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1.  Genome-Wide Diet-Gene Interaction Analyses for Risk of Colorectal Cancer 
PLoS Genetics  2014;10(4):e1004228.
Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention.
Author Summary
High intake of red and processed meat and low intake of fruits, vegetables and fiber are associated with a higher risk of colorectal cancer. We investigate if the effect of these dietary factors on colorectal cancer risk is modified by common genetic variants across the genome (total of about 2.7 million genetic variants), also known as gene-diet interactions. We included over 9,000 colorectal cancer cases and 9,000 controls that were not diagnosed with colorectal cancer. Our results provide strong evidence for a gene-diet interaction and colorectal cancer risk between a genetic variant (rs4143094) on chromosome 10p14 near the gene GATA3 and processed meat consumption (p = 8.7E-09). This genetic locus may have interesting biological significance given its location in the genome. Our results suggest that genetic variants may interact with diet and in combination affect colorectal cancer risk, which may have important implications for personalized cancer care and provide novel insights into prevention strategies.
doi:10.1371/journal.pgen.1004228
PMCID: PMC3990510  PMID: 24743840
3.  Mutations in Conserved Residues of the C. elegans microRNA Argonaute ALG-1 Identify Separable Functions in ALG-1 miRISC Loading and Target Repression 
PLoS Genetics  2014;10(4):e1004286.
microRNAs function in diverse developmental and physiological processes by regulating target gene expression at the post-transcriptional level. ALG-1 is one of two Caenorhabditis elegans Argonautes (ALG-1 and ALG-2) that together are essential for microRNA biogenesis and function. Here, we report the identification of novel antimorphic (anti) alleles of ALG-1 as suppressors of lin-28(lf) precocious developmental phenotypes. The alg-1(anti) mutations broadly impair the function of many microRNAs and cause dosage-dependent phenotypes that are more severe than the complete loss of ALG-1. ALG-1(anti) mutant proteins are competent for promoting Dicer cleavage of microRNA precursors and for associating with and stabilizing microRNAs. However, our results suggest that ALG-1(anti) proteins may sequester microRNAs in immature and functionally deficient microRNA Induced Silencing Complexes (miRISCs), and hence compete with ALG-2 for access to functional microRNAs. Immunoprecipitation experiments show that ALG-1(anti) proteins display an increased association with Dicer and a decreased association with AIN-1/GW182. These findings suggest that alg-1(anti) mutations impair the ability of ALG-1 miRISC to execute a transition from Dicer-associated microRNA processing to AIN-1/GW182 associated effector function, and indicate an active role for ALG/Argonaute in mediating this transition.
Author Summary
microRNAs are small non-coding RNAs that function in diverse processes by post-transcriptionally regulating gene expression. Argonautes form the core of the microRNA Induced Silencing Complex (miRISC) and are required for microRNA biogenesis and function. Here we describe the identification and characterization of a novel set of mutations in alg-1, a Caenorhabditis elegans microRNA specific Argonaute. This new class of alg-1 mutations causes phenotypes more severe than the complete loss of alg-1. Interestingly, the mutant ALG-1 proteins are able to promote microRNA biogenesis, but are defective in mediating microRNA target gene repression. We found that mutant ALG-1 associates more with Dicer, but less with miRISC effector AIN-1, compared to wild type ALG-1. We propose that these mutant ALG-1 proteins assemble nonfunctional complexes that effectively compete with the paralogous ALG-2 for critical miRISC components, including mature microRNAs. This new class of Argonaute mutants highlights the role of Argonaute in mediating a functional transition for miRISC from microRNA processing phase to target repression phase.
doi:10.1371/journal.pgen.1004286
PMCID: PMC3998888  PMID: 24763381
4.  Folliculin Regulates Ampk-Dependent Autophagy and Metabolic Stress Survival 
PLoS Genetics  2014;10(4):e1004273.
Dysregulation of AMPK signaling has been implicated in many human diseases, which emphasizes the importance of characterizing AMPK regulators. The tumor suppressor FLCN, responsible for the Birt-Hogg Dubé renal neoplasia syndrome (BHD), is an AMPK-binding partner but the genetic and functional links between FLCN and AMPK have not been established. Strikingly, the majority of naturally occurring FLCN mutations predisposing to BHD are predicted to produce truncated proteins unable to bind AMPK, pointing to the critical role of this interaction in the tumor suppression mechanism. Here, we demonstrate that FLCN is an evolutionarily conserved negative regulator of AMPK. Using Caenorhabditis elegans and mammalian cells, we show that loss of FLCN results in constitutive activation of AMPK which induces autophagy, inhibits apoptosis, improves cellular bioenergetics, and confers resistance to energy-depleting stresses including oxidative stress, heat, anoxia, and serum deprivation. We further show that AMPK activation conferred by FLCN loss is independent of the cellular energy state suggesting that FLCN controls the AMPK energy sensing ability. Together, our data suggest that FLCN is an evolutionarily conserved regulator of AMPK signaling that may act as a tumor suppressor by negatively regulating AMPK function.
