250 results on '"Bennett RL"'
Search Results
2. PRC2 Inhibitors Overcome Glucocorticoid Resistance Driven by NSD2 Mutation in Pediatric Acute Lymphoblastic Leukemia.
- Author
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Li, J, Hlavka-Zhang, J, Shrimp, JH, Piper, C, Dupéré-Richér, D, Roth, JS, Jing, D, Casellas Román, HL, Troche, C, Swaroop, A, Kulis, M, Oyer, JA, Will, CM, Shen, M, Riva, A, Bennett, RL, Ferrando, AA, Hall, MD, Lock, RB, Licht, JD, Li, J, Hlavka-Zhang, J, Shrimp, JH, Piper, C, Dupéré-Richér, D, Roth, JS, Jing, D, Casellas Román, HL, Troche, C, Swaroop, A, Kulis, M, Oyer, JA, Will, CM, Shen, M, Riva, A, Bennett, RL, Ferrando, AA, Hall, MD, Lock, RB, and Licht, JD
- Abstract
Mutations in epigenetic regulators are common in relapsed pediatric acute lymphoblastic leukemia (ALL). Here, we uncovered the mechanism underlying the relapse of ALL driven by an activating mutation of the NSD2 histone methyltransferase (p.E1099K). Using high-throughput drug screening, we found that NSD2-mutant cells were specifically resistant to glucocorticoids. Correction of this mutation restored glucocorticoid sensitivity. The transcriptional response to glucocorticoids was blocked in NSD2-mutant cells due to depressed glucocorticoid receptor (GR) levels and the failure of glucocorticoids to autoactivate GR expression. Although H3K27me3 was globally decreased by NSD2 p.E1099K, H3K27me3 accumulated at the NR3C1 (GR) promoter. Pretreatment of NSD2 p.E1099K cell lines and patient-derived xenograft samples with PRC2 inhibitors reversed glucocorticoid resistance in vitro and in vivo. PRC2 inhibitors restored NR3C1 autoactivation by glucocorticoids, increasing GR levels and allowing GR binding and activation of proapoptotic genes. These findings suggest a new therapeutic approach to relapsed ALL associated with NSD2 mutation. SIGNIFICANCE: NSD2 histone methyltransferase mutations observed in relapsed pediatric ALL drove glucocorticoid resistance by repression of the GR and abrogation of GR gene autoactivation due to accumulation of K3K27me3 at its promoter. Pretreatment with PRC2 inhibitors reversed resistance, suggesting a new therapeutic approach to these patients with ALL.This article is highlighted in the In This Issue feature, p. 1.
- Published
- 2022
3. PRC2 Inhibitors Overcome Glucocorticoid Resistance Driven by NSD2 Mutation in Pediatric Acute Lymphoblastic Leukemia
- Author
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Li, J, Hlavka-Zhang, J, Shrimp, JH, Piper, C, Dupéré-Richér, D, Roth, JS, Jing, D, Casellas Román, HL, Troche, C, Swaroop, A, Kulis, M, Oyer, JA, Will, CM, Shen, M, Riva, A, Bennett, RL, Ferrando, AA, Hall, MD, Lock, RB, and Licht, JD
- Subjects
Male ,Cell Survival ,Histone-Lysine N-Methyltransferase ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Repressor Proteins ,Drug Resistance, Neoplasm ,Cell Line, Tumor ,Mutation ,Histone Methyltransferases ,Humans ,1112 Oncology and Carcinogenesis ,Female ,Enzyme Inhibitors ,Child ,Glucocorticoids - Abstract
Mutations in epigenetic regulators are common in relapsed pediatric acute lymphoblastic leukemia (ALL). Here, we uncovered the mechanism underlying the relapse of ALL driven by an activating mutation of the NSD2 histone methyltransferase (p.E1099K). Using high-throughput drug screening, we found that NSD2-mutant cells were specifically resistant to glucocorticoids. Correction of this mutation restored glucocorticoid sensitivity. The transcriptional response to glucocorticoids was blocked in NSD2-mutant cells due to depressed glucocorticoid receptor (GR) levels and the failure of glucocorticoids to autoactivate GR expression. Although H3K27me3 was globally decreased by NSD2 p.E1099K, H3K27me3 accumulated at the NR3C1 (GR) promoter. Pretreatment of NSD2 p.E1099K cell lines and patient-derived xenograft samples with PRC2 inhibitors reversed glucocorticoid resistance in vitro and in vivo. PRC2 inhibitors restored NR3C1 autoactivation by glucocorticoids, increasing GR levels and allowing GR binding and activation of proapoptotic genes. These findings suggest a new therapeutic approach to relapsed ALL associated with NSD2 mutation. SIGNIFICANCE: NSD2 histone methyltransferase mutations observed in relapsed pediatric ALL drove glucocorticoid resistance by repression of the GR and abrogation of GR gene autoactivation due to accumulation of K3K27me3 at its promoter. Pretreatment with PRC2 inhibitors reversed resistance, suggesting a new therapeutic approach to these patients with ALL.This article is highlighted in the In This Issue feature, p. 1.
- Published
- 2021
4. Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone
- Author
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Stempel, Da, Raphiou, Ih, Kral, Km, Yeakey, Am, Emmett, Ah, Prazma, Cm, Buaron, Ks, Pascoe, Sj, Austri, Investigators, Altieri, Hh, Antuni, Jd, Bergna, Ma, Cuadrado, Ja, De Gennaro MS, Fazio Lizandrelo CL, Gattolin, G, Gosn, Am, Larrateguy, Ld, Marcipar, Am, Maspero, Jf, Medina, Iv, Perez Chada RD, Silva, D, Victorio, Cf, Bardin, Pg, Carroll, Pa, Clements, Bs, Dore, Nd, Robinson, Pd, Fitzgerald, Da, Robinson, Pj, Russo, Ma, Sajkov, D, Thomas, Ps, Upham, Jw, Forstner, B, Kaik, G, Koeberl, Gh, Studnicka, M, Wallner, G, Balthazar, Y, Bauler, A, Dupont, Lj, Martinot, Jb, Ninane, V, Peché, R, Pilette, C, Dimitrova, R, Dimova, D, Kissyova Ibrishimova, G, Loboshka Becheva, M, Machkovska, M, Madjarov, S, Mandazhieva Pepelanova, M, Naidenova, I, Noleva, K, Takovska, N, Terziev, C, Aggarwal, Nk, Chapman, Kr, Csanadi, Ma, Dhillon, R, Henein, S, Kelly, Aj, Lam, As, Liem, Jj, Lougheed, Md, Lowe, Dw, Rizvi, Q, van den Berg, L, Zidel, B, Barros Monge MJ, Calvo Gil MA, Castillo Hofer CR, Diaz Amor PV, Lezana Soya, V, Quilodran Silva CN, Bolivar Grimaldos, F, Solarte-Rodriguez, I, Butkovic-Tomljanovic, R, Hegedus-Jungvirth, M, Ivkovic-Jurekovic, I, Simunov-Karuza, G, Buresova, M, Bursova, J, Fratrik, J, Guttlerova, E, Hartman, P, Jirmanova, I, Kalina, P, Kolman, P, Kucera, M, Povysilova, L, Pravda, P, Svabkova, A, Zakova, L, Backer, V, Maltbaek, N, Johnsen, Cr, Aries, Sp, Babyesiza, A, Barth, D, Benedix, A, Berg, P, Bergtholdt, B, Bettig, U, Bindig, Hw, Botzen, U, Brehler, R, Breyer, Go, Bruckhaus-Walter, M, Dapper, T, Eckhard, Jg, Engelhard, R, Feldmeyer, F, Fissan, H, Franz, Kh, Frick, Bs, Funck, J, Gessner, Cm, Ginko, T, Grigat, Ce, Grimm-Sachs, V, Groth, G, Hampf, J, Hanf, G, Havasi-Jost, G, Heinz, Gu, Helm, K, Hoeltz, S, Hofmann, S, Jander, R, Jandl, M, Jasch-Hoppe, B, Jung, T, Junggeburth, Jj, Kardos, P, Knueppel, W, Koch, T, Kolorz, C, Korduan, M, Korth-Wiemann, B, Krezdorn, Hg, Kroker, A, Kruell, M, Kuehne, P, Lenk, U, Liefring, E, Merke, J, Micke, L, Mitlehner, W, Mueller, H, Naudts, If, Neumann, G, Oldenburg, W, Overlack, A, Panzer, F, Reinholz, N, Remppis, R, Riegel, P, Rueckert, P, Schaetzl, Rj, Schauer, U, Hamelmann, E, Schenkenberger, I, Schlegel, V, Scholz, G, Schroers, M, Schwittay, A, Sebert, M, Tyler, K, Soemantri, Pa, Stock, P, Stuchlik, G, Unland, M, von Mallinckrodt, C, Wachter, J, Weber, U, Weberling, F, Wehgartner-Winkler, S, Weimer, J, Wiemer, S, Winkelmann, Ej, Zeisler, Kh, Ziegner, A, Zimny, Hh, Andrasofszky, Z, Bartha, A, Farkas, M, Gömöri, K, Kis, S, Major, K, Mészáros, I, Mezei, M, Rakvacs, M, Szalai, Z, Szántó, J, Szentesi, M, Szolnoki, E, Valyon, E, Zibotics, H, Anwar, J, Arimah, C, Djajalaksana, S, Rai, Ib, Setijadi, Ar, Setyanto, Db, Susanti, F, Syafiuddin, T, Syamsi, Ln, Wijanarko, P, Yunus, F, Bonavia, M, Braga, M, Chetta, Aa, Cerveri, I, Luisetti, M, Crimi, N, Cutrera, R, De