Publications search
Found 37443 matches. Displaying 661-670
Nacev BA, Sanchez-Vega F, Smith SA, Antonescu CR, Rosenbaum E, Shi HY, Tang C, Socci ND, Rana S, Gularte-Merida R, Zehir A, Gounder MM, Bowler TG, Luthra A, Jadeja B, Okada A, Strong JA, Stoller J, Chan JE, Chi P, D'Angelo SP, Dickson MA, Kelly CM, Keohan ML, Movva S, Thornton K, Meyers PA, Wexler LH, Slotkin EK, Bender JLG, Shukla NN, Hensley ML, Healey JH, La Quaglia MP, Alektiar KM, Crago AM, Yoon SS, Untch BR, Chiang S, Agaram NP, Hameed MR, Berger MF, Solit DB, Schultz N, Ladanyi M, Singer S, Tap WD
Show All Authors
Clinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets (opens in new window)
NATURE COMMUNICATIONS 2022 JUN 15; 13(1):? Article 3405
Sarcomas are rare tumours with many different subtypes and clinical outcomes; a broader knowledge of their genetic features is required. Here, the authors analyse 2138 soft tissue and bone sarcomas across 45 subtypes using MSK-IMPACT targeted sequencing and find genomic groups that are distinct from histological subgroups. The genetic, biologic, and clinical heterogeneity of sarcomas poses a challenge for the identification of therapeutic targets, clinical research, and advancing patient care. Because there are > 100 sarcoma subtypes, in-depth genetic studies have focused on one or a few subtypes. Herein, we report a comparative genetic analysis of 2,138 sarcomas representing 45 pathological entities. This cohort is prospectively analyzed using targeted sequencing to characterize subtype-specific somatic alterations in targetable pathways, rates of whole genome doubling, mutational signatures, and subtype-agnostic genomic clusters. The most common alterations are in cell cycle control and TP53, receptor tyrosine kinases/PI3K/RAS, and epigenetic regulators. Subtype-specific associations include TERT amplification in intimal sarcoma and SWI/SNF alterations in uterine adenosarcoma. Tumor mutational burden, while low compared to other cancers, varies between and within subtypes. This resource will improve sarcoma models, motivate studies of subtype-specific alterations, and inform investigations of genetic factors and their correlations with treatment response.
Garshick MS, Drenkova K, Barrett TJ, Schlamp F, Fisher EA, Katz S, Jelic S, Neimann AL, Scher JU, Krueger J, Berger JS
Show All Authors
A Randomized Open-Label Clinical Trial of Lipid-Lowering Therapy in Psoriasis to Reduce Vascular Endothelial Inflammation (opens in new window)
JOURNAL OF INVESTIGATIVE DERMATOLOGY 2022 JUN; 142(6):1749-1752
Tumasyan A, Adam W, Andrejkovic JW, Bergauer T, Chatterjee S, Damanakis K, Dragicevic M, Del Valle AE, Fruhwirth R, Jeitler M, Krammer N, Lechner L, Liko D, Mikulec I, Paulitsch P, Pitters FM, Schieck J, Schofbeck R, Schwarz D, Templ S, Waltenberger W, Wulz CE, Chekhovsky V, Litomin A, Makarenko V, Darwish MR, De Wolf EA, Janssen T, Kello T, Lelek A, Sfar HR, Van Mechelen P, Van Putte S, Van Remortel N, Bols ES, D'Hondt J, De Moor A, Delcourt M, El Faham H, Lowette S, Moortgat S, Morton A, Muller D, Sahasransu AR, Tavernier S, Van Doninck W, Vannerom D, Stylianou N, Beghin D, Bilin B, Clerbaux B, De Lentdecker G, Favart L, Kalsi AK, Lee K, Mahdavikhorrami M, Makarenko I, Moureaux L, Paredes S, Petre L, Popov A, Postiau N, Starling E, Thomas L, Vanden Bemden M, Vander Velde C, Vanlaer P, Gao X, Cornelis T, Dobur D, Knolle J, Lambrecht L, Mestdach G, Niedziela M, Rendon C, Roskas C, Samalan A, Skovpen K, Tytgat M, Vermassen B, Wezenbeek L, Benecke A, Bethani A, Bruno G, Bury F, Caputo C, David P, Delaere C, Donertas IS, Giammanco A, Jaffel K, Jain S, Lemaitre V, Mondal K, Prisciandaro J, Taliercio A, Teklishyn M, Tran TT, Vischia P, Wertz S, Alves GA, Hensel C, Moraes A, Teles PR, Alda WL, Pereira MAG, Ferreira MB, Malbouisson HB, Carvalho W, Chinellato J, Da Costa EM, Da Silveira GG, Damiao DD, Sousa VD, De Souza SF, Herrera CM, Amarilo KM, Mundim L, Nogima H, Santoro A, Do Amaral SMS, Sznajder A, Thiel M, De Araujo FTD, Pereira AV, Bernardes CA, Calligaris L, Tomei TRFP, Gregores EM, Lemos DS, Mercadante PG, Novaes SF, Padula SS, Aleksandrov A, Antchev G, Hadjiiska R, Iaydjiev P, Misheva M, Rodozov M, Shopova M, Sultanov G, Dimitrov A, Ivanov T, Litov L, Pavlov B, Petkov P, Petrov A, Cheng T, Javaid T, Mittal M, Yuan L, Ahmad M, Bauer G, Dozen C, Hu Z, Martins J, Wang Y, Yi K, Chapon E, Chen GM, Chen HS, Chen M, Iemmi F, Kapoor A, Leggat D, Liao H, Liu ZA, Milosevic V, Monti F, Sharma R, Tao J, Thomas-Wilsker J, Wang J, Zhang H, Zhao J, Agapitos A, An Y, Ban Y, Chen C, Levin A, Li Q, Lyu X, Mao Y, Qian SJ, Wang D, Xiao J, Yang H, Lu M, You Z, Okawa H, Zhang Y, Zhang L, Lin Z, Xiao M, Avila C, Cabrera A, Florez C, Fraga J, Guisao JM, Ramirez F, Alvarez JDR, Giljanovic D, Godinovic N, Lelas D, Puljak I, Antunovic Z, Kovac M, Sculac T, Brigljevic V, Ferencek D, Majumder D, Roguljic M, Starodumov A, Susa T, Attikis A, Christoforou K, Kole G, Kolosova M, Konstantinou