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Research advances from the National Institutes of Health (NIH) Intramural Research Program (IRP) are often published in high-impact journals. Read some of our recent articles:

Authors: Machiela MJ, Zhou W, Sampson JN, Dean MC, Jacobs KB, Black A, Brinton LA, Chang IS, Chen C, Chen C, Chen K, Cook LS, Crous Bou M, De Vivo I, Doherty J, Friedenreich CM, Gaudet MM, Haiman CA, Hankinson SE, Hartge P, Henderson BE, Hong YC, Hosgood HD 3rd, Hsiung CA, Hu W, Hunter DJ, Jessop L, Kim HN, Kim YH, Kim YT, Klein R, Kraft P, Lan Q, Lin D, Liu J, Le Marchand L, Liang X, Lissowska J, Lu L, Magliocco AM, Matsuo K, Olson SH, Orlow I, Park JY, Pooler L, Prescott J, Rastogi R, Risch HA, Schumacher F, Seow A, Setiawan VW, Shen H, Sheng X, Shin MH, Shu XO, VanDen Berg D, Wang JC, Wentzensen N, Wong MP, Wu C, Wu T, Wu YL, Xia L, Yang HP, Yang PC, Zheng W, Zhou B, Abnet CC, Albanes D, Aldrich MC, Amos C, Amundadottir LT, Berndt SI, Blot WJ, Bock CH, Bracci PM, Burdett L, Buring JE, Butler MA, Carreón T, Chatterjee N, Chung CC, Cook MB, Cullen M, Davis FG, Ding T, Duell EJ, Epstein CG, Fan JH, Figueroa JD, Fraumeni JF Jr, Freedman ND, Fuchs CS, Gao YT, Gapstur SM, Patiño-Garcia A, Garcia-Closas M, Gaziano JM, Giles GG, Gillanders EM, Giovannucci EL, Goldin L, Goldstein AM, Greene MH, Hallmans G, Harris CC, Henriksson R, Holly EA, Hoover RN, Hu N, Hutchinson A, Jenab M, Johansen C, Khaw KT, Koh WP, Kolonel LN, Kooperberg C, Krogh V, Kurtz RC, LaCroix A, Landgren A, Landi MT, Li D, Liao LM, Malats N, McGlynn KA, McNeill LH, McWilliams RR, Melin BS, Mirabello L, Peplonska B, Peters U, Petersen GM, Prokunina-Olsson L, Purdue M, Qiao YL, Rabe KG, Rajaraman P, Real FX, Riboli E, Rodríguez-Santiago B, Rothman N, Ruder AM, Savage SA, Schwartz AG, Schwartz KL, Sesso HD, Severi G, Silverman DT, Spitz MR, Stevens VL, Stolzenberg-Solomon R, Stram D, Tang ZZ, Taylor PR, Teras LR, Tobias GS, Viswanathan K, Wacholder S, Wang Z, Weinstein SJ, Wheeler W, White E, Wiencke JK, Wolpin BM, Wu X, Wunder JS, Yu K, Zanetti KA, Zeleniuch-Jacquotte A, Ziegler RG, de Andrade M, Barnes KC, Beaty TH, Bierut LJ, Desch KC, Doheny KF, Feenstra B, Ginsburg D, Heit JA, Kang JH, Laurie CA, Li JZ, Lowe WL, Marazita ML, Melbye M, Mirel DB, Murray JC, Nelson SC, Pasquale LR, Rice K, Wiggs JL, Wise A, Tucker M, Pérez-Jurado LA, Laurie CC, Caporaso NE, Yeager M, Chanock SJ

Journal: Am J Hum Genet. 2015 Mar 5;96(3):487-97. doi: 10.1016/j.ajhg.2015.01.011

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

Authors: Gadalla SM, Wang T, Haagenson M, Spellman SR, Lee SJ, Williams KM, Wong JY, De Vivo I, Savage SA

