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href="/w/index.php?title=Paul_Negulescu&oldid=1117337363" title="Paul Negulescu">Revision as of 05:06, 21 October 2022</a> <span class="mw-diff-edit"><a href="/w/index.php?title=Paul_Negulescu&action=edit&oldid=1117337363" title="Paul Negulescu">edit</a></span><span class="mw-diff-timestamp" data-timestamp="2022-10-21T05:06:47Z"></span></strong></div><div id="mw-diff-otitle2"><a href="/wiki/User:Biruitorul" class="mw-userlink" title="User:Biruitorul" data-mw-revid="1117337363"><bdi>Biruitorul</bdi></a> <span class="mw-usertoollinks">(<a href="/wiki/User_talk:Biruitorul" class="mw-usertoollinks-talk" title="User talk:Biruitorul">talk</a> | <a href="/wiki/Special:Contributions/Biruitorul" class="mw-usertoollinks-contribs" title="Special:Contributions/Biruitorul">contribs</a>)</span><div class="mw-diff-usermetadata"><div class="mw-diff-userroles"><a href="/wiki/Wikipedia:Autopatrolled" title="Wikipedia:Autopatrolled">Autopatrolled</a>, <a href="/wiki/Wikipedia:Extended_confirmed_editors" 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It allows adding a reason in the summary.">undo</a></span></strong></div><div id="mw-diff-ntitle2"><a href="/wiki/Special:Contributions/12.171.24.133" class="mw-userlink mw-anonuserlink" title="Special:Contributions/12.171.24.133" data-mw-revid="1230293740"><bdi>12.171.24.133</bdi></a> <span class="mw-usertoollinks">(<a href="/w/index.php?title=User_talk:12.171.24.133&action=edit&redlink=1" class="new mw-usertoollinks-talk" title="User talk:12.171.24.133 (page does not exist)">talk</a>)</span><div class="mw-diff-usermetadata"></div></div><div id="mw-diff-ntitle3"><span class="comment mw-comment-none">No edit summary</span></div><div id="mw-diff-ntitle5"></div><div id="mw-diff-ntitle4"> </div></td> </tr><tr><td colspan="4" class="diff-multi" lang="en">(13 intermediate revisions by 9 users not shown)</td></tr><tr> <td colspan="2" class="diff-lineno">Line 25:</td> <td colspan="2" class="diff-lineno">Line 25:</td> </tr> <tr> <td class="diff-marker"></td> <td class="diff-context diff-side-deleted"><div>| thesis_url = https://search.library.berkeley.edu/permalink/01UCS_BER/s4lks2/cdi_proquest_journals_303683972</div></td> <td class="diff-marker"></td> <td class="diff-context diff-side-added"><div>| thesis_url = https://search.library.berkeley.edu/permalink/01UCS_BER/s4lks2/cdi_proquest_journals_303683972</div></td> </tr> <tr> <td class="diff-marker"></td> <td class="diff-context diff-side-deleted"><div>| known_for = Research of [[cystic fibrosis]]</div></td> <td class="diff-marker"></td> <td class="diff-context diff-side-added"><div>| known_for = Research of [[cystic fibrosis]]</div></td> </tr> <tr> <td class="diff-marker" data-marker="−"></td> <td class="diff-deletedline diff-side-deleted"><div>| awards = [[Warren Alpert Foundation Prize]] <br/> [[Shaw Prize|Shaw Prize in Life Science & Medicine]]</div></td> <td class="diff-marker" data-marker="+"></td> <td class="diff-addedline diff-side-added"><div>| awards = [[Warren Alpert Foundation Prize]] <ins class="diffchange diffchange-inline">(2018)</ins><br/> [[Shaw Prize|Shaw Prize in Life Science & Medicine]]<ins class="diffchange diffchange-inline"> (2022)<br/>[[Wiley Prize]] (2023)</ins></div></td> </tr> <tr> <td colspan="2" class="diff-empty diff-side-deleted"></td> <td class="diff-marker" data-marker="+"></td> <td class="diff-addedline diff-side-added"><div><br/>[[Breakthrough Prize in Life Sciences]] (2024)</div></td> </tr> <tr> <td class="diff-marker"></td> <td class="diff-context diff-side-deleted"><div>| spouse = </div></td> <td class="diff-marker"></td> <td class="diff-context diff-side-added"><div>| spouse = </div></td> </tr> <tr> <td class="diff-marker"></td> <td class="diff-context diff-side-deleted"><div>}}</div></td> <td class="diff-marker"></td> <td class="diff-context diff-side-added"><div>}}</div></td> </tr> <tr> <td class="diff-marker"></td> <td class="diff-context diff-side-deleted"><br /></td> <td class="diff-marker"></td> <td class="diff-context diff-side-added"><br /></td> </tr> <tr> <td class="diff-marker" data-marker="−"></td> <td class="diff-deletedline diff-side-deleted"><div>'''Paul Adrian Negulescu''' is an <del class="diffchange diffchange-inline">American</del> [[Cell biology|cell biologist]]. He is <del class="diffchange diffchange-inline">the</del> Senior Vice President <del class="diffchange diffchange-inline">and Site Head of the [[San Diego]] Research Center of</del> American [[Pharmaceutical industry|pharmaceutical company]] [[Vertex Pharmaceuticals]]. He received the 2022 [[Shaw Prize|Shaw Prize in Life science and medicine]], together with [[Michael J. Welsh (biologist)|Michael J. Welsh]], for their work that uncovered the [[etiology]] of [[cystic fibrosis]] and developed effective [[medication]]s.<ref>{{cite press release |title=Press Release |url=https://www.shawprize.org/prizes-and-laureates/life-science-and-medicine/2022/press-relesae |access-date=October 12, 2022 |publisher=Shaw Prize Foundation |date=May 24, 2022 |archive-url=https://web.archive.org/web/20221012140007/https://www.shawprize.org/prizes-and-laureates/life-science-and-medicine/2022/press-relesae |archive-date=October 12, 2022}}</ref></div></td> <td class="diff-marker" data-marker="+"></td> <td class="diff-addedline diff-side-added"><div>'''Paul Adrian Negulescu''' is an <ins class="diffchange diffchange-inline">American–[[Romanians|Romanian]]</ins> [[Cell biology|cell biologist]]. He is <ins class="diffchange diffchange-inline">a</ins> Senior Vice President <ins class="diffchange diffchange-inline">at</ins> American [[Pharmaceutical industry|pharmaceutical company]] [[Vertex Pharmaceuticals]]. He received the 2022 [[Shaw Prize|Shaw Prize in Life science and medicine]], together with [[Michael J. Welsh (biologist)|Michael J. Welsh]], for their work that uncovered the [[etiology]] of [[cystic fibrosis]] and developed effective [[medication]]s.<ref>{{cite press release |title=Press Release |url=https://www.shawprize.org/prizes-and-laureates/life-science-and-medicine/2022/press-relesae |access-date=October 12, 2022 |publisher=Shaw Prize Foundation |date=May 24, 2022 |archive-url=https://web.archive.org/web/20221012140007/https://www.shawprize.org/prizes-and-laureates/life-science-and-medicine/2022/press-relesae |archive-date=October 12, 2022}}</ref></div></td> </tr> <tr> <td class="diff-marker"></td> <td class="diff-context diff-side-deleted"><br /></td> <td class="diff-marker"></td> <td class="diff-context diff-side-added"><br /></td> </tr> <tr> <td class="diff-marker"></td> <td class="diff-context diff-side-deleted"><div>== Early life and education ==</div></td> <td class="diff-marker"></td> <td class="diff-context diff-side-added"><div>== Early life and education ==</div></td> </tr> <tr> <td colspan="2" class="diff-lineno">Line 40:</td> <td colspan="2" class="diff-lineno">Line 41:</td> </tr> <tr> <td class="diff-marker"></td> <td class="diff-context diff-side-deleted"><br /></td> <td class="diff-marker"></td> <td class="diff-context diff-side-added"><br /></td> </tr> <tr> <td class="diff-marker"></td> <td class="diff-context diff-side-deleted"><div>== Research ==</div></td> <td class="diff-marker"></td> <td class="diff-context diff-side-added"><div>== Research ==</div></td> </tr> <tr> <td class="diff-marker" data-marker="−"></td> <td class="diff-deletedline diff-side-deleted"><div>Negulescu's research focuses on the therapy of [[cystic fibrosis]]. Cystic fibrosis can be caused by any of the thousands of identified [[mutation]]s in the [[Cystic fibrosis transmembrane conductance regulator|CFTR]] protein, an [[ion channel]] that allows [[Chloride|chloride ions]] 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.