Author Summary
The FLCN gene is responsible for the hereditary human tumor disease called Birt-Hogg-Dube syndrome (BHD). Patients that inherit an inactivating mutation in the FLCN gene develop lung collapse as well as tumors in the kidney, colon, and skin. It is not clear yet what the exact function of this protein is in the cell or an organism. In this study, we used a simple model organism (the round worm C. elegans) to study the function of FLCN. We found that it is involved in the regulation of energy metabolism in the cell. FLCN normally binds and blocks the action of another protein (AMPK), which is involved in the maintenance of energy levels. When energy levels fall, AMPK is activated and drives a recycling pathway called autophagy, where cellular components are recycled producing energy. In the absence of FLCN in worms and mammalian cells, like in tumors of BHD patients, AMPK and autophagy are chronically activated leading to an increased energy level, which makes the cells/organism very resistant to many stresses that would normally kill them, which in the end could lead to progression of tumorigenesis.
doi:10.1371/journal.pgen.1004273
PMCID: PMC3998892  PMID: 24763318
5.  The Effects of Somatic Hypermutation on Neutralization and Binding in the PGT121 Family of Broadly Neutralizing HIV Antibodies 
PLoS Pathogens  2013;9(11):e1003754.
Broadly neutralizing HIV antibodies (bnAbs) are typically highly somatically mutated, raising doubts as to whether they can be elicited by vaccination. We used 454 sequencing and designed a novel phylogenetic method to model lineage evolution of the bnAbs PGT121–134 and found a positive correlation between the level of somatic hypermutation (SHM) and the development of neutralization breadth and potency. Strikingly, putative intermediates were characterized that show approximately half the mutation level of PGT121–134 but were still capable of neutralizing roughly 40–80% of PGT121–134 sensitive viruses in a 74-virus panel at median titers between 15- and 3-fold higher than PGT121–134. Such antibodies with lower levels of SHM may be more amenable to elicitation through vaccination while still providing noteworthy coverage. Binding characterization indicated a preference of inferred intermediates for native Env binding over monomeric gp120, suggesting that the PGT121–134 lineage may have been selected for binding to native Env at some point during maturation. Analysis of glycan-dependent neutralization for inferred intermediates identified additional adjacent glycans that comprise the epitope and suggests changes in glycan dependency or recognition over the course of affinity maturation for this lineage. Finally, patterns of neutralization of inferred bnAb intermediates suggest hypotheses as to how SHM may lead to potent and broad HIV neutralization and provide important clues for immunogen design.
Author Summary
A majority of the over 30 million HIV-1 infected individuals worldwide live in poorly resourced areas where multiple boost strategies, which are likely needed to generate highly mutated antibodies, present formidable logistical challenges. Accordingly, developing new vaccination strategies that are capable of generating highly mutated antibodies should be an active area of research. Another approach, that is not mutually exclusive, is to identify new bnAbs that are both broad and potent in neutralization, but are much less mutated than the bnAbs that currently exist. Here, we have identified bnAbs that are approximately half the mutation frequency of known bnAbs, but maintain high potency and moderate breadth. These less mutated bnAbs offer an important advantage in that they would likely be easier to induce through vaccination than more mutated antibodies. By characterizing these putative intermediates, we can also better estimate how affinity maturation proceeded to result in an antibody with broad and potent neutralization activity and offer more focused strategies for designing immunogens capable of eliciting these less mutated bnAbs.
