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A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.

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A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.

Nat Genet. 2018 Jun 18;:

Authors: Wu L, Shi W, Long J, Guo X, Michailidou K, Beesley J, Bolla MK, Shu XO, Lu Y, Cai Q, Al-Ejeh F, Rozali E, Wang Q, Dennis J, Li B, Zeng C, Feng H, Gusev A, Barfield RT, Andrulis IL, Anton-Culver H, Arndt V, Aronson KJ, Auer PL, Barrdahl M, Baynes C, Beckmann MW, Benitez J, Bermisheva M, Blomqvist C, Bogdanova NV, Bojesen SE, Brauch H, Brenner H, Brinton L, Broberg P, Brucker SY, Burwinkel B, Caldés T, Canzian F, Carter BD, Castelao JE, Chang-Claude J, Chen X, Cheng TD, Christiansen H, Clarke CL, NBCS Collaborators, Collée M, Cornelissen S, Couch FJ, Cox D, Cox A, Cross SS, Cunningham JM, Czene K, Daly MB, Devilee P, Doheny KF, Dörk T, Dos-Santos-Silva I, Dumont M, Dwek M, Eccles DM, Eilber U, Eliassen AH, Engel C, Eriksson M, Fachal L, Fasching PA, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Fritschi L, Gabrielson M, Gago-Dominguez M, Gapstur SM, García-Closas M, Gaudet MM, Ghoussaini M, Giles GG, Goldberg MS, Goldgar DE, González-Neira A, Guénel P, Hahnen E, Haiman CA, Håkansson N, Hall P, Hallberg E, Hamann U, Harrington P, Hein A, Hicks B, Hillemanns P, Hollestelle A, Hoover RN, Hopper JL, Huang G, Humphreys K, Hunter DJ, Jakubowska A, Janni W, John EM, Johnson N, Jones K, Jones ME, Jung A, Kaaks R, Kerin MJ, Khusnutdinova E, Kosma VM, Kristensen VN, Lambrechts D, Le Marchand L, Li J, Lindström S, Lissowska J, Lo WY, Loibl S, Lubinski J, Luccarini C, Lux MP, MacInnis RJ, Maishman T, Kostovska IM, Mannermaa A, Manson JE, Margolin S, Mavroudis D, Meijers-Heijboer H, Meindl A, Menon U, Meyer J, Mulligan AM, Neuhausen SL, Nevanlinna H, Neven P, Nielsen SF, Nordestgaard BG, Olopade OI, Olson JE, Olsson H, Peterlongo P, Peto J, Plaseska-Karanfilska D, Prentice R, Presneau N, Pylkäs K, Rack B, Radice P, Rahman N, Rennert G, Rennert HS, Rhenius V, Romero A, Romm J, Rudolph A, Saloustros E, Sandler DP, Sawyer EJ, Schmidt MK, Schmutzler RK, Schneeweiss A, Scott RJ, Scott CG, Seal S, Shah M, Shrubsole MJ, Smeets A, Southey MC, Spinelli JJ, Stone J, Surowy H, Swerdlow AJ, Tamimi RM, Tapper W, Taylor JA, Terry MB, Tessier DC, Thomas A, Thöne K, Tollenaar RAEM, Torres D, Truong T, Untch M, Vachon C, Van Den Berg D, Vincent D, Waisfisz Q, Weinberg CR, Wendt C, Whittemore AS, Wildiers H, Willett WC, Winqvist R, Wolk A, Xia L, Yang XR, Ziogas A, Ziv E, kConFab/AOCS Investigators, Dunning AM, Pharoah PDP, Simard J, Milne RL, Edwards SL, Kraft P, Easton DF, Chenevix-Trench G, Zheng W

Abstract
The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

PMID: 29915430 [PubMed - as supplied by publisher]

Disease Heritability Studies Harness the Healthcare System to Achieve Massive Scale.

Disease Heritability Studies Harness the Healthcare System to Achieve Massive Scale.