<ref>{{cite journal |first1=Michal |last1=Shteinberg |first2=Iram J |last2=Haq |first3=Deepika |last3=Polineni |first4=Jane C |last4=Davies |title=Cystic fibrosis |journal=[[The Lancet]] |date=2021 |volume=397 |issue=10290 |pages=2195–2211 |doi=10.1016/S0140-6736(20)32542-3 |pmid=34090606 |s2cid=235327978 |url=https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32542-3/fulltext |access-date=October 17, 2022}}</ref> Via [[high-throughput screening]], his team at [[Vertex Pharmaceuticals]] discovered [[ivacaftor]], a [[Small molecule|small-molecule]] [[potentiator]] that increases the probability that mutated CFTR gates will open.<ref>{{cite journal |first1=Fredrick |last1=Van Goor |first2=Sabine |last2=Hadida |first3=Peter D. J. |last3=Grootenhuis |first4=Bill |last4=Burton |first5=Dong |last5=Cao |first6=Tim |last6=Neuberger |first7=Amanda |last7=Turnbull |first8=Ashvani |last8=Singh |first9=John |last9=Joubran |first10=Anna |last10=Hazlewood |first11=Jinglan |last11=Zhou |first12=Jason |last12=McCartney |first13=Vijayalaksmi |last13=Arumugam |first14=Caroline |last14=Decker |first15=Jennifer |last15=Yang |first16=Chris |last16=Young |first17=Eric R. |last17=Olson |first18=Jeffery J. |last18=Wine |first19=Raymond A. |last19=Frizzell |first22=Melissa |last22=Ashlock |first23=Paul |last23=Negulescu |title=Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770 |journal=[[Proceedings of the National Academy of Sciences]] |date=2009 |volume=106 |issue=44 |pages=18825–18830 |doi=10.1073/pnas.0904709106 |pmid=19846789 |pmc=2773991|doi-access=free }}</ref><ref>{{cite journal |first1=Lawrence |last1=Lin |first2=Sook Wah |last2=Yee |first3=Richard B. |last3=Kim |first4=Kathleen M. |last4=Giacomini |title=SLC transporters as therapeutic targets: emerging opportunities |journal=[[Nature Reviews Drug Discovery]] |date=2015 |volume=14 |issue=8 |pages=543–560 |doi=10.1038/nrd4626 |pmid=26111766 |pmc=4698371 }}</ref> Ivacaftor was approved by the [[Food and Drug Administration]] (FDA) for cystic fibrosis patients with one specific Class III mutation in 2012, and has since been approved for mutation classes as well.<ref name="annurev">{{cite journal |first1=Michael M. |last1=Rey |first2=Michael P. |last2=Bonk |first3=Denis |last3=Hadjiliadis |title=Cystic Fibrosis: Emerging Understanding and Therapies |journal=[[Annual Review of Medicine]] |date=2019 |volume=70 |pages=197–210 |doi=10.1146/annurev-med-112717-094536 |pmid=30312551 |s2cid=52975540 |url=https://www.annualreviews.org/doi/abs/10.1146/annurev-med-112717-094536 |access-date=October 17, 2022}}</ref> Of note, the expanded approval in 2017 was based solely on ''[[in vitro]]'' data, due to the small number of patients carrying those rare mutations making [[clinical trial]]s impossible.<ref>{{cite journal |last1=Kingwell |first1=Katie |title=FDA OKs first ''in vitro'' route to expanded approval |journal=Nature Reviews Drug Discovery |date=2017 |volume=16 |issue=9 |pages=591–592 |doi=10.1038/nrd.2017.140 |pmid=28860581 |s2cid=2421594 |url=https://www.nature.com/articles/nrd.2017.140 |access-date=October 17, 2022}}</ref></div></td> <td class="diff-marker" data-marker="+"></td> <td class="diff-addedline diff-side-added"><div>Negulescu's research focuses on the therapy of [[cystic fibrosis]]. Cystic fibrosis can be caused by any of the thousands of identified [[mutation]]s in the [[Cystic fibrosis transmembrane conductance regulator|CFTR]] protein, an [[ion channel]] that allows [[Chloride|chloride ions]] 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.<ref>{{cite journal |first1=Michal |last1=Shteinberg |first2=Iram J |last2=Haq |first3=Deepika |last3=Polineni |first4=Jane C |last4=Davies |title=Cystic fibrosis |journal=[[The Lancet]] |date=2021 |volume=397 |issue=10290 |pages=2195–2211 |doi=10.1016/S0140-6736(20)32542-3 |pmid=34090606 |s2cid=235327978 |url=https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32542-3/fulltext |access-date=October 17, 2022}}</ref> Via [[high-throughput screening]], his team at [[Vertex Pharmaceuticals]] discovered [[ivacaftor]], a [[Small molecule|small-molecule]] [[potentiator]] that increases the probability that mutated CFTR gates will open.<ref>{{cite journal |first1=Fredrick |last1=Van Goor |first2=Sabine |last2=Hadida |first3=Peter D. J. |last3=Grootenhuis |first4=Bill |last4=Burton |first5=Dong |last5=Cao |first6=Tim |last6=Neuberger |first7=Amanda |last7=Turnbull |first8=Ashvani |last8=Singh |first9=John |last9=Joubran |first10=Anna |last10=Hazlewood |first11=Jinglan |last11=Zhou |first12=Jason |last12=McCartney |first13=Vijayalaksmi |last13=Arumugam |first14=Caroline |last14=Decker |first15=Jennifer |last15=Yang |first16=Chris |last16=Young |first17=Eric R. |last17=Olson |first18=Jeffery J. |last18=Wine |first19=Raymond A. |last19=Frizzell |first22=Melissa |last22=Ashlock |first23=Paul |last23=Negulescu |title=Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770 |journal=[[Proceedings of the National Academy of Sciences]] |date=2009 |volume=106 |issue=44 |pages=18825–18830 |doi=10.1073/pnas.0904709106 |pmid=19846789 |pmc=2773991<ins class="diffchange diffchange-inline">|bibcode=2009PNAS..10618825V </ins>|doi-access=free }}</ref><ref>{{cite journal |first1=Lawrence |last1=Lin |first2=Sook Wah |last2=Yee |first3=Richard B. |last3=Kim |first4=Kathleen M. |last4=Giacomini |title=SLC transporters as therapeutic targets: emerging opportunities |journal=[[Nature Reviews Drug Discovery]] |date=2015 |volume=14 |issue=8 |pages=543–560 |doi=10.1038/nrd4626 |pmid=26111766 |pmc=4698371 }}</ref> Ivacaftor was approved by the [[Food and Drug Administration]] (FDA) for cystic fibrosis patients with one specific Class III mutation in 2012, and has since been approved for mutation classes as well.<ref name="annurev">{{cite journal |first1=Michael M. |last1=Rey |first2=Michael P. |last2=Bonk |first3=Denis |last3=Hadjiliadis |title=Cystic Fibrosis: Emerging Understanding and Therapies |journal=[[Annual Review of Medicine]] |date=2019 |volume=70 |pages=197–210 |doi=10.1146/annurev-med-112717-094536 |pmid=30312551 |s2cid=52975540 |url=https://www.annualreviews.org/doi/abs/10.1146/annurev-med-112717-094536 |access-date=October 17, 2022<ins class="diffchange diffchange-inline">|doi-access=free </ins>}}</ref> Of note, the expanded approval in 2017 was based solely on ''[[in vitro]]'' data, due to the small number of patients carrying those rare mutations making [[clinical trial]]s impossible.<ref>{{cite journal |last1=Kingwell |first1=Katie |title=FDA OKs first ''in vitro'' route to expanded approval |journal=Nature Reviews Drug Discovery |date=2017 |volume=16 |issue=9 |pages=591–592 |doi=10.1038/nrd.2017.140 |pmid=28860581 |s2cid=2421594 |url=https://www.nature.com/articles/nrd.2017.140 |access-date=October 17, 2022}}</ref></div></td> </tr> <tr> <td class="diff-marker"></td> <td class="diff-context diff-side-deleted"><br /></td> <td class="diff-marker"></td> <td class="diff-context diff-side-added"><br /></td> </tr> <tr> <td class="diff-marker" data-marker="−"></td> <td class="diff-deletedline diff-side-deleted"><div>Negulescu also led the discovery of another cystic fibrosis drug, [[lumacaftor]], which is known as a "corrector" as it acts as a [[Chaperone (protein)|chaperone]] to help the CFTR protein fold correctly.<ref>{{cite journal |last1=Fiedorczuk |first1=Karol |last2=Chen |first2=Jue |title=Mechanism of CFTR correction by type I folding correctors |journal=[[Cell (journal)|Cell]] |date=2022 |volume=185 |issue=1 |pages=158–168 |doi=10.1016/j.cell.2021.12.009 |pmid=34995514 |s2cid=235649986 |<del class="diffchange diffchange-inline">url=https://www.sciencedirect.com/science/article/pii/S0092867421014471 |</del>access<del class="diffchange diffchange-inline">-date</del>=<del class="diffchange diffchange-inline">October</del> <del class="diffchange diffchange-inline">20, 2022 |archive-date=October 20, 2022 |archive-url=https://web.archive.org/web/20221020071146/https://www.sciencedirect.com/science/article/pii/S0092867421014471</del>}}</ref> Thus, it can be used in patients with Class II mutations, which create [[<del class="diffchange diffchange-inline">Misfold|misfolded</del>]] CFTR protein that cannot reaching the [[Cell membrane|cell surface]].