doi:10.1371/journal.ppat.1003754
PMCID: PMC3836729  PMID: 24278016
6.  New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes 
Sandholm, Niina | Salem, Rany M. | McKnight, Amy Jayne | Brennan, Eoin P. | Forsblom, Carol | Isakova, Tamara | McKay, Gareth J. | Williams, Winfred W. | Sadlier, Denise M. | Mäkinen, Ville-Petteri | Swan, Elizabeth J. | Palmer, Cameron | Boright, Andrew P. | Ahlqvist, Emma | Deshmukh, Harshal A. | Keller, Benjamin J. | Huang, Huateng | Ahola, Aila J. | Fagerholm, Emma | Gordin, Daniel | Harjutsalo, Valma | He, Bing | Heikkilä, Outi | Hietala, Kustaa | Kytö, Janne | Lahermo, Päivi | Lehto, Markku | Lithovius, Raija | Österholm, Anne-May | Parkkonen, Maija | Pitkäniemi, Janne | Rosengård-Bärlund, Milla | Saraheimo, Markku | Sarti, Cinzia | Söderlund, Jenny | Soro-Paavonen, Aino | Syreeni, Anna | Thorn, Lena M. | Tikkanen, Heikki | Tolonen, Nina | Tryggvason, Karl | Tuomilehto, Jaakko | Wadén, Johan | Gill, Geoffrey V. | Prior, Sarah | Guiducci, Candace | Mirel, Daniel B. | Taylor, Andrew | Hosseini, S. Mohsen | Parving, Hans-Henrik | Rossing, Peter | Tarnow, Lise | Ladenvall, Claes | Alhenc-Gelas, François | Lefebvre, Pierre | Rigalleau, Vincent | Roussel, Ronan | Tregouet, David-Alexandre | Maestroni, Anna | Maestroni, Silvia | Falhammar, Henrik | Gu, Tianwei | Möllsten, Anna | Cimponeriu, Danut | Ioana, Mihai | Mota, Maria | Mota, Eugen | Serafinceanu, Cristian | Stavarachi, Monica | Hanson, Robert L. | Nelson, Robert G. | Kretzler, Matthias | Colhoun, Helen M. | Panduru, Nicolae Mircea | Gu, Harvest F. | Brismar, Kerstin | Zerbini, Gianpaolo | Hadjadj, Samy | Marre, Michel | Groop, Leif | Lajer, Maria | Bull, Shelley B. | Waggott, Daryl | Paterson, Andrew D. | Savage, David A. | Bain, Stephen C. | Martin, Finian | Hirschhorn, Joel N. | Godson, Catherine | Florez, Jose C. | Groop, Per-Henrik | Maxwell, Alexander P. | Böger, Carsten A.
PLoS Genetics  2012;8(9):e1002921.
Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
Author Summary
The global prevalence of diabetes has reached epidemic proportions, constituting a major health care problem worldwide. Diabetic kidney disease, or diabetic nephropathy (DN)—the major long term microvascular complication of diabetes—is associated with excess mortality among patients with type 1 diabetes. Even though DN has been shown to cluster in families, the underlying genetic and molecular pathways remain poorly defined. We have undertaken the largest genome-wide association study and meta-analysis to date on DN and on its most severe form of kidney disease, end-stage renal disease (ESRD). We identified new loci significantly associated with diabetic ESRD: AFF3 and an intergenic locus on chromosome 15q26 residing between RGMA and MCTP2. Our functional analyses suggest that AFF3 influences renal tubule fibrosis, a pathological hallmark of severe DN. Another locus in ERBB4 was suggestively associated with DN and resides in the same intronic region as a variant affecting the expression of ERBB4. Subsequent pathway analysis of the genes co-expressed with ERBB4 indicated involvement of fibrosis.
doi:10.1371/journal.pgen.1002921
PMCID: PMC3447939  PMID: 23028342
7.  An Accessory to the ‘Trinity’: SR-As Are Essential Pathogen Sensors of Extracellular dsRNA, Mediating Entry and Leading to Subsequent Type I IFN Responses 
PLoS Pathogens  2010;6(3):e1000829.
Extracellular RNA is becoming increasingly recognized as a signaling molecule. Virally derived double stranded (ds)RNA released into the extracellular space during virus induced cell lysis acts as a powerful inducer of classical type I interferon (IFN) responses; however, the receptor that mediates this response has not been identified. Class A scavenger receptors (SR-As) are likely candidates due to their cell surface expression and ability to bind nucleic acids. In this study, we investigated a possible role for SR-As in mediating type I IFN responses induced by extracellular dsRNA in fibroblasts, a predominant producer of IFNβ. Fibroblasts were found to express functional SR-As, even SR-A species thought to be macrophage specific. SR-A specific competitive ligands significantly blocked extracellular dsRNA binding, entry and subsequent interferon stimulated gene (ISG) induction. Candidate SR-As were systematically investigated using RNAi and the most dramatic inhibition in responses was observed when all candidate SR-As were knocked down in unison. Partial inhibition of dsRNA induced antiviral responses was observed in vivo in SR-AI/II-/- mice compared with WT controls. The role of SR-As in mediating extracellular dsRNA entry and subsequent induced antiviral responses was observed in both murine and human fibroblasts. SR-As appear to function as ‘carriers’, facilitating dsRNA entry and delivery to the established dsRNA sensing receptors, specifically TLR3, RIGI and MDA-5. Identifying SR-As as gatekeepers of the cell, mediating innate antiviral responses, represents a novel function for this receptor family and provides insight into how cells recognize danger signals associated with lytic virus infections. Furthermore, the implications of a cell surface receptor capable of recognizing extracellular RNA may exceed beyond viral immunity to mediating other important innate immune functions.
