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2. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade

Author

Wang, Z, Aguilar, EG, Luna, JI, Dunai, C, Khuat, LT, Le, CT, Mirsoian, A, Minnar, CM, Stoffel, KM, Sturgill, IR, Grossenbacher, SK, Withers, SS, Rebhun, RB, Hartigan-O’Connor, DJ, Méndez-Lagares, G, Tarantal, AF, Isseroff, RR, Griffith, TS, Schalper, KA, Merleev, A, Saha, A, Maverakis, E, Kelly, K, Aljumaily, R, Ibrahimi, S, Mukherjee, S, Machiorlatti, M, Vesely, SK, Longo, DL, Blazar, BR, Canter, RJ, Murphy, WJ, and Monjazeb, AM

Subjects
Leptin, Adult, Male, Aging, T-Lymphocytes, Programmed Cell Death 1 Receptor, Immunology, Mice, Obese, Inbred C57BL, Medical and Health Sciences, Obese, Cell Line, Vaccine Related, Mice, Rare Diseases, Species Specificity, Clinical Research, Cell Line, Tumor, Neoplasms, Animals, Humans, 2.1 Biological and endogenous factors, Obesity, Aetiology, Cell Proliferation, Cancer, Nutrition, Tumor, Body Weight, Middle Aged, Tumor Burden, Diet, Mice, Inbred C57BL, Editorial, 5.1 Pharmaceuticals, Disease Progression, Female, Immunization, Immunotherapy, Development of treatments and therapeutic interventions, Digestive Diseases, Signal Transduction
Abstract

© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc. The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity.

Published
2019
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3. Trans-ethnic meta-analysis of white blood cell phenotypes

