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Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling.

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Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling.

J Clin Invest. 2017 Sep 18;:

Authors: Dai C, Hang Y, Shostak A, Poffenberger G, Hart N, Prasad N, Phillips N, Levy SE, Greiner DL, Shultz LD, Bottino R, Kim SK, Powers AC

Abstract
Inadequate pancreatic β cell function underlies type 1 and type 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering and controlling mechanisms that limit the proliferation of human β cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of β cell proliferation in human islets. We found that exendin-4 (Ex-4), an agonist of the glucagon-like peptide 1 receptor (GLP-1R), stimulates human β cell proliferation in juvenile but not adult islets. This age-dependent responsiveness does not reflect loss of GLP-1R signaling in adult islets, since Ex-4 treatment stimulated insulin secretion by both juvenile and adult human β cells. We show that the mitogenic effect of Ex-4 requires calcineurin/nuclear factor of activated T cells (NFAT) signaling. In juvenile islets, Ex-4 induced expression of calcineurin/NFAT signaling components as well as target genes for proliferation-promoting factors, including NFATC1, FOXM1, and CCNA1. By contrast, expression of these factors in adult islet β cells was not affected by Ex-4 exposure. These studies reveal age-dependent signaling mechanisms regulating human β cell proliferation, and identify elements that could be adapted for therapeutic expansion of human β cells.

PMID: 28920919 [PubMed - as supplied by publisher]

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

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Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Nat Genet. 2017 May;49(5):680-691