S, Mousa J, Nicolaou C, Ptochos F, Razis PA, Rykaczewski H, Saka H, Finger M, Finger M, Kveton A, Ayala E, Jarrin EC, Abdalla H, Abdelalim AA, Mahmoud MA, Mohammed Y, Bhowmik S, Dewanjee RK, Ehataht K, Kadastik M, Nandan S, Nielsen C, Pata J, Raidal M, Tani L, Veelken C, Eerola P, Kirschenmann H, Osterberg K, Voutilainen M, Bharthuar S, Brucken E, Garcia F, Havukainen J, Kim MS, Kinnunen R, Lampen T, Lassila-Perini K, Lehti S, Linden T, Lotti M, Martikainen L, Myllymaki M, Ott J, Rantanen MM, Siikonen H, Tuominen E, Tuominiemi J, Luukka P, Petrow H, Tuuva T, Amendola C, Besancon M, Couderc F, Dejardin M, Denegri D, Faure JL, Ferri F, Ganjour S, Gras P, de Monchenault GH, Jarry P, Lenzi B, Malcles J, Rander J, Rosowsky A, Sahin MO, Savoy-Navarro A, Titov M, Yu GB, Mijuskovic J, Ahuja S, Beaudette F, Bonanomi M, Perraguin AB, Busson P, Cappati A, Charlot C, Davignon O, Diab B, Falmagne G, Ghosh S, de Cassagnac RG, Hakimi A, Kucher I, Motta J, Nguyen M, Ochando C, Paganini P, Rembser J, Salerno R, Sarkar U, Sauvan JB, Sirois Y, Tarabini A, Zabi A, Zghiche A, Agram JL, Andrea J, Apparu D, Bloch D, Bourgatte G, Brom JM, Chabert EC, Collard C, Darej D, Fontaine JC, Goerlach U, Grimault C, Le Bihan AC, Nibigira E, Van Hove P, Asilar E, Beauceron S, Bernet C, Boudoul G, Camen C, Carle A, Chanon N, Contardo D, Depasse P, El Mamouni H, Fay J, Gascon S, Gouzevitch M, Ille B, Laktineh IB, Lattaud H, Lesauvage A, Lethuillier M, Mirabito L, Perries S, Shchablo K, Sordini V, Torterotot L, Touquet G, Vander Donckt M, Viret S, Bagaturia I, Lomidze I, Tsamalaidze Z, Mestvirishvili A, Botta V, Feld L, Klein K, Lipinski M, Meuser D, Pauls A, Rowert N, Schulz J, Teroerde M, Dodonova A, Eliseev D, Erdmann M, Fackeldey P, Fischer B, Hebbeker T, Hoepfner K, Ivone F, Mastrolorenzo L, Merschmeyer M, Meyer A, Mocellin G, Mondal S, Mukherjee S, Noll D, Novak A, Pozdnyakov A, Rath Y, Reithler H, Schmidt A, Schuler SC, Sharma A, Vigilante L, Wiedenbeck S, Zaleski S, Borras K, Kasem A, Coubez X, Dziwok C, Flugge G, Ahmad WH, Hlushchenko O, Kress T, Nowack A, Pooth O, Roy D, Stahl A, Ziemons T, Zotz A, Petersen HA, Martin MA, Asmuss P, Baxter S, Bayatmakou M, Behnke O, Martinez AB, Bhattacharya S, Bin Anuar AA, Blekman F, Brunner D, Campbell A, Cardini A, Cheng C, Colombina F, Rodriguez SC, Silva GC, De Silva M, Didukh L, Eckerlin G, Eckstein D, Banos LIE, Filatov O, Gallo E, Geiser A, Giraldi A, Grohsjean A, Guthoff M, Jafari A, Jomhari NZ, Jung H, Kasemann M, Kaveh H, Kleinwort C, Kogler R, Krucker D, Lange W, Lipka K, Lohmann W, Mankel R, Melzer-Pellmann IA, Morentin MM, Metwally J, Meyer AB, Meyer M, Mnich J, Mussgiller A, Nurnberg A, Otarid Y, Adan DP, Pitzl D, Raspereza A, Lopes BR, Rubenach J, Saggio A, Saibel A, Savitskyi M, Scham M, Scheurer V, Schnake S, Schutze P, Schwanenberger C, Shchedrolosiev M, Ricardo RES, Stafford D, Tonon N, Van de Klundert M, Vazzoler F, Walsh R, Walter D, Wang Q, Wen Y, Wichmann K, Wiens L, Wissing C, Wuchterl S, Bakhshiansohi H, Aggleton R, Albrecht S, Bein S, Benato L, Connor P, De Leo K, Eich M, El Morabit K, Feindt F, Frohlich A, Garbers C, Garutti E, Gunnellini P, Hajheidari M, Haller J, Hinzmann A, Kasieczka G, Klanner R, Kramer T, Kutzner V, Lange J, Lange T, Lobanov A, Malara A, Matthies C, Mehta A, Nigamova A, Rodriguez KJP, Rieger M, Rieger O, Schleper P, Schroder M, Schwandt J, Sonneveld J, Stadie H, Steinbruck G, Tews A, Zoi I, Bechtel J, Brommer S, Burkart M, Butz E, Caspart R, Chwalek T, De Boer W, Dierlamm A, Droll A, Faltermann N, Giffels M, Gosewisch JO, Gottmann A, Hartmann F, Heidecker C, Husemann U, Keicher P, Koppenhofer R, Maier S, Mitra S, Muller T, Neukum M, Quast G, Rabbertz K, Rauser J, Savoiu D, Schnepf M, Seith D, Shvetsov I, Simonis HJ, Ulrich R, Van der Linden J, Von Cube RF, Wassmer M, Weber M, Wieland S, Wolf R, Wozniewski S, Wunsch S, Anagnostou G, Daskalakis G, Kyriakis A, Loukas D, Stakia A, Diamantopoulou M, Karasavvas D, Kontaxakis P, Koraka CK, Manousakis-Katsikakis A, Panagiotou A, Papavergou I, Saoulidou N, Theofilatos K, Tziaferi E, Vellidis K, Vourliotis E, Sphicas P, Bakas G, Kousouris K, Papakrivopoulos I, Tsipolitis G, Zacharopoulou A, Adamidis K, Bestintzanos I, Evangelou I, Foudas C, Gianneios P, Katsoulis P, Kokkas P, Manthos N, Papadopoulos I, Strologas J, Csanad M, Farkas K, Gadallah MMA, Lokos S, Major P, Mandal K, Pasztor G, Radl AJ, Suranyi O, Veres GI, Trocsanyi ZL, Bartok M, Bencze G, Hajdu C, Horvath D, Sikler F, Veszpremi V, Csorgo T, Nemes F, Czellar S, Fasanella D, Fienga F, Karancsi J, Molnar J, Szillasi Z, Teyssier D, Raics P, Ujvari B, Novak T, Bahinipati S, Kar C, Mal P, Mishra T, Bindhu VKMN, Nayak A, Saha P, Sur N, Swain SK, Vats D, Bansal S, Beri SB, Bhatnagar V, Chaudhary G, Chauhan S, Dhingra N, Gupta R, Kaur A, Kaur H, Kaur M, Kumari P, Meena M, Sandeep K, Singh JB, Virdi AK, Ahmed A, Bhardwaj A, Choudhary BC, Gola M, Keshri S, Kumar A, Naimuddin M, Priyanka P, Ranjan K, Saumya