Author

Keller, Margaux F, Reiner, Alexander P, Okada, Yukinori, van Rooij, Frank J. A, Johnson, Andrew D, Chen, Ming Huei, Smith, Albert V, Morris, Andrew P, Tanaka, Toshiko, Ferrucci, Luigi, Zonderman, Alan B, Lettre, Guillaume, Harris, Tamara, Garcia, Melissa, Bandinelli, Stefania, Qayyum, Rehan, Yanek, Lisa R, Becker, Diane M, Becker, Lewis C, Kooperberg, Charles, Keating, Brendan, Reis, Jared, Tang, Hua, Boerwinkle, Eric, Kamatani, Yoichiro, Matsuda, Koichi, Kamatani, Naoyuki, Nakamura, Yusuke, Kubo, Michiaki, Liu, Simin, Dehghan, Abbas, Felix, Janine F, Hofman, Albert, Uitterlinden, André G, van Duijn, Cornelia M, Franco, Oscar H, Longo, Dan L, Singleton, Andrew B, Psaty, Bruce M, Evans, Michelle K, Cupples, L. Adrienne, Rotter, Jerome I, O'Donnell, Christopher J, Takahashi, Atsushi, Wilson, James G, Ganesh, Santhi K, Nalls, Mike A, Arepalli, S, Bandinelli, S, Biffi, A, Bis, Jc, Boerwinkle, E, Chakravarti, A, Chen, Mh, Chong, S, Coresh, J, Couper, Dj, Cupples, L, Dehghan, A, Do'Ring, A, Eiriksdottir, G, Felix, Jf, Ferrucci, L, Folsom, Ar, Fox, Cs, Frayling, Tm, Ganesh, Sk, Garcia, M, Garner, Sf, Gasparini, Paolo, Gieger, C, Glazer, Nl, Gouskova, Na, Greinacher, A, Gudnason, V, Harris, Tb, Hernandez, Dg, Hofman, A, Illig, T, Kamatani, Y, Kamatani, N, Kubo, M, Kuhnel, B, Lagou, V, Lettre, G, Levi, D, Lin, J, Liu, Y, Longo, Dl, Lumley, T, Mangino, M, Matsuda, K, Meisinger, C, Melzer, D, Menzel, S, Moore, M, Nakamura, Y, Nalls, Ma, Nauck, M, O'Donnell, Cj, Okada, Y, Oostra, Ba, Ouwehand, Wh, Patel, Kv, Pirastu, Nicola, Pistis, Giorgio, Prokisch, H, Prokopenko, I, Psaty, Bm, Reiner, Ap, Rendon, A, Sambrook, J, Singleton, Ab, Smith, Av, Soranzo, N, Spector, Td, Stephens, J, Stumvoll, M, Takahashi, A, Tanaka, T, Taylor, K, Teumer, A, Thein, Sl, To'Njes, A, Toniolo, D, Tsunoda, T, Uitterlinden, Ag, van Duijn CM, van Rooij FJ, Vo'Lker, U, Vo'Lzke, H, Wichmann, H., Wiggins, Kl, Wilson, Jg, Witteman, Jc, Wood, Ar, Yamamoto, K, Yang, Q, Zakai, Na, Austin, Ma, Becker, Dm, Britton, A, Chen, Z, Couper, D, Curb, J, Dean, E, Eaton, Cb, Evans, Mk, Fornage, M, Grant, Sf, Hernandez, D, Kamatini, N, Keating, Bj, Lacroix, A, Lange, La, Liu, S, Lohman, K, Mathias, R, Meng, Y, Mohler ER 3rd, Musani, S, Palmer, Cd, Papanicolaou, Gj, Snively, Bm, Tang, H, Taylor HA Jr, Thomson, C, Yanek, Lr, Yang, L, Ziv, E, Zonderman, Ab, Higasa, K, Hirota, T, Hosono, N, Kumasaka, N, Ohmiya, H, Tamari, M, Yamaguchi Kabata, Y, Yamamoto, K., Epidemiology, Medical Informatics, Urology, Erasmus MC other, Internal Medicine, Keller, Margaux F, Reiner, Alexander P, Okada, Yukinori, van Rooij, Frank J. A, Johnson, Andrew D, Chen, Ming Huei, Smith, Albert V, Morris, Andrew P, Tanaka, Toshiko, Ferrucci, Luigi, Zonderman, Alan B, Lettre, Guillaume, Harris, Tamara, Garcia, Melissa, Bandinelli, Stefania, Qayyum, Rehan, Yanek, Lisa R, Becker, Diane M, Becker, Lewis C, Kooperberg, Charle, Keating, Brendan, Reis, Jared, Tang, Hua, Boerwinkle, Eric, Kamatani, Yoichiro, Matsuda, Koichi, Kamatani, Naoyuki, Nakamura, Yusuke, Kubo, Michiaki, Liu, Simin, Dehghan, Abba, Felix, Janine F, Hofman, Albert, Uitterlinden, André G, van Duijn, Cornelia M, Franco, Oscar H, Longo, Dan L, Singleton, Andrew B, Psaty, Bruce M, Evans, Michelle K, Cupples, L. Adrienne, Rotter, Jerome I, O'Donnell, Christopher J, Takahashi, Atsushi, Wilson, James G, Ganesh, Santhi K, Nalls, Mike A, Arepalli, S, Bandinelli, S, Biffi, A, Bis, Jc, Boerwinkle, E, Chakravarti, A, Chen, Mh, Chong, S, Coresh, J, Couper, Dj, Cupples, L, Dehghan, A, Do'Ring, A, Eiriksdottir, G, Felix, Jf, Ferrucci, L, Folsom, Ar, Fox, C, Frayling, Tm, Ganesh, Sk, Garcia, M, Garner, Sf, Gasparini, Paolo, Gieger, C, Glazer, Nl, Gouskova, Na, Greinacher, A, Gudnason, V, Harris, Tb, Hernandez, Dg, Hofman, A, Illig, T, Kamatani, Y, Kamatani, N, Kubo, M, Kuhnel, B, Lagou, V, Lettre, G, Levi, D, Lin, J, Liu, Y, Longo, Dl, Lumley, T, Mangino, M, Matsuda, K, Meisinger, C, Melzer, D, Menzel, S, Moore, M, Nakamura, Y, Nalls, Ma, Nauck, M, O'Donnell, Cj, Okada, Y, Oostra, Ba, Ouwehand, Wh, Patel, Kv, Pirastu, Nicola, Pistis, Giorgio, Prokisch, H, Prokopenko, I, Psaty, Bm, Reiner, Ap, Rendon, A, Sambrook, J, Singleton, Ab, Smith, Av, Soranzo, N, Spector, Td, Stephens, J, Stumvoll, M, Takahashi, A, Tanaka, T, Taylor, K, Teumer, A, Thein, Sl, To'Njes, A, Toniolo, D, Tsunoda, T, Uitterlinden, Ag, van Duijn, Cm, van Rooij, Fj, Vo'Lker, U, Vo'Lzke, H, Wichmann, H., Wiggins, Kl, Wilson, Jg, Witteman, Jc, Wood, Ar, Yamamoto, K, Yang, Q, Zakai, Na, Austin, Ma, Becker, Dm, Britton, A, Chen, Z, Couper, D, Curb, J, Dean, E, Eaton, Cb, Evans, Mk, Fornage, M, Grant, Sf, Hernandez, D, Kamatini, N, Keating, Bj, Lacroix, A, Lange, La, Liu, S, Lohman, K, Mathias, R, Meng, Y, Mohler ER, 3rd, Musani, S, Palmer, Cd, Papanicolaou, Gj, Snively, Bm, Tang, H, Taylor HA, Jr, Thomson, C, Yanek, Lr, Yang, L, Ziv, E, Zonderman, Ab, Higasa, K, Hirota, T, Hosono, N, Kumasaka, N, Ohmiya, H, Tamari, M, Yamaguchi Kabata, Y, and Yamamoto, K.