Rosa, M, Esposito, S, Foresi, A, Gammeri, E, Iemoli, E, Legnani, Dl, Michetti, G, Pastorello, Ea, Pesci, A, Pistolesi, M, Riva, E, Romano, A, Scichilone, N, Terracciano, L, Tripodi, S, Choi, I, Kim, C, Kim, Js, Kim, Wj, Koh, Yy, Kwon, Ss, Lee, Sh, Lee, S, Lee, Sk, Park, Cs, Cirule, I, Eglite, R, Petrova, I, Poga, M, Smiltena, I, Chomiciene, A, Davoliene, I, Griskeviciene, V, Naudziunas, A, Naudziunas, S, Rudzeviciene, O, Sitkauskiene, B, Urbonas, G, Vaicius, D, Valavicius, A, Valiulis, A, Vebriene, J, bin Abdul Aziz FA, Daud, M, Ismail, Ai, Tengku Saifudin TI, Md Kassim RM, Mohd Fadzli FB, Wan Mohamad WH, Aguilar Dominguez PE, Aguilar-Orozco, Ra, Garza-Salinas, S, Ramirez-Diaz, Sp, Sánchez Llamas, F, Soto-Ramos, M, Velarde-Mora, Hj, Aguirre Sosa, I, Cisneros, Am, Estrella Viladegut RA, Matsuno Fuchigami, A, Adiaz-Baui, Tt, Bernan, Ap, Onia, Af, Sandagon, Mj, S-Naval, S, Yu, Cy, Bartuzi, Z, Bielous-Wilk, A, Błażowski, Ł, Bożek, A, Brzostek, J, Chorostowska-Wynimko, J, Ciekalska, K, Ziora, D, Cieslicki, J, Emeryk, A, Folcik, K, Gałuszka-Bilińska, A, Gawlik, R, Giejlo, M, Harat, R, Hofman, T, Jahnz-Różyk, K, Jedrzejczak, M, Kachel, T, Kamiński, D, Kelm Warchol, A, Konieczny, Z, Kwasniewski, A, Leszczyński, W, Mincewicz, G, Niezgoda, K, Olszewska-Ziąber, A, Onasz-Manitius, M, Pawlukiewicz, M, Piotrowicz, P, Piotrowski, W, Pisarczyk-Bogacka, E, Piskorz, P, Prokop-Staszecka, A, Roslan, A, Słomka, A, Smalera, E, Stelmach, I, Swierczynska-Krepa, M, Szmidt, M, Tarnowska-Matusiak, M, Tłuczykont, B, Tyminska, K, Waszkuc-Golonko, J, Wojciechowska, I, Alexandrescu, Ds, Neamtu, Ml, Todea, D, Alekseeva, E, Aleksandrova, E, Asherova, I, Barbarash, Ol, Bugrova, O, Bukreeva, Eb, Chermenskiy, A, Chizhova, O, Demko, I, Evdokimova, A, Giorgadze, Ml, Grigoryev, S, Irkhina, I, Khurkhurova, Nv, Kondyurina, Eg, Kostin, Vi, Kudelya, L, Laleko, Sl, Lenskaya, L, Levashov, S, Logvinenko, N, Martynov, A, Mizernitski, Y, Nemtsov, B, Novozhenov, Vg, Pavlishchuk, S, Popova, Vv, Reshetko, Ov, Sherenkov, A, Shirinsky, Vs, Shpagina, L, Soloviev, Ki, Tkachev, A, Trofimov, Vi, Vertkin, Al, Vorobeva, E, Idrisova, E, Yakushin, S, Zadionchenko, V, Zhiglinskaya, O, Zykov, K, Dopudja Pantic, V, Nadaskic, R, Nestorovic, B, Skodric Trifunovic, V, Stojanovic, A, Vukcevic, M, Vujic, T, Mitic Milikic, M, Banovcin, P, Horvathova, H, Karako, P Sr, Plutinsky, J, Pribulova, E, Szarazova, M, Zlatos, A, Adams, L, Badat, A, Bassa, A, Breedt, J, Bruning, A, Ellis, Gc, Emanuel, S, Fouche, Lf, Fulat, Ma, Gani, M, Ismail, Ms, Jurgens, Jc, Nell, H, Nieuwoudt, G, Noor, F, Bolliger, Ct, Puterman, As, Siddique, N, Trokis, Js, Vahed, Ya, Van Der Berg BJ, Van der Linden, M, Van Zyl, L, Visser, Ss, Antépara Ercoreca, I, Arnedillo Muñoz, A, Barbe Illa, F, Barreiro López, B, Blanco Aparicio, M, Boada Valmaseda, A, Bosque García, M, Bustamante Ruiz, A, Carretero Anibarro, P, Del Campo Matias, F, Echave-Sustaet, Jm, Espinosa de los Monteros Garde MJ, Garcia Hernandez GM, López Viña, A, Lores Obradors, L, Luengo Planas MT, Monsó Molas, E, Navarro Dourdil, A, Nieto García AJ, Perpina Tordera, M, Picado Valles, C, Rodriguez Alvarez Mdel, M, Saura Vinuesa, A, Serra Batlles, J, Soler Sempere MJ, Toran Montserrat, P, Valdés Cuadrado LG, Villasante Fernandez-Montes, C, Cheng, Sl, Chern, Jh, Chiu, Mh, Chung, Cl, Lai, Rs, Lin, Ck, Liu, Yc, Wang, Cc, Wei, Yf, Amer, L, Berenfus, Vi, Besh, L, Duka, Kd, Fushtey, Im, Garmash, N, Dudnyk, O, Godlevska, O, Vlasenko, Ma, Hospodarskyy, I, Iashyna, L, Kaladze, M, Khvelos, Si, Kostromina, Vp, Krakhmalova, O, Kryuchko, T, Kulynych, Ov, Krasko, Mp, Levchenko, O, Litvinova, T, Panina, Ss, Pasiyeshvili, Lm, Prystupa, Ln, Romaniuk, Li, Sirenko, I, Synenko, Vi, Vynnychenko, Lb, Yatsyshyn, Ri, Zaitsev, I, Zhebel, V, Zubarenko, O, Arthur, Cp, Brown, V, Burhan, H, Chaudhuri, R, Collier, D, Barnes, Nc, Davies, Ej, Ellery, A, Kwok, S, Lenney, W, Nordstrom, M, Pandya, Hc, Parker, Iw, Rajakulasingam, K, Seddon, P, Sharma, R, Thomas, Ec, Wakeling, Ja, Abalos-Galito, M, Abboy, C, Abreu, E, Ackerman, If, Acosta, Ia, Adaoag, Aa, Ahmed, M, Ali, Mi, Allen, Dr, Allen GG Jr, Diogo, Jj, Allison, Dc, Alwine, Lk, Apaliski, Sj, Arastu, Rs, Arora, Cm, Auerbach, D, Azzam, Sj, Badar FL 3rd, Baker, Jw, Barasch, Jp, Barber, Ma, Bardinas-Rodriguez, R, Barreiro, Tj, Baumbach, Rr, Baur, Ce, Baxter, Bs, Beach, Jl, Beasley, Rl, Beavins, Je, Beliveau, Wj, Benbow, Mj, Bennett, Nl, Bennett, Rl, Bernal, H, Bernstein, Di, Blaiss, Ms, Blumenthal, Kw, Boas, Sr, Borders, Jl, Boscia, Ja, Boulware, Wn, Bowling, Bt, Brabec, Ba, Bramlet, Dg, Figueroa, Dp, Brautigam, Df, Brownell, Jm, Bruce, Tr, Call, Rs, Campbell, Ca, Canaan, Ya, Cannon, Df, Carpio, Jm, Cathcart, Ws, Cevallos, Jp, Chauhan, Av, Chuang, Rb, Chevalier, D, Christensen, J, Christensen, Ta, Christina, Mo, Chrzanowski, Rr, Civitarese, Fa, Clark, Jp, Clifford, Dp, Lapidus, Rj, Coggi, Ja, Lenz, Jj, Cohen, Kr, Collins, Bg, Collins, H, Comellas, A, Condit, J, Cordasco EM Jr, Corder, Cn, Covar, Ra, Coverston, Kd, Croce, Sa, Cruz, H, Curtis, Ct, Daftary, Pk, Dalan, D, Dalawari, Sp, Daly, Wc, Davis, Kc, Dawes, Kw, Decotiis, Ba, Deluca, Rf, Desantis, Dm, De Valle OL, Diaz, Jl, Diaz, Jd, Dice, Jp, Elizalde, A, Hosler, Mr, Dixon, C, Dobkin, La, Dobrusin, Rs, Dransfield, Mt, Ebbeling, Wl, Edwards, Jd, Elacion, Jm, Elkayam, D, Ellison, Wt, Elsen, Jr, Engel, Lr, Ensz, Dj, Ericksen, Cl, Ervin, Je, Fang, C, Abrahamian, F, Farrah, Vb, Field, Jd, Fishman, Hj, Florea, R, Nayyar, S, Focil, A, Focauld, F, Franco MA Jr, Frandsen, Br, Ganti, K, Garcia, Fl, Lee, Wm, Garscadden, Ag, Gatti, Ea, Gellady, Am, George, Ar, Gibbon, Gw, Gleason, Gp, Goldberg, P, Goldstein, Mf, Gonzalez, Ge, Gower, Rg, Grande, Ja, Gregory, D, Grubb, Sd, Guthrie, Rp, Haas, Ta, Haft, Ks, Hajal, R, Hammond, Gd, Hansel, Nn, Hansen, Vr, Harris, Af, Hartman, An, Harvey, Rr, Hazan-Steinberg, S, Headley, Dm, Heigerick, Gc, Heller, Bn, Hendrix, El, Herrod, Jn, Hewitt, Mj, Hines, Rl, Hirdt, Ap, Hirschfield, Ja, Hoffman, Ks, Hogan, Ad, Howland, Wc, Hsu, Cc, Hsu, Fj, Hubbard, Wm, Hudson, Jd, Huffman, C, Hussain, M, Ioachimescu, Oc, Ismail, Ym, Jaffrani, Na, Jiang, N, Jones, Sw, Jordan, Rs, Joshi, Ke, Kaashmiri, Mw, Kalafer, M, Kamdar, Ba, Kanuga, Jg, Kao, Nl, Karetzky, M, Katsetos, Jc, Kay, Js, Kimmel, Ma, Kimura, Sh, Kingsley, Jk, Mahmood, Sm, Subich, Dc, Kirstein, Jl, Kleerup, Ec, Klein, Rm, Koh, Dw, Kohli, N, Koura, Fa, Kovacs, Sp, Kratzer, J, Kreit, Ci, Kreutter, Fm, Kubicki, Tm, Labuda, Jm, Latorre, Aj, Lara, Mm, Lechin, Ae, Lee, Jj, Lee, Md, Lentnek, Al, Lesh, Kw, Levins, Pf, Anspach, Rb, Levinsky, Dm, Lillestol, Mj, Lim, H, Livezey, Md, Lloyd-Turney, Cw, Lockey, Rf, Long, Ra, Lynch, Mj, Macgillivray, Bk, Mahadevan, Kp, Makam, Sk, Maloney, Mj, Mapel, D, Margolis, Bd, Margulies, J, Martin, Ef, Martin, Ee, Mascolo, M, Mataria, H, Sunbuli, M, Mathur, Rn, Mattar, Pn, Maynard, Km, Maynard, N, Mccormick, B, Mcelya, M, Mcevoy, Ce, Mckenzie, Wc, Medwedeff, Le, Mehta, Kd, Melamed, Ir, Meli, Jv, Merrick, Bh, Meyers, Pj, Miller, Bt, Minton, Sm, Miranda, Fg, Mohar, De, Montenegro, Ch, Morris, Fa, Morrison, Bs, Moss, Mh, Munoz, F, Naini, Gr, Nakamura, Ct, Naseeruddin, S, Nassim, C, Navazo, Lj, Nissim, Je, Norman, D, Oberoi, Ms, O'Connor, Tm, Offenberger, J, Orr, Rr, Osea, Ea, Paine, Wj, Rasmussen, Nl, Palatnik, M, Pangtay, D, Panuto, Ja, Patel, M, Perera, Ms, Perez, A, Peters