2815], 'Indeed,': [769], 'Methods': [771], 'section': [772], 'states': [773], 'enrolled': [778, 1828], 'if': [779], 'they': [780, 1109, 1610], 'pain': [783, 1402, 1553], 'nonhealing': [785], 'ulcers,': [786], 'included': [791, 1481], 'being': [793], 'It': [798, 818], 'also': [800], 'noted': [801, 1649], 'smoking': [803, 1126], 'cessation': [804], 'required': [806], 'before': [807, 1114, 2146], 'administration': [808, 1341, 1361, 3065], 'BM-MNC': [810], 'but': [811, 890, 1464], 'so': [813], 'group.': [817], 'therefore': [820, 2136], 'clear': [822], 'how': [823], 'statistical': [825], 'comparison': [826, 836, 2869], 'apparently': [829], 'different': [830, 1913], 'populations': [831], 'can': [832, 1676], 'meaningful.': [834], 'historical': [841], 'controls': [842, 859], 'might': [843], 'informative,': [846], 'although': [847], 'recent': [848], 'underscored': [854], 'contemporaneous': [858], 'blinded': [863], 'phase': [869, 896, 1661, 2040, 3019], 'II': [870, 1662, 2043], 'randomized': [871, 1242, 1328, 3021], 'controlled': [872, 2814, 3025], 'FGF1': [875], 'gene': [876, 3009], '107': [879], '1-year': [884], '34%15': [889], '21%': [893], 'III': [897], 'same': [901, 1631], 'agent': [902], '525': [904], 'patients.16The': [905], 'by': [910, 985, 1034, 1107, 1494, 2029, 2057, 2255, 2269, 2450, 2802, 3287, 3547], 'Idea': [911], 'al11': [913, 1049, 1870], 'replicates': [914], 'Therapeutic': [916, 2795, 2987, 3219], 'Angiogenesis': [917], 'Cell': [919, 1217, 3411, 3478, 3718, 3996, 4062, 4071, 4171, 4280], 'Transplantation': [920, 1218, 2630, 2753], '(TACT)': [921], 'study10;': [922], 'however,': [923, 1735, 1815], 'present': [925], 'investigation': [926], 'provides': [927, 1500, 1560], 'advances': [929], 'compared': [930, 1319, 1912], 'initial': [933, 1266], 'landmark': [934], 'study,': [935, 1046, 1202, 1238, 1791, 1814], 'much': [938], 'longer': [939], 'patients.': [943, 1172], 'regard,': [946], 'interesting': [949, 1043, 1148], 'note': [951], 'physiological': [954], 'points': [956, 1636, 1646], 'ankle-brachial': [958], 'index': [959], '(ABI)': [960], 'transcutaneous': [962, 1640, 1801], 'oximetry': [963, 1641], 'parallel': [964], 'those': [965, 1002, 1089, 2283], 'TACT': [968, 1790, 1813, 1866, 1879, 1918, 1974], 'up': [969], '6': [971, 1425], 'months,': [972], 'which': [973, 1038, 1792, 4205], 'final': [976], 'point': [978, 1588, 1608, 1696, 1703, 1719, 1731, 1778], 'study.': [982, 1235], 'Longer-term': [983], 'Idei': [986, 1047, 1177, 1352, 1868, 1881, 1920, 2820], 'al': [988, 1883, 1922], 'reveals': [989], 'persistent': [990], 'improvement': [991, 1380, 1621, 1626], 'parameters': [994, 1010], 'disease,': [1000, 4333], 'worsening': [1007], 'later': [1012], 'time': [1013, 1809], 'points.': [1014], 'finding': [1016, 1559], 'may': [1017, 1316, 1362, 1720], 'important': [1019, 1326, 1389, 1416, 1508, 1862, 2154], 'implications': [1020, 4329], 'role': [1023, 2709], 'readministration': [1025], 'strategies,': [1026], 'further': [1029, 1501, 2055], 'illustrated': [1030], 'Walter': [1035, 1203, 1672, 3042, 3138], 'al,17': [1037, 1674], 'discussed': [1040], 'later.In': [1041], 'an': [1042, 1259, 1507, 1934, 2153, 2176, 3990], 'vitro': [1045, 1496], 'provide': [1050], 'autologous': [1053, 1065, 1143, 1197, 1313, 2199, 2803], 'preserved': [1061], 'phenotypic': [1062], 'characteristics,': [1063], 'impaired.': [1073], 'number': [1077, 1185, 1414, 1484, 1518], 'lower': [1083], 'versus': [1088, 1409, 2158], 'Patients': [1093, 1229, 2444, 3926, 4183], 'generally': [1097], 'low': [1100], 'burden': [1101], 'factors': [1105, 1123, 1136, 3118], 'because,': [1106], 'definition,': [1108], 'onset': [1111], 'age': [1115], '50': [1116], 'absence': [1118], 'typical': [1120], 'other': [1124, 1651, 1848], 'than': [1125, 1554], 