<ref name="annurev"/> The most common Class II mutation is F508del.<ref>{{cite web |title=Types of CFTR Mutations |url=https://www.cff.org/research-clinical-trials/types-cftr-mutations |publisher=[[Cystic Fibrosis Foundation]] |access-date=October 18, 2022 |archive-url=https://web.archive.org/web/20221018143639/https://www.cff.org/research-clinical-trials/types-cftr-mutations |archive-date=October 18, 2022}}</ref> Again with high-throughput screening, Negulescu and his team found that lumacaftor can correct F508del-mutated CFTR protein.<ref>{{cite journal |first1=Fredrick |last1=Van Goor |first2=Sabine |last2=Hadida |first3=Peter D. J. |last3=Grootenhuis |first4=Bill |last4=Burton |first5=Jeffrey H. |last5=Stack |first6=Kimberly S. |last6=Straley |first7=Caroline J. |last7=Decker |first8=Mark |last8=Miller |first9=Jason |last9=McCartney |first10=Eric R. |last10=Olson |first11=Jeffrey J. |last11=Wine |first12=Ray A. |last12=Frizzell |first13=Melissa |last13=Ashlock |first14=Paul A. |last14=Negulescu |title=Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809 |journal=Proceedings of the National Academy of Sciences |date=2011 |volume=108 |issue=46 |pages=18843–18848 |doi=10.1073/pnas.1105787108 |pmid=21976485 |pmc=3219147 |doi-access=free }}</ref> It was later found that the drug was not effective enough when administered on its own,<ref>{{cite journal |first1=J. P. |last1=Clancy |first2=Steven M. |last2=Rowe |first3=Frank J. |last3=Accurso |first4=Moira L. |last4=Aitken |first5=Raouf S. |last5=Amin |first6=Melissa A. |last6=Ashlock |first7=Manfred |last7=Ballmann |first8=Michael P. |last8=Boyle |first9=Inez |last9=Bronsveld |first10=Preston W. |last10=Campbell |first11=Kris |last11=De Boeck |first12=Scott H. |last12=Donaldson |first13=Henry L. |last13=Dorkin |first14=Jordan M. |last14=Dunitz |first15=Peter R. |last15=Durie |first16=Manu |last16=Jain |first17=Anissa |last17=Leonard |first18=Karen S. |last18=McCoy |first19=Richard B. |last19=Moss |first20=Joseph M. |last20=Pilewski |first21=Daniel B. |last21=Rosenbluth |first22=Ronald C. |last22=Rubenstein |first23=Michael S. |last23=Schechter |first24=Martyn |last24=Botfield |first25=Claudia L |last25=Ordoñez |first26=George T. |last26=Spencer-Green |first27=Laurent |last27=Vernillet |first28=Steve |last28=Wisseh |first29=Karl |last29=Yen |first30=Michael W. |last30=Konstan |title=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 |journal=[[Thorax (journal)|Thorax]] |date=2012 |volume=67 |issue=1 |pages=12–18 |doi=10.1136/thoraxjnl-2011-200393 |pmid=21825083 |url=https://thorax.bmj.com/content/67/1/12.long |access-date=October 19, 2022 |pmc=3746507 |archive-date=October 19, 2022 |archive-url=<del class="diffchange diffchange-inline">http</del>://archive.today/<del class="diffchange diffchange-inline">2022.10.19-031143</del>/https://thorax.bmj.com/content/67/1/12}}</ref> but was so when administered together with ivacaftor.<ref>{{cite journal |first1=Claire E. |last1=Wainwright |first2=J. Stuart |last2=Elborn |first3=Bonnie W. |last3=Ramsey |first4=Gautham |last4=Marigowda |first5=Xiaohong |last5=Huang |first6=Marco |last6=Cipolli |first7=Carla |last7=Colombo |first8=Jane C. |last8=Davies |first9=Kris |last9=De Boeck |first10=Patrick A. |last10=Flume |first11=Michael W. |last11=Konstan |first12=Susanna A. |last12=McColley |first13=Karen |last13=McCoy |first14=Edward F. |last14=McKone |first15=Anne |last15=Munck |first16=Felix |last16=Ratjen |first17=Steven M. |last17=Rowe |first18=David |last18=Waltz |first19=Michael P. |last19=Boyle |author20=TRAFFIC Study Group |author21=TRANSPORT Study Group |title=Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR |journal=[[The New England Journal of Medicine]] |date=2015 |volume=373 |issue=3 |pages=220–231 |doi=10.1056/NEJMoa1409547 |pmid=25981758 |pmc=4764353 }}</ref> The FDA approved this drug combination in 2015.<ref>{{cite news |last1=Morgan |first1=David |title=FDA panel recommends Vertex cystic fibrosis treatment |url=https://www.reuters.com/article/us-vertex-fda-recommendation-idUSKBN0NX2EH20150512 |access-date=October 19, 2022 |work=[[Reuters]] |date=May 13, 2015 |archive-url=https://web.archive.org/web/20221019071722/https://www.reuters.com/article/us-vertex-fda-recommendation-idUSKBN0NX2EH20150512 |archive-date=October 19, 2022}}</ref> Further research led to the discovery of [[tezacaftor]] and [[elexacaftor]], 2 other correctors of the CFTR protein.<ref>{{cite web |title=Essay |url=https://www.shawprize.org/prizes-and-laureates/life-science-and-medicine/2022/essay |publisher=Shaw Prize Foundation |access-date=October 18, 2022 |archive-url=https://web.archive.org/web/20221012140641/https://www.shawprize.org/prizes-and-laureates/life-science-and-medicine/2022/essay |archive-date=October <del class="diffchange diffchange-inline">18</del>, 2022 |date=September 29, 2022}}</ref> The triple combination [[elexacaftor/tezacaftor/ivacaftor]] was approved by the FDA in 2019.<ref>{{cite press release |title=FDA approves new breakthrough therapy for cystic fibrosis |url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis |access-date=October 20, 2022 |publisher=[[Food and Drug Administration]] |date=October 21, 2019 |archive-url=https://web.archive.org/web/20221020072702/https://www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis |archive-date=October 20, 2022}}</ref></div></td> <td class="diff-marker" data-marker="+"></td> <td class="diff-addedline diff-side-added"><div>Negulescu also led the discovery of another cystic fibrosis drug, [[lumacaftor]], which is known as a "corrector" as it acts as a [[Chaperone (protein)|chaperone]] to help the CFTR protein fold correctly.<ref>{{cite journal |last1=Fiedorczuk |first1=Karol |last2=Chen |first2=Jue |title=Mechanism of CFTR correction by type I folding correctors |journal=[[Cell (journal)|Cell]] |date=2022 |volume=185 |issue=1 |pages=158–168 |doi=10.1016/j.cell.2021.12.009 |pmid=34995514 |s2cid=235649986 |<ins class="diffchange diffchange-inline">doi-</ins>access=<ins class="diffchange diffchange-inline">free</ins> }}</ref> Thus, it can be used in patients with Class II mutations, which create [[<ins class="diffchange diffchange-inline">misfold</ins>]]<ins class="diffchange diffchange-inline">ed</ins> CFTR protein that cannot reaching the [[Cell membrane|cell surface]].<ref name="annurev"/> The most common Class II mutation is F508del.<ref>{{cite web |title=Types of CFTR Mutations |url=https://www.cff.org/research-clinical-trials/types-cftr-mutations |publisher=[[Cystic Fibrosis Foundation]] |access-date=October 18, 2022 |archive-url=https://web.archive.org/web/20221018143639/https://www.cff.org/research-clinical-trials/types-cftr-mutations |archive-date=October 18, 2022}}</ref> Again with high-throughput screening, Negulescu and his team found that lumacaftor can correct F508del-mutated CFTR protein.