PH Jr, Pimentel SM Jr, Pluto, Tm, Pollock, Mt, Posner, Ls, Pritchard, Jc, Pudi, Kk, Puig, Cm, Qaqundah, Py, Radbill, Mk, Rahman, St, Raikhel, M, Raissy, Hh, Ramstad, Ds, Ranasinghe, Es, Rangel, Os, Rapo, Se, Raschal, Sp, Reddy, Dg, Rehman, Sm, Reyes, Sr, Rhodes, Rb, Riffer, E, Rihal, Ps, Riley ED 4th, Rodriguez, Dh, Rogers, Cm, Rohlf, Jl, Romeu, H, Roney, Cw, Ronsick, So, Rosen, Jb, Rowe, Ms, Ruoff, Ge, Ryan, Eh, Saff, Rh, Saini, N, Anand, S, Balakrishnan, K, Samuels, Bs, Samuelson, Rj, Saniuk, Rj, Sargeant, Wo, Saunders, Mk, Saway, W, Scarupa, Md, White, Mv, Schear, Mj, Schwarz, Cm, Scott, Rb, Segall, N, Seibert, Af, Seidmeyer, V, Seidner, Mr, Seifer, Fd, Serje, J, Shah, Ms, Shah, Sb, Shapero, Pa, Shearer, Sd, Sheikh, Sq, Shepherd, Ts, Sher, Er, Sher, Ld, Short, Bh, Silas, Pe, Alvey, Jc, Silverfield, Jc, Simon, Sj, Sitar, S, Skoner, Dp, Smallow, Sa, Smart, Ba, Smith, Ca, Smith, Ke, Smith, Sk, Snyders, Gc, Soong, W, Soufer, J, Spangenthal, S, Stahlman, Je, Steele, Lg, Stegemoller, Rk, Stocks, J, Storms, Ww, Suen, J, Surowitz, Rz, Swauger, Jr, Taber, La, Tan, Ae, Pratt, Se, Tanus, T, Tarpay, Mm, Tarshis, Ga, Tenney, Jw, Tilghman, Kg, Trevino, Me, Troyan, Be, Twiddy, Sk, Updegrove, Jd, Urval, Kr, Uusinarkaus, Kt, Vaela, R, Van Cleeff, M, Varano, S, Vo, Qd, Wainz, Rj, Wald, Ja, Wall, Sj, Wasserman, Rl, Weinstein, Dl, Welker, Ja, Wellmon, B 2nd, Wells, T, Wenocur, Hs, Williams, Dl, Williams, Sl, Win, Ph, Wingo, Td, Wisman PP Jr, Wyszomierski, Da, Yamada, Hm, Yarows, S, Yunger TM Jr, Ziering, Rw., the AUSTRI Investigators, Stempel, D., Raphiou, I., Kral, K., Yeakey, A., Emmett, A., Prazma, C., Buaron, K., and Pascoe, S. Scichilone N tra i collaboratori
- Subjects
Male ,asthma ,serious events ,fluticasone ,salmeterol ,AUSTRI ,Exacerbation ,Intention to Treat Analysi ,INHALED CORTICOSTEROIDS ,Severity of Illness Index ,law.invention ,0302 clinical medicine ,Randomized controlled trial ,law ,immune system diseases ,Ús terapèutic ,Broncodilatadors ,030212 general & internal medicine ,Child ,Fluticasone ,RISK ,ACTING BETA-AGONISTS ,EXACERBATIONS ,METAANALYSIS ,MORTALITY ,SAFETY ,DEATH ,FDA ,Medicine (all) ,Hazard ratio ,General Medicine ,Bronchodilator agents ,Middle Aged ,Fluticasone-Salmeterol Drug Combination ,Bronchodilator Agents ,Intention to Treat Analysis ,Anesthesia ,Female ,Salmeterol ,medicine.drug ,Human ,Adult ,medicine.medical_specialty ,Adolescent ,Settore MED/10 - Malattie Dell'Apparato Respiratorio ,Fluticasone propionate ,03 medical and health sciences ,Double-Blind Method ,Internal medicine ,Administration, Inhalation ,medicine ,Humans ,Asma ,Bronchodilator Agent ,Asthma ,Aged ,Proportional Hazards Models ,business.industry ,Therapeutic use ,medicine.disease ,respiratory tract diseases ,030228 respiratory system ,Fluticasone Propionate, Salmeterol Xinafoate Drug Combination ,Proportional Hazards Model ,business - Abstract
BACKGROUND The safe and appropriate use of long-acting beta-agonists (LABAs) for the treatment of asthma has been widely debated. In two large clinical trials, investigators found a potential risk of serious asthma-related events associated with LABAs. This study was designed to evaluate the risk of administering the LABA salmeterol in combination with an inhaled glucocorticoid, fluticasone propionate. METHODS In this multicenter, randomized, double-blind trial, adolescent and adult patients (age, ≥12 years) with persistent asthma were assigned to receive either fluticasone with salmeterol or fluticasone alone for 26 weeks. All the patients had a history of a severe asthma exacerbation in the year before randomization but not during the previous month. Patients were excluded from the trial if they had a history of lifethreatening or unstable asthma. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization). Noninferiority of fluticasone–salmeterol to fluticasone alone was defined as an upper boundary of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The efficacy end point was the first severe asthma exacerbation. RESULTS Of 11,679 patients who were enrolled, 67 had 74 serious asthma-related events, with 36 events in 34 patients in the fluticasone–salmeterol group and 38 events in 33 patients in the fluticasone-only group. The hazard ratio for a serious asthmarelated event in the fluticasone–salmeterol group was 1.03 (95% confidence interval [CI], 0.64 to 1.66), and noninferiority was achieved (P = 0.003). There were no asthma-related deaths; 2 patients in the fluticasone-only group underwent asthmarelated intubation. The risk of a severe asthma exacerbation was 21% lower in the fluticasone–salmeterol group than in the fluticasone-only group (hazard ratio, 0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring in 480 of 5834 patients (8%) in the fluticasone–salmeterol group, as compared with 597 of 5845 patients (10%) in the fluticasone-only group (P
- Published
- 2016
5. Audit feedback on reading performance of screening mammograms: An international comparison
- Author
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Hofvind, S, primary, Bennett, RL, additional, Brisson, J, additional, Lee, W, additional, Pelletier, E, additional, Flugelman, A, additional, and Geller, B, additional
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- 2016
- Full Text
- View/download PDF
6. Genetic Counseling and Testing for FMR1 Gene Mutations: Practice Guidelines of the National Society of Genetic Counselors
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Finucane, B, Abrams, L, Cronister, A, Archibald, AD, Bennett, RL, McConkie-Rosell, A, Finucane, B, Abrams, L, Cronister, A, Archibald, AD, Bennett, RL, and McConkie-Rosell, A
- Abstract
Fragile X syndrome (FXS) is one of several clinical disorders associated with mutations in the X-linked Fragile X Mental Retardation-1 (FMR1) gene. With evolving knowledge about the phenotypic consequences of FMR1 transcription and translation, sharp clinical distinctions between pre- and full mutations have become more fluid. The complexity of the issues surrounding genetic testing and management of FMR1-associated disorders has increased; and several aspects of genetic counseling for FMR1 mutations remain challenging, including risk assessment for intermediate alleles and the widely variable clinical prognosis for females with full mutations. FMR1 mutation testing is increasingly being offered to women without known risk factors, and newborn screening for FXS is underway in research-based pilot studies. Each diagnosis of an FMR1 mutation has far-reaching clinical and reproductive implications for the extended family. The interest in large-scale population screening is likely to increase due to patient demand and awareness, and as targeted pharmaceutical treatments for FXS become available over the next decade. Given these developments and the likelihood of more widespread screening, genetic counselors across a variety of healthcare settings will increasingly be called upon to address complex diagnostic, psychosocial, and management issues related to FMR1 gene mutations. The following guidelines are intended to assist genetic counselors in providing accurate risk assessment and appropriate educational and supportive counseling for individuals with positive test results and families affected by FMR1-associated disorders.