Subjects
Linkage disequilibrium, Genotype, Quantitative Trait Loci, White blood cell count, Single-nucleotide polymorphism, Genome-wide association study, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, white blood cell phenotypes, Leukocyte Count, SDG 3 - Good Health and Well-being, Asian People, Polymorphism (computer science), Genetics, Leukocytes, Humans, Allele, Molecular Biology, Genetics (clinical), White blood cell count, Trans-ethnic meta-analysis, white blood cell phenotypes, Genome, Human, Association Studies Articles, Bayes Theorem, General Medicine, Heritability, Black or African American, Phenotype, Trans-ethnic meta-analysis, Genome-Wide Association Study
Abstract

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.

Published
2014

4. The α-thalassemias

Author

Longo, DL, Piel, FB, and Weatherall, DJ

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, business.industry, Public health, Alternative medicine, MEDLINE, Prenatal diagnosis, General Medicine, 11 Medical And Health Sciences, Quality-adjusted life year, Geographic distribution, alpha-Thalassemia, hemic and lymphatic diseases, Family medicine, General & Internal Medicine, Prenatal Diagnosis, medicine, Humans, Quality-Adjusted Life Years, Geography, Medical, business, Child
Abstract

More than 100 varieties of α-thalassemia have been identified. Their geographic distribution and the challenges associated with screening, diagnosis, and management suggest that α-thalassemias should have a higher priority on global public health agendas.