Authors: Phelan CM, Kuchenbaecker KB, Tyrer JP, Kar SP, Lawrenson K, Winham SJ, Dennis J, Pirie A, Riggan MJ, Chornokur G, Earp MA, Lyra PC, Lee JM, Coetzee S, Beesley J, McGuffog L, Soucy P, Dicks E, Lee A, Barrowdale D, Lecarpentier J, Leslie G, Aalfs CM, Aben KKH, Adams M, Adlard J, Andrulis IL, Anton-Culver H, Antonenkova N, AOCS study group, Aravantinos G, Arnold N, Arun BK, Arver B, Azzollini J, Balmaña J, Banerjee SN, Barjhoux L, Barkardottir RB, Bean Y, Beckmann MW, Beeghly-Fadiel A, Benitez J, Bermisheva M, Bernardini MQ, Birrer MJ, Bjorge L, Black A, Blankstein K, Blok MJ, Bodelon C, Bogdanova N, Bojesen A, Bonanni B, Borg Å, Bradbury AR, Brenton JD, Brewer C, Brinton L, Broberg P, Brooks-Wilson A, Bruinsma F, Brunet J, Buecher B, Butzow R, Buys SS, Caldes T, Caligo MA, Campbell I, Cannioto R, Carney ME, Cescon T, Chan SB, Chang-Claude J, Chanock S, Chen XQ, Chiew YE, Chiquette J, Chung WK, Claes KBM, Conner T, Cook LS, Cook J, Cramer DW, Cunningham JM, D'Aloisio AA, Daly MB, Damiola F, Damirovna SD, Dansonka-Mieszkowska A, Dao F, Davidson R, DeFazio A, Delnatte C, Doheny KF, Diez O, Ding YC, Doherty JA, Domchek SM, Dorfling CM, Dörk T, Dossus L, Duran M, Dürst M, Dworniczak B, Eccles D, Edwards T, Eeles R, Eilber U, Ejlertsen B, Ekici AB, Ellis S, Elvira M, EMBRACE Study, Eng KH, Engel C, Evans DG, Fasching PA, Ferguson S, Ferrer SF, Flanagan JM, Fogarty ZC, Fortner RT, Fostira F, Foulkes WD, Fountzilas G, Fridley BL, Friebel TM, Friedman E, Frost D, Ganz PA, Garber J, García MJ, Garcia-Barberan V, Gehrig A, GEMO Study Collaborators, Gentry-Maharaj A, Gerdes AM, Giles GG, Glasspool R, Glendon G, Godwin AK, Goldgar DE, Goranova T, Gore M, Greene MH, Gronwald J, Gruber S, Hahnen E, Haiman CA, Håkansson N, Hamann U, Hansen TVO, Harrington PA, Harris HR, Hauke J, HEBON Study, Hein A, Henderson A, Hildebrandt MAT, Hillemanns P, Hodgson S, Høgdall CK, Høgdall E, Hogervorst FBL, Holland H, Hooning MJ, Hosking K, Huang RY, Hulick PJ, Hung J, Hunter DJ, Huntsman DG, Huzarski T, Imyanitov EN, Isaacs C, Iversen ES, Izatt L, Izquierdo A, Jakubowska A, James P, Janavicius R, Jernetz M, Jensen A, Jensen UB, John EM, Johnatty S, Jones ME, Kannisto P, Karlan BY, Karnezis A, Kast K, KConFab Investigators, Kennedy CJ, Khusnutdinova E, Kiemeney LA, Kiiski JI, Kim SW, Kjaer SK, Köbel M, Kopperud RK, Kruse TA, Kupryjanczyk J, Kwong A, Laitman Y, Lambrechts D, Larrañaga N, Larson MC, Lazaro C, Le ND, Le Marchand L, Lee JW, Lele SB, Leminen A, Leroux D, Lester J, Lesueur F, Levine DA, Liang D, Liebrich C, Lilyquist J, Lipworth L, Lissowska J, Lu KH, Lubinński J, Luccarini C, Lundvall L, Mai PL, Mendoza-Fandiño G, Manoukian S, Massuger LFAG, May T, Mazoyer S, McAlpine JN, McGuire V, McLaughlin JR, McNeish I, Meijers-Heijboer H, Meindl A, Menon U, Mensenkamp AR, Merritt MA, Milne RL, Mitchell G, Modugno F, Moes-Sosnowska J, Moffitt M, Montagna M, Moysich KB, Mulligan AM, Musinsky J, Nathanson KL, Nedergaard L, Ness RB, Neuhausen SL, Nevanlinna H, Niederacher D, Nussbaum RL, Odunsi K, Olah E, Olopade OI, Olsson H, Olswold C, O'Malley DM, Ong KR, Onland-Moret NC, OPAL study group, Orr N, Orsulic S, Osorio A, Palli D, Papi L, Park-Simon TW, Paul J, Pearce CL, Pedersen IS, Peeters PHM, Peissel B, Peixoto A, Pejovic T, Pelttari LM, Permuth JB, Peterlongo P, Pezzani L, Pfeiler G, Phillips KA, Piedmonte M, Pike MC, Piskorz AM, Poblete SR, Pocza T, Poole EM, Poppe B, Porteous ME, Prieur F, Prokofyeva D, Pugh E, Pujana MA, Pujol P, Radice P, Rantala J, Rappaport-Fuerhauser C, Rennert G, Rhiem K, Rice P, Richardson A, Robson M, Rodriguez GC, Rodríguez-Antona C, Romm J, Rookus MA, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Salvesen HB, Sandler DP, Schoemaker MJ, Senter L, Setiawan VW, Severi G, Sharma P, Shelford T, Siddiqui N, Side LE, Sieh W, Singer CF, Sobol H, Song H, Southey MC, Spurdle AB, Stadler Z, Steinemann D, Stoppa-Lyonnet D, Sucheston-Campbell LE, Sukiennicki G, Sutphen R, Sutter C, Swerdlow AJ, Szabo CI, Szafron L, Tan YY, Taylor JA, Tea MK, Teixeira MR, Teo SH, Terry KL, Thompson PJ, Thomsen LCV, Thull DL, Tihomirova L, Tinker AV, Tischkowitz M, Tognazzo S, Toland AE, Tone A, Trabert B, Travis RC, Trichopoulou A, Tung N, Tworoger SS, van Altena AM, Van Den Berg D, van der Hout AH, van der Luijt RB, Van Heetvelde M, Van Nieuwenhuysen E, van Rensburg EJ, Vanderstichele A, Varon-Mateeva R, Vega A, Edwards DV, Vergote I, Vierkant RA, Vijai J, Vratimos A, Walker L, Walsh C, Wand D, Wang-Gohrke S, Wappenschmidt B, Webb PM, Weinberg CR, Weitzel JN, Wentzensen N, Whittemore AS, Wijnen JT, Wilkens LR, Wolk A, Woo M, Wu X, Wu AH, Yang H, Yannoukakos D, Ziogas A, Zorn KK, Narod SA, Easton DF, Amos CI, Schildkraut JM, Ramus SJ, Ottini L, Goodman MT, Park SK, Kelemen LE, Risch HA, Thomassen M, Offit K, Simard J, Schmutzler RK, Hazelett D, Monteiro AN, Couch FJ, Berchuck A, Chenevix-Trench G, Goode EL, Sellers TA, Gayther SA, Antoniou AC, Pharoah PDP

Abstract
To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

PMID: 28346442 [PubMed - indexed for MEDLINE]

Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.

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Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.