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- 2012
7. Workforce issues in breast imaging: radiographers as screen readers
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Bennett, RL, primary, Blanks, RG, additional, and Moss, SM, additional
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- 2006
- Full Text
- View/download PDF
8. Pedigree parables
- Author
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Bennett, RL, primary
- Published
- 2000
- Full Text
- View/download PDF
9. ST segment monitoring in the pediatric ICU: detecting myocardial ischemia in children
- Author
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McCulley, ME, primary and Bennett, RL, additional
- Published
- 1997
- Full Text
- View/download PDF
10. Results from the UK NHS Breast Screening Programme 2000-05.
- Author
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Bennett RL, Blanks RG, Patnick J, and Moss SM
- Abstract
OBJECTIVE: To present results from the UK NHS breast screening programme (NHSBSP) for the six-year period from 1 April 1999 to 31 March 2005, and to compare these with targets. METHODS: Data are collected annually from all UK screening units on standard KC62 return forms. RESULTS: The prevalence of screen-positive cancer (cancer detection rate) has increased at both rounds during the six-year period. At the incident round, cancer detection rates increased by 24%, from 5.4 per 1000 in 2000 to 6.7 per 1000 in 2005 and the detection of small cancers (< or = 10 mm) has increased by 40%. Generally, quality measures in the programme continue to improve. However, while rates of recall at the incident screen decreased from 3.8% in 2000 to 3.6% in 2005, at the prevalent round, in 2005, 22% of units continued to recall more than 10% of women to assessment. CONCLUSIONS: The results suggest that the performance of the programme continues to improve. In the future, analysis of data on interval cancers will assist the interpretation of cancer detection rates. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
11. Developing standard recommendations (guidelines) for genetic counseling practice: a process of the National Society of Genetic Counselors.
- Author
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Bennett RL, Pettersen BJ, Niendorf KB, and Anderson RR
- Abstract
The National Society of Genetic Counselors (NSGC) supports the development of practice recommendations (guidelines) in the field of genetic counseling. This paper reviews the basic components of NSGC genetic counseling practice recommendations as well as the process for formal adoption of such documents, as approved by the Board of Directors of the NSGC. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
12. Postpartum home visits: extending the continuum of care from hospital to home.
- Author
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Bennett RL and Tandy LJ
- Published
- 1998
13. The genetic family history in primary care.
- Author
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Bennett RL
- Published
- 1997
14. The Application of Typing in the After-Care of Poliomyelitis
- Author
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Bennett Rl and Driver Mf
- Subjects
Occupational therapy ,Pediatrics ,medicine.medical_specialty ,Occupational Therapy ,business.industry ,Arm ,Humans ,Medicine ,Typing ,business ,medicine.disease ,Poliomyelitis - Published
- 1956
15. CONVALESCENT CARE OF THE WEAKENED SHOULDER
- Author
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Bennett Rl
- Subjects
medicine.medical_specialty ,Sling (implant) ,business.industry ,Physical therapy ,medicine ,General Medicine ,business - Published
- 1947
16. Cyclometallation reactions. XIV. Some reactions of nitrogen-donor ligands
- Author
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Bennett, RL, Bruce, MI, and Matsuda, I
- Abstract
The preparation of ortho-metallated complexes from reactions between MnR(CO)5 (R = Me or CH2Ph) or Li2PdCl4 and the following N-donor ligands is reported: azophenetole [Mn; also Ru, from Ru3(CO)12], Dimethyl Yellow (Pd), 4,4?-azobis(N,N-dimethylaniline) (Mn,Pd), azoxybenzene (Pd), 4,4?-azoxyanisole (Pd), benzylideneazine (Mn), N,N?-dimethylbenzylamine (Mn) and N-benzyl-aniline (Mn). The reactions between MnMe(CO)5 and azoxybenzene and azoxyanisole afford metallated derivatives of the corresponding azo compounds; the former derivative was also obtained from hydrazobenzene and MnMe(CO)5.
- Published
- 1975
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17. Cyclometallation reactions. XV. ortho-Metallation of a sulphur-donor ligand.
- Author
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Bennett, RL, Bruce, MI, and Matsuda, I
- Abstract
The reaction between benzyl methyl sulphide and Mn(CH2Ph)(CO)5 affords the ortho-metallated-complex Mn(C6H4CH2SMe)(CO)4. Some other, non- metallated complexes of the sulphur-donor ligand with ruthenium and palladium are described; with rhenium, a complex disproportionation reaction occurs, apparently giving mixed [Re(CO)3(SR)]4 (R = Me, Ph or CH2Ph) complexes.
- Published
- 1975
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18. Conservative management of the wrist and hand in rheumatoid arthritis: the art of self-defense
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Bennett Rl
- Subjects
Inflammation ,medicine.medical_specialty ,Orthotic Devices ,Conservative management ,business.industry ,Physical Exertion ,Anti-Inflammatory Agents ,Pain ,General Medicine ,Self defense ,Wrist ,medicine.disease ,Hand ,Physical and Rehabilitation Medicine ,Arthritis, Rheumatoid ,medicine.anatomical_structure ,Stress, Physiological ,Rheumatoid arthritis ,Physical therapy ,medicine ,Humans ,business - Published
- 1973
19. What is a rehabilitation center?
- Author
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Bennett Rl
- Subjects
Rehabilitation ,business.industry ,medicine.medical_treatment ,General Medicine ,medicine.disease ,Rehabilitation Centers ,Chronic Disease ,Medicine ,Humans ,Center (algebra and category theory) ,Disabled Persons ,Medical emergency ,business - Published
- 1955
20. Cyclometallation reactionds. VIII. Binuclear manganese carbonyl complexes derived from azobenzene
- Author
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Bennett, RL, primary, Bruce, MI, additional, Goodall, BL, additional, and Stone, FGA, additional
- Published
- 1974
- Full Text
- View/download PDF
21. An aldol condensation induced by a transition metal complex
- Author
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Bennett, RL, primary and Bruce, MI, additional
- Published
- 1975
- Full Text
- View/download PDF
22. Germline Mutation in MSH6 Associated With Multiple Malignant Neoplasms in a Patient With Muir-Torre Syndrome.
- Author
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Tavakkol Z, Keller JJ, Furmanczyk PS, Bennett RL, and Chien AJ
- Published
- 2012
- Full Text
- View/download PDF
23. KDM6A regulates immune response genes in multiple myeloma.
- Author
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Dupéré-Richer D, Riva A, Barwick BG, Maji S, Casellas Román H, Li J, De U, Sobh A, Quickstad G, Piper C, Kulis M, Ezponda T, Martín-Subero JI, Tonon G, Zhang W, Mitsiades CS, Boise LH, Bennett RL, and Licht JD
- Subjects
- Humans, Animals, Mice, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Nuclear Proteins genetics, Nuclear Proteins immunology, Nuclear Proteins metabolism, Cell Line, Tumor, Histones metabolism, Histones genetics, Trans-Activators, Multiple Myeloma genetics, Multiple Myeloma immunology, Gene Expression Regulation, Neoplastic, Histone Demethylases genetics, Histone Demethylases metabolism
- Abstract
Abstract: The histone H3 at lysine 27 (H3K27) demethylase lysine demethylase 6A (KDM6A) is a tumor suppressor in multiple cancers, including multiple myeloma (MM). We created isogenic MM cells disrupted for KDM6A and tagged the endogenous protein to facilitate genome-wide studies. KDM6A binds genes associated with immune recognition and cytokine signaling. Most importantly, KDM6A binds and activates NLRC5 and CIITA, which encode regulators of major histocompatibility complex genes. Patient data indicate that NLRC5 and CIITA are downregulated in MM with low KDM6A expression. Chromatin analysis shows that KDM6A binds poised and active enhancers and KDM6A loss led to decreased H3K27ac at enhancers, increased H3K27me3 levels in body of genes bound by KDM6A, and decreased gene expression. Reestablishing histone acetylation with an HDAC3 inhibitor leads to upregulation of major histocompatibility complex expression, offering a strategy to restore immunogenicity of KDM6A-deficient tumors. Loss of Kdm6a in Kirsten rat sarcoma virus (K-RAS)-transformed murine fibroblasts led to increased growth in vivo associated with decreased T-cell infiltration., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
- Published
- 2024
- Full Text
- View/download PDF
24. Genetic variation drives cancer cell adaptation to ECM stiffness.
- Author
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Wang TC, Sawhney S, Morgan D, Bennett RL, Rashmi R, Estecio MR, Brock A, Singh I, Baer CF, Licht JD, and Lele TP
- Subjects
- Humans, Cell Line, Tumor, Neoplasms genetics, Neoplasms pathology, Adaptation, Physiological genetics, Cell Proliferation genetics, Cell Movement genetics, Extracellular Matrix metabolism, Extracellular Matrix genetics, Genetic Variation
- Abstract
The progression of many solid tumors is accompanied by temporal and spatial changes in the stiffness of the extracellular matrix (ECM). Cancer cells adapt to soft and stiff ECM through mechanisms that are not fully understood. It is well known that there is significant genetic heterogeneity from cell to cell in tumors, but how ECM stiffness as a parameter might interact with that genetic variation is not known. Here, we employed experimental evolution to study the response of genetically variable and clonal populations of tumor cells to variable ECM stiffness. Proliferation rates of genetically variable populations cultured on soft ECM increased over a period of several weeks, whereas clonal populations did not evolve. Tracking of DNA barcoded cell lineages revealed that soft ECM consistently selected for the same few variants. These data provide evidence that ECM stiffness exerts natural selection on genetically variable tumor populations. Soft-selected cells were highly migratory, with enriched oncogenic signatures and unusual behaviors such as spreading and traction force generation on ECMs with stiffness as low as 1 kPa. Rho-regulated cell spreading was found to be the directly selected trait, with yes-associated protein 1 translocation to the nucleus mediating fitness on soft ECM. Overall, these data show that genetic variation can drive cancer cell adaptation to ECM stiffness., Competing Interests: Competing interests statement:J.D.L. serves as a consultant for AstraZeneca.
- Published
- 2024
- Full Text
- View/download PDF
25. NSD2 drives t(4;14) myeloma cell dependence on adenylate kinase 2 by diverting one-carbon metabolism to the epigenome.