Author Summary
Nearly all viruses produce dsRNA during their replication cycle. This molecule is not normally found in a healthy host cell and thus functions as a flag, alerting the host to a viral infection. Cells can die by lysis during virus infections, and the intracellular dsRNA is then released into the extracellular space. This dsRNA is stable in the extracellular milieu, and is able to function as a signaling molecule, detected by neighboring cells. This has been observed experimentally, as extracellular dsRNA has been used for years to trigger host antiviral responses. It has also been suggested that extracellular dsRNA plays a role in causing pathological symptoms in virus infected patients. Our data suggests that class A scavenger receptors (SR-As) function as cell surface receptors for dsRNA. SR-As bind extracellular, viral dsRNA and mediate its entry into the cell, where it delivers the dsRNA to other known intracellular dsRNA sensors, activating intracellular antiviral responses. These findings shed new light on how the host detects and responds to virus infection.
doi:10.1371/journal.ppat.1000829
PMCID: PMC2847946  PMID: 20360967
8.  The Future of Toxicity Testing: A Focus on In Vitro Methods Using a Quantitative High Throughput Screening Platform 
Drug discovery today  2010;15(23-24):997-1007.
The U.S. Tox21 collaborative program represents a paradigm shift in toxicity testing of chemical compounds from traditional in vivo tests to less expensive and higher throughput in vitro methods to prioritize compounds for further study, identify mechanisms of action, and ultimately develop predictive models for adverse health effects in humans. The NIH Chemical Genomics Center (NCGC) is an integral component of the Tox21 collaboration due to its quantitative high throughput screening (qHTS) paradigm, in which titration-based screening is used to profile hundreds of thousands of compounds per week. Here, we describe the Tox21 collaboration, qHTS-based compound testing, and the various Tox21 screening assays that have been validated and tested at the NCGC to date.
doi:10.1016/j.drudis.2010.07.007
PMCID: PMC2994991  PMID: 20708096
Tox21; National Research Council; National Toxicology Program; toxicity testing; in vitro assays; NIH Roadmap; NIH Chemical Genomics Center; quantitative high-throughput screening
9.  Sex Differences in Application, Success, and Funding Rates for NIH Extramural Programs 
Academic Medicine  2011;86(6):759-767.
Purpose
The authors provide an analysis of sex differences in National Institutes of Health (NIH) award programs to inform potential initiatives for promoting diversity in the research workforce.
Method
In 2010, the authors retrieved data for NIH extramural grants in the electronic Research Administration Information for Management, Planning, and Coordination II database, and used statistical analysis to determine any sex differences in securing NIH funding, as well as subsequent success of researchers who had already received independent NIH support.
Results
Success and funding rates for men and women were not significantly different in most award programs. Furthermore, in programs where participation was lower for women than men, the disparity was primarily related to a lower percentage of women applicants compared to men, rather than decreased success rates or funding rates. However, for subsequent grants, both application and funding rates were generally higher for men than for women.
Conclusions
Cross-sectional analysis showed that women and men were generally equally successful at all career stages, but longitudinal analysis showed that men with previous experience as NIH grantees had higher application and funding rates than women at similar career points. On average, although women received larger R01 awards than men, men had more R01 awards than women at all points in their careers. Therefore, while greater participation of women in NIH programs is underway, further action will be required to eradicate remaining sex differences.
doi:10.1097/ACM.0b013e31821836ff
PMCID: PMC3379556  PMID: 21512358
10.  Stepwise histone modifications are mediated by multiple enzymes that rapidly associate with nascent DNA during replication 
Nature communications  2013;4:10.1038/ncomms3841.
