391:. The most common Class II mutation is F508del. Again with high-throughput screening, Negulescu and his team found that lumacaftor can correct F508del-mutated CFTR protein. It was later found that the drug was not effective enough when administered on its own, but was so when administered together with ivacaftor. The FDA approved this drug combination in 2015. Further research led to the discovery of
1265:
Wainwright, Claire E.; Elborn, J. Stuart; Ramsey, Bonnie W.; Marigowda, Gautham; Huang, Xiaohong; Cipolli, Marco; Colombo, Carla; Davies, Jane C.; De Boeck, Kris; Flume, Patrick A.; Konstan, Michael W.; McColley, Susanna A.; McCoy, Karen; McKone, Edward F.; Munck, Anne; Ratjen, Felix; Rowe, Steven
828:
Van Goor, Fredrick; Hadida, Sabine; Grootenhuis, Peter D. J.; Burton, Bill; Cao, Dong; Neuberger, Tim; Turnbull, Amanda; Singh, Ashvani; Joubran, John; Hazlewood, Anna; Zhou, Jinglan; McCartney, Jason; Arumugam, Vijayalaksmi; Decker, Caroline; Yang, Jennifer; Young, Chris; Olson, Eric R.; Wine,
1201:
Clancy, J. P.; Rowe, Steven M.; Accurso, Frank J.; Aitken, Moira L.; Amin, Raouf S.; Ashlock, Melissa A.; Ballmann, Manfred; Boyle, Michael P.; Bronsveld, Inez; Campbell, Preston W.; De Boeck, Kris; Donaldson, Scott H.; Dorkin, Henry L.; Dunitz, Jordan M.; Durie, Peter R.; Jain, Manu; Leonard,
1202:
Anissa; McCoy, Karen S.; Moss, Richard B.; Pilewski, Joseph M.; Rosenbluth, Daniel B.; Rubenstein, Ronald C.; Schechter, Michael S.; Botfield, Martyn; Ordoñez, Claudia L; Spencer-Green, George T.; Vernillet, Laurent; Wisseh, Steve; Yen, Karl; Konstan, Michael W. (2012).
512:
1141:
Van Goor, Fredrick; Hadida, Sabine; Grootenhuis, Peter D. J.; Burton, Bill; Stack, Jeffrey H.; Straley, Kimberly S.; Decker, Caroline J.; Miller, Mark; McCartney, Jason; Olson, Eric R.; Wine, Jeffrey J.; Frizzell, Ray A.; Ashlock, Melissa; Negulescu, Paul A. (2011).
1431:
600:
362:(FDA) for cystic fibrosis patients with one specific Class III mutation in 2012, and has since been approved for mutation classes as well. Of note, the expanded approval in 2017 was based solely on
482:
711:
339:
to pass through. These mutations have been classified into Class I to V, with Class III mutations causing defective channel gates in CFTR despite normal expression of the protein. Via
1376:
608:
328:
2129:
568:
542:
835:
1487:
1350:
1318:
1204:"Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation"
2134:
2124:
490:
303:. Negulescu joined Aurora Biosciences in 1996 as one of the first employees. He became Senior Vice President of Discovery Biology in 1999. When
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636:
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1959:
684:
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80:
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acquired Aurora
Biosciences in 2001, he was appointed Senior Vice President of Research. Negulescu has been leading the
193:
1354:
773:
1328:
1754:
1738:
1115:
950:
340:
288:
383:
to help the CFTR protein fold correctly. Thus, it can be used in patients with Class II mutations, which create
1573:
1203:
1991:
1832:
276:
182:
2119:
945:
746:
513:"The role and regulation of intracellular calcium during stimulus-secretion coupling in the parietal cell"
344:
304:
233:
185:
131:
1695:
221:
145:
The role and regulation of intracellular calcium during stimulus-secretion coupling in the parietal cell
1144:"Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809"
1714:
1155:
844:
264:
58:
1444:"BREAKTHROUGH PRIZE ANNOUNCES 2024 LAUREATES IN LIFE SCIENCES, FUNDAMENTAL PHYSICS, AND MATHEMATICS"
1119:
2057:
1995:
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54:
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1035:
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127:
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that increases the probability that mutated CFTR gates will open. Ivacaftor was approved by the
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1933:
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1527:
320:
296:
201:
70:
1266:
M.; Waltz, David; Boyle, Michael P.; TRAFFIC Study Group; TRANSPORT Study Group (2015).