- Author
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Sobh A, Encinas E, Patel A, Surapaneni G, Bonilla E, Kaestner C, Poullard J, Clerio M, Vasan K, Freeman T, Lv D, Dupéré-Richer D, Riva A, Barwick BG, Zhou D, Boise LH, Mitsiades CS, Kim B, Bennett RL, Chandel NS, and Licht JD
- Subjects
- Humans, Chromosomes, Human, Pair 14 genetics, Epigenome, Chromosomes, Human, Pair 4 genetics, Carbon metabolism, Cell Line, Tumor, Repressor Proteins, Multiple Myeloma genetics, Multiple Myeloma metabolism, Multiple Myeloma pathology, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Translocation, Genetic, Adenylate Kinase metabolism, Adenylate Kinase genetics
- Abstract
Abstract: Chromosomal translocation (4;14), an adverse prognostic factor in multiple myeloma (MM), drives overexpression of the histone methyltransferase nuclear receptor binding SET domain protein 2 (NSD2). A genome-wide CRISPR screen in MM cells identified adenylate kinase 2 (AK2), an enzyme critical for high-energy phosphate transfer from the mitochondria, as an NSD2-driven vulnerability. AK2 suppression in t(4;14) MM cells decreased nicotinamide adenine dinucleotide phosphate (NADP[H]) critical for conversion of ribonucleotides to deoxyribonucleosides, leading to replication stress, DNA damage, and apoptosis. Driving a large genome-wide increase in chromatin methylation, NSD2 overexpression depletes S-adenosylmethionine, compromising the synthesis of creatine from its precursor, guanidinoacetate. Creatine supplementation restored NADP(H) levels, reduced DNA damage, and rescued AK2-deficient t(4;14) MM cells. As the creatine phosphate shuttle constitutes an alternative means for mitochondrial high-energy phosphate transport, these results indicate that NSD2-driven creatine depletion underlies the hypersensitivity of t(4;14) MM cells to AK2 loss. Furthermore, AK2 depletion in t(4;14) cells impaired protein folding in the endoplasmic reticulum, consistent with impaired use of mitochondrial adenosine triphosphate (ATP). Accordingly, AK2 suppression increased the sensitivity of MM cells to proteasome inhibition. These findings delineate a novel mechanism in which aberrant transfer of carbon to the epigenome creates a metabolic vulnerability, with direct therapeutic implications for t(4;14) MM., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
- Published
- 2024
- Full Text
- View/download PDF
26. Genetic factors for ILD-the path of precision medicine.
- Author
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Raghu G, Torres JM, and Bennett RL
- Subjects
- Humans, Genetic Predisposition to Disease, Precision Medicine methods, Lung Diseases, Interstitial genetics, Lung Diseases, Interstitial therapy
- Abstract
Competing Interests: GR reports consulting fees from Sanofi. JMT received partial funding for her paid fellowship training during the writing of this Comment from the Warren Alpert Foundation fellowship. RLB declares no competing interests. We thank Gail P Jarvik (Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA) for kindly reviewing the article and providing valuable input.
- Published
- 2024
- Full Text
- View/download PDF
27. HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis.
- Author
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Emmons MF, Bennett RL, Riva A, Gupta K, Carvalho LADC, Zhang C, Macaulay R, Dupéré-Richér D, Fang B, Seto E, Koomen JM, Li J, Chen YA, Forsyth PA, Licht JD, and Smalley KSM
- Subjects
- Humans, Chromatin metabolism, Melanocytes metabolism, Repressor Proteins metabolism, Transcription Factors metabolism, Brain Neoplasms secondary, E1A-Associated p300 Protein genetics, E1A-Associated p300 Protein metabolism, Histone Deacetylases genetics, Histone Deacetylases metabolism, Melanoma pathology
- Abstract
Melanomas can adopt multiple transcriptional states. Little is known about the epigenetic drivers of these cell states, limiting our ability to regulate melanoma heterogeneity. Here, we identify stress-induced HDAC8 activity as driving melanoma brain metastasis development. Exposure of melanocytes and melanoma cells to multiple stresses increases HDAC8 activation leading to a neural crest-stem cell transcriptional state and an amoeboid, invasive phenotype that increases seeding to the brain. Using ATAC-Seq and ChIP-Seq we show that increased HDAC8 activity alters chromatin structure by increasing H3K27ac and enhancing accessibility at c-Jun binding sites. Functionally, HDAC8 deacetylates the histone acetyltransferase EP300, causing its enzymatic inactivation. This, in turn, increases binding of EP300 to Jun-transcriptional sites and decreases binding to MITF-transcriptional sites. Inhibition of EP300 increases melanoma cell invasion, resistance to stress and increases melanoma brain metastasis development. HDAC8 is identified as a mediator of transcriptional co-factor inactivation and chromatin accessibility that drives brain metastasis., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
28. Histone mutations in cancer.
- Author
-
Espinoza Pereira KN, Shan J, Licht JD, and Bennett RL
- Subjects
- Humans, Child, Nucleosomes genetics, Mutation, Chromatin, Carcinogenesis genetics, Cell Transformation, Neoplastic genetics, Histones metabolism, Neoplasms genetics, Neoplasms pathology
- Abstract
Genes encoding histone proteins are recurrently mutated in tumor samples, and these mutations may impact nucleosome stability, histone post-translational modification, or chromatin dynamics. The prevalence of histone mutations across diverse cancer types suggest that normal chromatin structure is a barrier to tumorigenesis. Oncohistone mutations disrupt chromatin structure and gene regulatory mechanisms, resulting in aberrant gene expression and the development of cancer phenotypes. Examples of oncohistones include the histone H3 K27M mutation found in pediatric brain cancers that blocks post-translational modification of the H3 N-terminal tail and the histone H2B E76K mutation found in some solid tumors that disrupts nucleosome stability. Oncohistones may comprise a limited fraction of the total histone pool yet cause global effects on chromatin structure and drive cancer phenotypes. Here, we survey histone mutations in cancer and review their function and role in tumorigenesis., (© 2023 The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
29. Evaluating the Financial Performances of the Publicly Held Healthcare Companies in Crisis Periods in Türkiye.
- Author
-
Tengilimoğlu D, Tümer T, Bennett RL, and Younis MZ
- Abstract
The purpose of this study was to evaluate the financial performances of the publicly held healthcare companies in crisis periods in Türkiye. The 2018 economic crisis and the COVID-19 pandemic crisis were included in the study as the crisis periods. We collected the financial data of the publicly held healthcare companies and calculated three liquidity, three turnover, three leverage and three profitability ratios through ratio analysis to use as financial performance indicators. We then conducted Wilcoxon signed-rank tests and we performed separate analyses for the 2018 economic crisis and the COVID-19 pandemic crisis. The results of the analyses showed that there were no statistically significant differences between the publicly held healthcare companies' liquidity, turnover, leverage, profitability ratios and thus their financial performances before the crises and after the crises. While the results are reassuring and give valuable insights to managers and policy makers to determine the areas that needs to be strengthened to be better prepared for possible future crises, our sample was limited. Therefore, this study presents an exploratory foundation for future studies which are needed to make a case for financial stability for the publicly held healthcare companies before and after the crisis periods.
- Published
- 2023
- Full Text
- View/download PDF
30. SMYD3 represses tumor-intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck.
- Author
-
Nigam N, Bernard B, Sevilla S, Kim S, Dar MS, Tsai D, Robbins Y, Burkitt K, Sievers C, Allen CT, Bennett RL, Tettey TT, Carter B, Rinaldi L, Lingen MW, Sater H, Edmondson EF, Moshiri A, Saeed A, Cheng H, Luo X, Brennan K, Koparde V, Chen C, Das S, Andresson T, Abdelmaksoud A, Murali M, Sakata S, Takeuchi K, Chari R, Nakamura Y, Uppaluri R, Sunwoo JB, Van Waes C, Licht JD, Hager GL, and Saloura V
- Subjects
- Humans, CCAAT-Enhancer-Binding Proteins, CD8-Positive T-Lymphocytes, Ubiquitin-Protein Ligases, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms genetics, Histone-Lysine N-Methyltransferase genetics, Interferon Type I, Papillomavirus Infections, Squamous Cell Carcinoma of Head and Neck drug therapy, Squamous Cell Carcinoma of Head and Neck genetics
- Abstract
Cancers often display immune escape, but the mechanisms are incompletely understood. Herein, we identify SMYD3 as a mediator of immune escape in human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), an aggressive disease with poor response to immunotherapy with pembrolizumab. SMYD3 depletion induces upregulation of multiple type I interferon (IFN) response and antigen presentation machinery genes in HNSCC cells. Mechanistically, SMYD3 binds to and regulates the transcription of UHRF1, encoding for a reader of H3K9me3, which binds to H3K9me3-enriched promoters of key immune-related genes, recruits DNMT1, and silences their expression. SMYD3 further maintains the repression of immune-related genes through intragenic deposition of H4K20me3. In vivo, Smyd3 depletion induces influx of CD8
+ T cells and increases sensitivity to anti-programmed death 1 (PD-1) therapy. SMYD3 overexpression is associated with decreased CD8 T cell infiltration and poor response to neoadjuvant pembrolizumab. These data support combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in HPV-negative HNSCC., Competing Interests: Declaration of interests L.R. is currently an employee of Delfi Diagnostics in Baltimore, MD, USA. X.L. was an employee and shareholder of Ionis Pharmaceuticals in Carlsbad, CA, USA during the conduct of this study. Y.N. is employed as the president of the National Institutes of Biomedical Innovation, Health and Nutrition, and has 6% of stocks of OncoTherapy Science. J.L. has research support by Epizyme., (Published by Elsevier Inc.)- Published
- 2023
- Full Text
- View/download PDF
31. Both sides now: Changing a long-standing pedigree tradition of men on the left and women on the right.
- Author
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Resta RG, French KS, Bennett RL, and Austin J
- Subjects
- Male, Humans, Female, Pedigree
- Published
- 2023
- Full Text
- View/download PDF
32. First-in-class multifunctional TYMS nonclassical antifolate inhibitor with potent in vivo activity that prolongs survival.