<ref>{{cite journal |first1=Fredrick |last1=Van Goor |first2=Sabine |last2=Hadida |first3=Peter D. J. |last3=Grootenhuis |first4=Bill |last4=Burton |first5=Jeffrey H. |last5=Stack |first6=Kimberly S. |last6=Straley |first7=Caroline J. |last7=Decker |first8=Mark |last8=Miller |first9=Jason |last9=McCartney |first10=Eric R. |last10=Olson |first11=Jeffrey J. |last11=Wine |first12=Ray A. |last12=Frizzell |first13=Melissa |last13=Ashlock |first14=Paul A. |last14=Negulescu |title=Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809 |journal=Proceedings of the National Academy of Sciences |date=2011 |volume=108 |issue=46 |pages=18843–18848 |doi=10.1073/pnas.1105787108 |pmid=21976485 |pmc=3219147<ins class="diffchange diffchange-inline"> |bibcode=2011PNAS..10818843V</ins> |doi-access=free }}</ref> It was later found that the drug was not effective enough when administered on its own,<ref>{{cite journal |first1=J. P. |last1=Clancy |first2=Steven M. |last2=Rowe |first3=Frank J. |last3=Accurso |first4=Moira L. |last4=Aitken |first5=Raouf S. |last5=Amin |first6=Melissa A. |last6=Ashlock |first7=Manfred |last7=Ballmann |first8=Michael P. |last8=Boyle |first9=Inez |last9=Bronsveld |first10=Preston W. |last10=Campbell |first11=Kris |last11=De Boeck |first12=Scott H. |last12=Donaldson |first13=Henry L. |last13=Dorkin |first14=Jordan M. |last14=Dunitz |first15=Peter R. |last15=Durie |first16=Manu |last16=Jain |first17=Anissa |last17=Leonard |first18=Karen S. |last18=McCoy |first19=Richard B. |last19=Moss |first20=Joseph M. |last20=Pilewski |first21=Daniel B. |last21=Rosenbluth |first22=Ronald C. |last22=Rubenstein |first23=Michael S. |last23=Schechter |first24=Martyn |last24=Botfield |first25=Claudia L |last25=Ordoñez |first26=George T. |last26=Spencer-Green |first27=Laurent |last27=Vernillet |first28=Steve |last28=Wisseh |first29=Karl |last29=Yen |first30=Michael W. |last30=Konstan |title=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 |journal=[[Thorax (journal)|Thorax]] |date=2012 |volume=67 |issue=1 |pages=12–18 |doi=10.1136/thoraxjnl-2011-200393 |pmid=21825083 |url=https://thorax.bmj.com/content/67/1/12.long |access-date=October 19, 2022 |pmc=3746507 |archive-date=October 19, 2022 |archive-url=<ins class="diffchange diffchange-inline">https</ins>://archive.today/<ins class="diffchange diffchange-inline">20221019031143</ins>/https://thorax.bmj.com/content/67/1/12}}</ref> but was so when administered together with ivacaftor.<ref>{{cite journal |first1=Claire E. |last1=Wainwright |first2=J. Stuart |last2=Elborn |first3=Bonnie W. |last3=Ramsey |first4=Gautham |last4=Marigowda |first5=Xiaohong |last5=Huang |first6=Marco |last6=Cipolli |first7=Carla |last7=Colombo |first8=Jane C. |last8=Davies |first9=Kris |last9=De Boeck |first10=Patrick A. |last10=Flume |first11=Michael W. |last11=Konstan |first12=Susanna A. |last12=McColley |first13=Karen |last13=McCoy |first14=Edward F. |last14=McKone |first15=Anne |last15=Munck |first16=Felix |last16=Ratjen |first17=Steven M. |last17=Rowe |first18=David |last18=Waltz |first19=Michael P. |last19=Boyle |author20=TRAFFIC Study Group |author21=TRANSPORT Study Group |title=Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR |journal=[[The New England Journal of Medicine]] |date=2015 |volume=373 |issue=3 |pages=220–231 |doi=10.1056/NEJMoa1409547 |pmid=25981758 |pmc=4764353 }}</ref> The FDA approved this drug combination in 2015.<ref>{{cite news |last1=Morgan |first1=David |title=FDA panel recommends Vertex cystic fibrosis treatment |url=https://www.reuters.com/article/us-vertex-fda-recommendation-idUSKBN0NX2EH20150512 |access-date=October 19, 2022 |work=[[Reuters]] |date=May 13, 2015 |archive-url=https://web.archive.org/web/20221019071722/https://www.reuters.com/article/us-vertex-fda-recommendation-idUSKBN0NX2EH20150512 |archive-date=October 19, 2022}}</ref> Further research led to the discovery of [[tezacaftor]] and [[elexacaftor]], 2 other correctors of the CFTR protein.<ref>{{cite web |title=Essay |url=https://www.shawprize.org/prizes-and-laureates/life-science-and-medicine/2022/essay |publisher=Shaw Prize Foundation |access-date=October 18, 2022 |archive-url=https://web.archive.org/web/20221012140641/https://www.shawprize.org/prizes-and-laureates/life-science-and-medicine/2022/essay |archive-date=October <ins class="diffchange diffchange-inline">12</ins>, 2022 |date=September 29, 2022}}</ref> The triple combination [[elexacaftor/tezacaftor/ivacaftor]] was approved by the FDA in 2019.<ref>{{cite press release |title=FDA approves new breakthrough therapy for cystic fibrosis |url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis |access-date=October 20, 2022 |publisher=[[Food and Drug Administration]] |date=October 21, 2019 |archive-url=https://web.archive.org/web/20221020072702/https://www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis |archive-date=October 20, 2022}}</ref></div></td> </tr> <tr> <td class="diff-marker"></td> <td class="diff-context diff-side-deleted"><br /></td> <td class="diff-marker"></td> <td class="diff-context diff-side-added"><br /></td> </tr> <tr> <td class="diff-marker"></td> <td class="diff-context diff-side-deleted"><div>== Honors and awards ==</div></td> <td class="diff-marker"></td> <td class="diff-context diff-side-added"><div>== Honors and awards ==</div></td> </tr> <tr> <td class="diff-marker" data-marker="−"></td> <td class="diff-deletedline diff-side-deleted"><div>* [[Warren Alpert Foundation Prize]]<del class="diffchange diffchange-inline"> (2018)</del><ref name="warrenalpert"/></div></td> <td class="diff-marker" data-marker="+"></td> <td class="diff-addedline diff-side-added"><div>*<ins class="diffchange diffchange-inline"> 2018 -</ins> [[Warren Alpert Foundation Prize]]<ref name="warrenalpert"/></div></td> </tr> <tr> <td class="diff-marker" data-marker="−"></td> <td class="diff-deletedline diff-side-deleted"><div>* [[Shaw Prize|Shaw Prize in Life Science & Medicine]]<del class="diffchange diffchange-inline"> (2022)</del><ref>{{cite web |title=The 2022 Prize in Life Science & Medicine |url=https://www.shawprize.org/laureates/life-science-medicine/2022 |publisher=Shaw Prize Foundation |access-date=5 October 2022 |archive-url=https://web.archive.org/web/20221005032240/https://www.shawprize.org/laureates/life-science-medicine/2022 |archive-date=5 October 2022}}</ref></div></td> <td class="diff-marker" data-marker="+"></td> <td class="diff-addedline diff-side-added"><div>*<ins class="diffchange diffchange-inline"> 2022 -</ins> [[Shaw Prize|Shaw Prize in Life Science & Medicine]]<ref>{{cite web |title=The 2022 Prize in Life Science & Medicine |url=https://www.shawprize.org/laureates/life-science-medicine/2022 |publisher=Shaw Prize Foundation |access-date=5 October 2022 |archive-url=https://web.archive.org/web/20221005032240/https://www.shawprize.org/laureates/life-science-medicine/2022 |archive-date=5 October 2022}}</ref></div></td> </tr> <tr> <td colspan="2" class="diff-empty diff-side-deleted"></td> <td class="diff-marker" data-marker="+"></td> <td class="diff-addedline diff-side-added"><div>* 2023 - [[Wiley Prize]]<ref>[http://johnwiley2020news.q4web.com/press-releases/press-release-details/2023/-The-21st-Annual-Wiley-Prize-in-Biomedical-Sciences-Awarded-for-Novel-Cystic-Fibrosis-Treatment/default.aspx Wiley Prize 2023]</ref> </div></td> </tr> <tr> <td colspan="2" class="diff-empty diff-side-deleted"></td> <td class="diff-marker" data-marker="+"></td> <td class="diff-addedline diff-side-added"><div>* 2024 - [[Breakthrough Prize in Life Sciences]]<ref>{{Cite web |date=September 14, 2023 |title=BREAKTHROUGH PRIZE ANNOUNCES 2024 LAUREATES IN LIFE SCIENCES, FUNDAMENTAL PHYSICS, AND MATHEMATICS |url=https://breakthroughprize.org/News/83 |access-date=September 14, 2023 |website=BREAKTHROUGH PRIZE}}</ref> </div></td> </tr> <tr> <td class="diff-marker"></td> <td class="diff-context diff-side-deleted"><br /></td> <td class="diff-marker"></td> <td class="diff-context diff-side-added"><br /></td> </tr> <tr> <td class="diff-marker"></td> <td class="diff-context diff-side-deleted"><div>== Personal life ==</div></td> <td class="diff-marker"></td> <td class="diff-context diff-side-added"><div>== Personal life ==</div></td> </tr> <tr> <td colspan="2" class="diff-lineno">Line 62:</td> <td colspan="2" class="diff-lineno">Line 65:</td> </tr> <tr> <td class="diff-marker"></td> <td class="diff-context diff-side-deleted"><div>[[Category:University of California, Berkeley alumni]]</div></td> <td class="diff-marker"></td> <td class="diff-context diff-side-added"><div>[[Category:University of California, Berkeley alumni]]</div></td> </tr> <tr> <td class="diff-marker"></td> <td class="diff-context diff-side-deleted"><div>[[Category:American people of Romanian descent]]</div></td> <td class="diff-marker"></td> <td class="diff-context diff-side-added"><div>[[Category:American people of Romanian descent]]</div></td> </tr> <tr> <td colspan="2" class="diff-empty diff-side-deleted"></td> <td class="diff-marker" data-marker="+"></td> <td