Cell. 2018 Jun 14;173(7):1568-1570

Authors: Denny JC, Mosley JD

Abstract
Heritability studies are essential for defining genetic influences on disease risk and trait variability. Polubriaginof et al. show how massive amounts of data contained in electronic health records can be used for heritability studies on hundreds of phenotypes. Mining emergency contact information with comparison to existing gold standards showcases the broad utility of the approach.

PMID: 29906443 [PubMed - in process]

Response by Weinberg et al to Letter Regarding Article, "Carotid Stent Fractures Are Not Associated With Adverse Events: Results From the ACT-1 Multicenter Randomized Trial (Carotid Angioplasty and Stenting Versus Endarterectomy in Asymptomatic Subjects

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Response by Weinberg et al to Letter Regarding Article, "Carotid Stent Fractures Are Not Associated With Adverse Events: Results From the ACT-1 Multicenter Randomized Trial (Carotid Angioplasty and Stenting Versus Endarterectomy in Asymptomatic Subjects Who Are at Standard Risk for Carotid Endarterectomy With Significant Extracranial Carotid Stenotic Disease)".

Circulation. 2018 Jun 12;137(24):2676-2677

Authors: Weinberg I, Beckman JA, Shu Y, Jaff MR

PMID: 29891632 [PubMed - in process]

Multi-ethnic genome-wide association study for atrial fibrillation.

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Multi-ethnic genome-wide association study for atrial fibrillation.

Nat Genet. 2018 Jun 11;:

Authors: Roselli C, Chaffin MD, Weng LC, Aeschbacher S, Ahlberg G, Albert CM, Almgren P, Alonso A, Anderson CD, Aragam KG, Arking DE, Barnard J, Bartz TM, Benjamin EJ, Bihlmeyer NA, Bis JC, Bloom HL, Boerwinkle E, Bottinger EB, Brody JA, Calkins H, Campbell A, Cappola TP, Carlquist J, Chasman DI, Chen LY, Chen YI, Choi EK, Choi SH, Christophersen IE, Chung MK, Cole JW, Conen D, Cook J, Crijns HJ, Cutler MJ, Damrauer SM, Daniels BR, Darbar D, Delgado G, Denny JC, Dichgans M, Dörr M, Dudink EA, Dudley SC, Esa N, Esko T, Eskola M, Fatkin D, Felix SB, Ford I, Franco OH, Geelhoed B, Grewal RP, Gudnason V, Guo X, Gupta N, Gustafsson S, Gutmann R, Hamsten A, Harris TB, Hayward C, Heckbert SR, Hernesniemi J, Hocking LJ, Hofman A, Horimoto ARVR, Huang J, Huang PL, Huffman J, Ingelsson E, Ipek EG, Ito K, Jimenez-Conde J, Johnson R, Jukema JW, Kääb S, Kähönen M, Kamatani Y, Kane JP, Kastrati A, Kathiresan S, Katschnig-Winter P, Kavousi M, Kessler T, Kietselaer BL, Kirchhof P, Kleber ME, Knight S, Krieger JE, Kubo M, Launer LJ, Laurikka J, Lehtimäki T, Leineweber K, Lemaitre RN, Li M, Lim HE, Lin HJ, Lin H, Lind L, Lindgren CM, Lokki ML, London B, Loos RJF, Low SK, Lu Y, Lyytikäinen LP, Macfarlane PW, Magnusson PK, Mahajan A, Malik R, Mansur AJ, Marcus GM, Margolin L, Margulies KB, März W, McManus DD, Melander O, Mohanty S, Montgomery JA, Morley MP, Morris AP, Müller-Nurasyid M, Natale A, Nazarian S, Neumann B, Newton-Cheh C, Niemeijer MN, Nikus K, Nilsson P, Noordam R, Oellers H, Olesen MS, Orho-Melander M, Padmanabhan S, Pak HN, Paré G, Pedersen NL, Pera J, Pereira A, Porteous D, Psaty BM, Pulit SL, Pullinger CR, Rader DJ, Refsgaard L, Ribasés M, Ridker PM, Rienstra M, Risch L, Roden DM, Rosand J, Rosenberg MA, Rost N, Rotter JI, Saba S, Sandhu RK, Schnabel RB, Schramm K, Schunkert H, Schurman C, Scott SA, Seppälä I, Shaffer C, Shah S, Shalaby AA, Shim J, Shoemaker MB, Siland JE, Sinisalo J, Sinner MF, Slowik A, Smith AV, Smith BH, Smith JG, Smith JD, Smith NL, Soliman EZ, Sotoodehnia N, Stricker BH, Sun A, Sun H, Svendsen JH, Tanaka T, Tanriverdi K, Taylor KD, Teder-Laving M, Teumer A, Thériault S, Trompet S, Tucker NR, Tveit A, Uitterlinden AG, Van Der Harst P, Van Gelder IC, Van Wagoner DR, Verweij N, Vlachopoulou E, Völker U, Wang B, Weeke PE, Weijs B, Weiss R, Weiss S, Wells QS, Wiggins KL, Wong JA, Woo D, Worrall BB, Yang PS, Yao J, Yoneda ZT, Zeller T, Zeng L, Lubitz SA, Lunetta KL, Ellinor PT