- Author
-
Guijarro MV, Kellish PC, Dib PE, Paciaroni NG, Nawab A, Andring J, Kulemina L, Borrero NV, Modenutti C, Feely M, Nasri E, Seifert RP, Luo X, Bennett RL, Shabashvili D, Licht JD, McKenna R, Roitberg A, Huigens RW 3rd, Kaye FJ, and Zajac-Kaye M
- Subjects
- Mice, Animals, Humans, Enzyme Inhibitors pharmacology, Drug Resistance, Thymidylate Synthase, Folic Acid Antagonists pharmacology, Folic Acid Antagonists therapeutic use, Folic Acid Antagonists chemistry
- Abstract
Although thymidylate synthase (TYMS) inhibitors have served as components of chemotherapy regimens, the currently available inhibitors induce TYMS overexpression or alter folate transport/metabolism feedback pathways that tumor cells exploit for drug resistance, limiting overall benefit. Here we report a small molecule TYMS inhibitor that i) exhibited enhanced antitumor activity as compared with current fluoropyrimidines and antifolates without inducing TYMS overexpression, ii) is structurally distinct from classical antifolates, iii) extended survival in both pancreatic xenograft tumor models and an hTS/Ink4a/Arf null genetically engineered mouse tumor model, and iv) is well tolerated with equal efficacy using either intraperitoneal or oral administration. Mechanistically, we verify the compound is a multifunctional nonclassical antifolate, and using a series of analogs, we identify structural features allowing direct TYMS inhibition while maintaining the ability to inhibit dihydrofolate reductase. Collectively, this work identifies nonclassical antifolate inhibitors that optimize inhibition of thymidylate biosynthesis with a favorable safety profile, highlighting the potential for enhanced cancer therapy.
- Published
- 2023
- Full Text
- View/download PDF
33. Words matter: The language of difference in human genetics.
- Author
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Cho MK, Duque Lasio ML, Amarillo I, Mintz KT, Bennett RL, and Brothers KB
- Subjects
- Humans, Delivery of Health Care, Gender Identity, Human Genetics, Genetic Research, Publishing
- Abstract
Diversity, equity, and inclusion efforts in academia are leading publishers and journals to re-examine their use of terminology for commonly used scientific variables. This reassessment of language is particularly important for human genetics, which is focused on identifying and explaining differences between individuals and populations. Recent guidance on the use of terms and symbols in clinical practice, research, and publications is beginning to acknowledge the ways that language and concepts of difference can be not only inaccurate but also harmful. To stop perpetuating historical wrongs, those of us who conduct and publish genetic research and provide genetic health care must understand the context of the terms we use and why some usages should be discontinued. In this article, we summarize critiques of terminology describing disability, sex, gender, race, ethnicity, and ancestry in research publications, laboratory reports, diagnostic codes, and pedigrees. We also highlight recommendations for alternative language that aims to make genetics more inclusive, rigorous, and ethically sound. Even though norms of acceptable language use are ever changing, it is the responsibility of genetics professionals to uncover biases ingrained in professional practice and training and to continually reassess the words we use to describe human difference because they cause harm to patients., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
34. Practice resource-focused revision: Standardized pedigree nomenclature update centered on sex and gender inclusivity: A practice resource of the National Society of Genetic Counselors.
- Author
-
Bennett RL, French KS, Resta RG, and Austin J
- Subjects
- Male, Female, Infant, Newborn, Humans, Pedigree, Gender Identity, Societies, Counselors, Transgender Persons
- Abstract
This focused revision builds on the expert opinions from the original publications of 'Recommendations for human standardized pedigree nomenclature' published in 1995 and updated in 2008. Our review of medical publications since 2008 did not identify any fundamental systematic alternative pedigree nomenclature. These findings attest to the relevance of most of the nomenclature with the critical exception of the nomenclature used to denote sex assigned at birth and gender. While we are not recommending the creation of any new pedigree symbols, a major focus of this publication is clarification of the use of symbols and language in the description of the distinction between sex and gender, with a view to ensuring safe and inclusive practice for people who are gender-diverse or transgender. In addition, we recommend modifications to the way that carrier status is depicted. Our goal is to respect individual differences and identities while maintaining biologically, clinically, and genetically meaningful information., (© 2022 National Society of Genetic Counselors.)
- Published
- 2022
- Full Text
- View/download PDF
35. Evaluation of mRNA-1273 Vaccine in Children 6 Months to 5 Years of Age.
- Author
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Anderson EJ, Creech CB, Berthaud V, Piramzadian A, Johnson KA, Zervos M, Garner F, Griffin C, Palanpurwala K, Turner M, Gerber J, Bennett RL, Ali K, Ampajwala M, Berman G, Nayak J, Chronis C, Rizzardi B, Muller WJ, Smith CA, Fuchs G, Hsia D, Tomassini JE, DeLucia D, Reuter C, Kuter B, Zhao X, Deng W, Zhou H, Ramirez Schrempp D, Hautzinger K, Girard B, Slobod K, McPhee R, Pajon R, Aunins A, Das R, Miller JM, and Schnyder Ghamloush S
- Subjects
- Child, Child, Preschool, Humans, Infant, Young Adult, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, COVID-19 Vaccines adverse effects, Double-Blind Method, Vaccine Efficacy, Treatment Outcome, Adolescent, Adult, 2019-nCoV Vaccine mRNA-1273 immunology, 2019-nCoV Vaccine mRNA-1273 therapeutic use, COVID-19 epidemiology, COVID-19 immunology, COVID-19 prevention & control, Immunogenicity, Vaccine immunology
- Abstract
Background: The safety, reactogenicity, immunogenicity, and efficacy of the mRNA-1273 coronavirus disease 2019 (Covid-19) vaccine in young children are unknown., Methods: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled evaluation of the selected dose. In part 2, we randomly assigned young children (6 months to 5 years of age) in a 3:1 ratio to receive two 25-μg injections of mRNA-1273 or placebo, administered 28 days apart. The primary objectives were to evaluate the safety and reactogenicity of the vaccine and to determine whether the immune response in these children was noninferior to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives were to determine the incidences of Covid-19 and severe acute respiratory syndrome coronavirus 2 infection after administration of mRNA-1273 or placebo., Results: On the basis of safety and immunogenicity results in part 1 of the trial, the 25-μg dose was evaluated in part 2. In part 2, 3040 children 2 to 5 years of age and 1762 children 6 to 23 months of age were randomly assigned to receive two 25-μg injections of mRNA-1273; 1008 children 2 to 5 years of age and 593 children 6 to 23 months of age were randomly assigned to receive placebo. The median duration of follow-up after the second injection was 71 days in the 2-to-5-year-old cohort and 68 days in the 6-to-23-month-old cohort. Adverse events were mainly low-grade and transient, and no new safety concerns were identified. At day 57, neutralizing antibody geometric mean concentrations were 1410 (95% confidence interval [CI], 1272 to 1563) among 2-to-5-year-olds and 1781 (95% CI, 1616 to 1962) among 6-to-23-month-olds, as compared with 1391 (95% CI, 1263 to 1531) among young adults, who had received 100-μg injections of mRNA-1273, findings that met the noninferiority criteria for immune responses for both age cohorts. The estimated vaccine efficacy against Covid-19 was 36.8% (95% CI, 12.5 to 54.0) among 2-to-5-year-olds and 50.6% (95% CI, 21.4 to 68.6) among 6-to-23-month-olds, at a time when B.1.1.529 (omicron) was the predominant circulating variant., Conclusions: Two 25-μg doses of the mRNA-1273 vaccine were found to be safe in children 6 months to 5 years of age and elicited immune responses that were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.)., (Copyright © 2022 Massachusetts Medical Society.)
- Published
- 2022
- Full Text
- View/download PDF
36. The epigenetic underpinnings of lower back pain.
- Author
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Bennett RL
- Subjects
- Epigenesis, Genetic genetics, Epigenomics, Humans, Low Back Pain genetics
- Published
- 2022
- Full Text
- View/download PDF
37. DNMT3A Harboring Leukemia-Associated Mutations Directs Sensitivity to DNA Damage at Replication Forks.
- Author
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Venugopal K, Feng Y, Nowialis P, Xu H, Shabashvili DE, Berntsen CM, Kaur P, Krajcik KI, Taragjini C, Zaroogian Z, Casellas Román HL, Posada LM, Gunaratne C, Li J, Dupéré-Richer D, Bennett RL, Pondugula S, Riva A, Cogle CR, Opavsky R, Law BK, Bhaduri-McIntosh S, Kubicek S, Staber PB, Licht JD, Bird JE, and Guryanova OA
- Subjects
- Animals, Humans, Mice, Mutation, Prognosis, DNA Damage, DNA Methyltransferase 3A genetics, DNA Replication genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
Purpose: In acute myeloid leukemia (AML), recurrent DNA methyltransferase 3A (DNMT3A) mutations are associated with chemoresistance and poor prognosis, especially in advanced-age patients. Gene-expression studies in DNMT3A-mutated cells identified signatures implicated in deregulated DNA damage response and replication fork integrity, suggesting sensitivity to replication stress. Here, we tested whether pharmacologically induced replication fork stalling, such as with cytarabine, creates a therapeutic vulnerability in cells with DNMT3A(R882) mutations., Experimental Design: Leukemia cell lines, genetic mouse models, and isogenic cells with and without DNMT3A(mut) were used to evaluate sensitivity to nucleoside analogues such as cytarabine in vitro and in vivo, followed by analysis of DNA damage and signaling, replication restart, and cell-cycle progression on treatment and after drug removal. Transcriptome profiling identified pathways deregulated by DNMT3A(mut) expression., Results: We found increased sensitivity to pharmacologically induced replication stress in cells expressing DNMT3A(R882)-mutant, with persistent intra-S-phase checkpoint activation, impaired PARP1 recruitment, and elevated DNA damage, which was incompletely resolved after drug removal and carried through mitosis. Pulse-chase double-labeling experiments with EdU and BrdU after cytarabine washout demonstrated a higher rate of fork collapse in DNMT3A(mut)-expressing cells. RNA-seq studies supported deregulated cell-cycle progression and p53 activation, along with splicing, ribosome biogenesis, and metabolism., Conclusions: Together, our studies show that DNMT3A mutations underlie a defect in recovery from replication fork arrest with subsequent accumulation of unresolved DNA damage, which may have therapeutic tractability. These results demonstrate that, in addition to its role in epigenetic control, DNMT3A contributes to preserving genome integrity during replication stress. See related commentary by Viny, p. 573., (©2021 The Authors; Published by the American Association for Cancer Research.)