class="diff-addedline diff-side-added"><div>[[Category:Year of birth missing (living people)]]</div></td> </tr> </table><hr class='diff-hr' id='mw-oldid' /> <h2 class='diff-currentversion-title'>Latest revision as of 21:41, 21 June 2024</h2> <div class="mw-content-ltr mw-parser-output" lang="en" dir="ltr"><div class="shortdescription nomobile noexcerpt noprint searchaux" style="display:none">American cell biologist</div> <p class="mw-empty-elt"> </p> <style data-mw-deduplicate="TemplateStyles:r1257001546">.mw-parser-output .infobox-subbox{padding:0;border:none;margin:-3px;width:auto;min-width:100%;font-size:100%;clear:none;float:none;background-color:transparent}.mw-parser-output .infobox-3cols-child{margin:auto}.mw-parser-output .infobox .navbar{font-size:100%}@media screen{html.skin-theme-clientpref-night .mw-parser-output .infobox-full-data:not(.notheme)>div:not(.notheme)[style]{background:#1f1f23!important;color:#f8f9fa}}@media screen and (prefers-color-scheme:dark){html.skin-theme-clientpref-os .mw-parser-output .infobox-full-data:not(.notheme) div:not(.notheme){background:#1f1f23!important;color:#f8f9fa}}@media(min-width:640px){body.skin--responsive .mw-parser-output .infobox-table{display:table!important}body.skin--responsive .mw-parser-output .infobox-table>caption{display:table-caption!important}body.skin--responsive .mw-parser-output .infobox-table>tbody{display:table-row-group}body.skin--responsive .mw-parser-output .infobox-table tr{display:table-row!important}body.skin--responsive .mw-parser-output .infobox-table th,body.skin--responsive .mw-parser-output .infobox-table td{padding-left:inherit;padding-right:inherit}}</style><table class="infobox biography vcard"><tbody><tr><th colspan="2" class="infobox-above" style="font-size:125%;"><div class="fn">Paul Negulescu</div></th></tr><tr><th scope="row" class="infobox-label">Born</th><td class="infobox-data"><div style="display:inline" class="nickname">Paul Adrian Negulescu<sup id="cite_ref-thesis_2-0" class="reference"><a href="#cite_note-thesis-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup></div><br /><div style="display:inline" class="birthplace"><a href="/wiki/San_Francisco" title="San Francisco">San Francisco</a><sup id="cite_ref-autobio_1-2" class="reference"><a href="#cite_note-autobio-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup></div></td></tr><tr><th scope="row" class="infobox-label">Education</th><td class="infobox-data"><a href="/wiki/University_of_California,_Berkeley" title="University of California, Berkeley">University of California, Berkeley</a> (<a href="/wiki/Bachelor_of_Science" title="Bachelor of Science">BSc</a>, <a href="/wiki/Doctor_of_Philosophy" title="Doctor of Philosophy">PhD</a>)<sup id="cite_ref-autobio_1-3" class="reference"><a href="#cite_note-autobio-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup></td></tr><tr><th scope="row" class="infobox-label">Known for</th><td class="infobox-data">Research of <a href="/wiki/Cystic_fibrosis" title="Cystic fibrosis">cystic fibrosis</a></td></tr><tr><th scope="row" class="infobox-label">Awards</th><td class="infobox-data"><a href="/wiki/Warren_Alpert_Foundation_Prize" title="Warren Alpert Foundation Prize">Warren Alpert Foundation Prize</a> (2018)<br /> <a href="/wiki/Shaw_Prize" title="Shaw Prize">Shaw Prize in Life Science & Medicine</a> (2022)<br /><a href="/wiki/Wiley_Prize" title="Wiley Prize">Wiley Prize</a> (2023) <br /><a href="/wiki/Breakthrough_Prize_in_Life_Sciences" title="Breakthrough Prize in Life Sciences">Breakthrough Prize in Life Sciences</a> (2024)</td></tr><tr><td colspan="2" class="infobox-full-data"><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1257001546"><b>Scientific career</b></td></tr><tr><th scope="row" class="infobox-label">Fields</th><td class="infobox-data category"><a href="/wiki/Cell_biology" title="Cell biology">Cell biology</a></td></tr><tr><th scope="row" class="infobox-label">Institutions</th><td class="infobox-data"><a href="/wiki/University_of_California,_Irvine" title="University of California, Irvine">University of California, Irvine</a> <br /> <a href="/wiki/Aurora_Biosciences" title="Aurora Biosciences">Aurora Biosciences</a> <br /> <a href="/wiki/Vertex_Pharmaceuticals" title="Vertex Pharmaceuticals">Vertex Pharmaceuticals</a><sup id="cite_ref-autobio_1-0" class="reference"><a href="#cite_note-autobio-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup></td></tr><tr><th scope="row" class="infobox-label"><a href="/wiki/Thesis" title="Thesis">Thesis</a></th><td class="infobox-data"><i><a rel="nofollow" class="external text" href="https://search.library.berkeley.edu/permalink/01UCS_BER/s4lks2/cdi_proquest_journals_303683972">The role and regulation of intracellular calcium during stimulus-secretion coupling in the parietal cell</a></i> <span style="font-size:97%;">(1988)</span></td></tr><tr><th scope="row" class="infobox-label"><a href="/wiki/Doctoral_advisor" title="Doctoral advisor">Doctoral advisor</a></th><td class="infobox-data">Terry Machen<sup id="cite_ref-autobio_1-1" class="reference"><a href="#cite_note-autobio-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup></td></tr><tr style="display:none"><td colspan="2"> </td></tr></tbody></table> <p><b>Paul Adrian Negulescu</b> is an American–<a href="/wiki/Romanians" title="Romanians">Romanian</a> <a href="/wiki/Cell_biology" title="Cell biology">cell biologist</a>. He is a Senior Vice President at American <a href="/wiki/Pharmaceutical_industry" title="Pharmaceutical industry">pharmaceutical company</a> <a href="/wiki/Vertex_Pharmaceuticals" title="Vertex Pharmaceuticals">Vertex Pharmaceuticals</a>. He received the 2022 <a href="/wiki/Shaw_Prize" title="Shaw Prize">Shaw Prize in Life science and medicine</a>, together with <a href="/wiki/Michael_J._Welsh_(biologist)" title="Michael J. Welsh (biologist)">Michael J. Welsh</a>, for their work that uncovered the <a href="/wiki/Etiology" title="Etiology">etiology</a> of <a href="/wiki/Cystic_fibrosis" title="Cystic fibrosis">cystic fibrosis</a> and developed effective <a href="/wiki/Medication" title="Medication">medications</a>.<sup id="cite_ref-3" class="reference"><a href="#cite_note-3"><span class="cite-bracket">[</span>3<span class="cite-bracket">]</span></a></sup> </p> <meta property="mw:PageProp/toc" /> <div class="mw-heading mw-heading2"><h2 id="Early_life_and_education">Early life and education</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Paul_Negulescu&action=edit&section=1" title="Edit section: Early life and education"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Negulescu was born in <a href="/wiki/San_Francisco" title="San Francisco">San Francisco</a> to <a href="/wiki/Immigrant_generations#First_generation" title="Immigrant generations">first-generation immigrants</a> from <a href="/wiki/Romania" title="Romania">Romania</a>. His father was a <a href="/wiki/Surgery" title="Surgery">surgeon</a>,<sup id="cite_ref-autobio_1-4" class="reference"><a href="#cite_note-autobio-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup> and his grandfather, <a href="/wiki/Constantin_Vi%C8%99oianu" title="Constantin Vișoianu">Constantin Vișoianu</a>, was a former <a href="/wiki/Ministry_of_Foreign_Affairs_(Romania)" title="Ministry of Foreign Affairs (Romania)">Minister of Foreign Affairs</a> of Romania.<sup id="cite_ref-4" class="reference"><a href="#cite_note-4"><span class="cite-bracket">[</span>4<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-5" class="reference"><a href="#cite_note-5"><span class="cite-bracket">[</span>5<span class="cite-bracket">]</span></a></sup> He has a brother.