PLoS Med. 2017 Sep;14(9):e1002383

Authors: Wheeler E, Leong A, Liu CT, Hivert MF, Strawbridge RJ, Podmore C, Li M, Yao J, Sim X, Hong J, Chu AY, Zhang W, Wang X, Chen P, Maruthur NM, Porneala BC, Sharp SJ, Jia Y, Kabagambe EK, Chang LC, Chen WM, Elks CE, Evans DS, Fan Q, Giulianini F, Go MJ, Hottenga JJ, Hu Y, Jackson AU, Kanoni S, Kim YJ, Kleber ME, Ladenvall C, Lecoeur C, Lim SH, Lu Y, Mahajan A, Marzi C, Nalls MA, Navarro P, Nolte IM, Rose LM, Rybin DV, Sanna S, Shi Y, Stram DO, Takeuchi F, Tan SP, van der Most PJ, Van Vliet-Ostaptchouk JV, Wong A, Yengo L, Zhao W, Goel A, Martinez Larrad MT, Radke D, Salo P, Tanaka T, van Iperen EPA, Abecasis G, Afaq S, Alizadeh BZ, Bertoni AG, Bonnefond A, Böttcher Y, Bottinger EP, Campbell H, Carlson OD, Chen CH, Cho YS, Garvey WT, Gieger C, Goodarzi MO, Grallert H, Hamsten A, Hartman CA, Herder C, Hsiung CA, Huang J, Igase M, Isono M, Katsuya T, Khor CC, Kiess W, Kohara K, Kovacs P, Lee J, Lee WJ, Lehne B, Li H, Liu J, Lobbens S, Luan J, Lyssenko V, Meitinger T, Miki T, Miljkovic I, Moon S, Mulas A, Müller G, Müller-Nurasyid M, Nagaraja R, Nauck M, Pankow JS, Polasek O, Prokopenko I, Ramos PS, Rasmussen-Torvik L, Rathmann W, Rich SS, Robertson NR, Roden M, Roussel R, Rudan I, Scott RA, Scott WR, Sennblad B, Siscovick DS, Strauch K, Sun L, Swertz M, Tajuddin SM, Taylor KD, Teo YY, Tham YC, Tönjes A, Wareham NJ, Willemsen G, Wilsgaard T, Hingorani AD, EPIC-CVD Consortium, EPIC-InterAct Consortium, Lifelines Cohort Study, Egan J, Ferrucci L, Hovingh GK, Jula A, Kivimaki M, Kumari M, Njølstad I, Palmer CNA, Serrano Ríos M, Stumvoll M, Watkins H, Aung T, Blüher M, Boehnke M, Boomsma DI, Bornstein SR, Chambers JC, Chasman DI, Chen YI, Chen YT, Cheng CY, Cucca F, de Geus EJC, Deloukas P, Evans MK, Fornage M, Friedlander Y, Froguel P, Groop L, Gross MD, Harris TB, Hayward C, Heng CK, Ingelsson E, Kato N, Kim BJ, Koh WP, Kooner JS, Körner A, Kuh D, Kuusisto J, Laakso M, Lin X, Liu Y, Loos RJF, Magnusson PKE, März W, McCarthy MI, Oldehinkel AJ, Ong KK, Pedersen NL, Pereira MA, Peters A, Ridker PM, Sabanayagam C, Sale M, Saleheen D, Saltevo J, Schwarz PE, Sheu WHH, Snieder H, Spector TD, Tabara Y, Tuomilehto J, van Dam RM, Wilson JG, Wilson JF, Wolffenbuttel BHR, Wong TY, Wu JY, Yuan JM, Zonderman AB, Soranzo N, Guo X, Roberts DJ, Florez JC, Sladek R, Dupuis J, Morris AP, Tai ES, Selvin E, Rotter JI, Langenberg C, Barroso I, Meigs JB

Abstract
BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.
METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.
CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

PMID: 28898252 [PubMed - in process]

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.

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Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.

Nat Genet. 2017 Jun;49(6):946-952

Authors: Christophersen IE, Rienstra M, Roselli C, Yin X, Geelhoed B, Barnard J, Lin H, Arking DE, Smith AV, Albert CM, Chaffin M, Tucker NR, Li M, Klarin D, Bihlmeyer NA, Low SK, Weeke PE, Müller-Nurasyid M, Smith JG, Brody JA, Niemeijer MN, Dörr M, Trompet S, Huffman J, Gustafsson S, Schurmann C, Kleber ME, Lyytikäinen LP, Seppälä I, Malik R, Horimoto ARVR, Perez M, Sinisalo J, Aeschbacher S, Thériault S, Yao J, Radmanesh F, Weiss S, Teumer A, Choi SH, Weng LC, Clauss S, Deo R, Rader DJ, Shah SH, Sun A, Hopewell JC, Debette S, Chauhan G, Yang Q, Worrall BB, Paré G, Kamatani Y, Hagemeijer YP, Verweij N, Siland JE, Kubo M, Smith JD, Van Wagoner DR, Bis JC, Perz S, Psaty BM, Ridker PM, Magnani JW, Harris TB, Launer LJ, Shoemaker MB, Padmanabhan S, Haessler J, Bartz TM, Waldenberger M, Lichtner P, Arendt M, Krieger JE, Kähönen M, Risch L, Mansur AJ, Peters A, Smith BH, Lind L, Scott SA, Lu Y, Bottinger EB, Hernesniemi J, Lindgren CM, Wong JA, Huang J, Eskola M, Morris AP, Ford I, Reiner AP, Delgado G, Chen LY, Chen YI, Sandhu RK, Li M, Boerwinkle E, Eisele L, Lannfelt L, Rost N, Anderson CD, Taylor KD, Campbell A, Magnusson PK, Porteous D, Hocking LJ, Vlachopoulou E, Pedersen NL, Nikus K, Orho-Melander M, Hamsten A, Heeringa J, Denny JC, Kriebel J, Darbar D, Newton-Cheh C, Shaffer C, Macfarlane PW, Heilmann-Heimbach S, Almgren P, Huang PL, Sotoodehnia N, Soliman EZ, Uitterlinden AG, Hofman A, Franco OH, Völker U, Jöckel KH, Sinner MF, Lin HJ, Guo X, METASTROKE Consortium of the ISGC, Neurology Working Group of the CHARGE Consortium, Dichgans M, Ingelsson E, Kooperberg C, Melander O, Loos RJF, Laurikka J, Conen D, Rosand J, van der Harst P, Lokki ML, Kathiresan S, Pereira A, Jukema JW, Hayward C, Rotter JI, März W, Lehtimäki T, Stricker BH, Chung MK, Felix SB, Gudnason V, Alonso A, Roden DM, Kääb S, Chasman DI, Heckbert SR, Benjamin EJ, Tanaka T, Lunetta KL, Lubitz SA, Ellinor PT, AFGen Consortium

Abstract
Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

PMID: 28416818 [PubMed - indexed for MEDLINE]

Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation.