1159:
848:
2091:
2023:
2013:
1969:
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1828:
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2039:
2029:
2019:
1985:
1945:
1788:
1718:
1623:
1593:
1567:
1535:
1268:"Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR"
1097:
831:"Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770"
807:
750:
388:
260:
217:
39:
981:
2097:
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2007:
1939:
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1637:
1511:
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data, due to the small number of patients carrying those rare mutations making
1750:
1627:
1607:
1563:
1531:
1496:
1243:
890:
Lin, Lawrence; Yee, Sook Wah; Kim, Richard B.; Giacomini, Kathleen M. (2015).
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85:
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1031:
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927:
876:
799:
772:
Shteinberg, Michal; Haq, Iram J; Polineni, Deepika; Davies, Jane C (2021).
1285:
1587:
1023:
364:
336:
324:
243:
Thanks to his childhood experience, he initially wanted to graduate with
197:
1443:
1465:
1323:
384:
244:
229:
225:
323:. Cystic fibrosis can be caused by any of the thousands of identified
632:"The Chemistry of Fluorescent Indicators: the Work of Roger Y. Tsien"
138:
909:
545:(Press release). Shaw Prize Foundation. May 24, 2022. Archived from
259:
had a great influence on
Negulescu, who eventually graduated with a
375:
Negulescu also led the discovery of another cystic fibrosis drug,
892:"SLC transporters as therapeutic targets: emerging opportunities"
399:, 2 other correctors of the CFTR protein. The triple combination
1469:
712:"TECHNOLOGY; Vertex Buys Biotechnology Rival for $ 592 Million"
263:
in history and physiology in 1986. He then went on and studied
944:
Rey, Michael M.; Bonk, Michael P.; Hadjiliadis, Denis (2019).
1377:"FDA approves new breakthrough therapy for cystic fibrosis"
1353:. Shaw Prize Foundation. September 29, 2022. Archived from
1062:"Mechanism of CFTR correction by type I folding correctors"
630:
Kresge, Nicole; Simoni, Robert D.; Hill, Robert L. (2006).
267:
in physiology under Terry Machen, completing it in 1990.
1319:"FDA panel recommends Vertex cystic fibrosis treatment"
946:"Cystic Fibrosis: Emerging Understanding and Therapies"
442:
Negulescu met his wife, Debbie, during his time at the
311:
1924:
1705:
1504:
155:
137:
119:
109:
76:
65:
46:
30:
23:
379:, which is known as a "corrector" as it acts as a
1407:"The 2022 Prize in Life Science & Medicine"
1148:Proceedings of the National Academy of Sciences
836:Proceedings of the National Academy of Sciences
319:Negulescu's research focuses on the therapy of
675:
673:
601:"Constantin Vișoianu, Romanian official, dies"
1481:
8:
181:. He is a Senior Vice President at American
1488:
1474:
1466:
939:
937:
20:
2130:University of California, Berkeley alumni
1293:
1229:
1177:
1167:
1079:
963:
917:
866:
856:
829:Jeffery J.; Frizzell, Raymond A. (2009).
649:
477:
475:
473:
471:
469:
467:
465:
463:
461:
459:
420:Shaw Prize in Life Science & Medicine
86:Shaw Prize in Life Science & Medicine
1409:. Shaw Prize Foundation. Archived from
455:
190:Shaw Prize in Life science and medicine
387:CFTR protein that cannot reaching the
1060:Fiedorczuk, Karol; Chen, Jue (2022).