Abstract
Atrial fibrillation (AF) affects more than 33 million individuals worldwide 1 and has a complex heritability 2 . We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

PMID: 29892015 [PubMed - as supplied by publisher]

YES1 amplification is a mechanism of acquired resistance to EGFR inhibitors identified by transposon mutagenesis and clinical genomics.

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YES1 amplification is a mechanism of acquired resistance to EGFR inhibitors identified by transposon mutagenesis and clinical genomics.

Proc Natl Acad Sci U S A. 2018 Jun 06;:

Authors: Fan PD, Narzisi G, Jayaprakash AD, Venturini E, Robine N, Smibert P, Germer S, Yu HA, Jordan EJ, Paik PK, Janjigian YY, Chaft JE, Wang L, Jungbluth AA, Middha S, Spraggon L, Qiao H, Lovly CM, Kris MG, Riely GJ, Politi K, Varmus H, Ladanyi M

Abstract
In ∼30% of patients with EGFR-mutant lung adenocarcinomas whose disease progresses on EGFR inhibitors, the basis for acquired resistance remains unclear. We have integrated transposon mutagenesis screening in an EGFR-mutant cell line and clinical genomic sequencing in cases of acquired resistance to identify mechanisms of resistance to EGFR inhibitors. The most prominent candidate genes identified by insertions in or near the genes during the screen were MET, a gene whose amplification is known to mediate resistance to EGFR inhibitors, and the gene encoding the Src family kinase YES1. Cell clones with transposon insertions that activated expression of YES1 exhibited resistance to all three generations of EGFR inhibitors and sensitivity to pharmacologic and siRNA-mediated inhibition of YES1 Analysis of clinical genomic sequencing data from cases of acquired resistance to EGFR inhibitors revealed amplification of YES1 in five cases, four of which lacked any other known mechanisms of resistance. Preinhibitor samples, available for two of the five patients, lacked YES1 amplification. None of 136 postinhibitor samples had detectable amplification of other Src family kinases (SRC and FYN). YES1 amplification was also found in 2 of 17 samples from ALK fusion-positive lung cancer patients who had progressed on ALK TKIs. Taken together, our findings identify acquired amplification of YES1 as a recurrent and targetable mechanism of resistance to EGFR inhibition in EGFR-mutant lung cancers and demonstrate the utility of transposon mutagenesis in discovering clinically relevant mechanisms of drug resistance.

PMID: 29875142 [PubMed - as supplied by publisher]

Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1.

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Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1.