Published
2016

5. Novel genetic loci associated with hippocampal volume

Author

Hibar, DP, Adams, HHH, Jahanshad, N, Chauhan, G, Stein, JL, Hofer, E, Renteria, ME, Bis, JC, Arias-Vasquez, A, Ikram, MK, Desrivieres, S, Vernooij, MW, Abramovic, L, Alhusaini, S, Amin, N, Andersson, M, Arfanakis, K, Aribisala, BS, Armstrong, NJ, Athanasiu, L, Axelsson, T, Beecham, AH, Beiser, A, Bernard, M, Blanton, SH, Bohlken, MM, Boks, MP, Bralten, J, Brickman, AM, Carmichael, O, Chakravarty, MM, Chen, Q, Ching, CRK, Chouraki, V, Cuellar-Partida, G, Crivello, F, Den Braber, A, Nhat, TD, Ehrlich, S, Giddaluru, S, Goldman, AL, Gottesman, RF, Grimm, O, Griswold, ME, Guadalupe, T, Gutman, BA, Hass, J, Haukvik, UK, Hoehn, D, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Jorgensen, KN, Karbalai, N, Kasperaviciute, D, Kim, S, Klein, M, Kraemer, B, Lee, PH, Liewald, DCM, Lopez, LM, Luciano, M, Macare, C, Marquand, AF, Matarin, M, Mather, KA, Mattheisen, M, McKay, DR, Milaneschi, Y, Maniega, SM, Nho, K, Nugent, AC, Nyquist, P, Loohuis, LMO, Oosterlaan, J, Papmeyer, M, Pirpamer, L, Puetz, B, Ramasamy, A, Richards, JS, Risacher, SL, Roiz-Santianez, R, Rommelse, N, Ropele, S, Rose, EJ, Royle, NA, Rundek, T, Saemann, PG, Saremi, A, Satizabal, CL, Schmaal, L, Schork, AJ, Shen, L, Shin, J, Shumskaya, E, Smith, AV, Sprooten, E, Strike, LT, Teumer, A, Tordesillas-Gutierrez, D, Toro, R, Trabzuni, D, Trompet, S, Vaidya, D, Van der Grond, J, Van der Lee, SJ, Van der Meer, D, Van Donkelaar, MMJ, Van Eijk, KR, Van Erp, TGM, Van Rooij, D, Walton, E, Westlye, LT, Whelan, CD, Windham, BG, Winkler, AM, Wittfeld, K, Woldehawariat, G, Wolf, C, Wolfers, T, Yanek, LR, Yang, J, Zijdenbos, A, Zwiers, MP, Agartz, I, Almasy, L, Ames, D, Amouyel, P, Andreassen, OA, Arepalli, S, Assareh, AA, Barral, S, Bastin, ME, Becker, DM, Becker, JT, Bennett, DA, Blangero, J, van Bokhoven, H, Boomsma, DI, Brodaty, H, Brouwer, RM, Brunner, HG, Buckner, RL, Buitelaar, JK, Bulayeva, KB, Cahn, W, Calhoun, VD, Cannon, DM, Cavalleri, GL, Cheng, C-Y, Cichon, S, Cookson, MR, Corvin, A, Crespo-Facorro, B, Curran, JE, Czisch, M, Dale, AM, Davies, GE, De Craen, AJM, De Geus, EJC, De Jager, PL, De Zubicaray, GI, Deary, IJ, Debette, S, DeCarli, C, Delanty, N, Depondt, C, DeStefano, A, Dillman, A, Djurovic, S, Donohoe, G, Drevets, WC, Duggirala, R, Dyer, TD, Enzinger, C, Erk, S, Espeseth, T, Fedko, IO, Fernandez, G, Ferrucci, L, Fisher, SE, Fleischman, DA, Ford, I, Fornage, M, Foroud, TM, Fox, PT, Francks, C, Fukunaga, M, Gibbs, JR, Glahn, DC, Gollub, RL, Goring, HHH, Green, RC, Gruber, O, Gudnason, V, Guelfi, S, Haberg, AK, Hansell, NK, Hardy, J, Hartman, CA, Hashimoto, R, Hegenscheid, K, Heinz, A, Le Hellard, S, Hernandez, DG, Heslenfeld, DJ, Ho, B-C, Hoekstra, PJ, Hoffmann, W, Hofman, A, Holsboer, F, Homuth, G, Hosten, N, Hottenga, J-J, Huentelman, M, Pol, HEH, Ikeda, M, Jack, CR, Jenkinson, M, Johnson, R, Joensson, EG, Jukema, JW, Kahn, RS, Kanai, R, Kloszewska, I, Knopman, DS, Kochunov, P, Kwok, JB, Lawrie, SM, Lemaitre, H, Liu, X, Longo, DL, Lopez, OL, Lovestone, S, Martinez, O, Martinot, J-L, Mattay, VS, McDonald, C, McIntosh, AM, McMahon, FJ, McMahon, KL, Mecocci, P, Melle, I, Meyer-Lindenberg, A, Mohnke, S, Montgomery, GW, Morris, DW, Mosley, TH, Muhleisen, TW, Mueller-Myhsok, B, Nalls, MA, Nauck, M, Nichols, TE, Niessen, WJ, Nothen, MM, Nyberg, L, Ohi, K, Olvera, RL, Ophoff, RA, Pandolfo, M, Paus, T, Pausova, Z, Penninx, BWJH, Pike, GB, Potkin, SG, Psaty, BM, Reppermund, S, Rietschel, M, Roffman, JL, Romanczuk-Seiferth, N, Rotter, JI, Ryten, M, Sacco, RL, Sachdev, PS, Saykin, AJ, Schmidt, R, Schmidt, H, Schofield, PR, Sigursson, S, Simmons, A, Singleton, A, Sisodiya, SM, Smith, C, Smoller, JW, Soininen, H, Steen, VM, Stott, DJ, Sussmann, JE, Thalamuthu, A, Toga, AW, Traynor, BJ, Troncoso, J, Tsolaki, M, Tzourio, C, Uitterlinden, AG, Hernandez, MCV, Van der Brug, M, van der Lugt, A, van der Wee, NJA, Van Haren, NEM, van't Ent, D, Van Tol, M-J, Vardarajan, BN, Vellas, B, Veltman, DJ, Voelzke, H, Walter, H, Wardlaw, JM, Wassink, TH, Weale, ME, Weinberger, DR, Weiner, MW, Wen, W, Westman, E, White, T, Wong, TY, Wright, CB, Zielke, RH, Zonderman, AB, Martin, NG, Van