Journal: JAMA. 2015 Feb 10;313(6):594-602. doi: 10.1001/jama.2015.7

IMPORTANCE: Telomeres protect chromosome ends and are markers of cellular aging and replicative capacity.
OBJECTIVE: To evaluate the association between recipient and donor pretransplant leukocyte telomere length with outcomes after unrelated donor allogeneic hematopoietic cell transplantation (HCT) for patients with severe aplastic anemia.
DESIGN, PARTICIPANTS, AND SETTING: The study included 330 patients (235 acquired, 85 Fanconi anemia, and 10 Diamond-Blackfan anemia) and their unrelated donors who had pre-HCT blood samples and clinical and outcome data available at the Center for International Blood and Marrow Transplant Research. Patients underwent HCT between 1989 and 2007 in 84 centers and were followed-up to March 2013.
EXPOSURES: Recipient and donor pre-HCT leukocyte telomere length classified into long (third tertile) and short (first and second tertiles combined) based on donor telomere length distribution.
MAIN OUTCOMES AND MEASURES: Overall survival, neutrophil recovery, and acute and chronic graft-vs-host disease, as ascertained by transplant centers through regular patient follow-up.
RESULTS: Longer donor leukocyte telomere length was associated with higher survival probability (5-year overall survival, 56%; number at risk, 57; cumulative deaths, 50) than shorter donor leukocyte telomere length (5-year overall survival, 40%; number at risk, 71; cumulative deaths, 128; P = .009). The association remained statistically significant after adjusting for donor age, disease subtype, Karnofsky performance score, graft type, HLA matching, prior aplastic anemia therapy, race/ethnicity, and calendar year of transplant (hazard ratio [HR], 0.61; 95% CI, 0.44-0.86). Similar results were noted in analyses stratified on severe aplastic anemia subtype, recipient age, HLA matching, calendar year of transplant, and conditioning regimen. There was no association between donor telomere length and neutrophil engraftment at 28 days (cumulative incidence, 86% vs 85%; HR, 0.94; 95% CI, 0.73-1.22), acute graft-vs-host disease grades III-IV at 100 days (cumulative incidence, 22% vs 28%; HR, 0.77; 95% CI, 0.48-1.23), or chronic graft-vs-host disease at 1-year (cumulative incidence, 28% vs 30%; HR, 0.81; 95% CI, 0.53-1.24) for long vs short, respectively. Pretransplant leukocyte telomere length in the recipients was not associated with posttransplant survival (HR, 0.91; 95% CI, 0.64-1.30).
CONCLUSIONS AND RELEVANCE: Longer donor leukocyte telomere length was associated with increased 5-year survival in patients who received HCT for severe aplastic anemia. Patient leukocyte telomere length was not associated with survival. The results of this observational study suggest that donor leukocyte telomere length may have a role in long-term posttransplant survival.

Authors: Robbins HA, Pfeiffer RM, Shiels MS, Li J, Hall HI, Engels EA

Journal: J Natl Cancer Inst. 2015 Feb 6;107(4). pii: dju503. doi: 10.1093/jnci/dju503. Print 2015 Apr.

BACKGROUND: Nearly 900 000 people in the United States are living with diagnosed human immunodeficiency virus (HIV) infection and therefore increased cancer risk. The total number of cancers occurring among HIV-infected people and the excess number above expected background cases are unknown.
METHODS: We derived cancer incidence rates for the United States HIV-infected and general populations from Poisson models applied to linked HIV and cancer registry data and from Surveillance, Epidemiology, and End Results program data, respectively. We applied these rates to estimates of people living with diagnosed HIV at mid-year 2010 to estimate total and expected cancer counts, respectively. We subtracted expected from total cancers to estimate excess cancers.
RESULTS: An estimated 7760 (95% confidence interval [CI] = 7330 to 8320) cancers occurred in 2010 among HIV-infected people, of which 3920 cancers (95% CI = 3480 to 4470) or 50% (95% CI = 48 to 54%) were in excess of expected. The most common excess cancers were non-Hodgkin's lymphoma (NHL; n = 1440 excess cancers, occurring in 88% excess), Kaposi's sarcoma (KS, n = 910, 100% excess), anal cancer (n = 740, 97% excess), and lung cancer (n = 440, 52% excess). The proportion of excess cancers that were AIDS defining (ie, KS, NHL, cervical cancer) declined with age and time since AIDS diagnosis (both P < .001). For anal cancer, 83% of excess cases occurred among men who have sex with men, and 71% among those living five or more years since AIDS onset. Among injection drug users, 22% of excess cancers were lung cancer, and 16% were liver cancer.
CONCLUSIONS: The excess cancer burden in the US HIV population is substantial, and patterns across groups highlight opportunities for cancer control initiatives targeted to HIV-infected people.