Nat Med. 2018 Jun 04;:

Authors: Xu K, Acharya P, Kong R, Cheng C, Chuang GY, Liu K, Louder MK, O'Dell S, Rawi R, Sastry M, Shen CH, Zhang B, Zhou T, Asokan M, Bailer RT, Chambers M, Chen X, Choi CW, Dandey VP, Doria-Rose NA, Druz A, Eng ET, Farney SK, Foulds KE, Geng H, Georgiev IS, Gorman J, Hill KR, Jafari AJ, Kwon YD, Lai YT, Lemmin T, McKee K, Ohr TY, Ou L, Peng D, Rowshan AP, Sheng Z, Todd JP, Tsybovsky Y, Viox EG, Wang Y, Wei H, Yang Y, Zhou AF, Chen R, Yang L, Scorpio DG, McDermott AB, Shapiro L, Carragher B, Potter CS, Mascola JR, Kwong PD

Abstract
A central goal of HIV-1 vaccine research is the elicitation of antibodies capable of neutralizing diverse primary isolates of HIV-1. Here we show that focusing the immune response to exposed N-terminal residues of the fusion peptide, a critical component of the viral entry machinery and the epitope of antibodies elicited by HIV-1 infection, through immunization with fusion peptide-coupled carriers and prefusion stabilized envelope trimers, induces cross-clade neutralizing responses. In mice, these immunogens elicited monoclonal antibodies capable of neutralizing up to 31% of a cross-clade panel of 208 HIV-1 strains. Crystal and cryoelectron microscopy structures of these antibodies revealed fusion peptide conformational diversity as a molecular explanation for the cross-clade neutralization. Immunization of guinea pigs and rhesus macaques induced similarly broad fusion peptide-directed neutralizing responses, suggesting translatability. The N terminus of the HIV-1 fusion peptide is thus a promising target of vaccine efforts aimed at eliciting broadly neutralizing antibodies.

PMID: 29867235 [PubMed - as supplied by publisher]

Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer.

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Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer.

N Engl J Med. 2018 Jun 03;:

Authors: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE, Dees EC, Goetz MP, Olson JA, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW

Abstract
Background The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. Methods We performed a prospective trial involving 10,273 women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease-free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). Results Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease-free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease-free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local-regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease-free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25. Conclusions Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger. (Funded by the National Cancer Institute and others; TAILORx ClinicalTrials.gov number, NCT00310180 .).

PMID: 29860917 [PubMed - as supplied by publisher]

Deletion of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Accelerates Atherosclerosis Regression and Increases CCR7 Expression in Plaque Macrophages.

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Deletion of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Accelerates Atherosclerosis Regression and Increases CCR7 Expression in Plaque Macrophages.

Circulation. 2018 May 24;:

Authors: Mueller PA, Zhu L, Tavori H, Huynh K, Giunzioni I, Stafford JM, Linton MF, Fazio S

Abstract
Background -We previously showed that mice lacking LDL receptor-related protein 1 in macrophages (MΦLRP1-/-) undergo accelerated atherosclerotic plaque formation due to changes in macrophages including increased apoptosis, decreased efferocytosis, and exaggerated transition to the inflammatory M1 phenotype. Here we sought to explore the role of macrophage LRP1 during regression of atherosclerosis since regressing plaques are characterized by transitioning of macrophages to M2 status as inflammation resolves. Methods -ApoE-/- mice on a high-fat diet for 12 weeks were reconstituted with bone marrow from apoE-producing wildtype (WT) or MΦLRP1-/- mice and then placed on chow diet for 10 weeks (n=9-11 mice/group). A cohort of apoE-/- mice reconstituted with apoE-/- bone marrow served as baseline controls (n=9). Results -Plaques of both WT and MΦLRP1-/- bone marrow recipients regressed compared with controls (11% and 22%, respectively; p<0.05), and plaques of MΦLRP1-/- recipients were 13% smaller than those of WT recipients (p<0.05). Recipients of MΦLRP1-/- marrow had 36% fewer M1 macrophages (p<0.01) and 2.5-fold more CCR7+ macrophages in the plaque relative to WT mice (p<0.01). Additionally, in vivo studies of cellular egress showed a 4.6-fold increase in EdU-labeled CCR7+ macrophages in mediastinal lymph nodes. Finally, in vivo studies of reverse cholesterol transport (RCT) showed a 1.4-fold higher RCT in MΦLRP1-/- recipient mice (p<0.01). Conclusions -Absence of macrophage LRP1 unexpectedly accelerates atherosclerosis regression, enhances RCT, and increases expression of the motility receptor CCR7 which drives macrophage egress from lesions.