Duijn, CM, Wright, MJ, Longstreth, WT, Schumann, G, Grabe, HJ, Franke, B, Launer, LJ, Medland, SE, Seshadri, S, Thompson, PM, Ikram, MA, Hibar, DP, Adams, HHH, Jahanshad, N, Chauhan, G, Stein, JL, Hofer, E, Renteria, ME, Bis, JC, Arias-Vasquez, A, Ikram, MK, Desrivieres, S, Vernooij, MW, Abramovic, L, Alhusaini, S, Amin, N, Andersson, M, Arfanakis, K, Aribisala, BS, Armstrong, NJ, Athanasiu, L, Axelsson, T, Beecham, AH, Beiser, A, Bernard, M, Blanton, SH, Bohlken, MM, Boks, MP, Bralten, J, Brickman, AM, Carmichael, O, Chakravarty, MM, Chen, Q, Ching, CRK, Chouraki, V, Cuellar-Partida, G, Crivello, F, Den Braber, A, Nhat, TD, Ehrlich, S, Giddaluru, S, Goldman, AL, Gottesman, RF, Grimm, O, Griswold, ME, Guadalupe, T, Gutman, BA, Hass, J, Haukvik, UK, Hoehn, D, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Jorgensen, KN, Karbalai, N, Kasperaviciute, D, Kim, S, Klein, M, Kraemer, B, Lee, PH, Liewald, DCM, Lopez, LM, Luciano, M, Macare, C, Marquand, AF, Matarin, M, Mather, KA, Mattheisen, M, McKay, DR, Milaneschi, Y, Maniega, SM, Nho, K, Nugent, AC, Nyquist, P, Loohuis, LMO, Oosterlaan, J, Papmeyer, M, Pirpamer, L, Puetz, B, Ramasamy, A, Richards, JS, Risacher, SL, Roiz-Santianez, R, Rommelse, N, Ropele, S, Rose, EJ, Royle, NA, Rundek, T, Saemann, PG, Saremi, A, Satizabal, CL, Schmaal, L, Schork, AJ, Shen, L, Shin, J, Shumskaya, E, Smith, AV, Sprooten, E, Strike, LT, Teumer, A, Tordesillas-Gutierrez, D, Toro, R, Trabzuni, D, Trompet, S, Vaidya, D, Van der Grond, J, Van der Lee, SJ, Van der Meer, D, Van Donkelaar, MMJ, Van Eijk, KR, Van Erp, TGM, Van Rooij, D, Walton, E, Westlye, LT, Whelan, CD, Windham, BG, Winkler, AM, Wittfeld, K, Woldehawariat, G, Wolf, C, Wolfers, T, Yanek, LR, Yang, J, Zijdenbos, A, Zwiers, MP, Agartz, I, Almasy, L, Ames, D, Amouyel, P, Andreassen, OA, Arepalli, S, Assareh, AA, Barral, S, Bastin, ME, Becker, DM, Becker, JT, Bennett, DA, Blangero, J, van Bokhoven, H, Boomsma, DI, Brodaty, H, Brouwer, RM, Brunner, HG, Buckner, RL, Buitelaar, JK, Bulayeva, KB, Cahn, W, Calhoun, VD, Cannon, DM, Cavalleri, GL, Cheng, C-Y, Cichon, S, Cookson, MR, Corvin, A, Crespo-Facorro, B, Curran, JE, Czisch, M, Dale, AM, Davies, GE, De Craen, AJM, De Geus, EJC, De Jager, PL, De Zubicaray, GI, Deary, IJ, Debette, S, DeCarli, C, Delanty, N, Depondt, C, DeStefano, A, Dillman, A, Djurovic, S, Donohoe, G, Drevets, WC, Duggirala, R, Dyer, TD, Enzinger, C, Erk, S, Espeseth, T, Fedko, IO, Fernandez, G, Ferrucci, L, Fisher, SE, Fleischman, DA, Ford, I, Fornage, M, Foroud, TM, Fox, PT, Francks, C, Fukunaga, M, Gibbs, JR, Glahn, DC, Gollub, RL, Goring, HHH, Green, RC, Gruber, O, Gudnason, V, Guelfi, S, Haberg, AK, Hansell, NK, Hardy, J, Hartman, CA, Hashimoto, R, Hegenscheid, K, Heinz, A, Le Hellard, S, Hernandez, DG, Heslenfeld, DJ, Ho, B-C, Hoekstra, PJ, Hoffmann, W, Hofman, A, Holsboer, F, Homuth, G, Hosten, N, Hottenga, J-J, Huentelman, M, Pol, HEH, Ikeda, M, Jack, CR, Jenkinson, M, Johnson, R, Joensson, EG, Jukema, JW, Kahn, RS, Kanai, R, Kloszewska, I, Knopman, DS, Kochunov, P, Kwok, JB, Lawrie, SM, Lemaitre, H, Liu, X, Longo, DL, Lopez, OL, Lovestone, S, Martinez, O, Martinot, J-L, Mattay, VS, McDonald, C, McIntosh, AM, McMahon, FJ, McMahon, KL, Mecocci, P, Melle, I, Meyer-Lindenberg, A, Mohnke, S, Montgomery, GW, Morris, DW, Mosley, TH, Muhleisen, TW, Mueller-Myhsok, B, Nalls, MA, Nauck, M, Nichols, TE, Niessen, WJ, Nothen, MM, Nyberg, L, Ohi, K, Olvera, RL, Ophoff, RA, Pandolfo, M, Paus, T, Pausova, Z, Penninx, BWJH, Pike, GB, Potkin, SG, Psaty, BM, Reppermund, S, Rietschel, M, Roffman, JL, Romanczuk-Seiferth, N, Rotter, JI, Ryten, M, Sacco, RL, Sachdev, PS, Saykin, AJ, Schmidt, R, Schmidt, H, Schofield, PR, Sigursson, S, Simmons, A, Singleton, A, Sisodiya, SM, Smith, C, Smoller, JW, Soininen, H, Steen, VM, Stott, DJ, Sussmann, JE, Thalamuthu, A, Toga, AW, Traynor, BJ, Troncoso, J, Tsolaki, M, Tzourio, C, Uitterlinden, AG, Hernandez, MCV, Van der Brug, M, van der Lugt, A, van der Wee, NJA, Van Haren, NEM, van't Ent, D, Van Tol, M-J, Vardarajan, BN, Vellas, B, Veltman, DJ, Voelzke, H, Walter, H, Wardlaw, JM, Wassink, TH, Weale, ME, Weinberger, DR, Weiner, MW, Wen, W, Westman, E, White, T, Wong, TY, Wright, CB, Zielke, RH, Zonderman, AB, Martin, NG, Van Duijn, CM, Wright, MJ, Longstreth, WT, Schumann, G, Grabe, HJ, Franke, B, Launer, LJ, Medland, SE, Seshadri, S, Thompson, PM, and Ikram, MA