S, Shah A, Bharti M, Bhattacharya R, Bhowmik D, Dutta S, Gomber B, Maity M, Palit P, Rout PK, Saha G, Sahu B, Sarkar S, Sharan M, Behera PK, Behera SC, Kalbhor P, Komaragiri JR, Kumar D, Muhammad A, Panwar L, Pradhan R, Pujahari PR, Sikdar AK, Tiwari PC, Naskar K, Aziz T, Dugad S, Kumar M, Banerjee S, Chudasama R, Guchait M, Karmakar S, Kumar S, Majumder G, Mazumdar K, Alpana A, Dube S, Kansal B, Laha A, Pandey S, Rastogi A, Sharma S, Khazaie E, Zeinali M, Chenarani S, Etesami SM, Khakzad M, Najafabadi MM, Grunewald M, Abbrescia, Aly R, Aruta C, Colaleo A, Creanza D, De Filippis, De Palma M, Di Florio A, Di Pilato A, Elmetenawee W, Errico F, Fiore L, Iaselli G, Ince M, Lezki S, Maggi G, Maggi M, Margjeka I, Mastrapasqua V, My S, Nuzzo S, Pellecchia A, Pompili A, Pugliese G, Ramos D, Ranieri A, Selvaggi G, Silvestris L, Simone FM, Venditti R, Verwilligen P, Abbiendi G, Battilana C, Bonacorsi D, Borgonovi L, Brigliadori L, Campanini R, Capiluppi P, Castro A, Cavallo FR, Ciocca C, Cuffiani M, Dallavalle GM, Diotalevi T, Fabbri F, Fanfani A, Giacomelli P, Giommi L, Grandi C, Guiducci L, Lo Meo S, Lunerti L, Marcellini S, Masetti G, Navarria FL, Perrotta A, Primavera F, Rossi AM, Rovelli T, Siroli GP, Albergo S, Costa S, Di Mattia A, Potenza R, Tricomi A, Tuve C, Barbagli G, Cassese A, Ceccarelli R, Ciulli V, Civinini C, D'Alessandro R, Focardi E, Latino G, Lenzi P, Lizzo M, Meschini M, Paoletti S, Seidita R, Sguazzoni G, Viliani L, Benussi L, Bianco S, Piccolo D, Bozzo M, Ferro F, Mulargia R, Robutti E, Tosi S, Benaglia A, Brivio F, Cetorelli F, De Guio F, Dinardo ME, Dini P, Gennai S, Ghezzi A, Govoni P, Guzzi L, Lucchini MT, Malberti M, Malvezzi S, Massironi A, Menasce D, Moroni L, Paganoni M, Pedrini D, Ragazzi S, Redaelli N, de Fatis TT, Valsecchi D, Zuolo D, Buontempo S, Carnevali F, Cavallo N, De Iorio A, Fabozzi F, Iorio AOM, Lista L, Meola S, Paolucci P, Rossi B, Sciacca C, Layer L, Azzi P, Bacchetta N, Bisello D, Bortignon P, Bragagnolo A, Carlin R, Checchia P, Dorigo T, Dosselli U, Gasparini F, Gasparini U, Margoni M, Meneguzzo AT, Pazzini J, Ronchese P, Rossin R, Simonetto F, Strong G, Tosi M, Yarar H, Zanetti M, Zotto P, Zucchetta A, Zumerle G, Aime C, Braghieri A, Calzaferri S, Fiorina D, Montagna P, Ratti SP, Re V, Riccardi C, Salvini P, Vai I, Vitulo P, Fallavollita F, Asenov P, Bilei GM, Ciangottini D, Fano L, Mantovani G, Mariani V, Menichelli M, Moscatelli F, Piccinelli A, Presilla M, Rossi A, Santocchia A, Spiga D, Tedeschi T, Magherini M, Azzurri P, Bagliesi G, Bertacchi V, Bianchini L, Boccali T, Bossini E, Castaldi R, Ciocci MA, D'Amante V, Dell'Orso R, Di Domenico MR, Donato S, Giassi A, Ligabue F, Manca E, Mandorli G, Messineo A, Musich M, Palla F, Parolia S, Ramirez-Sanchez G, Rizzi A, Rolandi G, Chowdhury SR, Scribano A, Shafiei N, Spagnolo P, Tenchini R, Tonelli G, Turini N, Venturi A, Verdini PG, Barria P, Campana M, Cavallari F, Del Re D, Di Marco E, Diemoz M, Longo E, Meridiani P, Organtini G, Pandolfi F, Paramatti R, Quaranta C, Rahatlou S, Rovelli C, Santanastasio F, Soffi L, Tramontano R, Amapane N, Arcidiacono R, Argiro S, Arneodo M, Bartosik N, Bellan R, Bellora A, Antequera JB, Biino C, Cartiglia N, Costa M, Covarelli R, Demaria N, Grippo M, Kiani B, Legger F, Mariotti C, Maselli S, Mecca A, Migliore E, Monteil E, Monteno M, Obertino MM, Ortona G, Pacher L, Pastrone N, Pelliccioni M, Ruspa M, Shchelina K, Siviero F, Sola V, Solano A, Soldi D, Staiano A, Tornago M, Trocino D, Umoret G, Vagnerini A, Rumerio P, Belforte S, Candelise V, Casarsa M, Cossutti F, Da Rold A, Della Ricca G, Sorrentino G, Dogra S, Huh C, Kim B, Kim DH, Kim GN, Kim J, Lee J, Lee SW, Moon CS, Oh YD, Pak SI, Sekmen S, Yang YC, Kamon T, Kim H, Moon DH, Francois B, Kim TJ, Park J, Cho S, Choi S, Hong B, Lee KS, Lim J, Park SK, Yoo J, Goh J, Gurtu A, Kim HS, Kim Y, Almond J, Bhyun JH, Choi J, Jeon S, Kim JS, Ko S, Kwon H, Lee H, Lee S, Oh BH, Oh M, Oh SB, Seo H, Yang UK, Yoon I, Jang W, Kang DY, Kang Y, Kim S, Ko B, Lee JSH, Lee Y, Merlin JA, Park IC, Roh Y, Ryu MS, Song D, Watson IJ, Yang S, Ha S, Yoo HD, Choi M, Yu I, Beyrouthy T, Maghrbi Y, Dreimanis K, Veckalns V, Ambrozas M, De Oliveira ACA, Juodagalvis A, Rinkevicius A, Tamulaitis G, Bin Norjoharuddeen N, Zolkapli Z, Benitez JF, Hernandez AC, Acosta HAE, Marinez LGG, Coello ML, Quijada JAM, Sehrawat A, Palomo LV, Ayala G, Castilla-Valdez H, De la Cruz-Burelo E, Heredia-De la Cruz I, Lopez-Fernandez R, Herrera CAM, Navarro DAP, Reyes-Almanza R, Hernandez AS, Moreno SC, Barrera CO, Valencia FV, Pedraza I, Ibarguen HAS, Estrada CU, Raicevic N, Krofcheck D, Butler PH, Ahmad A, Asghar MI, Awais A, Awan MIM, Gul M, Hoorani HR, Khan WA, Shah MA, Shoaib M, Waqas M, Avati V, Grzanka L, Malawski M, Bialkowska H, Bluj M, Boimska B, Gorski M, Kazana M, Szleper M, Zalewski P, Bunkowski K, Doroba K, Kalinowski A, Konecki M, Krolikowski J, Araujo M, Bargassa P, Bastos D, Boletti A, Faccioli P, Gallinaro M, Hollar J, Leonardo