PMID: 29794082 [PubMed - as supplied by publisher]

Multimorbidity in Older Adults With Cardiovascular Disease.

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Multimorbidity in Older Adults With Cardiovascular Disease.

J Am Coll Cardiol. 2018 May 15;71(19):2149-2161

Authors: Forman DE, Maurer MS, Boyd C, Brindis R, Salive ME, Horne FM, Bell SP, Fulmer T, Reuben DB, Zieman S, Rich MW

Abstract
Multimorbidity occurs in adults of all ages, but the number and complexity of comorbid conditions commonly increase with advancing age such that cardiovascular disease (CVD) in older adults typically occurs in a context of multimorbidity. Current clinical practice and research mainly target single disease-specific care that does not embrace the complexities imposed by concurrent conditions. In this paper, emerging concepts regarding CVD in combination with multimorbidity are reviewed, including recommendations for incorporating multimorbidity into clinical decision making, critical knowledge gaps, and research priorities to optimize care of complex older patients.

PMID: 29747836 [PubMed - in process]

B-Type Natriuretic Peptide Levels and Mortality in Patients With and Without Heart Failure.

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B-Type Natriuretic Peptide Levels and Mortality in Patients With and Without Heart Failure.

J Am Coll Cardiol. 2018 May 15;71(19):2079-2088

Authors: York MK, Gupta DK, Reynolds CF, Farber-Eger E, Wells QS, Bachmann KN, Xu M, Harrell FE, Wang TJ

Abstract
BACKGROUND: Circulating B-type natriuretic peptide (BNP) concentrations strongly predict mortality in patients with heart failure (HF). Both cardiac and extracardiac stimuli influence BNP levels, suggesting that BNP might have similar prognostic value in patients without HF.
OBJECTIVES: The aim of this study was to compare the prognostic value of BNP between patients with and those without HF.
METHODS: Using the Vanderbilt University Medical Center electronic health record, 30,487 patients (median age 63 years, 50% men, 17% black, 38% with HF) who had a first plasma BNP measurement between 2002 and 2013, with follow-up through 2015, were studied. The risk for death according to BNP level was quantified using multivariate Cox proportional hazards models.
RESULTS: BNP levels were lower in patients without HF (median 89 pg/ml; interquartile range: 34 to 238 pg/ml) compared with those with HF (median 388 pg/ml; interquartile range: 150 to 940 pg/ml) (p < 0.0001). Over 90,898 person-years of follow-up, 5,903 patients without HF (31%) and 6,181 patients with HF (53%) died. In multivariate models including demographic and clinical characteristics, BNP and age were the strongest predictors of death in both patients with and those without HF. In acute care settings and even among outpatients with modestly elevated BNP, the risk for death according to BNP was similar between patients with and those without HF. For instance, a BNP level of 400 pg/ml was associated with a 3-year risk for death of 21% (95% confidence interval: 20% to 23%) and 19% (95% confidence interval: 17% to 20%) in patients with and those without HF, respectively.
CONCLUSIONS: Among patients without HF, plasma BNP level is a stronger predictor of death than traditional risk factors. The risk for death associated with any given BNP level is similar between patients with and those without HF, particularly in the acute care setting.