Abstract

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

Published
2017

7. Transient reversal of bone marrow aplasia associated with lymphocyte depleted hodgkin's disease after combination chemotherapy

Author

Ruscetti Fw, Johnston Pg, Francis J. Sullivan, Connaghan Dg, and Longo Dl

Subjects
Adult, Pathology, medicine.medical_specialty, Time Factors, Biopsy, medicine.medical_treatment, Lymphocyte, Disease, Bone Marrow Aplasia, Bone Marrow, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Lymphocytes, Mechlorethamine, Aplastic anemia, Pathological, Neoplasm Staging, Chemotherapy, business.industry, Combination chemotherapy, Hematology, medicine.disease, Hodgkin Disease, Radiography, medicine.anatomical_structure, Vincristine, Procarbazine, Prednisone, Female, Bone marrow, business
Abstract

This report describes a patient with lymphocyte depleted Hodgkin's disease who presented with bone marrow aplasia. The aplastic marrow reverted to normal after initiation of MOPP chemotherapy; however, 4 months after completion of therapy, bone marrow aplasia recurred in the absence of recurrent Hodgkin's disease. The patient remains free of Hodgkin's disease 34 months after completion of chemotherapy. Bone marrow abnormalities in Hodgkin's disease are reviewed and the current understanding of the pathological mechanisms leading to aplastic anemia is discussed.