Authors: Kim YJ, Igiesuorobo O, Ramos CI, Bao H, Zhang B, Serpe M

Journal: PLoS Genet. 2015 Feb 27;11(2):e1004988. doi: 10.1371/journal.pgen.1004988. eCollection 2015

Stabilization of neurotransmitter receptors at postsynaptic specializations is a key step in the assembly of functional synapses. Drosophila Neto (Neuropillin and Tolloid-like protein) is an essential auxiliary subunit of ionotropic glutamate receptor (iGluR) complexes required for the iGluRs clustering at the neuromuscular junction (NMJ). Here we show that optimal levels of Neto are crucial for stabilization of iGluRs at synaptic sites and proper NMJ development. Genetic manipulations of Neto levels shifted iGluRs distribution to extrajunctional locations. Perturbations in Neto levels also produced small NMJs with reduced synaptic transmission, but only Neto-depleted NMJs showed diminished postsynaptic components. Drosophila Neto contains an inhibitory prodomain that is processed by Furin1-mediated limited proteolysis. neto null mutants rescued with a Neto variant that cannot be processed have severely impaired NMJs and reduced iGluRs synaptic clusters. Unprocessed Neto retains the ability to engage iGluRs in vivo and to form complexes with normal synaptic transmission. However, Neto prodomain must be removed to enable iGluRs synaptic stabilization and proper postsynaptic differentiation.

Authors: Tiano JP, Springer DA, Rane SG

Journal: J Biol Chem. 2015 Feb 3. pii: jbc.M114.617399. [Epub ahead of print]

Beige adipose cells are a distinct and inducible type of thermogenic fat cell that express the mitochondrial uncoupling protein-1 and thus represent a powerful target for treating obesity. Mice lacking the transforming growth factor-beta (TGF-β) effector protein SMAD3 are protected against diet-induced obesity due to browning of their white adipose tissue (WAT) leading to increased whole body energy expenditure. However, the role SMAD3 plays in WAT browning is not clearly understood. Irisin is an exercise-induced skeletal muscle hormone that induces WAT browning similar to that observed in SMAD3 deficient mice. Together these observations suggested that SMAD3 may negatively regulate irisin production and/or secretion from skeletal muscle. To address this question we used wild type and SMAD3 knockout (Smad3-/-) mice subjected to an exercise regime and C2C12 myotubes treated with TGF-β, a TGF-β receptor-1 pharmacological inhibitor, adenovirus expressing constitutively active SMAD3 or siRNA against SMAD3. We find that in Smad3-/- mice exercise increases serum irisin and skeletal muscle FNDC5 (irisin precursor) and its upstream activator peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) to a greater extent than in wild type mice. In C2C12 myotubes TGF-β suppresses FNDC5 and PGC-1α mRNA and protein levels via SMAD3 and promotes SMAD3 binding to the FNDC5 and PGC-1α promoters. These data establish that SMAD3 suppresses FNDC5 and PGC-1α in skeletal muscle cells. These findings shed light on the poorly understood regulation of irisin/FNDC5 by demonstrating a novel association between irisin and SMAD3 signaling in skeletal muscle.