PMID: 29747827 [PubMed - in process]

Letter by Mitchell et al Regarding Article, "Urinary Prostaglandin Metabolites: An Incomplete Reckoning and a Flush to Judgment".

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Letter by Mitchell et al Regarding Article, "Urinary Prostaglandin Metabolites: An Incomplete Reckoning and a Flush to Judgment".

Circ Res. 2018 May 11;122(10):e84-e85

Authors: Mitchell JA, Knowles RB, Kirkby NS, Reed DM, Edin ML, White WE, Chan MV, Longhurst H, Yaqoob MM, Milne GL, Zeldin DC, Warner TD

PMID: 29748370 [PubMed - in process]

The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia.

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The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia.

Blood. 2018 May 03;:

Authors: Stein EM, Garcia-Manero G, Rizzieri DA, Tibes R, Berdeja JG, Savona MR, Jongen-Lavrenic M, Altman JK, Thomson B, Blakemore SJ, Daigle SR, Waters NJ, Suttle AB, Clawson A, Pollock R, Krivtsov A, Armstrong SA, DiMartino J, Hedrick E, Löwenberg B, Tallman MS

Abstract
Pinometostat (EPZ-5676) is a first-in-class, small-molecule inhibitor of the histone methyltransferase DOT1L. In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving MLL rearrangements (MLL-r) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose escalation cohorts (n=26) and 2 expansion cohorts (n=25) at pinometostat doses of 54 and 90 mg/m2/day by continuous intravenous infusion in 28-day cycles. As a maximum tolerated dose was not established in the dose escalation phase, the expansion doses were selected based upon safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remissions at 54 mg/m2/day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as no. NCT01684150.

PMID: 29724899 [PubMed - as supplied by publisher]

Interpreting heterogeneity in intestinal tuft cell structure and function.

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Interpreting heterogeneity in intestinal tuft cell structure and function.

J Clin Invest. 2018 May 01;128(5):1711-1719

Authors: Banerjee A, McKinley ET, von Moltke J, Coffey RJ, Lau KS

Abstract
Intestinal tuft cells are a morphologically unique cell type, best characterized by striking microvilli that form an apical tuft. These cells represent approximately 0.5% of gut epithelial cells depending on location. While they are known to express chemosensory receptors, their function has remained unclear. Recently, numerous groups have revealed startling insights into intestinal tuft cell biology. Here, we review the latest developments in understanding this peculiar cell type's structure and function. Recent advances in volumetric microscopy have begun to elucidate tuft cell ultrastructure with respect to its cellular neighbors. Moreover, single-cell approaches have revealed greater diversity in the tuft cell population than previously appreciated and uncovered novel markers to characterize this heterogeneity. Finally, advanced model systems have revealed tuft cells' roles in mucosal healing and orchestrating type 2 immunity against eukaryotic infection. While much remains unknown about intestinal tuft cells, these critical advances have illuminated the physiological importance of these previously understudied cells and provided experimentally tractable tools to interrogate this rare cell population. Tuft cells act as luminal sensors, linking the luminal microbiome to the host immune system, which may make them a potent clinical target for modulating host response to a variety of acute or chronic immune-driven conditions.

PMID: 29714721 [PubMed - in process]

Preventability of Early Versus Late Hospital Readmissions in a National Cohort of General Medicine Patients.

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Preventability of Early Versus Late Hospital Readmissions in a National Cohort of General Medicine Patients.