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Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation.

Nat Genet. 2017 Jan;49(1):125-130

Authors: Chu AY, Deng X, Fisher VA, Drong A, Zhang Y, Feitosa MF, Liu CT, Weeks O, Choh AC, Duan Q, Dyer TD, Eicher JD, Guo X, Heard-Costa NL, Kacprowski T, Kent JW, Lange LA, Liu X, Lohman K, Lu L, Mahajan A, O'Connell JR, Parihar A, Peralta JM, Smith AV, Zhang Y, Homuth G, Kissebah AH, Kullberg J, Laqua R, Launer LJ, Nauck M, Olivier M, Peyser PA, Terry JG, Wojczynski MK, Yao J, Bielak LF, Blangero J, Borecki IB, Bowden DW, Carr JJ, Czerwinski SA, Ding J, Friedrich N, Gudnason V, Harris TB, Ingelsson E, Johnson AD, Kardia SL, Langefeld CD, Lind L, Liu Y, Mitchell BD, Morris AP, Mosley TH, Rotter JI, Shuldiner AR, Towne B, Völzke H, Wallaschofski H, Wilson JG, Allison M, Lindgren CM, Goessling W, Cupples LA, Steinhauser ML, Fox CS

Abstract
Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10(-8); false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.

PMID: 27918534 [PubMed - indexed for MEDLINE]

Innate and adaptive immunity shape circulating HCV strains.

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Innate and adaptive immunity shape circulating HCV strains.

Nat Genet. 2017 Apr 26;49(5):657-658

Authors: Gaudieri S, Lucas M

Abstract
An unbiased genome-to-genome analysis in chronic hepatitis C virus (HCV) infection confirms the innate and adaptive arms of the immune system as drivers of viral evolution. Viral adaptation has a critical role in the interaction between host and pathogen and has important clinical implications for infection outcome.

PMID: 28442794 [PubMed - indexed for MEDLINE]

Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease.

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Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease.

Nat Genet. 2017 Sep 04;:

Authors: Zhao W, Rasheed A, Tikkanen E, Lee JJ, Butterworth AS, Howson JMM, Assimes TL, Chowdhury R, Orho-Melander M, Damrauer S, Small A, Asma S, Imamura M, Yamauch T, Chambers JC, Chen P, Sapkota BR, Shah N, Jabeen S, Surendran P, Lu Y, Zhang W, Imran A, Abbas S, Majeed F, Trindade K, Qamar N, Mallick NH, Yaqoob Z, Saghir T, Rizvi SNH, Memon A, Rasheed SZ, Memon FU, Mehmood K, Ahmed N, Qureshi IH, Tanveer-Us-Salam, Iqbal W, Malik U, Mehra N, Kuo JZ, Sheu WH, Guo X, Hsiung CA, Juang JJ, Taylor KD, Hung YJ, Lee WJ, Quertermous T, Lee IT, Hsu CC, Bottinger EP, Ralhan S, Teo YY, Wang TD, Alam DS, Di Angelantonio E, Epstein S, Nielsen SF, Nordestgaard BG, Tybjaerg-Hansen A, Young R, CHD Exome+ Consortium, Benn M, Frikke-Schmidt R, Kamstrup PR, EPIC-CVD Consortium, EPIC-Interact Consortium, Michigan Biobank, Jukema JW, Sattar N, Smit R, Chung RH, Liang KW, Anand S, Sanghera DK, Ripatti S, Loos RJF, Kooner JS, Tai ES, Rotter JI, Chen YI, Frossard P, Maeda S, Kadowaki T, Reilly M, Pare G, Melander O, Salomaa V, Rader DJ, Danesh J, Voight BF, Saleheen D

Abstract
To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D-CHD analysis identified eight variants-two of which are coding-where T2D and CHD associations appear to colocalize, including a new joint T2D-CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.

PMID: 28869590 [PubMed - as supplied by publisher]

Reaching for the next branch on the biobank tree of knowledge.

Reaching for the next branch on the biobank tree of knowledge.

Nat Genet. 2017 Aug 30;49(9):1295-1296

Authors: Cox NJ

Abstract
An innovative study analyzing genetic association across tree-structured routine healthcare data in the UK Biobank represents a new branch on a tree that is poised to grow rapidly and offer new kinds of insights on how genome variation relates to human health and disease. Indeed, this tree is likely to offer new kinds of insights into the very nature of human disease.

PMID: 28854181 [PubMed - in process]

Outcomes of Patients With Double-Hit Lymphoma Who Achieve First Complete Remission.

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Outcomes of Patients With Double-Hit Lymphoma Who Achieve First Complete Remission.