7:
196:, for their work that uncovered the
2135:American people of Romanian descent
1273:The New England Journal of Medicine
483:"Autobiography of Paul A Negulescu"
432:Breakthrough Prize in Life Sciences
96:Breakthrough Prize in Life Sciences
1383:. October 21, 2019. Archived from
517:University of California, Berkeley
281:University of California, Berkeley
275:Negulescu started his career as a
249:University of California, Berkeley
51:University of California, Berkeley
14:
965:10.1146/annurev-med-112717-094536
607:. January 5, 1994. Archived from
403:was approved by the FDA in 2019.
287:. He was planning to move to the
283:and under Michael Cahalan at the
2125:21st-century American biologists
577:. April 10, 2005. Archived from
444:University of California, Irvine
401:elexacaftor/tezacaftor/ivacaftor
285:University of California, Irvine
124:University of California, Irvine
710:Pollack, Andrew (May 1, 2001).
637:Journal of Biological Chemistry
1317:Morgan, David (May 13, 2015).
414:Warren Alpert Foundation Prize
240:of Romania. He has a brother.
81:Warren Alpert Foundation Prize
1:
1222:10.1136/thoraxjnl-2011-200393
1012:Nature Reviews Drug Discovery
897:Nature Reviews Drug Discovery
792:10.1016/S0140-6736(20)32542-3
651:10.1016/S0021-9258(19)34942-7
1381:Food and Drug Administration
360:Food and Drug Administration
1008:route to expanded approval"
569:"Florica Visoianu Obituary"
238:Minister of Foreign Affairs
222:first-generation immigrants
2151:
1116:Cystic Fibrosis Foundation
1081:10.1016/j.cell.2021.12.009
1112:"Types of CFTR Mutations"
951:Annual Review of Medicine
341:high-throughput screening
289:University of Connecticut
165:
102:
1002:Kingwell, Katie (2017).
685:Warren Alpert Foundation
212:Early life and education
204:and developed effective
1992:Demetrios Christodoulou
1833:Everett Peter Greenberg
1169:10.1073/pnas.1105787108
858:10.1073/pnas.0904709106
744:"Paul Negulescu, Ph.D."
277:postdoctoral researcher
232:, and his grandfather,
188:. He received the 2022
16:American cell biologist
747:Vertex Pharmaceuticals
345:Vertex Pharmaceuticals
305:Vertex Pharmaceuticals
299:he was forming called
216:Negulescu was born in
186:Vertex Pharmaceuticals
183:pharmaceutical company
132:Vertex Pharmaceuticals
1696:Shrinivas R. Kulkarni
1286:10.1056/NEJMoa1409547
487:Shaw Prize Foundation
172:Paul Adrian Negulescu
35:Paul Adrian Negulescu
1755:Keith H. S. Campbell
1715:Stanley Norman Cohen
1450:. September 14, 2023
1024:10.1038/nrd.2017.140
786:(10290): 2195–2211.
295:asked him to join a
2058:Alexander Beilinson
1996:Richard S. Hamilton
1666:Chryssa Kouveliotou
1387:on October 20, 2022
1357:on October 12, 2022
1331:on October 19, 2022
1246:on October 19, 2022
1160:2011PNAS..10818843V
1154:(46): 18843–18848.
1122:on October 18, 2022
849:2009PNAS..10618825V
843:(44): 18825–18830.
724:on October 16, 2022
691:on October 15, 2022
658:on October 15, 2022
611:on October 15, 2022
605:The Washington Post
581:on October 15, 2022
574:The Washington Post
549:on October 12, 2022
523:on October 12, 2022
493:on October 12, 2022
234:Constantin Vișoianu
228:. His father was a
2068:Jean-Michel Bismut
1795:Franz-Ulrich Hartl
1618:William J. Borucki
1448:BREAKTHROUGH PRIZE
1413:on October 5, 2022
717:The New York Times
301:Aurora Biosciences
128:Aurora Biosciences
2107:
2106:
2088:Vladimir Drinfeld
1934:Shiing-Shen Chern
1891:Paul A. Negulescu
1799:Arthur L. Horwich
1672:Lennart Lindegren
1604:Daniel Eisenstein
1379:(Press release).