Ann Intern Med. 2018 May 01;:

Authors: Graham KL, Auerbach AD, Schnipper JL, Flanders SA, Kim CS, Robinson EJ, Ruhnke GW, Thomas LR, Kripalani S, Vasilevskis EE, Fletcher GS, Sehgal NJ, Lindenauer PK, Williams MV, Metlay JP, Davis RB, Yang J, Marcantonio ER, Herzig SJ

Abstract
Background: Many experts believe that hospitals with more frequent readmissions provide lower-quality care, but little is known about how the preventability of readmissions might change over the postdischarge time frame.
Objective: To determine whether readmissions within 7 days of discharge differ from those between 8 and 30 days after discharge with respect to preventability.
Design: Prospective cohort study.
Setting: 10 academic medical centers in the United States.
Patients: 822 adults readmitted to a general medicine service.
Measurements: For each readmission, 2 site-specific physician adjudicators used a structured survey instrument to determine whether it was preventable and measured other characteristics.
Results: Overall, 36.2% of early readmissions versus 23.0% of late readmissions were preventable (median risk difference, 13.0 percentage points [interquartile range, 5.5 to 26.4 percentage points]). Hospitals were identified as better locations for preventing early readmissions (47.2% vs. 25.5%; median risk difference, 22.8 percentage points [interquartile range, 17.9 to 31.8 percentage points]), whereas outpatient clinics (15.2% vs. 6.6%; median risk difference, 10.0 percentage points [interquartile range, 4.6 to 12.2 percentage points]) and home (19.4% vs. 14.0%; median risk difference, 5.6 percentage points [interquartile range, -6.1 to 17.1 percentage points]) were better for preventing late readmissions.
Limitation: Physician adjudicators were not blinded to readmission timing, community hospitals were not included in the study, and readmissions to nonstudy hospitals were not included in the results.
Conclusion: Early readmissions were more likely to be preventable and amenable to hospital-based interventions. Late readmissions were less likely to be preventable and were more amenable to ambulatory and home-based interventions.
Primary Funding Source: American Association of Medical Colleges.

PMID: 29710243 [PubMed - as supplied by publisher]

LPA Variants are Associated with Residual Cardiovascular Risk in Patients Receiving Statins.

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LPA Variants are Associated with Residual Cardiovascular Risk in Patients Receiving Statins.

Circulation. 2018 Apr 27;:

Authors: Wei WQ, Li X, Feng Q, Kubo M, Kullo IJ, Peissig PL, Karlson EW, Jarvik GP, Lee MTM, Shang N, Larson EA, Edwards T, Shaffer C, Mosley JD, Maeda S, Horikoshi M, Ritchie M, Williams MS, Larson EB, Crosslin DR, Bland ST, Pacheco JA, Rasmussen-Torvik LJ, Cronkite D, Hripcsak G, Cox NJ, Wilke RA, Stein CM, Rotter JI, Momozawa Y, Roden DM, Krauss RM, Denny JC

Abstract
Background -Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with HMG-CoA reductase inhibitors (statins) decreases circulating levels of low-density lipoprotein cholesterol (LDL-C) and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. Methods -We performed a two-stage genome-wide association study (GWAS) of CHD events during statin therapy. We first identified 3,099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7,681 controls without CHD events during comparable intensity and duration of statin therapy from four sites in the Electronic Medical Records and Genomics (eMERGE) Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth eMERGE site, which joined the network after the initial GWAS. Finally, we performed a phenome-wide association study (PheWAS) for other traits linked to the most significant locus. Results -The meta-analysis identified seven SNPs at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic SNP within LPA/PLG (rs10455872, MAF=0.069, Odds Ratio [OR]=1.58, 95% CI [1.35-1.86], P=2.6×10-10). In the replication cohort, rs10455872 was also associated with CHD events (OR=1.71, 95% CI [1.14-2.57], p=0.009). The association of this SNP with CHD events was independent of statin-induced change in LDL-C (OR=1.62, 95% CI [1.17-2.24], p=0.004) and persisted in individuals with LDL-C≤70mg/dL (OR=2.43, 95% CI [1.18-4.75], p=0.015). PheWAS supported the effect of this region on coronary heart disease and did not identify non-cardiovascular phenotypes. Conclusions -Genetic variations at the LPA locus is associated with CHD events during statin therapy independent of the extent of LDL-C lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins.

PMID: 29703846 [PubMed - as supplied by publisher]