J Clin Oncol. 2017 Jul 10;35(20):2260-2267

Authors: Landsburg DJ, Falkiewicz MK, Maly J, Blum KA, Howlett C, Feldman T, Mato AR, Hill BT, Li S, Medeiros LJ, Torka P, Hernandez-Ilizaliturri F, Reddy NM, Singavi A, Fenske TS, Chavez JC, Kaplan JB, Behdad A, Petrich AM, Bast MA, Vose JM, Olszewski AJ, Costa C, Lansigan F, Gerson JN, Barta SK, Calzada O, Cohen JB, Lue JK, Amengual JE, Rivera X, Persky DO, Peace DJ, Nathan S, Cassaday RD

Abstract
Purpose Patients with double-hit lymphoma (DHL) rarely achieve long-term survival following disease relapse. Some patients with DHL undergo consolidative autologous stem-cell transplantation (autoSCT) to reduce the risk of relapse, although the benefit of this treatment strategy is unclear. Methods Patients with DHL who achieved first complete remission following completion of front-line therapy with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or intensive front-line therapy, and deemed fit for autoSCT, were included. A landmark analysis was performed, with time zero defined as 3 months after completion of front-line therapy. Patients who experienced relapse before or who were not followed until that time were excluded. Results Relapse-free survival (RFS) and overall survival (OS) rates at 3 years were 80% and 87%, respectively, for all patients (n = 159). Three-year RFS and OS rates did not differ significantly for autoSCT (n = 62) versus non-autoSCT patients (n = 97), but 3-year RFS was inferior in patients who received R-CHOP compared with intensive therapy (56% v 88%; P = .002). Three-year RFS and OS did not differ significantly for patients in the R-CHOP or intensive therapy cohorts when analyzed by receipt of autoSCT. The median OS following relapse was 8.6 months. Conclusion In the largest reported series, to our knowledge, of patients with DHL to achieve first complete remission, consolidative autoSCT was not associated with improved 3-year RFS or OS. In addition, patients treated with R-CHOP experienced inferior 3-year RFS compared with those who received intensive front-line therapy. When considered in conjunction with reports of patients with newly diagnosed DHL, which demonstrate lower rates of disease response to R-CHOP compared with intensive front-line therapy, our findings further support the use of intensive front-line therapy for this patient population.

PMID: 28475457 [PubMed - indexed for MEDLINE]

Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions.

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Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions.

Circulation. 2017 Jun 13;135(24):2336-2353

Authors: Saleheen D, Zhao W, Young R, Nelson CP, Ho W, Ferguson JF, Rasheed A, Ou K, Nurnberg ST, Bauer RC, Goel A, Do R, Stewart AFR, Hartiala J, Zhang W, Thorleifsson G, Strawbridge RJ, Sinisalo J, Kanoni S, Sedaghat S, Marouli E, Kristiansson K, Hua Zhao J, Scott R, Gauguier D, Shah SH, Smith AV, van Zuydam N, Cox AJ, Willenborg C, Kessler T, Zeng L, Province MA, Ganna A, Lind L, Pedersen NL, White CC, Joensuu A, Edi Kleber M, Hall AS, März W, Salomaa V, O'Donnell C, Ingelsson E, Feitosa MF, Erdmann J, Bowden DW, Palmer CNA, Gudnason V, Faire U, Zalloua P, Wareham N, Thompson JR, Kuulasmaa K, Dedoussis G, Perola M, Dehghan A, Chambers JC, Kooner J, Allayee H, Deloukas P, McPherson R, Stefansson K, Schunkert H, Kathiresan S, Farrall M, Marcel Frossard P, Rader DJ, Samani NJ, Reilly MP

Abstract
BACKGROUND: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk.
METHODS: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of <1.0×10(-3) (Bonferroni correction for 50 tests).
RESULTS: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P=1.3×10(-16)) in comparison with 5% in ever-smokers (P=2.5×10(-4)), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value=8.7×10(-5)). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.

PMID: 28461624 [PubMed - indexed for MEDLINE]

Cell-Free DNA and Active Rejection in Kidney Allografts.

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Cell-Free DNA and Active Rejection in Kidney Allografts.

J Am Soc Nephrol. 2017 Jul;28(7):2221-2232

Authors: Bloom RD, Bromberg JS, Poggio ED, Bunnapradist S, Langone AJ, Sood P, Matas AJ, Mehta S, Mannon RB, Sharfuddin A, Fischbach B, Narayanan M, Jordan SC, Cohen D, Weir MR, Hiller D, Prasad P, Woodward RN, Grskovic M, Sninsky JJ, Yee JP, Brennan DC, Circulating Donor-Derived Cell-Free DNA in Blood for Diagnosing Active Rejection in Kidney Transplant Recipients (DART) Study Investigators

Abstract
Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), P<0.001 (receiver operating characteristic area under the curve [AUC], 0.74; 95% confidence interval [95% CI], 0.61 to 0.86). Positive and negative predictive values for active rejection at a cutoff of 1.0% dd-cfDNA were 61% and 84%, respectively. The AUC for discriminating ABMR from samples without ABMR was 0.87 (95% CI, 0.75 to 0.97). Positive and negative predictive values for ABMR at a cutoff of 1.0% dd-cfDNA were 44% and 96%, respectively. Median dd-cfDNA was 2.9% (ABMR), 1.2% (T cell-mediated types ≥IB), 0.2% (T cell-mediated type IA), and 0.3% in controls (P=0.05 for T cell-mediated rejection types ≥IB versus controls). Thus, dd-cfDNA may be used to assess allograft rejection and injury; dd-cfDNA levels <1% reflect the absence of active rejection (T cell-mediated type ≥IB or ABMR) and levels >1% indicate a probability of active rejection.