The mechanism of epigenetic inheritance following DNA replication may involve dissociation of chromosomal proteins from parental DNA and reassembly on daughter strands in a specific order. Here we investigated the behavior of different types of chromosomal proteins using newly developed methods that allow assessment of the assembly of proteins during DNA replication. Unexpectedly, most chromatin-modifying proteins tested, including methylases, demethylases, acetyltransferases and a deacetylase, are found in close proximity to PCNA or associate with short nascent DNA. Histone modifications occur in a temporal order following DNA replication, mediated by complex activities of different enzymes. In contrast, components of several major nucleosome remodeling complexes are dissociated from parental DNA, and are later recruited to nascent DNA following replication. Epigenetic inheritance of gene expression patterns may require many aspects of chromatin structure to remain in close proximity to the replication complex followed by re-assembly on nascent DNA shortly after replication.
doi:10.1038/ncomms3841
PMCID: PMC3874871  PMID: 24276476
11.  Norepinephrine Inhibits Macrophage Migration by Decreasing CCR2 Expression 
PLoS ONE  2013;8(7):e69167.
Increased incidences of infectious and septic complications during post-burn courses represent the main contributor to burn injury mortality. Sustained increases in catecholamine levels, especially norepinephrine (NE), contribute to immune disturbances in severely burned patients. The precise mechanisms underlying NE-mediated immunoregulation are not fully understood. Here we hypothesize that persistently elevated NE levels are associated with immunodysfunctions. We examined the effects of NE on the phenotype and functions of bone marrow-derived macrophages (BMMs). Whole mouse bone marrow cells were treated in vitro with 40 ng/mL of M-CSF and with 1 x 10-6 M or 1 x 10-8 M of NE or without NE for 7 days; cells were collected and stained with antibodies for CD11b, F4/80, MHC II and the inflammatory CC chemokine receptor 2 (CCR2). We found 1 x 10-6 M of NE inhibited MHC II and CCR2 expression on CD11b+/F4/80+ BMM cells. It also inhibited BMM proliferation by inhibiting CSF-1R expression. On the contrary, 1 x 10-8 M of NE slightly increased both MHC II and CCR2 expression on CD11b+/F4/80+ BMM cells but inhibited CD11b+/F4/80+ BMM proliferation. MCP-1 based migration assay showed that the migration of 1 x 10-6 M of NE-treated BMM toward MCP-1 was significantly decreased compared to BMM without NE treatment. Both 1 x 10-8 M and 1 x 10-6 M of NE enhanced TNF-α production and phagocytosis of FITC-Dextran. Intracellular staining of transcriptional factor MafB showed that 1 x 10-6 M of NE treatment enhanced its expression, whereas 1 x 10-8 M of NE decreased expression. Stimulation with LPS in the last 24-hours of BMM culture further decreased CCR2 and MHC II expression of these BMM, suggesting the synergistic effect of LPS and NE on macrophage. Our results demonstrate that NE regulates macrophage differentiation, proliferation and function, and may play a critical role in the dysfunctional immune response post-burn.
doi:10.1371/journal.pone.0069167
PMCID: PMC3699643  PMID: 23844252
12.  An Update: NIH Research Funding for Palliative Medicine 2006 to 2010 
Journal of Palliative Medicine  2013;16(2):125-129.
Abstract
Background
Palliative care clinical and educational programs are expanding to meet the needs of seriously ill patients and their families. Multiple reports call for an enhanced palliative care evidence base.
Objective
To examine current National Institutes of Health (NIH) funding of palliative medicine research and changes since our 2008 report.1
Methods
We sought to identify NIH funding of palliative medicine from 2006 to 2010 in two stages. First, we searched the NIH grants database RePorter2 for grants with key words “palliative care,” “end-of-life care,” “hospice,” and “end of life.” Second, we identified palliative care researchers likely to have secured NIH funding using three strategies: (1) We abstracted the first and last authors' names from original investigations published in major palliative medicine journals from 2008 to 2010; (2) we abstracted these names from a PubMed generated list of all original articles published in major medicine, nursing, and subspecialty journals using the above key words Medical Subject Headings (MESH) terms “palliative care,” “end-of-life care,” “hospice,” and “end of life;” and (3) we identified editorial board members of palliative medicine journals and key members of palliative medicine research initiatives. We crossmatched the pooled names against NIH grants funded from 2006 to 2010.
Results
The NIH RePorter search yielded 653 grants and the author search identified an additional 352 grants. Compared to 2001 to 2005, 589 (240%) more grants were NIH funded. The 391 grants categorized as relevant to palliative medicine represented 294 unique PIs, an increase of 185 (269%) NIH funded palliative medicine researchers. The NIH supported 21% of the 1253 original palliative medicine research articles identified. Compared to 2001 to 2005, the percentage of grants funded by institutes other than the National Cancer Institute (NCI), the National Institute for Nursing Research (NINR), and the National Institute of Aging (NIA) increased from 15% to 20% of all grants.