Authors: Aroda VR, Christophi CA, Edelstein SL, Zhang P, Herman WH, Barrett-Connor E, Delahanty LM, Montez MG, Ackermann RT, Zhuo X, Knowler WC, Ratner RE; for the Diabetes Prevention Program Research Group

Journal: J Clin Endocrinol Metab. 2015 Feb 23:jc20143761. [Epub ahead of print]

Context: Gestational diabetes (GDM) confers a high risk of type 2 diabetes. In the Diabetes Prevention Program (DPP), intensive lifestyle (ILS) and metformin prevented or delayed diabetes in women with a history of GDM. Objective: The objective of the study was to evaluate the impact of ILS and metformin intervention over 10 years in women with and without a history of GDM in the DPP/Diabetes Prevention Program Outcomes Study. Design: This was a randomized controlled clinical trial with an observational follow-up. Setting: The study was conducted at 27 clinical centers. Participants: Three hundred fifty women with a history of GDM and 1416 women with previous live births but no history of GDM participated in the study. The participants had an elevated body mass index and fasting glucose and impaired glucose tolerance at study entry. Interventions: Interventions included placebo, ILS, or metformin. Outcomes Measure: Outcomes measure was diabetes mellitus. Results: Over 10 years, women with a history of GDM assigned to placebo had a 48% higher risk of developing diabetes compared with women without a history of GDM. In women with a history of GDM, ILS and metformin reduced progression to diabetes compared with placebo by 35% and 40%, respectively. Among women without a history of GDM, ILS reduced the progression to diabetes by 30%, and metformin did not reduce the progression to diabetes. Conclusions: Women with a history of GDM are at an increased risk of developing diabetes. In women with a history of GDM in the DPP/Diabetes Prevention Program Outcomes Study, both lifestyle and metformin were highly effective in reducing progression to diabetes during a 10-year follow-up period. Among women without a history of GDM, lifestyle but not metformin reduced progression to diabetes.

Authors: Naik S, Bouladoux N, Linehan JL, Han SJ, Harrison OJ, Wilhelm C, Conlan S, Himmelfarb S, Byrd AL, Deming C, Quinones M, Brenchley JM, Kong HH, Tussiwand R, Murphy KM, Merad M, Segre JA, Belkaid Y

Journal: Nature. 2015 Jan 5. doi: 10.1038/nature14052. [Epub ahead of print]

The skin represents the primary interface between the host and the environment. This organ is also home to trillions of microorganisms that play an important role in tissue homeostasis and local immunity. Skin microbial communities are highly diverse and can be remodelled over time or in response to environmental challenges. How, in the context of this complexity, individual commensal microorganisms may differentially modulate skin immunity and the consequences of these responses for tissue physiology remains unclear. Here we show that defined commensals dominantly affect skin immunity and identify the cellular mediators involved in this specification. In particular, colonization with Staphylococcus epidermidis induces IL-17A+ CD8+ T cells that home to the epidermis, enhance innate barrier immunity and limit pathogen invasion. Commensal-specific T-cell responses result from the coordinated action of skin-resident dendritic cell subsets and are not associated with inflammation, revealing that tissue-resident cells are poised to sense and respond to alterations in microbial communities. This interaction may represent an evolutionary means by which the skin immune system uses fluctuating commensal signals to calibrate barrier immunity and provide heterologous protection against invasive pathogens. These findings reveal that the skin immune landscape is a highly dynamic environment that can be rapidly and specifically remodelled by encounters with defined commensals, findings that have profound implications for our understanding of tissue-specific immunity and pathologies.

Authors: Piaggi P, Thearle MS, Bogardus C, Krakoff J

Journal: J Clin Endocrinol Metab. 2015 Jan 5:jc20143582. [Epub ahead of print]

Context: Increased adiposity and insulin resistance are associated with hyperglycemia and previous studies have reported that higher glucoses are associated with lower rates of weight gain. One possible mechanism is via increased energy expenditure (EE). Objective: To assess the relationships between changes in EE during spontaneous weight gain and concomitant changes in glucose levels. Design and Participants: Body composition, metabolic and glycemic data were available from non-diabetic Native Americans who underwent two measurements of 24-h EE during eucaloric feeding in a metabolic chamber (N=144; time between measurements: 5.0±3.3 years) or resting EE by ventilated hood system during the euglycemic-hyperinsulinemic clamp (N=261; 4.5±3.2 years). Long-term follow-up data (8.3±4.3 years) for weight and body composition were available in 131 and 122 subjects, respectively. Main Outcome Measures: 24-h EE and respiratory quotient (RQ), resting (RMR) and sleeping (SMR) metabolic rates, glucose and insulin levels, basal glucose output (BGO). Results: Weight gain-associated increase in fasting plasma glucose (FPG) levels was accompanied with decreased 24-h RQ (partial R=-0.24, P=0.002) and increased 24-h EE, RMR, SMR and fat oxidation after accounting for changes in body composition (partial R: 0.12 to 0.19, all P≤0.05). Upon weight gain, BGO tended to increase (P=0.07) while insulin infusion induced a decrease in EE (P=0.04). Higher baseline FPG predicted lower rates of future weight gain (partial R=-0.18, P=0.04). Conclusions: Higher FPG after weight gain was associated with greater-than-expected increase in EE. The rise in BGO and the insulin-induced EE suppression at follow-up indicate that increased hepatic gluconeogenesis may be an important mediator of EE changes associated with weight gain.