774:"Cystic fibrosis"
407:Honors and awards
169:
168:
104:Scientific career
2142:
2052:Michel Talagrand
2002:Maxim Kontsevich
1956:Robert Langlands
1895:Michael J. Welsh
1859:Mary-Claire King
1813:Michael W. Young
1785:Ruslan Medzhitov
1769:Jeffrey Friedman
1745:Robert Lefkowitz
1733:Michael Berridge
1690:Maura McLaughlin
1676:Michael Perryman
1490:
1483:
1476:
1467:
1460:
1459:
1457:
1455:
1440:
1434:
1432:Wiley Prize 2023
1429:
1423:
1422:
1420:
1418:
1403:
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1394:
1392:
1373:
1367:
1366:
1364:
1362:
1347:
1341:
1340:
1338:
1336:
1327:. Archived from
1314:
1308:
1307:
1297:
1262:
1256:
1255:
1253:
1251:
1242:. Archived from
1233:
1198:
1192:
1191:
1181:
1171:
1138:
1132:
1131:
1129:
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1118:. Archived from
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1048:
1046:
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993:
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881:
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819:
818:
816:
814:
769:
763:
762:
760:
758:
749:. Archived from
740:
734:
733:
731:
729:
720:. Archived from
707:
701:
700:
698:
696:
687:. Archived from
681:"Paul Negulescu"
677:
668:
667:
665:
663:
654:. Archived from
653:
627:
621:
620:
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597:
591:
590:
588:
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559:
558:
556:
554:
539:
533:
532:
530:
528:
519:. Archived from
509:
503:
502:
500:
498:
489:. Archived from
479:
255:class taught by
194:Michael J. Welsh
192:, together with
157:Doctoral advisor
151:
21:
2150:
2149:
2145:
2144:
2143:
2141:
2140:
2139:
2110:
2109:
2108:
2103:
2082:Ehud Hrushovski
2046:Luis Caffarelli
1980:Clifford Taubes
1976:Simon Donaldson
1966:Vladimir Arnold
1926:
1920:
1911:Stuart H. Orkin
1871:Gero Miesenböck
1809:Michael Rosbash
1805:Jeffrey C. Hall
1765:Douglas Coleman
1759:Shinya Yamanaka
1707:
1701:
1656:Roger Blandford
1650:Edward C. Stone
1644:Jean-Loup Puget
1612:John A. Peacock
1584:David C. Jewitt
1560:Charles Bennett
1548:Reinhard Genzel
1542:Peter Goldreich
1528:Saul Perlmutter
1500:
1494:
1464:
1463:
1453:
1451:
1442:
1441:
1437:
1430:
1426:
1416:
1414:
1405:
1404:
1400:
1390:
1388:
1375:
1374:
1370:
1360:
1358:
1349:
1348:
1344:
1334:
1332:
1316:
1315:
1311:
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1263:
1259:
1249:
1247:
1200:
1199:
1195:
1140:
1139:
1135:
1125:
1123:
1110:
1109:
1105:
1059:
1058:
1054:
1044:
1042:
1004:"FDA OKs first
1001:
1000:
996:
986:
984:
943:
942:
935:
910:10.1038/nrd4626
889:
888:
884:
827:
826:
822:
812:
810:
771:
770:
766:
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754:
742:
741:
737:
727:
725:
709:
708:
704:
694:
692:
679:
678:
671:
661:
659:
644:(37): e29–e31.