Conclusions
When compared to 2001–2005, more palliative medicine investigators received NIH funding; and research funding has improved. Nevertheless, additional initiatives to further support palliative care research are needed.
doi:10.1089/jpm.2012.0427
PMCID: PMC3607902  PMID: 23336358
13.  Faculty experiences with the National Institutes of Health (NIH) public access policy, compliance issues, and copyright practices 
Objectives:
The research assessed faculty awareness of the National Institutes of Health (NIH) public access policy and faculty experiences with the copyright terms in their author agreements with publishers.
Methods:
During the fall of 2011, 198 faculty members receiving funding from NIH at a large urban academic institution were invited to participate in an anonymous online survey. A total of 94 faculty members responded to the survey, representing a response rate of 47%.
Results:
Thirty percent of the survey respondents were either unaware of or not familiar with the NIH policy. Further, a significant number of faculty members (97.8%) indicated that they usually signed their copyright forms “as is.” The findings show that time, confusing instructions, and unclear journal policies are challenges experienced by NIH-funded faculty in complying with the federal mandate.
Conclusion:
There is a need to educate faculty with respect to the value of retaining their copyrights and self-archiving their publications to help advance public access and open access scholarship.
doi:10.3163/1536-5050.101.1.004
PMCID: PMC3543125  PMID: 23405043
14.  Are Race, Ethnicity, and Medical School Affiliation Associated With NIH R01 Type Award Probability for Physician Investigators? 
Purpose
To analyze the relationship among NIH R01 Type 1 applicant degree, institution type, and race/ethnicity, and application award probability.
Method
The authors used 2000–2006 data from the NIH IMPAC II grants database and other sources to determine which individual and institutional characteristics of applicants may affect the probability of applications being awarded funding. They used descriptive statistics and probit models to estimate correlations between race/ethnicity, degree (MD or PhD), and institution type (medical school or other institution), and application award probability, controlling for a large set of observable characteristics.
Results
Applications from medical schools were significantly more likely than those from other institutions to receive funding, as were applications from MDs versus PhDs. Overall, applications from blacks and Asians were less likely than those from whites to be awarded funding; however, among applications from MDs at medical schools, there was no difference in funding probability between whites and Asians and the difference between blacks and whites decreased to 7.8 percentage points. The inclusion of human subjects significantly decreased the likelihood of receiving funding.
Conclusions
Compared with applications from whites, applications from blacks have a lower probability of being awarded R01 Type 1 funding, regardless of the investigator’s degree. However, funding probability is increased for applications with MD investigators and for those from medical schools. To some degree, these advantages combine so that applications from black MDs at medical schools have the smallest difference in funding probability compared with those from whites.
doi:10.1097/ACM.0b013e31826d726b
PMCID: PMC3485449  PMID: 23018334
15.  Pancreatic Cancer and Exposure to Dietary Nitrate and Nitrite in the NIH-AARP Diet and Health Study 
American Journal of Epidemiology  2011;174(3):305-315.
Nitrate and nitrite are precursors of N-nitroso compounds, which induce tumors of the pancreas in animals. The authors evaluated the relation of dietary nitrate and nitrite to pancreatic cancer risk in the NIH-AARP Diet and Health Study. Nitrate and nitrite intakes were assessed at baseline using a 124-item food frequency questionnaire. During approximately 10 years of follow-up between 1995 and 2006, 1,728 incident pancreatic cancer cases were identified. There was no association between total nitrate or nitrite intake and pancreatic cancer in men or women. However, men in the highest quintile of summed nitrate/nitrite intake from processed meat had a nonsignificantly elevated risk of pancreatic cancer (hazard ratio = 1.18, 95% confidence interval: 0.95, 1.47; P-trend = 0.11). The authors observed a stronger increase in risk among men for nitrate/nitrite intake from processed meat at ages 12–13 years (highest quintile vs. lowest: hazard ratio = 1.32, 95% confidence interval: 0.99, 1.76; P-trend = 0.11), though the relation did not achieve statistical significance. The authors found no associations between adult or adolescent nitrate or nitrite intake from processed meats and pancreatic cancer among women. These results provide modest evidence that processed meat sources of dietary nitrate and nitrite may be associated with pancreatic cancer among men and provide no support for the hypothesis in women.