'history.': [1127], 'Because': [1128], 'now': [1131], 'established': [1133], 'impair': [1139], 'function': [1141, 1187, 1505, 2134, 2197], 'cells,18–21': [1145], 'contemplate': [1150], 'greater': [1155, 1490, 1546, 1979, 1987], 'response': [1156, 1511, 2182], 'partly': [1164], 'due': [1165], 'higher-functioning': [1167], 'observations': [1175, 1417], 'colleagues': [1179], 'importance': [1182, 2128], 'potentially': [1189], 'determinants': [1191], 'therapy.In': [1199], 'second': [1201, 1296], 'colleagues17': [1205], 'double-blind,': [1212], 'placebo-controlled': [1213, 3079], 'PROVASA': [1214, 1256, 1305, 1369, 1534, 1580, 1874, 1889, 1949, 2149], '(Intraarterial': [1215], 'Progenitor': [1216, 3410], 'Bone': [1220, 3539, 3581, 3716, 4319], 'Marrow': [1221, 3540, 3717], 'Mononuclear': [1222], 'Cells': [1223, 3544, 3734, 3970, 3984, 3988, 4179, 4236, 4241], 'Induction': [1225], 'Neovascularization': [1227], 'With': [1230, 2445, 4184], 'Peripheral': [1231, 2446, 3253], 'Arterial': [1232, 2447], 'Occlusive': [1233], 'Disease)': [1234], '40': [1239], '1:1': [1245], 'fashion': [1246], 'intraarterial': [1248, 1891], 'delivery': [1249, 1914, 1958, 1990], 'either': [1251, 1271], 'placebo.': [1254, 1410], 'used': [1258, 1338, 1885, 1890], 'innovative': [1260], 'randomized-start': [1261, 1754], 'After': [1265], 'randomization': [1267], 'placebo,': [1274], 'followed': [1277], '3': [1279, 1767, 3020], 'months.': [1280], 'At': [1281], 'point,': [1283, 1750], 'placebo-treated': [1284, 1758], 'crossed': [1286], 'over': [1287, 1762], 'active': [1289, 1764], 'active-treated': [1292], 'received': [1294], 'protocol': [1302, 1950, 1975], 'allowed': [1303, 1756], 'determine': [1308, 1901], 'repeated': [1310, 1486, 2167], 'treatments': [1311, 1539, 1573, 2169], 'beneficial': [1318], 'treatment.': [1323, 1557, 1972, 2186], 'because': [1327, 1609, 1752, 1902, 2007], 'date': [1335], 'primarily': [1337], 'data': [1350], 'al,11': [1354], 'limited': [1365], 'duration': [1366], 'effect.The': [1368], 'difference': [1374, 1746, 1897], 'primary': [1377, 1586, 1606, 1776], 'outcome': [1378, 1462], 'ABI.': [1382], 'However,': [1383], 'highly': [1391, 4325], 'clinically': [1392], 'relevant': [1393], 'secondary': [1394], 'ulcer': [1398, 1479, 1549, 1623], 'healing': [1399, 1480, 1550, 1624], 'reduction': [1403], 'made.': [1419], 'First,': [1420, 1877], 'Rutherford': [1423], 'class': [1424], '(gangrene': [1427], 'loss)': [1431], 'did': [1434, 1578, 1611, 1816], 'respond': [1436], 'therapy.': [1438, 1513, 2110, 3180], 'All': [1439], 'outcomes,': [1444], 'likely': [1446, 2164], 'owing': [1447], 'fact': [1450], 'process': [1454], 'too': [1456], 'far': [1457], 'all': [1463], 'predetermined': [1465], 'unfortunate': [1468], 'individuals.': [1469], 'Second,': [1470, 1916], 'identified': [1473], 'predictors': [1476], 'successful': [1478], 'delivered,': [1485], 'administration,': [1488], 'functionality': [1492], 'measured': [1493, 2020], 'assays.': [1497], 'predictor': [1509], 'higher': [1517], 'CD34+': [1523, 1945, 1968, 1992, 3969, 4113], 'correlated': [1526], 'superior': [1528], 'outcomes.': [1529], 'Perhaps': [1530], 'importantly,': [1532], 'demonstrated': [1536, 1793], 'significantly': [1545], 'rationale': [1562], 'future': [1564, 2162, 4289], 'include': [1571, 2166], 'design.Why': [1577], 'fail': [1582], 'meet': [1584], 'its': [1585], 'change': [1590, 1597, 1617, 1771], 'ABI?': [1592], 'authors': [1594, 1694], 'believe': [1595], 'ABI': [1599, 1619, 1638, 1688, 1773, 1797], 'find': [1613], 'correlation': [1615], 'between': [1616, 1633, 1864, 3670], 'pain.': [1629], 'divergence': [1632], 'surrogate': [1634], 'like': [1637], 'hard': [1643, 1729], 'remains': [1655], 'challenge': [1658, 2051], 'designing': [1660], 'condition.22': [1666], 'Looking': [1667], 