629:
628:
624:
614:
612:
599:
598:
594:
584:
582:
567:
566:
562:
552:
550:
543:"Press Release"
541:
540:
536:
526:
524:
511:
510:
506:
496:
494:
481:
480:
457:
452:
440:
409:
370:clinical trials
321:cystic fibrosis
317:
297:startup company
273:
251:. A third-year
236:, was a former
214:
202:cystic fibrosis
174:is an American–
149:
130:
126:
94:
89:
84:
71:cystic fibrosis
42:
37:
36:
26:
17:
12:
11:
5:
2148:
2146:
2138:
2137:
2132:
2127:
2122:
2112:
2111:
2105:
2104:
2102:
2101:
2095:
2092:Shing-Tung Yau
2085:
2075:
2065:
2055:
2049:
2043:
2033:
2027:
2024:Henryk Iwaniec
2017:
2014:George Lusztig
2011:
2005:
1999:
1989:
1983:
1973:
1970:Ludwig Faddeev
1963:
1960:Richard Taylor
1953:
1943:
1937:
1930:
1928:
1922:
1921:
1919:
1918:
1915:Swee Lay Thein
1908:
1901:Patrick Cramer
1898:
1888:
1882:
1875:Peter Hegemann
1868:
1862:
1856:
1849:Ian R. Gibbons
1846:
1836:
1829:Bonnie Bassler
1826:
1819:Kazutoshi Mori
1816:
1802:
1792:
1781:Jules Hoffmann
1778:
1772:
1762:
1748:
1742:
1736:
1730:
1711:
1709:
1703:
1702:
1700:
1699:
1693:
1686:Duncan Lorimer
1682:Matthew Bailes
1679:
1669:
1662:Victoria Kaspi
1659:
1653:
1647:
1641:
1635:
1621:
1615:
1601:
1598:John F. Hawley
1591:
1581:
1578:Gerald Fishman
1571:
1557:
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1545:
1539:
1525:
1518:Geoffrey Marcy
1515:
1508:
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1502:
1501:
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1492:
1485:
1478:
1470:
1462:
1461:
1435:
1424:
1398:
1368:
1342:
1309:
1280:(3): 220–231.
1257:
1193:
1133:
1103:
1074:(1): 158–168.
1052:
1018:(9): 591–592.
994:
933:
904:(8): 543–560.
882:
820:
764:
753:on May 8, 2019
735:
702:
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560:
534:
504:
454:
453:
451:
448:
439:
436:
435:
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428:
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353:small-molecule
343:, his team at
316:
313:
293:Roger Y. Tsien
272:
269:
257:Roger Y. Tsien
213:
210:
179:cell biologist
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166:
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135:
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78:
74:
73:
67:
66:Known for
63:
62:
48:
44:
43:
38:
34:
32:
28:
27:
25:Paul Negulescu
24:
15:
13:
10:
9:
6:
4:
3:
2:
2147:
2136:
2133:
2131:
2128:
2126:
2123:
2121:
2120:Living people
2118:
2117:
2115:
2099:
2096:
2093:
2089:
2086:
2083:
2079:
2076:
2073:
2069:
2066:
2063:
2062:David Kazhdan
2059:
2056:
2053:
2050:
2047:
2044:
2041:
2040:Claire Voisin
2037:
2034:
2031:
2030:Nigel Hitchin
2028:
2025:
2021:
2020:Gerd Faltings
2018:
2015:
2012:
2009:
2006:
2003:
2000:
1997:
1993:
1990:
1987:
1986:Jean Bourgain
1984:
1981:
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1971:
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1957:
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1946:David Mumford
1944:
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1796:
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1790:
1789:Bruce Beutler
1786:
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1823:Peter Walter
1775:David Julius
1727:Richard Doll
1723:Yuet-Wai Kan
1708:and medicine
1706:Life science
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120:Institutions
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1879:Georg Nagel
1865:Maria Jasin
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1512:Jim Peebles
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728:October 16,
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662:October 15,
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585:October 15,
553:October 12,
527:October 12,
497:October 12,
426:Wiley Prize
397:elexacaftor
356:potentiator
347:discovered
333:ion channel
261:dual degree
206:medications
91:Wiley Prize
2114:Categories
1950:Wentsun Wu
1751:Ian Wilmut
1628:Kip Thorne
1608:Shaun Cole
1564:Lyman Page
1532:Adam Riess
1497:Shaw Prize
1417:October 5,
779:The Lancet
450:References
393:tezacaftor
377:lumacaftor
253:physiology
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1554:Frank Shu
1505:Astronomy
1499:laureates
1098:235649986
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385:misfolded
381:chaperone
349:ivacaftor
325:mutations
309:San Diego
247:from the
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315:Research
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424:2023 -
418:2022 -
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327:in the
279:at the
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230:surgeon
226:Romania
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