N, Niknejad T, Pisano M, Seixas J, Toldaiev O, Varela J, Afanasiev S, Budkouski D, Golutvin I, Gorbunov I, Karjavine V, Korenkov V, Lanev A, Malakhov A, Matveev V, Palichik V, Perelygin V, Savina M, Shalaev V, Shmatov S, Shulha S, Smirnov V, Teryaev O, Voytishin N, Yuldashev BS, Zarubin A, Zhizhin I, Gavrilov G, Golovtcov V, Ivanov Y, Kim V, Kuznetsova E, Murzin V, Oreshkin V, Smirnov I, Sosnov D, Sulimov V, Uvarov L, Volkov S, Vorobyev A, Andreev Y, Dermenev A, Gninenko S, Golubev N, Karneyeu A, Kirpichnikov D, Kirsanov M, Krasnikov N, Pashenkov A, Pivovarov G, Toropin A, Musienko Y, Epshteyn V, Gavrilov V, Lychkovskaya N, Nikitenko A, Popov V, Stepennov A, Toms M, Vlasov E, Zhokin A, Aushev T, Bychkova O, Chadeeva M, Oskin A, Parygin P, Popova E, Rusinov V, Andreev V, Azarkin M, Dremin I, Kirakosyan M, Terkulov A, Belyaev A, Boos E, Bunichev V, Dubinin M, Dudko L, Ershov A, Gribushin A, Klyukhin V, Kodolova O, Lokhtin I, Obraztsov S, Perfilov M, Savrin V, Blinov V, Dimova T, Kardapoltsev L, Kozyrev A, Ovtin I, Radchenko O, Skovpen Y, Azhgirey I, Bayshev I, Elumakhov D, Kachanov V, Konstantinov D, Mandrik P, Petrov V, Ryutin R, Slabospitskii S, Sobol A, Troshin S, Tyurin N, Uzunian A, Volkov A, Babaev A, Okhotnikov V, Borshch V, Ivanchenko V, Tcherniaev E, Adzic P, Dordevic M, Milenovic P, Milosevic J, Aguilar-Benitez M, Maestre JA, Fernandez AA, Bachiller I, Luna MB, Bedoya CF, Montoya CAC, Cepeda M, Cerrada M, Colino N, De la Cruz B, Peris AD, Ramos JPF, Flix J, Fouz MC, Lopez OG, Lopez SG, Hernandez JM, Josa MI, Holgado JL, Moran D, Tobar AN, Dengra CP, Yzquierdo APC, Pelayo JP, Redondo I, Romero L, Navas SS, Gomez LU, Willmott C, de Troconiz JF, Gonzalez BA, Cuevas J, Erice C, Menendez JF, Folgueras S, Caballero IG, Fernandez JRG, Cortezon EP, Alvarez CR, Bouza VR, Rodriguez AS, Trapote A, Trevisani N, Villalba CV, Cifuentes JAB, Cabrillo IJ, Calderon A, Campderros JD, Fernandez M, Madrazo CF, Manteca PJF, Alonso AG, Gomez G, Rivero CM, del Arbol PMR, Matorras F, Cuevas PM, Gomez JP, Prieels C, Ruiz-Jimeno A, Scodellaro L, Vila I, Garcia JMV, Jayananda MK, Kailasapathy B, Sonnadara DUJ, Wickramarathna DDC, Dharmaratna WGD, Liyanage K, Perera N, Wickramage N, Aarrestad TK, Abbaneo D, Alimena J, Auffray E, Auzinger G, Baechler J, Baillon P, Barney D, Bendavid J, Bianco M, Bocci A, Caillol C, Camporesi T, Garrido MC, Cerminara G, Chernyavskaya N, Chhibra SS, Choudhury S, Cipriani M, Cristella L, D'Enterria D, Dabrowski A, David A, De Roeck A, Defranchis MM, Deile M, Dobson M, Dunser M, Dupont N, Elliott-Peisert A, Florent A, Forthomme L, Franzoni G, Funk W, Giani S, Gigi D, Gill K, Glege F, Gouskos L, Govorkova E, Haranko M, Hegeman J, Innocente V, James T, Janot P, Kaspar J, Kieseler J, Komm M, Kratochwil N, Lange C, Laurila S, Lecoq P, Lintuluoto A, Long K, Lourenco C, Maier B, Malgeri L, Mallios S, Mannelli M, Marini AC, Meijers F, Mersi S, Meschi E, Moortgat F, Mulders M, Orfanelli S, Orsini L, Pantaleo F, Perez E, Peruzzi M, Petrilli A, Petrucciani G, Pfeiffer A, Pierini M, Piparo D, Pitt M, Qu H, Quast T, Rabady D, Racz A, Gutierrez GR, Rovere M, Sakulin H, Salfeld-Nebgen J, Scarfi S, Schwick C, Selvaggi M, Silva P, Snoeys W, Summers S, Tatar K, Tavolaro VR, Treille D, Tropea P, Tsirou A, Wanczyk J, Wozniak KA, Zeuner WD, Virdee T, Caminada L, Ebrahimi A, Erdmann W, Horisberger R, Ingram Q, Kaestli HC, Kotlinski D, Langenegger U, Missiroli M, Noehte L, Rohe T, Androsov K, Backhaus M, Berger P, Calandri A, De Cosa A, Dissertori G, Dittmar M, Donega M, Dorfer C, Eble F, Gedia K, Glessgen F, Espinosa TAG, Grab C, Hits D, Lustermann W, Lyon AM, Manzoni RA, Marchese L, Perez CM, Meinhard MT, Nessi-Tedaldi F, Niedziela J, Pauss F, Perovic V, Pigazzini S, Ratti MG, Reichmann M, Reissel C, Reitenspiess T, Ristic B, Ruini D, Becerra DAS, Stampf V, Steggemann J, Wallny R, Amsler C, Bartschi P, Botta C, Brzhechko D, Canelli MF, Cormier K, De Wit A, Del Burgo R, Heikkila JK, Huwiler M, Jin W, Jofrehei A, Kilminster B, Leontsinis S, Liechti SP, Macchiolo A, Meiring P, Mikuni VM, Molinatti U, Neutelings I, Rauco G, Reimers A, Robmann P, Cruz SS, Schweiger K, Senger M, Takahashi Y, Adloff C, Kuo CM, Lin W, Roy A, Sarkar T, Yu SS, Ceard L, Chao Y, Chen KF, Chen PH, Chen PS, Cheng H, Hou WS, Li YY, Lu RS, Paganis E, Psallidas A, Steen A, Wu HY, Yazgan E, Yu PR, Asavapibhop B, Asawatangtrakuldee C, Srimanobhas N, Boran F, Damarseckin S, Demiroglu ZS, Dolek F, Dumanoglu I, Eskut E, Guler Y, Guler EG, Isik C, Kara O, Topaksu AK, Kiminsu U, Onengut G, Ozdemir K, Polatoz A, Simsek AE, Tali B, Tok UG, Turkcapar S, Zorbakir IS, Karapinar G, Ocalan K, Yalvac M, Akgun B, Atakisi IO, Gulmez E, Kaya M, Kaya O, Tekten S, Yetkin EA, Cakir A, Cankocak K, Komurcu Y, Sen S, Cerci S, Hos I, Isildak B, Kaynak B, Ozkorucuklu S, Sert H, Simsek C, Cerci DS, Zorbilmez C, Grynyov B, Levchuk L, Anthony D, Bhal E, Bologna S, Brooke JJ, Bundock A, Clement E, Cussans D, Flacher H, Glowacki