'Figure': [1669], 'tell': [1677], 'variation': [1682], 'within': [1683], 'each': [1684, 1971], 'measurement,': [1689], 'even': [1690], 'baseline.': [1692], 'correctly': [1695], 'out': [1697], 'best': [1700], 'population': [1710], 'still': [1712], 'uncertain': [1713], 'composite': [1717], 'appropriate.': [1723], 'Amputation-free': [1724], 'good': [1728], 'studies;': [1734], 'designed': [1740], 'powered': [1742], 'demonstrate': [1744], 'especially': [1751], 'design': [1755, 2151], 'cross': [1761], 'after': [1766, 2183, 3679, 3835], 'months.The': [1768], 'choice': [1769], 'power': [1781], 'calculations': [1782], 'based': [1787], 'oxygen': [1802], 'pressure,': [1803], 'pain-free': [1807], 'walking': [1808], 'BM-MNCs.10': [1811], 'conventional': [1820], 'group;': [1822], 'arm': [1824], 'bilateral': [1831], 'served': [1835], 'own': [1838], 'controls,': [1839], 'peripheral': [1850, 2388, 2498, 2872], 'blood': [1851], 'MNCs': [1852], 'control.': [1855], 'Beyond': [1856], 'difference,': [1858], 'study17': [1875], 'protocols.': [1876], 'injection,': [1887], 'injection.': [1892], 'effect': [1894], 'human': [1906, 3823], 'strategies.': [1915], 'protocols': [1923, 2173], 'involved': [1924, 1951], 'large': [1926], 'aspiration': [1929], '≈500': [1931], 'mL': [1932], '≈1.6': [1937], '1.8×109': [1939], '3.5': [1942], '3.9×107': [1944], '50-mL': [1953], 'aspirate': [1956, 1984], '1.53': [1960], '1.65×108': [1962], '2.7': [1965], '2.9×106': [1967], 'during': [1970, 3256, 3503], '10-fold': [1978], 'volume': [1980], '≈10-fold': [1986], 'delivery.': [1994], 'Choosing': [1995], 'optimal': [1997, 2077], 'task': [2006], 'traditional': [2008], 'properties': [2010], 'absorption,': [2012], 'distribution,': [2013], 'metabolism,': [2014], 'excretion': [2016], 'easily': [2019], 'applicable.': [2023], 'Dosing': [2024], 'decisions': [2025], 'currently': [2026, 2229], 'made': [2028], 'extrapolation': [2030], 'animal': [2032], 'empirically': [2035], 'signals': [2038], 'I': [2041, 3963], 'compare': [2047], 'doses.': [2049], 'dosing': [2053, 2079], 'complicated': [2056], 'nonlinear': [2059], 'dose-response': [2060], 'relationship': [2061], 'manipulations': [2063], 'documented': [2069], 'settings.': [2074], 'Finding': [2075], 'strategy': [2080, 3829], 'remain': [2082], 'ongoing': [2088, 2119], 'translation': [2090, 2106], 'therapy.Overall,': [2094], 'add': [2098], 'growing': [2101], 'knowledge': [2102], 'about': [2103], 'highlight': [2112], 'opportunities': [2113], 'emphasize': [2118], 'challenges.': [2120], 'Both': [2121], 'yield': [2123, 3678], 'insights': [2124], 'regarding': [2125], 'potential': [2127], 'trigger': [2138], 'consideration': [2139], 'methods': [2141], 'enhance': [2143, 3831], 'potency': [2145], 'administration.': [2147], 'addresses': [2152], 'question': [2155], 'treatments,': [2160], 'main': [2172], 'option': [2177], 'inadequate': [2181], 'Addressing': [2187], 'issues': [2190], 'optimization': [2193], 'improving': [2195], 'themes': [2209], 'we': [2211], 'work': [2212], 'maximize': [2214], 'position': [2219], 'move': [2223], 'forward': [2224], 'help': [2226], 'untreatable': [2230], 'conditions.AcknowledgmentsWe': [2231], 'thank': [2232], 'Kevin': [2234], 'Meisner,': [2235], 'PhD,': [2236], 'ELS,': [2237], 'editorial': [2239], 'support': [2240], 'Ashley': [2242], 'Peterson': [2243], 'Kari': [2245], 'Krueger': [2246], 'administrative': [2248], 'assistance.Sources': [2249], 'FundingDr': [2251], 'supported': [2254, 2268], 'National': [2256, 2270, 2459], 'Institutes': [2257, 2271], 'Health': [2259, 2273], 'grantsHL-53354,': [2260], 'HL-77428,': [2261], 'HL-80137,': [2262], 'HL95874.': [2264], 'Dr': [2265], 'grantHL-99283.DisclosuresNone.FootnotesThe': [2274], 'opinions': [2275], 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