PMID: 28280140 [PubMed - indexed for MEDLINE]

Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema.

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Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema.

J Allergy Clin Immunol. 2017 Jul;140(1):242-248.e2

Authors: Straka BT, Ramirez CE, Byrd JB, Stone E, Woodard-Grice A, Nian H, Yu C, Banerji A, Brown NJ

Abstract
BACKGROUND: The B2 receptor antagonist icatibant is approved for treatment of attacks of hereditary angioedema. Icatibant has been reported to decrease time-to-resolution of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema in 1 study of European patients.
OBJECTIVE: We sought to test the hypothesis that a bradykinin B2 receptor antagonist would shorten time-to-resolution from ACE inhibitor-associated angioedema.
METHODS: Patients with ACE inhibitor-associated angioedema (defined as swelling of lips, tongue, pharynx, or face during ACE inhibitor use and no swelling in the absence of ACE inhibitor use) were enrolled at Vanderbilt University Medical Center from October 2007 through September 2015 and at Massachusetts General Hospital in 2012. C1 inhibitor deficiency and patients with bowel edema only were excluded. Patients were randomized within 6 hours of presentation to subcutaneous icatibant 30 mg or placebo at 0 and 6 hours later. Patients assessed severity of swelling using a visual analog scale serially following study drug administration or until discharge.
RESULTS: Thirty-three patients were randomized and 31 received treatment, with 13 receiving icatibant and 18 receiving placebo. One patient randomized to icatibant did not complete the visual analog scale and was excluded from analyses. Two-thirds of patients were black and two-thirds were women. Time-to-resolution of symptoms was similar in placebo and icatibant treatment groups (P = .19 for the primary symptom and P > .16 for individual symptoms of face, lip, tongue, or eyelid swelling). Frequency of administration of H1 and H2 blockers, corticosteroids, and epinephrine was similar in the 2 treatment groups. Time-to-resolution of symptoms was similar in black and white patients.
CONCLUSIONS: This study does not support clinical efficacy of a bradykinin B2 receptor antagonist in ACE inhibitor-associated angioedema.

PMID: 27913306 [PubMed - indexed for MEDLINE]

Multimodality Strategy for Cardiovascular Risk Assessment: Performance in 2 Population-Based Cohorts.

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Multimodality Strategy for Cardiovascular Risk Assessment: Performance in 2 Population-Based Cohorts.

Circulation. 2017 May 30;135(22):2119-2132

Authors: de Lemos JA, Ayers CR, Levine B, deFilippi CR, Wang TJ, Hundley WG, Berry JD, Seliger SL, McGuire DK, Ouyang P, Drazner MH, Budoff M, Greenland P, Ballantyne CM, Khera A

Abstract
BACKGROUND: Current strategies for cardiovascular disease (CVD) risk assessment among adults without known CVD are limited by suboptimal performance and a narrow focus on only atherosclerotic CVD (ASCVD). We hypothesized that a strategy combining promising biomarkers across multiple different testing modalities would improve global and atherosclerotic CVD risk assessment among individuals without known CVD.
METHODS: We included participants from MESA (Multi-Ethnic Study of Atherosclerosis) (n=6621) and the Dallas Heart Study (n=2202) who were free from CVD and underwent measurement of left ventricular hypertrophy by ECG, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein. Associations of test results with the global composite CVD outcome (CVD death, myocardial infarction, stroke, coronary or peripheral revascularization, incident heart failure, or atrial fibrillation) and ASCVD (fatal or nonfatal myocardial infarction or stroke) were assessed over >10 years of follow-up. Multivariable analyses for the primary global CVD end point adjusted for traditional risk factors plus statin use and creatinine (base model).
RESULTS: Each test result was independently associated with global composite CVD events in MESA after adjustment for the components of the base model and the other test results (P<0.05 for each). When the 5 tests were added to the base model, the c-statistic improved from 0.74 to 0.79 (P=0.001), significant integrated discrimination improvement (0.07, 95% confidence interval [CI] 0.06-0.08, P<0.001) and category free net reclassification improvement (0.47; 95% CI, 0.38-0.56; P=0.003) were observed, and the model was well calibrated (χ(2)=12.2, P=0.20). Using a simple integer score counting the number of abnormal tests, compared with those with a score of 0, global CVD risk was increased among participants with a score of 1 (adjusted hazard ratio, 1.9; 95% CI, 1.4-2.6), 2 (hazard ratio, 3.2; 95% CI, 2.3-4.4), 3 (hazard ratio, 4.7; 95% CI, 3.4-6.5), and ≥4 (hazard ratio, 7.5; 95% CI, 5.2-10.6). Findings replicated in the Dallas Health Study were similar for the ASCVD outcome.
CONCLUSIONS: Among adults without known CVD, a novel multimodality testing strategy using left ventricular hypertrophy by ECG, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein significantly improved global CVD and ASCVD risk assessment.