M, Goldstein J, Heath GP, Heath HF, Kreczko L, Krikler B, Paramesvaran S, El Nasr-Storey SS, Smith VJ, Pass KW, White R, Bell KW, Brew C, Brown RM, Cockerill DJA, Cooke C, Ellis KV, Harder K, Harper S, Holmberg ML, Linacre J, Manolopoulos K, Newbold DM, Olaiya E, Petyt D, Reis T, Schuh T, Shepherd-Themistocleous CH, Tomalin IR, Williams T, Bainbridge R, Bloch P, Bonomally S, Borg J, Breeze S, Buchmuller O, Cepaitis V, Chahal GS, Colling D, Dauncey P, Davies G, Della Negra M, Fayer S, Fedi G, Hall G, Hassanshahi MH, Iles G, Langford J, Lyons L, Magnan AM, Malik S, Martelli A, Monk DG, Nash J, Pesaresi M, Radburn-Smith BC, Raymond DM, Richards A, Rose A, Scott E, Seez C, Shtipliyski A, Tapper A, Uchida K, Vojinovic M, Wardle N, Webb SN, Winterbottom D, Coldham K, Cole JE, Khan A, Kyberd P, Reid ID, Teodorescu L, Zahid S, Abdullin S, Brinkerhoff A, Caraway B, Dittmann J, Hatakeyama K, Kanuganti AR, McMaster B, Saunders M, Sawant S, Sutantawibul C, Wilson J, Bartek R, Dominguez A, Uniyal R, Hernandez AMV, Buccilli A, Cooper SI, Di Croce D, Gleyzer SV, Henderson C, Perez CU, West C, Akpinar A, Albert A, Arcaro D, Cosby C, Demiragli Z, Fontanesi E, Gastler D, May S, Rohlf J, Salyer K, Sperka D, Spitzbart D, Suarez I, Tsatsos A, Yuan S, Zou D, Benelli G, Burkle B, Cutts D, Hadley M, Heintz U, Hogan JM, Kwon T, Landsberg G, Lau KT, Li D, Lukasik M, Luo J, Narain M, Pervan N, Sagir S, Simpson F, Usai E, Wong WY, Yan X, Yu D, Zhang W, Bonilla J, Brainerd C, Breedon R, Sanchez MCD, Chertok M, Conway J, Cox PT, Erbacher R, Haza G, Jensen F, Kukral O, Lander R, Mulhearn M, Pellett D, Regnery B, Taylor D, Yao Y, Zhang F, Bachtis M, Cousins R, Datta A, Hamilton D, Hauser J, Ignatenko M, Iqbal MA, Lam T, Nash WA, Regnard S, Saltzberg D, Stone B, Valuev V, Chen Y, Clare R, Gary JW, Gordon M, Hanson G, Karapostoli G, Long OR, Manganelli N, Si W, Wimpenny S, Branson JG, Chang P, Cittolin S, Cooperstein S, Diaz D, Duarte J, Gerosa R, Giannini L, Guiang J, Kansal R, Krutelyov V, Lee R, Letts J, Masciovecchio M, Mokhtar F, Pieri M, Narayanan BVS, Sharma V, Tadel M, Wurthwein F, Xiang Y, Yagil A, Amin N, Campagnari C, Citron M, Collura G, Dorsett A, Dutta V, Incandela J, Kilpatrick M, Marsh B, Mei H, Oshiro M, Quinnan M, Richman J, Sarica U, Setti F, Sheplock J, Siddireddy P, Stuart D, Wang S, Bornheim A, Cerri O, Dutta I, Lawhorn JM, Lu N, Mao J, Newman HB, Nguyen TQ, Spiropulu M, Vlimant JR, Wang C, Xie S, Zhang Z, Zhu RY, Pena C, Alison J, An S, Andrews MB, Bryant P, Ferguson T, Harilal A, Liu C, Mudholkar T, Paulini M, Sanchez A, Terrill W, Cumalat JP, Ford WT, Hassani A, Karathanasis G, MacDonald E, Patel R, Perloff A, Savard C, Schonbeck N, Stenson K, Ulmer KA, Wagner SR, Zipper N, Alexander J, Bright-Thonney S, Chen X, Cheng Y, Cranshaw DJ, Hogan S, Monroy J, Patterson JR, Quach D, Reichert J, Reid M, Ryd A, Sun W, Thom J, Wittich P, Zou R, Albrow M, Alyari M, Apollinari G, Apresyan A, Apyan A, Bauerdick LAT, Berry D, Berryhill J, Bhat PC, Burkett K, Butler JN, Canepa A, Cerati GB, Cheung HWK, Chlebana F, Di Petrillo KF, Dickinson J, Elvira VD, Feng Y, Freeman J, Gecse Z, Gray L, Green D, Grunendahl S, Gutsche O, Harris RM, Heller R, Herwig TC, Hirschauer J, Jayatilaka B, Jindariani S, Johnson M, Joshi U, Klijnsma T, Klima B, Kwok KHM, Lammel S, Lincoln D, Lipton R, Liu T, Madrid C, Maeshima K, Mantilla C, Mason D, McBride P, Merkel P, Mrenna S, Nahn S, Ngadiuba J, Papadimitriou V, Pastika N, Pedro K, Ravera F, Hall AR, Ristori L, Sexton-Kennedy E, Smith N, Soha A, Spiegel L, Stoynev S, Strait J, Taylor L, Tkaczyk S, Tran NV, Uplegger L, Vaandering EW, Weber HA, Avery P, Bourilkov D, Cadamuro L, Cherepanov V, Field RD, Guerrero D, Kim M, Koenig E, Konigsberg J, Korytov A, Lo KH, Matchev K, Menendez N, Mitselmakher G, Madhu AM, Rawal N, Rosenzweig D, Rosenzweig S, Shi K, Wu Z, Yigitbasi E, Zuo X, Adams T, Askew A, Habibullah R, Hagopian V, Johnson KF, Khurana R, Kolberg T, Martinez G, Prosper H, Schiber C, Viazlo O, Yohay R, Zhang J, Baarmand MM, Butalla S, Elkafrawy T, Hohlmann M, Verma RK, Noonan D, Rahmani M, Yumiceva F, Adams MR, Gonzalez HB, Cavanaugh R, Dittmer S, Evdokimov O, Gerber CE, Hofman DJ, Merrit AH, Mills C, Oh G, Roy T, Rudrabhatla S, Tonjes MB, Varelas N, Viinikainen J, Wang X, Ye Z, Alhusseini M, Dilsiz K, Emediato L, Gandrajula RP, Koseyan OK, Merlo JP, Nachtman J, Ogul H, Onel Y, Penzo A, Snyder C, Tiras E, Amram O, Blumenfeld B, Corcodilos L, Davis J, Gritsan AV, Kyriacou S, Maksimovic P, Roskes J, Swartz M, Vami TA, Abreu A, Anguiano J, Barrera CB, Baringer P, Bean A, Flowers Z, Isidori T, Khalil S, King J, Krintiras G, Kropivnitskaya A, Lazarovits M, Le Mahieu C, Lindsey C, Marquez J, Minafra N, Murray M, Nickel M, Rogan C, Royon C, Salvatico R, Sanders S, Schmitz E, Smith C, Warner Z, Williams J, Wilson G, Duric S, Ivanov A, Kaadze K, Kim D, Maravin Y, Mitchell T, Modak A, Nam K, Rebassoo F, Wright D, Adams E, Baden A, Baron O, Belloni A, Eno SC, Hadley