<sup id="cite_ref-autobio_1-5" class="reference"><a href="#cite_note-autobio-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup> </p><p>Thanks to his childhood experience, he initially wanted to graduate with <a href="/wiki/History" title="History">history</a> from the <a href="/wiki/University_of_California,_Berkeley" title="University of California, Berkeley">University of California, Berkeley</a>. A third-year <a href="/wiki/Physiology" title="Physiology">physiology</a> class taught by <a href="/wiki/Roger_Y._Tsien" title="Roger Y. Tsien">Roger Y. Tsien</a> had a great influence on Negulescu, who eventually graduated with a <a href="/wiki/Double_degree" class="mw-redirect" title="Double degree">dual degree</a> in history and physiology in 1986. He then went on and studied <a href="/wiki/Doctor_of_Philosophy" title="Doctor of Philosophy">PhD</a> in physiology under Terry Machen, completing it in 1990.<sup id="cite_ref-autobio_1-6" class="reference"><a href="#cite_note-autobio-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading2"><h2 id="Career">Career</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Paul_Negulescu&action=edit&section=2" title="Edit section: Career"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Negulescu started his career as a <a href="/wiki/Postdoctoral_researcher" title="Postdoctoral researcher">postdoctoral researcher</a> at the <a href="/wiki/University_of_California,_Berkeley" title="University of California, Berkeley">University of California, Berkeley</a> and under Michael Cahalan at the <a href="/wiki/University_of_California,_Irvine" title="University of California, Irvine">University of California, Irvine</a>. He was planning to move to the <a href="/wiki/University_of_Connecticut" title="University of Connecticut">University of Connecticut</a> when <a href="/wiki/Roger_Y._Tsien" title="Roger Y. Tsien">Roger Y. Tsien</a> asked him to join a <a href="/wiki/Startup_company" title="Startup company">startup company</a> he was forming called <a href="/wiki/Aurora_Biosciences" title="Aurora Biosciences">Aurora Biosciences</a>.<sup id="cite_ref-autobio_1-7" class="reference"><a href="#cite_note-autobio-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-6" class="reference"><a href="#cite_note-6"><span class="cite-bracket">[</span>6<span class="cite-bracket">]</span></a></sup> Negulescu joined Aurora Biosciences in 1996 as one of the first employees.<sup id="cite_ref-warrenalpert_7-0" class="reference"><a href="#cite_note-warrenalpert-7"><span class="cite-bracket">[</span>7<span class="cite-bracket">]</span></a></sup> He became Senior Vice President of Discovery Biology in 1999. When <a href="/wiki/Vertex_Pharmaceuticals" title="Vertex Pharmaceuticals">Vertex Pharmaceuticals</a> acquired Aurora Biosciences in 2001,<sup id="cite_ref-8" class="reference"><a href="#cite_note-8"><span class="cite-bracket">[</span>8<span class="cite-bracket">]</span></a></sup> he was appointed Senior Vice President of Research.<sup id="cite_ref-autobio_1-8" class="reference"><a href="#cite_note-autobio-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup> Negulescu has been leading the <a href="/wiki/San_Diego" title="San Diego">San Diego</a> Research Center of Vertex Pharmaceuticals since 2003.<sup id="cite_ref-9" class="reference"><a href="#cite_note-9"><span class="cite-bracket">[</span>9<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading2"><h2 id="Research">Research</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Paul_Negulescu&action=edit&section=3" title="Edit section: Research"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Negulescu's research focuses on the therapy of <a href="/wiki/Cystic_fibrosis" title="Cystic fibrosis">cystic fibrosis</a>. Cystic fibrosis can be caused by any of the thousands of identified <a href="/wiki/Mutation" title="Mutation">mutations</a> in the <a href="/wiki/Cystic_fibrosis_transmembrane_conductance_regulator" title="Cystic fibrosis transmembrane conductance regulator">CFTR</a> protein, an <a href="/wiki/Ion_channel" title="Ion channel">ion channel</a> that allows <a href="/wiki/Chloride" title="Chloride">chloride ions</a> 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.<sup id="cite_ref-10" class="reference"><a href="#cite_note-10"><span class="cite-bracket">[</span>10<span class="cite-bracket">]</span></a></sup> Via <a href="/wiki/High-throughput_screening" title="High-throughput screening">high-throughput screening</a>, his team at <a href="/wiki/Vertex_Pharmaceuticals" title="Vertex Pharmaceuticals">Vertex Pharmaceuticals</a> discovered <a href="/wiki/Ivacaftor" title="Ivacaftor">ivacaftor</a>, a <a href="/wiki/Small_molecule" title="Small molecule">small-molecule</a> <a href="/wiki/Potentiator" title="Potentiator">potentiator</a> that increases the probability that mutated CFTR gates will open.<sup id="cite_ref-11" class="reference"><a href="#cite_note-11"><span class="cite-bracket">[</span>11<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-12" class="reference"><a href="#cite_note-12"><span class="cite-bracket">[</span>12<span class="cite-bracket">]</span></a></sup> Ivacaftor was approved by the <a href="/wiki/Food_and_Drug_Administration" title="Food and Drug Administration">Food and Drug Administration</a> (FDA) for cystic fibrosis patients with one specific Class III mutation in 2012, and has since been approved for mutation classes as well.<sup id="cite_ref-annurev_13-0" class="reference"><a href="#cite_note-annurev-13"><span class="cite-bracket">[</span>13<span class="cite-bracket">]</span></a></sup> Of note, the expanded approval in 2017 was based solely on <i><a href="/wiki/In_vitro" title="In vitro">in vitro</a></i> data, due to the small number of patients carrying those rare mutations making <a href="/wiki/Clinical_trial" title="Clinical trial">clinical trials</a> impossible.<sup id="cite_ref-14" class="reference"><a href="#cite_note-14"><span class="cite-bracket">[</span>14<span class="cite-bracket">]</span></a></sup> </p><p>Negulescu also led the discovery of another cystic fibrosis drug, <a href="/wiki/Lumacaftor" title="Lumacaftor">lumacaftor</a>, which is known as a "corrector" as it acts as a <a href="/wiki/Chaperone_(protein)" title="Chaperone (protein)">chaperone</a> to help the CFTR protein fold correctly.<sup id="cite_ref-15" class="reference"><a href="#cite_note-15"><span class="cite-bracket">[</span>15<span class="cite-bracket">]</span></a></sup> Thus, it can be used in patients with Class II mutations, which create <a href="/wiki/Misfold" class="mw-redirect" title="Misfold">misfolded</a> CFTR protein that cannot reaching the <a href="/wiki/Cell_membrane" title="Cell membrane">cell surface</a>.<sup id="cite_ref-annurev_13-1" class="reference"><a href="#cite_note-annurev-13"><span class="cite-bracket">[</span>13<span class="cite-bracket">]</span></a></sup> The most common Class II mutation is F508del.<sup id="cite_ref-16" class="reference"><a href="#cite_note-16"><span class="cite-bracket">[</span>16<span class="cite-bracket">]</span></a></sup> Again with high-throughput screening, Negulescu and his team found that lumacaftor can correct F508del-mutated CFTR protein.<sup id="cite_ref-17" class="reference"><a href="#cite_note-17"><span class="cite-bracket">[</span>17<span class="cite-bracket">]</span></a></sup> It was later found that the drug was not effective enough when administered on its own,<sup id="cite_ref-18" class="reference"><a href="#cite_note-18"><span class="cite-bracket">[</span>18<span class="cite-bracket">]</span></a></sup> but was so when administered together with ivacaftor.<sup id="cite_ref-19" class="reference"><a href="#cite_note-19"><span class="cite-bracket">[</span>19<span class="cite-bracket">]</span></a></sup> The FDA approved this drug combination in 2015.<sup id="cite_ref-20" class="reference"><a href="#cite_note-20"><span class="cite-bracket">[</span>20<span class="cite-bracket">]</span></a></sup> Further research led to the discovery of <a href="/wiki/Tezacaftor" title="Tezacaftor">tezacaftor</a> and <a href="/wiki/Elexacaftor" title="Elexacaftor">elexacaftor</a>, 2 other correctors of the CFTR protein.