Published
1991
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41. Correlates of D-dimer in older persons.

Author

Tita-Nwa F, Bos A, Adjei A, Ershler WB, Longo DL, and Ferrucci L

Abstract

BACKGROUND AND AIMS: D-dimer is a marker of active fibrinolysis. Understanding how age-related factors affect D-dimer levels may help the interpretation of high D-dimer levels in older individuals. METHODS: 776 Baltimore Longitudinal Study on Aging (BLSA) participants (mean age 68.4+/-13.9 yrs) were divided into three groups according to baseline D-dimer levels >200 ng/mL; 100-200 ng/mL and <100 ng/mL. RESULTS: D-dimer level increased with age (p<0.0001). Using polychotomous logistic regression models, we found that age, cholesterol, triglycerides, creatinine, erythrocyte sedimentation rate, hemoglobin and body mass index were independently associated with D-dimer level. CONCLUSIONS: Rising levels of D-dimer with age can be explained in part by the high prevalence of pro-inflammatory conditions and increasing burden of lipid abnormalities, anemia and obesity. These factors compromise the specificity of D-dimer levels as a diagnostic aid to thrombosis in older individuals. [ABSTRACT FROM AUTHOR]

Published
2010
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42. Monoclonal antibody to an endogenous bufadienolide, marinobufagenin, reverses preeclampsia-induced Na/K-ATPase inhibition and lowers blood pressure in NaCl-sensitive hypertension.

Author

Fedorova OV, Simbirtsev AS, Kolodkin NI, Kotov AY, Agalakova NI, Kashkin VA, Tapilskaya NI, Bzhelyansky A, Reznik VA, Frolova EV, Nikitina ER, Budny GV, Longo DL, Lakatta EG, Bagrov AY, Fedorova, Olga V, Simbirtsev, Andrey S, Kolodkin, Nikolai I, Kotov, Alexander Y, and Agalakova, Natalia I

Published
2008
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45. Combination chemotherapy followed by an immunotoxin (anti-B4-blocked ricin) in patients with indolent lymphoma: results of a phase II study.

Author

Longo DL, Duffey PL, Gribben JG, Jaffe ES, Curti BD, Gause BL, Janik JE, Braman VM, Esseltine D, Wilson WH, Kaufman D, Wittes RE, Nadler LM, and Urba WJ

Abstract

The purpose of this article was to evaluate the antitumor effects of a combination chemotherapy program based on ProMACE (prednisone, methotrexate, doxorubicin [Adriamycin], cyclophosphamide, etoposide) followed by a B cell-specific immunotoxin in the treatment of patients with advanced-stage indolent histology non-Hodgkin's lymphomas. We performed a prospective phase II clinical trial in a referral-based patient population. After confirmation of diagnosis and staging evaluation, 44 patients (10 small lymphocytic lymphoma, 27 follicular lymphoma, 7 mantle cell lymphoma; 30 without prior therapy, 14 previously treated) received six cycles of ProMACE-CytaBOM (cytarabine, bleomycin, vincristine [Oncovin], mechlorethamine) combination chemotherapy (with etoposide given orally daily for five days) followed by a 7-day continuous infusion of anti-B4-blocked ricin immunotoxin at 30 microg/kg/day given every 14 days for up to six cycles. A complete response was achieved in 25 of 44 patients (57%), 21 from the chemotherapy alone, 3 converted from partial to complete response with the immunotoxin, and 1 patient became a complete responder after a surgical procedure to remove an enlarged spleen that was histologically negative for lymphoma. With a median follow-up of 5 years, 14 of 25 complete responders have relapsed (56%); median remission duration was 2 years, and overall survival was 61%. Forty-two percent of the complete responders have been in continuous remission for more than 4 years. The median number of courses of immunotoxin delivered was two usually because of the development of human anti-ricin antibodies. ProMACE-CytaBOM plus anti-B4-blocked ricin does not produce durable complete remissions in the majority of patients with indolent lymphoma. However, the remissions appear quite durable (> 4 years) in about 40% of the complete responders. [ABSTRACT FROM AUTHOR]