PMID: 28360032 [PubMed - indexed for MEDLINE]

Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study.

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Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study.

J Clin Oncol. 2017 May 10;35(14):1542-1549

Authors: Bauml J, Seiwert TY, Pfister DG, Worden F, Liu SV, Gilbert J, Saba NF, Weiss J, Wirth L, Sukari A, Kang H, Gibson MK, Massarelli E, Powell S, Meister A, Shu X, Cheng JD, Haddad R

Abstract
Purpose There are no approved treatments for recurrent/metastatic head and neck squamous cell carcinoma refractory to platinum and cetuximab. In the single-arm, phase II KEYNOTE-055 study, we evaluated pembrolizumab, an anti-programmed death 1 receptor antibody, in this platinum- and cetuximab-pretreated population with poor prognosis. Methods Eligibility stipulated disease progression within 6 months of platinum and cetuximab treatment. Patients received pembrolizumab 200 mg every 3 weeks. Imaging was performed every 6 to 9 weeks. Primary end points: overall response rate (Response Evaluation Criteria in Solid Tumors v1.1, central review) and safety. Efficacy was assessed in all dosed patients and in subgroups on the basis of programmed death ligand 1 (PD-L1) expression and human papillomavirus (HPV) status. Results Among 171 patients treated, 75% received two or more prior lines of therapy for metastatic disease, 82% were PD-L1 positive, and 22% were HPV positive. At the time of analysis, 109 patients (64%) experienced a treatment-related adverse event; 26 patients (15%) experienced a grade ≥ 3 event. Seven patients (4%) discontinued treatment, and one died of treatment-related adverse events. Overall response rate was 16% (95% CI, 11% to 23%), with a median duration of response of 8 months (range, 2+ to 12+ months); 75% of responses were ongoing at the time of analysis. Response rates were similar in all HPV and PD-L1 subgroups. Median progression-free survival was 2.1 months, and median overall survival was 8 months. Conclusion Pembrolizumab exhibited clinically meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab.

PMID: 28328302 [PubMed - indexed for MEDLINE]

Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression.

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Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression.

Nat Med. 2016 May;22(5):497-505

Authors: Laklai H, Miroshnikova YA, Pickup MW, Collisson EA, Kim GE, Barrett AS, Hill RC, Lakins JN, Schlaepfer DD, Mouw JK, LeBleu VS, Roy N, Novitskiy SV, Johansen JS, Poli V, Kalluri R, Iacobuzio-Donahue CA, Wood LD, Hebrok M, Hansen K, Moses HL, Weaver VM

Abstract
Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype.

PMID: 27089513 [PubMed - indexed for MEDLINE]

Mucosal Expression of Type 2 and Type 17 Immune Response Genes Distinguishes Ulcerative Colitis From Colon-Only Crohn's Disease in Treatment-Naive Pediatric Patients.

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Mucosal Expression of Type 2 and Type 17 Immune Response Genes Distinguishes Ulcerative Colitis From Colon-Only Crohn's Disease in Treatment-Naive Pediatric Patients.

Gastroenterology. 2017 May;152(6):1345-1357.e7

Authors: Rosen MJ, Karns R, Vallance JE, Bezold R, Waddell A, Collins MH, Haberman Y, Minar P, Baldassano RN, Hyams JS, Baker SS, Kellermayer R, Noe JD, Griffiths AM, Rosh JR, Crandall WV, Heyman MB, Mack DR, Kappelman MD, Markowitz J, Moulton DE, Leleiko NS, Walters TD, Kugathasan S, Wilson KT, Hogan SP, Denson LA

Abstract
BACKGROUND & AIMS: There is controversy regarding the role of the type 2 immune response in the pathogenesis of ulcerative colitis (UC)-few data are available from treatment-naive patients. We investigated whether genes associated with a type 2 immune response in the intestinal mucosa are up-regulated in treatment-naive pediatric patients with UC compared with patients with Crohn's disease (CD)-associated colitis or without inflammatory bowel disease (IBD), and whether expression levels are associated with clinical outcomes.
METHODS: We used a real-time reverse-transcription quantitative polymerase chain reaction array to analyze messenger RNA (mRNA) expression patterns in rectal mucosal samples from 138 treatment-naive pediatric patients with IBD and macroscopic rectal disease, as well as those from 49 children without IBD (controls), enrolled in a multicenter prospective observational study from 2008 to 2012. Results were validated in real-time reverse-transcription quantitative polymerase chain reaction analyses of rectal RNA from an independent cohort of 34 pediatric patients with IBD and macroscopic rectal disease and 17 controls from Cincinnati Children's Hospital Medical Center.
RESULTS: We measured significant increases in mRNAs associated with a type 2 immune response (interleukin [IL]5 gene, IL13, and IL13RA2) and a type 17 immune response (IL17A and IL23) in mucosal samples from patients with UC compared with patients with colon-only CD. In a regression model, increased expression of IL5 and IL17A mRNAs distinguished patients with UC from patients with colon-only CD (P = .001; area under the receiver operating characteristic curve, 0.72). We identified a gene expression pattern in rectal tissues of patients with UC, characterized by detection of IL13 mRNA, that predicted clinical response to therapy after 6 months (odds ratio [OR], 6.469; 95% confidence interval [CI], 1.553-26.94), clinical response after 12 months (OR, 6.125; 95% CI, 1.330-28.22), and remission after 12 months (OR, 5.333; 95% CI, 1.132-25.12).
CONCLUSIONS: In an analysis of rectal tissues from treatment-naive pediatric patients with IBD, we observed activation of a type 2 immune response during the early course of UC. We were able to distinguish patients with UC from those with colon-only CD based on increased mucosal expression of genes that mediate type 2 and type 17 immune responses. Increased expression at diagnosis of genes that mediate a type 2 immune response is associated with response to therapy and remission in pediatric patients with UC.