Authors: Wentzensen N, Walker JL, Gold MA, Smith KM, Zuna RE, Mathews C, Dunn ST, Zhang R, Moxley K, Bishop E, Tenney M, Nugent E, Graubard BI, Wacholder S, Schiffman M

Journal: J Clin Oncol. 2015 Jan 1;33(1):83-9. doi: 10.1200/JCO.2014.55.9948

PURPOSE: Women with abnormal cervical cancer screening results are referred to colposcopy and biopsy for diagnosis of cervical cancer precursors (high-grade squamous intraepithelial lesions [HSILs]). Colposcopy with a single biopsy can miss identification of HSILs. No systematic study has quantified the improved detection of HSIL by taking multiple lesion-directed biopsies.
METHODS: The Biopsy Study was an observational study of 690 women referred to colposcopy after abnormal cervical cancer screening results. Up to four directed biopsies were taken from distinct acetowhite lesions and ranked by colposcopic impression. A nondirected biopsy of a normal-appearing area was added if fewer than four directed biopsies were taken. HSIL identified by any biopsy was the reference standard of disease used to evaluate the incremental yield and sensitivity of multiple biopsies.
RESULTS: In the overall population, sensitivities for detecting HSIL increased from 60.6% (95% CI, 54.8% to 66.6%) from a single biopsy to 85.6% (95% CI, 80.3% to 90.2%) after two biopsies and to 95.6% (95% CI, 91.3% to 99.2%) after three biopsies. A significant increase in sensitivity of multiple biopsies was observed in all subgroups. The highest increase in yield of HSIL was observed for women with a high-grade colposcopic impression, HSIL cytology, and human papillomavirus (HPV) type 16 positivity. Only 2% of all HSILs diagnosed in the participants were detected by biopsies of normal-appearing transformation zone.
CONCLUSION: Collection of additional lesion-directed biopsies during colposcopy increased detection of histologic HSIL, regardless of patient characteristics. Taking additional biopsies when multiple lesions are present should become the standard practice of colposcopic biopsy.

Authors: Andres SN, Appel CD, Westmoreland JW, Williams JS, Nguyen Y, Robertson PD, Resnick MA, Williams RS

Journal: Nat Struct Mol Biol. 2015 Jan 12. doi: 10.1038/nsmb.2945. [Epub ahead of print]

Ctp1 (also known as CtIP or Sae2) collaborates with Mre11-Rad50-Nbs1 to initiate repair of DNA double-strand breaks (DSBs), but its functions remain enigmatic. We report that tetrameric Schizosaccharomyces pombe Ctp1 contains multivalent DNA-binding and DNA-bridging activities. Through structural and biophysical analyses of the Ctp1 tetramer, we define the salient features of Ctp1 architecture: an N-terminal interlocking tetrameric helical dimer-of-dimers (THDD) domain and a central intrinsically disordered region (IDR) linked to C-terminal 'RHR' DNA-interaction motifs. The THDD, IDR and RHR are required for Ctp1 DNA-bridging activity in vitro, and both the THDD and RHR are required for efficient DSB repair in S. pombe. Our results establish non-nucleolytic roles of Ctp1 in binding and coordination of DSB-repair intermediates and suggest that ablation of human CtIP DNA binding by truncating mutations underlie the CtIP-linked Seckel and Jawad syndromes.

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