<sup id="cite_ref-21" class="reference"><a href="#cite_note-21"><span class="cite-bracket">[</span>21<span class="cite-bracket">]</span></a></sup> The triple combination <a href="/wiki/Elexacaftor/tezacaftor/ivacaftor" title="Elexacaftor/tezacaftor/ivacaftor">elexacaftor/tezacaftor/ivacaftor</a> was approved by the FDA in 2019.<sup id="cite_ref-22" class="reference"><a href="#cite_note-22"><span class="cite-bracket">[</span>22<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading2"><h2 id="Honors_and_awards">Honors and awards</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Paul_Negulescu&action=edit&section=4" title="Edit section: Honors and awards"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <ul><li>2018 - <a href="/wiki/Warren_Alpert_Foundation_Prize" title="Warren Alpert Foundation Prize">Warren Alpert Foundation Prize</a><sup id="cite_ref-warrenalpert_7-1" class="reference"><a href="#cite_note-warrenalpert-7"><span class="cite-bracket">[</span>7<span class="cite-bracket">]</span></a></sup></li> <li>2022 - <a href="/wiki/Shaw_Prize" title="Shaw Prize">Shaw Prize in Life Science & Medicine</a><sup id="cite_ref-23" class="reference"><a href="#cite_note-23"><span class="cite-bracket">[</span>23<span class="cite-bracket">]</span></a></sup></li> <li>2023 - <a href="/wiki/Wiley_Prize" title="Wiley Prize">Wiley Prize</a><sup id="cite_ref-24" class="reference"><a href="#cite_note-24"><span class="cite-bracket">[</span>24<span class="cite-bracket">]</span></a></sup></li> <li>2024 - <a href="/wiki/Breakthrough_Prize_in_Life_Sciences" title="Breakthrough Prize in Life Sciences">Breakthrough Prize in Life Sciences</a><sup id="cite_ref-25" class="reference"><a href="#cite_note-25"><span class="cite-bracket">[</span>25<span class="cite-bracket">]</span></a></sup></li></ul> <div class="mw-heading mw-heading2"><h2 id="Personal_life">Personal life</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Paul_Negulescu&action=edit&section=5" title="Edit section: Personal life"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Negulescu met his wife, Debbie, during his time at the <a href="/wiki/University_of_California,_Irvine" title="University of California, Irvine">University of California, Irvine</a>.<sup id="cite_ref-autobio_1-9" class="reference"><a href="#cite_note-autobio-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading2"><h2 id="References">References</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Paul_Negulescu&action=edit&section=6" title="Edit section: References"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <style data-mw-deduplicate="TemplateStyles:r1239543626">.mw-parser-output .reflist{margin-bottom:0.5em;list-style-type:decimal}@media screen{.mw-parser-output .reflist{font-size:90%}}.mw-parser-output .reflist .references{font-size:100%;margin-bottom:0;list-style-type:inherit}.mw-parser-output .reflist-columns-2{column-width:30em}.mw-parser-output .reflist-columns-3{column-width:25em}.mw-parser-output .reflist-columns{margin-top:0.3em}.mw-parser-output .reflist-columns ol{margin-top:0}.mw-parser-output .reflist-columns li{page-break-inside:avoid;break-inside:avoid-column}.mw-parser-output .reflist-upper-alpha{list-style-type:upper-alpha}.mw-parser-output .reflist-upper-roman{list-style-type:upper-roman}.mw-parser-output .reflist-lower-alpha{list-style-type:lower-alpha}.mw-parser-output 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title="Saul Perlmutter">Saul Perlmutter</a>, <a href="/wiki/Adam_Riess" title="Adam Riess">Adam Riess</a> and <a href="/wiki/Brian_Schmidt" title="Brian Schmidt">Brian Schmidt</a> (2006)</li> <li><a href="/wiki/Peter_Goldreich" title="Peter Goldreich">Peter Goldreich</a> (2007)</li> <li><a href="/wiki/Reinhard_Genzel" title="Reinhard Genzel">Reinhard Genzel</a> (2008)</li> <li><a href="/wiki/Frank_Shu" title="Frank Shu">Frank Shu</a> (2009)</li> <li><a href="/wiki/Charles_L._Bennett" title="Charles L. Bennett">Charles Bennett</a>, <a href="/wiki/Lyman_Page" title="Lyman Page">Lyman Page</a> and <a href="/wiki/David_Spergel" title="David Spergel">David Spergel</a> (2010)</li> <li><a href="/wiki/Enrico_Costa_(physicist)" title="Enrico Costa (physicist)">Enrico Costa</a> and <a href="/wiki/Gerald_J._Fishman" title="Gerald J. Fishman">Gerald Fishman</a> (2011)</li> <li><a href="/wiki/David_C._Jewitt" title="David C. Jewitt">David C. Jewitt</a> and <a href="/wiki/Jane_Luu" title="Jane Luu">Jane Luu</a> (2012)</li> <li><a href="/wiki/Steven_Balbus" title="Steven Balbus">Steven Balbus</a> and <a href="/wiki/John_F._Hawley" title="John F. Hawley">John F. Hawley</a> (2013)</li> <li><a href="/wiki/Daniel_Eisenstein" title="Daniel Eisenstein">Daniel Eisenstein</a>, <a href="/wiki/Shaun_Cole" title="Shaun Cole">Shaun Cole</a> and <a href="/wiki/John_A._Peacock" title="John A. Peacock">John A. Peacock</a> (2014)</li> <li><a href="/wiki/William_J._Borucki" title="William J. Borucki">William J. Borucki</a> (2015)</li> <li><a href="/wiki/Ronald_Drever" title="Ronald Drever">Ronald Drever</a>, <a href="/wiki/Kip_Thorne" title="Kip Thorne">Kip Thorne</a> and <a href="/wiki/Rainer_Weiss" title="Rainer Weiss">Rainer Weiss</a> (2016)</li> <li><a href="/wiki/Simon_White" title="Simon White">Simon White</a> (2017)</li> <li><a href="/wiki/Jean-Loup_Puget" title="Jean-Loup Puget">Jean-Loup Puget</a> (2018)</li> <li><a href="/wiki/Edward_C._Stone" title="Edward C. Stone">Edward C. Stone</a> (2019)</li> <li><a href="/wiki/Roger_Blandford" title="Roger Blandford">Roger Blandford</a> (2020)</li> <li><a href="/wiki/Victoria_Kaspi" title="Victoria Kaspi">Victoria Kaspi</a> and <a href="/wiki/Chryssa_Kouveliotou" title="Chryssa Kouveliotou">Chryssa Kouveliotou</a> (2021)</li> <li><a href="/wiki/Lennart_Lindegren" title="Lennart Lindegren">Lennart Lindegren</a> and <a href="/wiki/Michael_Perryman" title="Michael Perryman">Michael Perryman</a> (2022)</li> <li><a href="/wiki/Matthew_Bailes" title="Matthew Bailes">Matthew Bailes</a>, <a href="/wiki/Duncan_Lorimer" title="Duncan Lorimer">Duncan Lorimer</a> and <a href="/wiki/Maura_McLaughlin" title="Maura McLaughlin">Maura McLaughlin</a> (2023)</li> <li><a href="/wiki/Shrinivas_R._Kulkarni" class="mw-redirect" title="Shrinivas R. Kulkarni">Shrinivas R. Kulkarni</a> (2024)</li></ul> </div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%;background:#d3d3d3;">Life science<br />and medicine</th><td class="navbox-list-with-group navbox-list navbox-even hlist" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Stanley_Norman_Cohen" title="Stanley Norman Cohen">Stanley Norman Cohen</a>, <a href="/wiki/Herbert_Boyer" title="Herbert Boyer">Herbert Boyer</a>, <a href="/wiki/Yuet_Wai_Kan" title="Yuet Wai Kan">Yuet-Wai Kan</a> and <a href="/wiki/Richard_Doll" title="Richard Doll">Richard Doll</a> (2004)</li> <li><a href="/wiki/Michael_Berridge" title="Michael Berridge">Michael Berridge</a> (2005)</li> <li><a href="/wiki/Xiaodong_Wang_(biochemist)" title="Xiaodong Wang (biochemist)">Xiaodong Wang</a> (2006)</li> <li><a href="/wiki/Robert_Lefkowitz" title="Robert Lefkowitz">Robert Lefkowitz</a> (2007)</li> <li><a href="/wiki/Ian_Wilmut" title="Ian Wilmut">Ian Wilmut</a>, <a href="/wiki/Keith_Campbell_(biologist)" title="Keith Campbell (biologist)">Keith H. S. Campbell</a> and <a href="/wiki/Shinya_Yamanaka" title="Shinya Yamanaka">Shinya Yamanaka</a> (2008)</li> <li><a href="/wiki/Douglas_L._Coleman" title="Douglas L. Coleman">Douglas Coleman</a> and <a href="/wiki/Jeffrey_M._Friedman" title="Jeffrey M. Friedman">Jeffrey Friedman</a> (2009)</li> <li><a href="/wiki/David_Julius" title="David Julius">David Julius</a> (2010)</li> <li><a href="/wiki/Jules_A._Hoffmann" title="Jules A. Hoffmann">Jules Hoffmann</a>, <a href="/wiki/Ruslan_Medzhitov" title="Ruslan Medzhitov">Ruslan Medzhitov</a> and <a href="/wiki/Bruce_Beutler" title="Bruce Beutler">Bruce Beutler</a> (2011)</li> <li><a href="/wiki/Franz-Ulrich_Hartl" title="Franz-Ulrich Hartl">Franz-Ulrich Hartl</a> and <a href="/wiki/Arthur_L._Horwich" title="Arthur L. Horwich">Arthur L. Horwich</a> (2012)</li> <li><a