doi:10.1093/aje/kwr092
PMCID: PMC3202160  PMID: 21685410
diet; nitrates; nitrites; nitroso compounds; pancreatic neoplasms
16.  Reproductive Factors and Exogenous Hormone Use and Risk of Adult Glioma in Women in the NIH-AARP Diet and Health Study 
Experimental evidence suggests that estrogen and other steroid hormones may protect against glioma. Although epidemiologic studies provide only weak support for a role of exogenous or endogenous hormones in gliogenesis, few cohort studies have addressed this question. The authors therefore examined the association between menstrual and reproductive factors, exogenous hormone use, and glioma risk among 225,355 women aged 50 to 71 years who completed the baseline questionnaire in the NIH-AARP Diet and Health Study. During 7 years of follow-up 174 cases of incident, primary glioma were ascertained. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for exposures taking potential confounders into account. Older age at menarche was positively associated with risk: HR 1.67 (95% CI: 1.03, 2.69). Other reproductive factors, including age at first live birth, parity, age at menopause, type of menopause (natural vs. medical), and exogenous hormone use showed no association with glioma risk. The results were similar when the analysis was restricted to cases with glioblastoma (N = 130). The present study provides only limited support for the hypothesis that menstrual/reproductive factors or exogenous hormone use play a role in gliogenesis.
doi:10.1002/ijc.25413
PMCID: PMC3491883  PMID: 20473903
17.  Geographic Variation in Colorectal Cancer Survival and the Role of Small-Area Socioeconomic Deprivation: A Multilevel Survival Analysis of the NIH-AARP Diet and Health Study Cohort 
American Journal of Epidemiology  2011;174(7):828-838.
Adverse socioeconomic conditions, at both the individual and the neighborhood level, increase the risk of colorectal cancer (CRC) death, but little is known regarding whether CRC survival varies geographically and the extent to which area-level socioeconomic deprivation affects this geographic variation. Using data from the National Institutes of Health (NIH)-AARP Diet and Health Study, the authors examined geographic variation and the role of area-level socioeconomic deprivation in CRC survival. CRC cases (n = 7,024), identified during 1995–2003, were followed for their CRC-specific vital status through 2005 and overall vital status through 2006. Bayesian multilevel survival models showed that there was significant geographic variation in overall (variance = 0.2, 95% confidence interval (CI): 0.1, 0.2) and CRC-specific (variance = 0.3, 95% CI: 0.1, 0.4) risk of death. More socioeconomically deprived neighborhoods had a higher overall risk of death (most deprived quartile vs. least deprived: hazard ratio = 1.2, 95% CI: 1.1, 1.4) and a higher CRC-specific risk of death (most deprived quartile vs. least deprived: hazard ratio = 1.2, 95% CI: 1.1, 1.5). However, neighborhood socioeconomic deprivation did not account for the geographic variation in overall and CRC-specific risks of death. In future studies, investigators should evaluate other neighborhood characteristics to help explain geographic heterogeneity in CRC survival. Such research could facilitate interventions for reducing geographic disparity in CRC survival.
doi:10.1093/aje/kwr162
PMCID: PMC3203377  PMID: 21836166
cohort studies; colorectal neoplasms; geography; multilevel analysis; residence characteristics; socioeconomic factors; survival
18.  Intakes of fruit, vegetables, and specific botanical groups in relation to lung cancer risk in the NIH-AARP Diet and Health Study 
American journal of epidemiology  2008;168(9):1024-1034.
Increased fruit and vegetable consumption may protect against lung cancer, although epidemiologic findings are inconclusive. The authors prospectively examined associations between lung cancer risk and intakes of fruit, vegetables, and botanical subgroups in 472,081 participants aged 50-71 years in the National Institutes of Health (NIH)-AARP Diet and Health Study. Diet was assessed at baseline with a 124-item dietary questionnaire. A total of 6,035 incident lung cancer cases were identified between 1995 and 2003. Total fruit and vegetable intake was unrelated to lung cancer risk in both men and women. Higher consumption of several botanical subgroups, however, was significantly inversely associated with risk, but only in men. For example, the relative risks (RR) and 95% confidence intervals (CI) for lung cancer among men in the highest versus lowest quintiles of intake of rosaceae, convolvulaceae, and umbelliferae were 0.82 (0.73, 0.91), 0.86 (0.78, 0.96), and 0.86 (0.78, 0.96), respectively; corresponding RRs in women were 0.97 (0,85, 1.12), 0.95 (0.83, 1.09), and 0.92 (0.80, 1.06). These results provide support for a protective role of specific botanical subgroups of fruit and vegetables in lung cancer prevention in men, although these findings could also be due to residual confounding by smoking or chance.
doi:10.1093/aje/kwn212
PMCID: PMC2631557  PMID: 18791192
cohort studies; fruit; lung neoplasms; vegetables
19.  Intakes of Fruit, Vegetables, and Specific Botanical Groups in Relation to Lung Cancer Risk in the NIH-AARP Diet and Health Study 
American Journal of Epidemiology  2008;168(9):1024-1034.