Published
2000

46. Elevations in serum soluble interleukin-2 receptor levels predict relapse in patients with hairy cell leukemia.

Author

Arun B, Curti BD, Longo DL, Stevens D, Alvord WG, Gause BL, Watson T, Kopp WC, and Janik JE

Abstract

PURPOSE Interferon-alfa, 2'-deoxycoformycin, and 2-chlorodeoxyadenosine (2-CdA) are effective in the management of patients with hairy cell leukemia. These agents produce remissions in most patients, but relapses occur with all three drugs. The optimal means to follow patients for relapse alter treatment has not been determined. METHODS We retrospectively examined serial serum soluble interleukin-2 receptor levels (sIL-2R) and absolute granulocyte counts in eight patients with relapsed hairy cell leukemia. All were treated with 2-CdA at the time of relapse. Serum samples were available at 3- to 6-month intervals from 5 to 9 years before relapse and 2-CdA treatment. RESULTS sIL-2R levels increase only in patients who go on to relapse. sIL-2R levels doubled a mean of 17.1 months (range, 4-36 months) before absolute granulocyte count decreased by 50%. DISCUSSION Demonstration of a rising serum sIL-2R level in patients with hairy cell leukemia identified those with an increased risk of relapse who need more frequent observation than patients who maintain a stable sIL-2R level. Early intervention may ameliorate the toxicity of salvage therapy because disease-related neutropenia may be anticipated. (Cancer J Sci Am 2000;6:21-24) [ABSTRACT FROM AUTHOR]

Published
2000

48. Phase II trial of interleukin 1 alpha and indomethacin in treatment of metastatic melanoma.

Author

Janik JE, Miller LL, Longo DL, Powers GC, Urba WJ, Kopp WC, Gause BL, Curti BD, Fenton RG, Oppenheim JJ, Conlon KC, Holmlund JT, Sznol M, Sharfman WH, Steis RG, Creekmore SP, Alvord WG, Beauchamp AE, Smith JW 2nd, and Janik, J E

Abstract

Background: The rising incidence of malignant melanoma and the lack of curative therapies for metastatic disease represent a therapeutic challenge. New agents effective in treating this disease are needed.Purpose: Because of the additive antitumor effects of interleukin 1 alpha (IL-1 alpha) and indomethacin in vivo, we conducted a phase II trial of this combination in patients with melanoma. We used the recommended dose determined from our phase I trial to ascertain the antitumor activity of the combination.Methods: From August 1, 1990, through July 28, 1992, 49 patients entered the study. They were stratified into two groups based on the presence of visceral (n = 14) and nonvisceral (n = 35) metastases. The patients received 7 days of both IL-1 alpha (O.1 micrograms/kg per day by intravenous bolus) infusion) and indomethacin (50 mg orally every 8 hours). At least two cycles of therapy, repeated at 21-day intervals, were planned. Additional treatment was given to those patients who had stable or responding lesions. A chi-squared test for homogeneity of proportions was used to compare groups on several measures. All P values resulted from two-sided tests.Results: Fever, chills, and hypotension were among the most common side effects. None of the 14 patients with visceral metastases responded to the treatment. Of the 35 patients with non-visceral metastases, three showed a partial response for 6 months each and one showed a complete response for more than 34 months; the response rate was 11% (95% confidence interval [CI] = 5%-26%). All responding patients required phenylephrine for treatment of IL-1 alpha-induced hypotension, whereas six (19%) of 31 of the nonresponding patients with nonvisceral metastases required phenylephrine (P = .0008). The response rate in women was higher; three of 10 women (30%; 95% CI = 11%-60%) responded, whereas one of 25 men (4%; 95% CI = 0%-20%) responded (P = .029). All three women were positive for human leukocyte antigen (HLA) B7 expression (P = .011).Conclusions: The combination of IL-1 alpha and indomethacin has minimal antitumor activity in melanoma patients. All responses were confined to patients with nonvisceral metastases. IL-1 alpha-induced hypotension, gender, and HLA B7 expression were positively associated with response.Implications: Administration of higher doses of IL-1 alpha alone has been shown to produce hypotension in a large proportion of patients but can be given safely with phenylephrine support. Because of the association of hypotension with antitumor activity, treatment with higher IL-1 alpha doses alone may be a strategy for attaining better response rates. [ABSTRACT FROM AUTHOR]

Published
1996
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