href="/wiki/Jeffrey_C._Hall" title="Jeffrey C. Hall">Jeffrey C. Hall</a>, <a href="/wiki/Michael_Rosbash" title="Michael Rosbash">Michael Rosbash</a> and <a href="/wiki/Michael_W._Young" title="Michael W. Young">Michael W. Young</a> (2013)</li> <li><a href="/wiki/Kazutoshi_Mori" title="Kazutoshi Mori">Kazutoshi Mori</a> and <a href="/wiki/Peter_Walter" title="Peter Walter">Peter Walter</a> (2014)</li> <li><a href="/wiki/Bonnie_Bassler" title="Bonnie Bassler">Bonnie Bassler</a> and <a href="/wiki/Everett_Peter_Greenberg" title="Everett Peter Greenberg">Everett Peter Greenberg</a> (2015)</li> <li><a href="/wiki/Adrian_Bird" title="Adrian Bird">Adrian Bird</a> and <a href="/wiki/Huda_Zoghbi" title="Huda Zoghbi">Huda Zoghbi</a> (2016)</li> <li><a href="/wiki/Ian_R._Gibbons" title="Ian R. Gibbons">Ian R. Gibbons</a> and <a href="/wiki/Ronald_Vale" title="Ronald Vale">Ronald Vale</a> (2017)</li> <li><a href="/wiki/Mary-Claire_King" title="Mary-Claire King">Mary-Claire King</a> (2018)</li> <li><a href="/wiki/Maria_Jasin" title="Maria Jasin">Maria Jasin</a> (2019)</li> <li><a href="/wiki/Gero_Miesenb%C3%B6ck" title="Gero Miesenböck">Gero Miesenböck</a>, <a href="/wiki/Peter_Hegemann" title="Peter Hegemann">Peter Hegemann</a> and <a href="/wiki/Georg_Nagel" title="Georg Nagel">Georg Nagel</a> (2020)</li> <li><a href="/wiki/Scott_D._Emr" title="Scott D. Emr">Scott D. Emr</a> (2021)</li> <li><a class="mw-selflink selflink">Paul A. Negulescu</a> and <a href="/wiki/Michael_J._Welsh_(biologist)" title="Michael J. Welsh (biologist)">Michael J. Welsh</a> (2022)</li> <li><a href="/wiki/Patrick_Cramer" title="Patrick Cramer">Patrick Cramer</a> and <a href="/wiki/Eva_Nogales" title="Eva Nogales">Eva Nogales</a> (2023)</li> <li><a href="/wiki/Stuart_H._Orkin" class="mw-redirect" title="Stuart H. Orkin">Stuart H. Orkin</a> and <a href="/wiki/Swee_Lay_Thein" title="Swee Lay Thein">Swee Lay Thein</a> (2024)</li></ul> </div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%;background:#d3d3d3;">Mathematical<br />science</th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Shiing-Shen_Chern" title="Shiing-Shen Chern">Shiing-Shen Chern</a> (2004)</li> <li><a href="/wiki/Andrew_Wiles" title="Andrew Wiles">Andrew Wiles</a> (2005)</li> <li><a href="/wiki/David_Mumford" title="David Mumford">David Mumford</a> and <a href="/wiki/Wu_Wenjun" title="Wu Wenjun">Wentsun Wu</a> (2006)</li> <li><a href="/wiki/Robert_Langlands" title="Robert Langlands">Robert Langlands</a> and <a href="/wiki/Richard_Taylor_(mathematician)" title="Richard Taylor (mathematician)">Richard Taylor</a> (2007)</li> <li><a href="/wiki/Vladimir_Arnold" title="Vladimir Arnold">Vladimir Arnold</a> and <a href="/wiki/Ludvig_Faddeev" title="Ludvig Faddeev">Ludwig Faddeev</a> (2008)</li> <li><a href="/wiki/Simon_Donaldson" title="Simon Donaldson">Simon Donaldson</a> and <a href="/wiki/Clifford_Taubes" title="Clifford Taubes">Clifford Taubes</a> (2009)</li> <li><a href="/wiki/Jean_Bourgain" title="Jean Bourgain">Jean Bourgain</a> (2010)</li> <li><a href="/wiki/Demetrios_Christodoulou" title="Demetrios Christodoulou">Demetrios Christodoulou</a> and <a href="/wiki/Richard_S._Hamilton" title="Richard S. Hamilton">Richard S. Hamilton</a> (2011)</li> <li><a href="/wiki/Maxim_Kontsevich" title="Maxim Kontsevich">Maxim Kontsevich</a> (2012)</li> <li><a href="/wiki/David_Donoho" title="David Donoho">David Donoho</a> (2013)</li> <li><a href="/wiki/George_Lusztig" title="George Lusztig">George Lusztig</a> (2014)</li> <li><a href="/wiki/Gerd_Faltings" title="Gerd Faltings">Gerd Faltings</a> and <a href="/wiki/Henryk_Iwaniec" title="Henryk Iwaniec">Henryk Iwaniec</a> (2015)</li> <li><a href="/wiki/Nigel_Hitchin" title="Nigel Hitchin">Nigel Hitchin</a> (2016)</li> <li><a href="/wiki/J%C3%A1nos_Koll%C3%A1r" title="János Kollár">János Kollár</a> and <a href="/wiki/Claire_Voisin" title="Claire Voisin">Claire Voisin</a> (2017)</li> <li><a href="/wiki/Luis_Caffarelli" title="Luis Caffarelli">Luis Caffarelli</a> (2018)</li> <li><a href="/wiki/Michel_Talagrand" title="Michel Talagrand">Michel Talagrand</a> (2019)</li> <li><a href="/wiki/Alexander_Beilinson" title="Alexander Beilinson">Alexander Beilinson</a> and <a href="/wiki/David_Kazhdan" title="David Kazhdan">David Kazhdan</a> (2020)</li> <li><a href="/wiki/Jean-Michel_Bismut" title="Jean-Michel Bismut">Jean-Michel Bismut</a> and <a href="/wiki/Jeff_Cheeger" title="Jeff Cheeger">Jeff Cheeger</a> (2021)</li> <li><a href="/wiki/Noga_Alon" title="Noga Alon">Noga Alon</a> and <a href="/wiki/Ehud_Hrushovski" title="Ehud Hrushovski">Ehud Hrushovski</a> (2022)</li> <li><a href="/wiki/Vladimir_Drinfeld" title="Vladimir Drinfeld">Vladimir Drinfeld</a> and <a href="/wiki/Shing-Tung_Yau" title="Shing-Tung Yau">Shing-Tung Yau</a> (2023)</li> <li><a href="/wiki/Peter_Sarnak" title="Peter Sarnak">Peter Sarnak</a> (2024)</li></ul> </div></td></tr></tbody></table></div></div><noscript><img src="https://login.wikimedia.org/wiki/Special:CentralAutoLogin/start?type=1x1" alt="" width="1" height="1" style="border: none; position: absolute;"></noscript> <div class="printfooter" data-nosnippet="">Retrieved from "<a dir="ltr" href="https://en.wikipedia.org/w/index.php?title=Paul_Negulescu&oldid=1230293740">https://en.wikipedia.org/w/index.php?title=Paul_Negulescu&oldid=1230293740</a>"</div></div> <div id="catlinks" class="catlinks" data-mw="interface"><div id="mw-normal-catlinks" class="mw-normal-catlinks"><a href="/wiki/Help:Category" title="Help:Category">Categories</a>: <ul><li><a href="/wiki/Category:Living_people" title="Category:Living people">Living people</a></li><li><a href="/wiki/Category:21st-century_American_biologists" title="Category:21st-century American biologists">21st-century American biologists</a></li><li><a href="/wiki/Category:University_of_California,_Berkeley_alumni" title="Category:University of California, Berkeley alumni">University of California, Berkeley alumni</a></li><li><a href="/wiki/Category:American_people_of_Romanian_descent" title="Category:American people of Romanian descent">American people of Romanian descent</a></li></ul></div><div id="mw-hidden-catlinks" class="mw-hidden-catlinks mw-hidden-cats-hidden">Hidden categories: <ul><li><a href="/wiki/Category:Articles_with_short_description" title="Category:Articles with short description">Articles with short description</a></li><li><a href="/wiki/Category:Short_description_matches_Wikidata" title="Category:Short description matches Wikidata">Short description matches Wikidata</a></li><li><a href="/wiki/Category:Use_American_English_from_October_2022" title="Category:Use American English from October 2022">Use American English from October 2022</a></li><li><a href="/wiki/Category:All_Wikipedia_articles_written_in_American_English" title="Category:All Wikipedia articles written in American English">All Wikipedia articles written in American English</a></li><li><a href="/wiki/Category:Use_mdy_dates_from_October_2022" title="Category:Use mdy dates from October 2022">Use mdy dates from October 2022</a></li><li><a href="/wiki/Category:Articles_with_hCards" title="Category:Articles with hCards">Articles with hCards</a></li><li><a href="/wiki/Category:Year_of_birth_missing_(living_people)" title="Category:Year of birth missing (living people)">Year of birth missing (living people)</a></li></ul></div></div> </div> </main> </div> <div class="mw-footer-container"> <footer id="footer" class="mw-footer" > <ul id="footer-info"> <li id="footer-info-lastmod"> This page was last edited on 21 June 2024, at 21:41<span class="anonymous-show"> (UTC)</span>.</li> <li id="footer-info-copyright">Text is available under the <a href="/wiki/Wikipedia:Text_of_the_Creative_Commons_Attribution-ShareAlike_4.0_International_License" title="Wikipedia:Text of the Creative Commons Attribution-ShareAlike 4.0 International License">Creative Commons Attribution-ShareAlike 4.0 License</a>; additional terms may apply. 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