NJ, Jabeen S, Kellogg RG, Koeth T, Lai Y, Lascio S, Mignerey AC, Nabili S, Palmer C, Seidel M, Skuja A, Wang L, Wong K, Abercrombie D, Andreassi G, Bi R, Busza W, Cali IA, D'Alfonso M, Eysermans J, Freer C, Ceballos GG, Goncharov M, Harris P, Hu M, Klute M, Kovalskyi D, Krupa J, Lee YJ, Mironov C, Paus C, Rankin D, Roland C, Roland G, Shi Z, Stephans GSF, Wang Z, Wyslouch B, Chatterjee RM, Evans A, Hiltbrand J, Jain S, Joshi BM, Krohn M, Kubota Y, Mans J, Revering M, Rusack R, Saradhy R, Schroeder N, Strobbe N, Wadud MA, Bloom K, Bryson M, Claes DR, Fangmeier C, Finco L, Golf F, Joo C, Kravchenko I, Reed I, Siado JE, Snow GR, Tabb W, Wightman A, Yan F, Zecchinelli AG, Agarwal G, Bandyopadhyay H, Hay L, Iashvili I, Kharchilava A, McLean C, Nguyen D, Pekkanen J, Rappoccio S, Williams A, Alverson G, Barberis E, Haddad Y, Han Y, Hortiangtham A, Krishna A, Li J, Lidrych J, Madigan G, Marzocchi B, Morse DM, Nguyen V, Orimoto T, Parker A, Skinnari L, Tishelman-Charny A, Wamorkar T, Wang B, Wisecarver A, Wood D, Bueghly J, Chen Z, Gilbert A, Gunter T, Hahn KA, Liu Y, Odell N, Schmitt MH, Velasco M, Band R, Bucci R, Cremonesi M, Das A, Dev N, Goldouzian R, Hildreth M, Anampa KH, Jessop C, Lannon K, Lawrence J, Loukas N, Lutton D, Mariano J, Marinelli N, Mcalister I, McCauley T, Mcgrady C, Mohrman K, Moore C, Ruchti R, Townsend A, Wayne M, Zarucki M, Zygala L, Bylsma B, Durkin LS, Francis B, Hill C, Ornelas MN, Wei K, Winer BL, Yates BR, Addesa FM, Bonham B, Das P, Dezoort G, Elmer P, Frankenthal A, Greenberg B, Haubrich N, Higginbotham S, Kalogeropoulos A, Kopp G, Kwan S, Lange D, Marlow D, Mei K, Ojalvo I, Olsen J, Stickland D, Tully C, Norberg S, Bakshi AS, Barnes VE, Chawla R, Das S, Gutay L, Jones M, Jung AW, Kondratyev D, Koshy AM, Liu M, Negro G, Neumeister N, Paspalaki G, Piperov S, Purohit A, Schulte JF, Stojanovic M, Thieman J, Wang F, Xiao R, Xie W, Dolen J, Parashar N, Acosta D, Baty A, Carnahan T, Decaro M, Dildick S, Ecklund KM, Freed S, Gardner P, Geurts FJM, Li W, Padley BP, Redjimi R, Rotter J, Shi W, Leiton AGS, Bodek A, de Barbaro P, Demina R, Dulemba JL, Fallon C, Ferbel T, Galanti M, Garcia-Bellido A, Hindrichs O, Khukhunaishvili A, Ranken E, Tan CL, Taus R, Van Onsem GP, Goulianos K, Chiarito B, Chou JP, Gandrakota A, Gershtein Y, Halkiadakis E, Hart A, Heindl M, Karacheban O, Laflotte I, Lath A, Montalvo R, Nash K, Osherson M, Salur S, Schnetzer S, Somalwar S, Stone R, Thayil SA, Thomas S, Wang H, Acharya H, Delannoy AG, Fiorendi S, Spanier S, Bouhali O, Dalchenko M, Delgado A, Eusebi R, Gilmore J, Huang T, Luo S, Malhotra S, Mueller R, Overton D, Rathjens D, Safonov A, Akchurin N, Damgov J, Hegde V, Lamichhane K, Mengke T, Muthumuni S, Peltola T, Volobouev I, Whitbeck A, Appelt E, Greene S, Gurrola A, Johns W, Melo A, Padeken K, Romeo F, Sheldon P, Tuo S, Velkovska J, Arenton MW, Cardwell B, Cox B, Cummings G, Hakala J, Hirosky R, Joyce M, Ledovskoy A, Li A, Neu C, Lara CEP, Tannenwald B, White S, Poudyal N, Black K, Bose T, Dasu S, De Bruyn I, Everaerts P, Galloni C, He H, Herndon M, Herve A, Hussain U, Lanaro A, Loeliger A, Loveless R, Sreekala JM, Mallampalli A, Mohammadi A, Pinna D, Savin A, Shang V, Smith WH, Teague D, Trembath-Reichert S, Vetens W
Show All Authors
Search for resonant production of strongly coupled dark matter in proton-proton collisions at 13 TeV (opens in new window)
JOURNAL OF HIGH ENERGY PHYSICS 2022 JUN 29; ?(6):? Article 156
The first collider search for dark matter arising from a strongly coupled hidden sector is presented and uses a data sample corresponding to 138 fb(-1), collected with the CMS detector at the CERN LHC, at root s = 13 TeV. The hidden sector is hypothesized to couple to the standard model (SM) via a heavy leptophobic Z' mediator produced as a resonance in proton-proton collisions. The mediator decay results in two "semivisible" jets, containing both visible matter and invisible dark matter. The final state therefore includes moderate missing energy aligned with one of the jets, a signature ignored by most dark matter searches. No structure in the dijet transverse mass spectra compatible with the signal is observed. Assuming the Z' boson has a universal coupling of 0.25 to the SM quarks, an inclusive search, relevant to any model that exhibits this kinematic behavior, excludes mediator masses of 1.5-4.0 TeV at 95% confidence level, depending on the other signal model parameters. To enhance the sensitivity of the search for this particular class of hidden sector models, a boosted decision tree (BDT) is trained using jet substructure variables to distinguish between semivisible jets and SM jets from background processes. When the BDT is employed to identify each jet in the dijet system as semivisible, the mediator mass exclusion increases to 5.1 TeV, for wider ranges of the other signal model parameters. These limits exclude a wide range of strongly coupled hidden sector models for the first time.