PMID: 28132889 [PubMed - indexed for MEDLINE]

Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis.

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Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis.

J Clin Oncol. 2017 Apr 01;35(10):1070-1077

Authors: Magnuson WJ, Lester-Coll NH, Wu AJ, Yang TJ, Lockney NA, Gerber NK, Beal K, Amini A, Patil T, Kavanagh BD, Camidge DR, Braunstein SE, Boreta LC, Balasubramanian SK, Ahluwalia MS, Rana NG, Attia A, Gettinger SN, Contessa JN, Yu JB, Chiang VL

Abstract
Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are treatment options for brain metastases in patients with EGFR-mutant non-small-cell lung cancer (NSCLC). This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI. Materials and Methods A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study. Exclusion criteria included prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after WBRT/SRS, or insufficient follow-up. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. Overall survival (OS) and intracranial progression-free survival were measured from the date of brain metastases. Results The median OS for the SRS (n = 100), WBRT (n = 120), and EGFR-TKI (n = 131) cohorts was 46, 30, and 25 months, respectively ( P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. Although the SRS and EGFR-TKI cohorts shared similar prognostic features, the WBRT cohort was more likely to have a less favorable prognosis ( P = .001). Conclusion This multi-institutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed.

PMID: 28113019 [PubMed - indexed for MEDLINE]

Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes.

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Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes.

Nat Med. 2016 Dec;22(12):1482-1487

Authors: Babon JA, DeNicola ME, Blodgett DM, Crèvecoeur I, Buttrick TS, Maehr R, Bottino R, Naji A, Kaddis J, Elyaman W, James EA, Haliyur R, Brissova M, Overbergh L, Mathieu C, Delong T, Haskins K, Pugliese A, Campbell-Thompson M, Mathews C, Atkinson MA, Powers AC, Harlan DM, Kent SC

Abstract
A major therapeutic goal for type 1 diabetes (T1D) is to induce autoantigen-specific tolerance of T cells. This could suppress autoimmunity in those at risk for the development of T1D, as well as in those with established disease who receive islet replacement or regeneration therapy. Because functional studies of human autoreactive T cell responses have been limited largely to peripheral blood-derived T cells, it is unclear how representative the peripheral T cell repertoire is of T cells infiltrating the islets. Our knowledge of the insulitic T cell repertoire is derived from histological and immunohistochemical analyses of insulitis, the identification of autoreactive CD8(+) T cells in situ, in islets of human leukocyte antigen (HLA)-A2(+) donors and isolation and identification of DQ8 and DQ2-DQ8 heterodimer-restricted, proinsulin-reactive CD4(+) T cells grown from islets of a single donor with T1D. Here we present an analysis of 50 of a total of 236 CD4(+) and CD8(+) T cell lines grown from individual handpicked islets or clones directly sorted from handpicked, dispersed islets from nine donors with T1D. Seventeen of these T cell lines and clones reacted to a broad range of studied native islet antigens and to post-translationally modified peptides. These studies demonstrate the existence of a variety of islet-infiltrating, islet-autoantigen reactive T cells in individuals with T1D, and these data have implications for the design of successful immunotherapies.

PMID: 27798614 [PubMed - indexed for MEDLINE]

Classification of common human diseases derived from shared genetic and environmental determinants.

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Classification of common human diseases derived from shared genetic and environmental determinants.

Nat Genet. 2017 Aug 07;:

Authors: Wang K, Gaitsch H, Poon H, Cox NJ, Rzhetsky A

Abstract
In this study, we used insurance claims for over one-third of the entire US population to create a subset of 128,989 families (481,657 unique individuals). We then used these data to (i) estimate the heritability and familial environmental patterns of 149 diseases and (ii) infer the genetic and environmental correlations for disease pairs from a set of 29 complex diseases. The majority (52 of 65) of our study's heritability estimates matched earlier reports, and 84 of our estimates appear to have been obtained for the first time. We used correlation matrices to compute environmental and genetic disease classifications and corresponding reliability measures. Among unexpected observations, we found that migraine, typically classified as a disease of the central nervous system, appeared to be most genetically similar to irritable bowel syndrome and most environmentally similar to cystitis and urethritis, all of which are inflammatory diseases.

PMID: 28783162 [PubMed - as supplied by publisher]