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- 2022
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38. PRC2 Inhibitors Overcome Glucocorticoid Resistance Driven by NSD2 Mutation in Pediatric Acute Lymphoblastic Leukemia.
- Author
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Li J, Hlavka-Zhang J, Shrimp JH, Piper C, Dupéré-Richér D, Roth JS, Jing D, Casellas Román HL, Troche C, Swaroop A, Kulis M, Oyer JA, Will CM, Shen M, Riva A, Bennett RL, Ferrando AA, Hall MD, Lock RB, and Licht JD
- Subjects
- Cell Line, Tumor drug effects, Cell Survival, Child, Drug Resistance, Neoplasm, Enzyme Inhibitors pharmacology, Female, Glucocorticoids pharmacology, Humans, Male, Mutation, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Enzyme Inhibitors therapeutic use, Glucocorticoids therapeutic use, Histone Methyltransferases antagonists & inhibitors, Histone-Lysine N-Methyltransferase genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Repressor Proteins genetics
- Abstract
Mutations in epigenetic regulators are common in relapsed pediatric acute lymphoblastic leukemia (ALL). Here, we uncovered the mechanism underlying the relapse of ALL driven by an activating mutation of the NSD2 histone methyltransferase (p.E1099K). Using high-throughput drug screening, we found that NSD2 -mutant cells were specifically resistant to glucocorticoids. Correction of this mutation restored glucocorticoid sensitivity. The transcriptional response to glucocorticoids was blocked in NSD2 -mutant cells due to depressed glucocorticoid receptor (GR) levels and the failure of glucocorticoids to autoactivate GR expression. Although H3K27me3 was globally decreased by NSD2 p.E1099K, H3K27me3 accumulated at the NR3C1 (GR) promoter. Pretreatment of NSD2 p.E1099K cell lines and patient-derived xenograft samples with PRC2 inhibitors reversed glucocorticoid resistance in vitro and in vivo . PRC2 inhibitors restored NR3C1 autoactivation by glucocorticoids, increasing GR levels and allowing GR binding and activation of proapoptotic genes. These findings suggest a new therapeutic approach to relapsed ALL associated with NSD2 mutation. SIGNIFICANCE: NSD2 histone methyltransferase mutations observed in relapsed pediatric ALL drove glucocorticoid resistance by repression of the GR and abrogation of GR gene autoactivation due to accumulation of K3K27me3 at its promoter. Pretreatment with PRC2 inhibitors reversed resistance, suggesting a new therapeutic approach to these patients with ALL. This article is highlighted in the In This Issue feature, p. 1 ., (©2021 American Association for Cancer Research.)
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- 2022
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39. Genetic counseling and screening of consanguineous couples and their offspring practice resource: Focused Revision.
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Bennett RL, Malleda NR, Byers PH, Steiner RD, and Barr KM
- Subjects
- Consanguinity, Humans, Mass Screening, Family, Genetic Counseling
- Abstract
There are no evidence-based guidelines to inform genetic counseling for consanguineous couples and their offspring. This focused revision builds on the expert opinions from the original publication of "Genetic Counseling and Screening of Consanguineous Couples and Their Offspring," based on a review of literature published since 2002., (© 2021 National Society of Genetic Counselors.)
- Published
- 2021
- Full Text
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40. Targeted long-read sequencing identifies missing disease-causing variation.
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Miller DE, Sulovari A, Wang T, Loucks H, Hoekzema K, Munson KM, Lewis AP, Fuerte EPA, Paschal CR, Walsh T, Thies J, Bennett JT, Glass I, Dipple KM, Patterson K, Bonkowski ES, Nelson Z, Squire A, Sikes M, Beckman E, Bennett RL, Earl D, Lee W, Allikmets R, Perlman SJ, Chow P, Hing AV, Wenger TL, Adam MP, Sun A, Lam C, Chang I, Zou X, Austin SL, Huggins E, Safi A, Iyengar AK, Reddy TE, Majoros WH, Allen AS, Crawford GE, Kishnani PS, King MC, Cherry T, Chong JX, Bamshad MJ, Nickerson DA, Mefford HC, Doherty D, and Eichler EE
- Subjects
- DNA Copy Number Variations, Female, Genetic Testing, High-Throughput Nucleotide Sequencing, Humans, Karyotyping, Male, Sequence Analysis, DNA, Chromosome Aberrations, Cytogenetic Analysis methods, Genetic Diseases, Inborn diagnosis, Genetic Diseases, Inborn genetics, Genetic Predisposition to Disease, Genome, Human, Mutation
- Abstract
Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
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- 2021
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41. Targeting epigenetic mechanisms to overcome venetoclax resistance.
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Prado G, Kaestner CL, Licht JD, and Bennett RL
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- Antineoplastic Agents chemistry, Bridged Bicyclo Compounds, Heterocyclic chemistry, Drug Resistance, Neoplasm genetics, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Epigenesis, Genetic genetics, Humans, Neoplasms metabolism, Neoplasms pathology, Sulfonamides chemistry, Antineoplastic Agents pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Drug Resistance, Neoplasm drug effects, Epigenesis, Genetic drug effects, Neoplasms drug therapy, Sulfonamides pharmacology
- Abstract
The BH-3 mimetic venetoclax overcomes apoptosis and therapy resistance caused by high expression of BCL2 or loss of BH3-only protein function. Although a promising therapy for hematologic malignancies, increased expression of anti-apoptotic MCL-1 or BCL-XL, as well as other resistance mechanisms prevent a durable response to venetoclax. Recent studies demonstrate that agents targeting epigenetic mechanisms such as DNA methyltransferase inhibitors, histone deacetylase (HDAC) inhibitors, histone methyltransferase EZH2 inhibitors, or bromodomain reader protein inhibitors may disable oncogenic gene expression signatures responsible for venetoclax resistance. Combination therapies including venetoclax and epigenetic therapies are effective in preclinical models and the subject of many current clinical trials. Here we review epigenetic strategies to overcome venetoclax resistance mechanisms in hematologic malignancies., (Copyright © 2021 Elsevier B.V. All rights reserved.)
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- 2021
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42. Assessment with clinical data of a coupled bio-hemodynamics numerical model to predict leukocyte adhesion in coronary arteries.
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Ciri U, Bennett RL, Bhui R, Molony DS, Samady H, Meyer CA, Hayenga HN, and Leonardi S
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- Coronary Angiography, Coronary Artery Disease diagnostic imaging, Coronary Circulation, Coronary Vessels diagnostic imaging, Humans, Stress, Mechanical, Ultrasonography, Cell Adhesion, Coronary Artery Disease physiopathology, Coronary Vessels physiopathology, Hemodynamics, Leukocytes physiology, Models, Cardiovascular
- Abstract
Numerical simulations of coupled hemodynamics and leukocyte transport and adhesion inside coronary arteries have been performed. Realistic artery geometries have been obtained for a set of four patients from intravascular ultrasound and angiography images. The numerical model computes unsteady three-dimensional blood hemodynamics and leukocyte concentration in the blood. Wall-shear stress dependent leukocyte adhesion is also computed through agent-based modeling rules, fully coupled to the hemodynamics and leukocyte transport. Numerical results have a good correlation with clinical data. Regions where high adhesion is predicted by the simulations coincide to a good approximation with artery segments presenting plaque increase, as documented by clinical data from baseline and six-month follow-up exam of the same artery. In addition, it is observed that the artery geometry and, in particular, the tortuosity of the centerline are a primary factor in determining the spatial distribution of wall-shear stress, and of the resulting leukocyte adhesion patterns. Although further work is required to overcome the limitations of the present model and ultimately quantify plaque growth in the simulations, these results are encouraging towards establishing a predictive methodology for atherosclerosis progress.
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- 2021
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43. Taking an antiracist posture in scientific publications in human genetics and genomics.
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Brothers KB, Bennett RL, and Cho MK
- Subjects
- Genomics, Human Genetics, Humans, Posture, Editorial Policies, Publications
- Abstract
From its earliest days, the field of human genetics has had a complex, and at times troubling, connection with racist ideologies. Although the modern field of human genetics and genomics has come a long way from those earlier errors, systemic racism remains ingrained in its institutions and practices. Although a variety of efforts are needed to excise systemic racism, we focus in this commentary on the work that must be done in scientific publishing in genetics and genomics. We propose eight principles that are both scientifically grounded and antiracist that we hope will serve as a foundation for the development of policies by publishers and editorial boards that address the unique needs of the field of genetics and genomics. Publishers and journals must go beyond mere policies, however. Editors and reviewers will need training on these policies and principles, and will benefit from resources like rubrics that can be used for evaluating the adherence of submissions to these guidelines.
- Published
- 2021
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44. Leveraging epigenetics to enhance the efficacy of immunotherapy.
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Licht JD and Bennett RL
- Subjects
- Epigenesis, Genetic immunology, Humans, Neoplasms genetics, Epigenomics methods, Immunotherapy methods, Neoplasms immunology, Neoplasms therapy
- Abstract
Background: Epigenetic mechanisms regulate chromatin accessibility patterns that govern interaction of transcription machinery with genes and their cis-regulatory elements. Mutations that affect epigenetic mechanisms are common in cancer. Because epigenetic modifications are reversible many anticancer strategies targeting these mechanisms are currently under development and in clinical trials., Main Body: Here we review evidence suggesting that epigenetic therapeutics can deactivate immunosuppressive gene expression or reprogram tumor cells to activate antigen presentation mechanisms. In addition, the dysregulation of epigenetic mechanisms commonly observed in cancer may alter the immunogenicity of tumor cells and effectiveness of immunotherapies., Conclusions: Therapeutics targeting epigenetic mechanisms may be helpful to counter immune evasion and improve the effectiveness of immunotherapies.