Serganov AA, Udi Y, Stein ME, Patel V, Fridy PC, Rice CM, Saeed M, Jacobs EY, Chait BT, Rout MP
Show All Authors
Proteomic elucidation of the targets and primary functions of the picornavirus 2A protease (opens in new window)
JOURNAL OF BIOLOGICAL CHEMISTRY 2022 JUN; 298(6):? Article 101882
Picornaviruses are small RNA viruses that hijack host cell machinery to promote their replication. During infection, these viruses express two proteases, 2Apro and 3Cpro, which process viral proteins. They also subvert a number of host functions, including innate immune responses, host protein synthesis, and intracellular transport, by utilizing poorly understood mechanisms for rapidly and specifically targeting critical host proteins. Here, we used proteomic tools to characterize 2Apro interacting partners, functions, and targeting mechanisms. Our data indicate that, initially, 2Apro primarily targets just two cellular proteins: eukaryotic translation initiation factor eIF4G (a critical component of the protein synthesis machinery) and Nup98 (an essential component of the nuclear pore complex, responsible for nucleocytoplasmic transport). The protease appears to employ two different cleavage mechanisms; it likely interacts with eIF3L, utilizing the eIF3 complex to proteolytically access the eIF4G protein but also directly binds and degrades Nup98. This Nup98 cleavage results in only a marginal effect on nuclear import of proteins, while nuclear export of proteins and mRNAs were more strongly affected. Collectively, our data indicate that 2Apro selectively inhibits protein translation, key nuclear export pathways, and cellular mRNA localization early in infection to benefit viral replication at the expense of particular cell functions.
Zhang Q, Matuozzo D, Le Pen J, Lee D, Moens L, Asano T, Bohlen J, Liu ZY, Moncada-Velez M, Kendir-Demirkol Y, Jing HE, Bizien L, Marchal A, Abolhassani H, Delafontaine S, Bucciol G, Bayhan GI, Keles S, Kiykim A, Hancerli S, Haerynck F, Florkin B, Hatipoglu N, Ozcelik T, Morelle G, Zatz M, Ng LFP, Lye DC, Young BE, Leo YS, Dalgard CL, Lifton RP, Renia L, Meyts I, Jouanguy E, Hammarstrom L, Pan-Hammarstrom Q, Boisson B, Bastard P, Su HC, Boisson-Dupuis S, Abel L, Rice CM, Zhang SY, Cobat A, Casanova JL
Show All Authors
Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia (opens in new window)
JOURNAL OF EXPERIMENTAL MEDICINE 2022 JUN 16; 219(8):? Article e20220131
In an international cohort of 112 children hospitalized for moderate to critical COVID-19 pneumonia, we identified 12 children with one of four known recessive inborn errors of type I interferon immunity: X-linked TLR7 and autosomal IFNAR1, STAT2, and TYK2 deficiencies. Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5-13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 x 10(-11)) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie similar to 10% of hospitalizations for COVID-19 pneumonia in children.
Dong WL, Kaymakcalan H, Jin SC, Diab NS, Tanidir C, Yalcin ASY, Ercan-Sencicek AG, Mane S, Gunel M, Lifton RP, Bilguvar K, Brueckner M
Show All Authors
Mutation spectrum of congenital heart disease in a consanguineous Turkish population (opens in new window)
MOLECULAR GENETICS & GENOMIC MEDICINE 2022 JUN; 10(6):? Article e1944
Backgrounds: While many studies agree that consanguinity increases the rate of congenital heart disease (CHD), few genome analyses have been conducted with consanguineous CHD cohorts. Methods: We recruited 73 CHD probands from consanguineous families in Turkey and used whole-exome sequencing (WES) to identify genetic lesions in these patients. Results: On average, each patient had 6.95 rare damaging homozygous variants, 0.68 of which are loss-of-function (LoF) variants. Seven patients (9.6%) carried damaging homozygous variants in five causal CHD genes. Six of those patients exhibited laterality defects (six HTX and one D-TGA). Three additional patients (4.1%) harbored other types of CHD-associated genomic alterations, which overall explained 13.7% (10/73) of the cohort. The contribution from recessive variants in our cohort is higher than 1.8% reported from a cohort of 2871 CHD subjects where 5.6% of subjects met the criteria for consanguinity. Conclusions: Our WES screen of a Turkish consanguineous population with structural CHD revealed its unique genetic architecture. Six of seven damaging homozygous variants in CHD causal genes occur in the setting of laterality defects implies a strong contribution from consanguinity to these defects specifically. Our study thus provided valuable information about the genetic landscape of CHD in consanguineous families in Turkey.
Suryawanshi H, Max K, Bogardus KA, Sopeyin A, Chang MS, Morozov P, Castano PM, Tuschl T, Williams Z
Show All Authors
Dynamic genome-wide gene expression and immune cell composition in the developing human placenta (opens in new window)
JOURNAL OF REPRODUCTIVE IMMUNOLOGY 2022 JUN; 151(?):? Article 103624
Despite the central role of the placenta in supporting a pregnancy, relatively little is known about transcriptomic and immune-cell changes that occur across gestation. To generate a reference gene expression map of first (T1), second (T2) and third (T3) trimester human placenta, and assess differences in transcriptome in maternal versus fetal side tissues sections of full-term placenta, we performed RNA-Seq analysis on 64 biopsy samples from 18 placentas across all three gestations. We identified 1120 differentially expressed genes in placenta tissues from T1 and T3 samples using a generalized linear model within DESeq2. In total, 411 and 709 genes were positively associated with T1 and T3 placenta, respectively. Comparison of the top 200 differentially expressed genes in the T1 placenta with T3 showed that most of the top enriched biological processes were related to cell division and proliferation. T1 and T2 tissues shared expression of fibroblast-specific COL6A2, HGF, and SPP1 genes. In T3 samples, the expression of genes relating to vasculature development and regulation were highly enriched. Monocytes and NK cell population increased in T3 compared to T1 and T2, whereas Hofbauer cell proportion expanded significantly in T2 and then decreased in T3 samples. There were no significant gene expression dif-ferences in the maternal vs. fetal side in T3 placentas. Gene expression patterns shift temporally across trimesters but not spatially across the placenta, at least at the resolution of the biopsy samples. The genes and gene set we identified here represent a valuable resource for studying pathology in pregnancy-related disorders.
Readnour BM, Ayinuola YA, Russo BT, Liang Z, Lee SW, Ploplis VA, Fischetti VA, Castellino FJ
Show All Authors
Evolution of Streptococcus pyogenes has maximized the efficiency of the Sortase A cleavage motif for cell wall transpeptidation (opens in new window)
JOURNAL OF BIOLOGICAL CHEMISTRY 2022 JUN; 298(6):? Article 101940
Trafficking of M-protein (Mprt) from the cytosol of Group A Streptococcus pyogenes (GAS) occurs via Sec translocase membrane channels that associate with Sortase A (SrtA), an enzyme that catalyzes cleavage of Mprt at the proximal C-terminal [-LPST(355*)GEAA-] motif and subsequent transpeptidation of the Mprt-containing product to the cell wall (CW). These steps facilitate stable exposure of the N-terminus of Mprt to the extracellular milieu where it interacts with ligands. Previously, we found that inactivation of SrtA in GAS cells eliminated Mprt CW transpeptidation but effected little reduction in its cell surface exposure, indicating that the C-terminus of Mprt retained in the cytoplasmic membrane (CM) extends its N-terminus to the cell surface. Herein, we assessed the effects of mutating the Thr(355) residue in the WT SrtA consensus sequence (LPST(355*)GEAA-) in a specific Mprt, PAM. In vitro, we found that synthetic peptides with mutations (LPSX(355)GEAA) in the SrtA cleavage site displayed slower cleavage activities with rSrtA than the WT peptide. Aromatic residues at X had the lowest activities. Nonetheless, PAM/[Y(355)G] still transpeptidated the CW in vivo. However, when using isolated CMs from srtA-inactivated GAS cells, rapid cleavage of PAM/[LPSY(355)GEAA] occurred at E-357* but transpeptidation did not take place. These results show that another CM-resident enzyme nonproductively cleaved PAM/[LPSYGE(357*)AA]. However, SrtA associated with the translocon channel in vivo cleaved and transpeptidated PAM/ [LPSX(355*)GEAA] variants. These CM features allow diverse cleavage site variants to covalently attach to the CW despite the presence of other potent nonproductive CM proteases.
D'Angelo SP, Richards AL, Conley AP, Woo HJ, Dickson MA, Gounder M, Kelly C, Keohan ML, Movva S, Thornton K, Rosenbaum E, Chi P, Nacev B, Chan JE, Slotkin EK, Kiesler H, Adamson T, Ling LL, Rao P, Patel S, Livingston JA, Singer S, Agaram NP, Antonescu CR, Koff A, Erinjeri JP, Hwang SC, Qin LX, Donoghue MTA, Tap WD
Show All Authors
Pilot study of bempegaldesleukin in combination with nivolumab in patients with metastatic sarcoma (opens in new window)
NATURE COMMUNICATIONS 2022 JUN 16; 13(1):? Article 3477
PD-1 blockade (nivolumab) efficacy remains modest for metastatic sarcoma. In this paper, we present an open-label, non-randomized, non-comparative pilot study of bempegaldesleukin, a CD122-preferential interleukin-2 pathway agonist, with nivolumab in refractory sarcoma at Memorial Sloan Kettering/MD Anderson Cancer Centers (NCT03282344). We report on the primary outcome of objective response rate (ORR) and secondary endpoints of toxicity, clinical benefit, progression-free survival, overall survival, and durations of response/treatment. In 84 patients in 9 histotype cohorts, all patients experienced >= 1 adverse event and treatment-related adverse event; 1 death was possibly treatment-related. ORR was highest in angiosarcoma (3/8) and undifferentiated pleomorphic sarcoma (2/10), meeting predefined endpoints. Results of our exploratory investigation of predictive biomarkers show: CD8 + T cell infiltrates and PD-1 expression correlate with improved ORR; upregulation of immune-related pathways correlate with improved efficacy; Hedgehog pathway expression correlate with resistance. Exploration of this combination in selected sarcomas, and of Hedgehog signaling as a predictive biomarker, warrants further study in larger cohorts. The activity of PD-1 blockade in patients with sarcoma has been modest so far. Here, the authors report the results of a pilot clinical trial to assess the efficacy and safety of bempegaldesleukin, a CD122-preferential interleukin-2 (IL-2) pathway agonist, in combination with the PD1 blockade (nivolumab) in patients with locally advanced or metastatic high-grade sarcoma.
Martino C, McDonald D, Cantrell K, Dilmore AH, Vazquez-Baeza Y, Shenhav L, Shaffer JP, Rahman G, Armstrong G, Allaband C, Song SJ, Knight R
Show All Authors
Compositionally Aware Phylogenetic Beta-Diversity Measures Better Resolve Microbiomes Associated with Phenotype (opens in new window)
MSYSTEMS 2022 JUN 28; 7(3):?
Microbiome data have several specific characteristics (sparsity and compositionality) that introduce challenges in data analysis. The integration of prior information regarding the data structure, such as phylogenetic structure and repeated-measure study designs, into analysis, is an effective approach for revealing robust patterns in microbiome data. Past methods have addressed some but not all of these challenges and features: for example, robust principal-component analysis (RPCA) addresses sparsity and compositionality; compositional tensor factorization (CIF) addresses sparsity, compositionality, and repeated measure study designs; and UniFrac incorporates phylogenetic information. Here we introduce a strategy of incorporating phylogenetic information into RPCA and CTF. The resulting methods, phylo-RPCA, and phylo-CTF, provide substantial improvements over state-of-the-art methods in terms of discriminatory power of underlying clustering ranging from the mode of delivery to adult human lifestyle. We demonstrate quantitatively that the addition of phylogenetic information improves effect size and classification accuracy in both data-driven simulated data and real microbiome data. IMPORTANCE Microbiome data analysis can be difficult because of particular data features, some unavoidable and some due to technical limitations of DNA sequencing instruments. The first step in many analyses that ultimately reveals patterns of similarities and differences among sets of samples (e.g., separating samples from sick and healthy people or samples from seawater versus soil) is calculating the difference between each pair of samples. We introduce two new methods to calculate these differences that combine features of past methods, specifically being able to take into account the principles that most types of microbes are not in most samples (sparsity), that abundances are relative rather than absolute (compositionality), and that all microbes have a shared evolutionary history (phylogeny). We show using simulated and real data that our new methods provide improved classification accuracy of ordinal sample clusters and increased effect size between sample groups on beta-diversity distances.