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- 2021
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45. Assessing transgender and gender non-conforming pedigree nomenclature in current genetic counselors' practice: The case for geometric inclusivity.
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Sheehan E, Bennett RL, Harris M, and Chan-Smutko G
- Subjects
- Confidentiality, Counselors, Female, Humans, Male, Pedigree, Genetic Counseling, Terminology as Topic, Transgender Persons
- Abstract
Healthcare professionals rely on national organizations for guidance; the National Society of Genetic Counselors (NSGC) and the National Comprehensive Cancer Network (NCCN) have differing guidelines for acceptable pedigree symbols to represent transgender patients and minimal recommendations for gender non-conforming (GNC) patients. Inconsistency in accepted pedigree symbols to represent these patients is a barrier to providing them appropriate care. We assess variability in pedigree practice among genetic counselors and students, as well as reported education on serving the needs of the transgender and GNC communities, through a survey distributed through NSGC. Participants felt symbols similar to NSGC's (41.1%) and NCCN's (29.7%) recommendations for transgender patients are appropriate and emphasized a desire to affirm gender identity. We identified greater variability in symbols representing a GNC patient; 19.2% of participants selected 'other', explaining they were unsure of the appropriate choice. A high interest (99%) in further training demonstrates a recognition of education as an effective strategy for improving awareness and competency. Promotion of existing resources could help address the fact that 81% of participants were unaware of any standardized symbols used to represent transgender individuals. Creating affirming, standardized pedigree nomenclature is necessary for appropriate and consistent care., (© 2020 National Society of Genetic Counselors.)
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- 2020
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46. Efficacy testing of the SAVOR (Sisters Adding Fruits and Vegetables for Optimal Results) intervention among African American women: A randomized controlled trial.
- Author
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Brown L, Sharma M, Leggett S, Sung JH, Bennett RL, and Azevedo M
- Abstract
Background: In the United States, only about 15% of individuals meet daily fruit intake recommendations of 2 cups per day and only 10% meet the vegetable intake recommendations of3 cups per day. African American women are a high-risk group. In this study, a fourth-generation multi-theory model (MTM) of health behavior change was used to design and evaluate a SistersAdding Fruits and Vegetables for Optimal Results (SAVOR) intervention for AA women. Methods: The study utilized a randomized controlled trial (RCT) with measurements taken at pretest, posttest (after the three-week intervention) and follow-up (at the end of eight weeks).SAVOR (n=26) was compared to an equivalent knowledge-based intervention (n=28). Process evaluation was done for program fidelity and satisfaction. A validated 38-item self-reported questionnaire was used to measure changes in MTM constructs and past 24-hour consumption of fruits and vegetables. Results: The SAVOR intervention resulted in improvement of mean consumption of fruits and vegetables in the experimental group from pre-test (2.78) to posttest (4.77) to recommended levels at follow-up (5.04) while in the comparison group they remained at around 3 (P<0.0001)Statistically significant changes (P<0.05) were noted for all MTM constructs except for participatory dialogue. Conclusion: The SAVOR intervention was found to be efficacious and established the robustness of MTM. SAVOR can be replicated for future effectiveness trials., (© 2020 The Author(s).)
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- 2020
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47. Simultaneous germline and somatic sequencing in ovarian carcinoma: mutation rate and impact on clinical decision-making.
- Author
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Jorge S, McFaddin AS, Doll KM, Pennington KP, Norquist BM, Bennett RL, Pritchard CC, and Swisher EM
- Subjects
- Adult, Aged, BRCA1 Protein genetics, BRCA2 Protein genetics, Carcinoma, Ovarian Epithelial pathology, Carcinoma, Ovarian Epithelial therapy, Female, Genes, BRCA1, Genes, BRCA2, Germ-Line Mutation, Humans, Middle Aged, Mutation Rate, Neoplasm Recurrence, Local genetics, Neoplasm Staging, Ovarian Neoplasms pathology, Ovarian Neoplasms therapy, Carcinoma, Ovarian Epithelial genetics, Clinical Decision-Making methods, Genetic Testing methods, Mutation, Ovarian Neoplasms genetics
- Abstract
Objective: Germline and somatic BRCA1 and BRCA2 (BRCA) mutations predict treatment response in patients with epithelial ovarian, peritoneal or fallopian tube cancer (OC), yet only germline testing is routinely pursued or reimbursed at diagnosis. We report our experience with clinical testing of paired tumor and germline DNA for OC mutations., Methods: Simultaneous sequencing using the BROCA assay of DNA from paired blood and neoplastic tissue became clinically available at our institution in 2017. We retrospectively reviewed the medical records of OC cases tested from 7/2017 to 7/2018. We calculated the rates of known pathogenic germline mutations and actionable somatic mutations, defined as those for which targeted therapies exist., Results: We identified 43 women (36 new diagnoses, seven recurrences) who underwent testing. Average age at diagnosis was 60. OC samples came from surgical specimens in 31 cases (72.1%), from biopsy in 11 cases (25.6%), and from cytology in one case (2.3%). We identified pathogenic germline mutations in six cases (14%), actionable somatic mutations in 15 cases (35%), and both a somatic and germline mutation in one case (2%). BRCA mutations accounted for 59% of all mutations. Of 40 cases with sufficient follow-up, providers documented reviewing results of genetic testing in 34 (85%), which influenced clinical decisions in 12 (30%)., Conclusions: Simultaneous germline and tumor sequencing is an efficient way to provide enhanced information to guide the care of OC patients. This approach can identify somatic BRCA mutations at diagnosis, allowing physicians to provide PARP inhibitor maintenance and improve outcomes for those patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2020
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48. Insurance coverage does not predict outcomes of genetic testing: The search for meaning in payer decisions for germline cancer tests.
- Author
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Amendola LM, Hart MR, Bennett RL, Horike-Pyne M, Dorschner M, Shirts B, and Jarvik GP
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Exome Sequencing, Genetic Predisposition to Disease, Genetic Testing standards, Germ-Line Mutation, Insurance Coverage, Neoplasms genetics
- Abstract
In this work, we explore the results of germline cancer genetic tests in individuals whose insurance would not cover this testing. We enrolled 31 patients with a personal history of cancer whose health insurer denied coverage for a clinical germline cancer panel genetic test recommended by a medical genetics provider into a study providing exome sequencing and return of cancer-related results. Five participants (16%) had a pathogenic variant identified related to increased cancer risk. Three participants (10%) had a variant of uncertain significance (VUS) in a gene related to their cancer history. These rates are not significantly different than the 12% rate of pathogenic or likely pathogenic (P/LP) variants and VUS in 1,462 patients approved by insurance to have a similar clinical germline cancer test (p = .59 for P/LP variants; p = .87 for VUS; Shirts et al., Genet Med, 18:974, 2016). Health insurance guidelines may not meaningfully differentiate between patients with cancer who are likely to benefit from germline cancer genetic testing and those who will not. Failure to identify pathogenic variants in this research cohort would have led to suboptimal care. Strategic evaluation of current germline cancer genetic testing coverage policies is needed to appropriately deliver precision medicine., (© 2019 National Society of Genetic Counselors.)
- Published
- 2019
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49. Family Health History: The First Genetic Test in Precision Medicine.
- Author
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Bennett RL
- Subjects
- Humans, Pedigree, Risk Assessment, Genetic Testing methods, Medical History Taking methods, Precision Medicine
- Abstract
The collection of family history has always been a tool for genetic evaluation, but it remains an essential tool even in the age of genomic medicine. Patients may have a risk for a disease based on family history regardless of the results of genetic and genomic tests. How this information is collected is less important than that relevant information is collected in the first place. There are many tools for collecting medical and family history information both by hand and electronically. Genetic and genomic testing should always be interpreted in the context of the personal and family history., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
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50. A Mutation in Histone H2B Represents a New Class of Oncogenic Driver.
- Author
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Bennett RL, Bele A, Small EC, Will CM, Nabet B, Oyer JA, Huang X, Ghosh RP, Grzybowski AT, Yu T, Zhang Q, Riva A, Lele TP, Schatz GC, Kelleher NL, Ruthenburg AJ, Liphardt J, and Licht JD
- Subjects
- Alleles, Cell Line, Tumor, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Gene Expression, Gene Expression Profiling, Histones chemistry, Histones metabolism, Humans, Mutation, Missense, Neoplasms metabolism, Nucleosomes metabolism, Protein Multimerization, Yeasts genetics, Yeasts metabolism, Histones genetics, Mutation, Neoplasms genetics, Oncogenes
- Abstract
By examination of the cancer genomics database, we identified a new set of mutations in core histones that frequently recur in cancer patient samples and are predicted to disrupt nucleosome stability. In support of this idea, we characterized a glutamate to lysine mutation of histone H2B at amino acid 76 (H2B-E76K), found particularly in bladder and head and neck cancers, that disrupts the interaction between H2B and H4. Although H2B-E76K forms dimers with H2A, it does not form stable histone octamers with H3 and H4 in vitro, and when reconstituted with DNA forms unstable nucleosomes with increased sensitivity to nuclease. Expression of the equivalent H2B mutant in yeast restricted growth at high temperature and led to defective nucleosome-mediated gene repression. Significantly, H2B-E76K expression in the normal mammary epithelial cell line MCF10A increased cellular proliferation, cooperated with mutant PIK3CA to promote colony formation, and caused a significant drift in gene expression and fundamental changes in chromatin accessibility, particularly at gene regulatory elements. Taken together, these data demonstrate that mutations in the globular domains of core histones may give rise to an oncogenic program due to nucleosome dysfunction and deregulation of gene expression. SIGNIFICANCE: Mutations in the core histones frequently occur in cancer and represent a new mechanism of epigenetic dysfunction that involves destabilization of the nucleosome, deregulation of chromatin accessibility, and alteration of gene expression to drive cellular transformation. See related commentary by Sarthy and Henikoff, p. 1346 . This article is highlighted in the In This Issue feature, p. 1325 ., (©2019 American Association for Cancer Research.)
- Published
- 2019
- Full Text
- View/download PDF
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