Increased fruit and vegetable consumption may protect against lung cancer, although epidemiologic findings are inconclusive. The authors prospectively examined associations between lung cancer risk and intakes of fruit, vegetables, and botanical subgroups in 472,081 participants aged 50–71 years in the National Institutes of Health (NIH)-AARP Diet and Health Study. Diet was assessed at baseline (1995–1996) with a 124-item dietary questionnaire. A total of 6,035 incident lung cancer cases were identified between 1995 and 2003. Total fruit and vegetable intake was unrelated to lung cancer risk in both men and women. Higher consumption of several botanical subgroups, however, was significantly inversely associated with risk, but only in men. For example, the relative risks of lung cancer among men in the highest versus lowest quintiles of intake of rosaceae, convolvulaceae, and umbelliferae were 0.82 (95% confidence interval (CI): 0.73, 0.91), 0.86 (95% CI: 0.75, 0.96), and 0.86 (95% CI: 0.78, 0.96), respectively; corresponding relative risks in women were 0.97 (95% CI: 0.85, 1.12), 0.95 (95% CI: 0.83, 1.09), and 0.92 (95% CI: 0.80, 1.06). These results provide support for a protective role of specific botanical subgroups of fruits and vegetables in lung cancer prevention in men, although the findings could also be due to residual confounding by smoking or chance.
doi:10.1093/aje/kwn212
PMCID: PMC2631557  PMID: 18791192
cohort studies; fruit; lung neoplasms; vegetables
20.  Twenty-five Years of Translating Service at NIH 
The growth of the Translating Unit of the National Institutes of Health Library, founded in 1938, was slow until 1950, when seventeen translators and clerical assistants comprised its staff. Today eleven staff members translate, type, and distribute translations from eighteen European languages. Contract service is arranged for those languages for which the Unit has little or no competency. Three recent innovations have improved the translating service: (1) production standards, (2) fee for service, and (3) microfilmed translations. A monthly bulletin, Recent Translations, a Selected List, includes those articles translated by the Translating Unit of the NIH Library. An author index to all translations cited in the Selected List is now available upon request.
PMCID: PMC198298  PMID: 14306030
21.  The Race Is On Human Embryonic Stem Cell Research Goes Global 
Stem cell reviews  2012;8(4):1043-1047.
More nations are joining the human embryonic stem cell (hESC) “race” by aggressively publishing in the peer-reviewed journals. Here we present data on the international use and distribution of hESC using a dataset taken from the primary research literature. We extracted these papers from a comprehensive dataset of articles using hESC and human induced pluripotent cells (hiPSC). We find that the rate of publication by US-based authors is slowing in comparison to international labs, and then declines over the final year of the period 2008–2010. Non-US authors published more frequently and at a significantly higher rate, significantly increasing the number of their papers. In addition, international labs use a more diverse set of hESC lines and Obama-era additions are used more in non-US locations. Even considering the flood of new lines in the US and abroad, we see that researchers continue to rely on a few lines derived before the turn of the century. These data suggest the “embargo” effects of restrictive policy on the US stem cell field. Over time, non-US labs have freely used lines on the US registries, while federally funded US scientists have been limited to using those lines approved by the NIH.
doi:10.1007/s12015-012-9391-6
PMCID: PMC3933365  PMID: 22715049
policy; ethics; law; human embryonic stem cell research; induced pluripotent stem cells; NIH; Obama; G.W. Bush
22.  A New Mechanism for Tracking Publicly Available Study Volunteer Demographics 
Drug information journal  2011;45(1):55-64.
The importance of gathering and monitoring aggregate demographic data on the annual population of study volunteers in FDA-regulated clinical trials is widely acknowledged. To date, no formal mechanism exists to capture this information. The Tufts Center for the Study of Drug Development identified and tested a publicly available source of information on clinical trial participant data, NDA Reviews stored in the FDA’s drugs@FDA database, to determine its accuracy, reliability, and feasibility. Thirty-seven new drug applications approved between 2006 and 2008 were evaluated and compared with published sources of demographic data. The authors conclude that the approach described here—NDA review extraction—provides reasonably reliable and conservative estimates of study volunteer demographics and can serve as a useful baseline until Clinicaltrials.gov or other, more complete, public sources become available.
PMCID: PMC3103243  PMID: 21625297
Clinical trial; FDA; NDA; NIH; Demographic data
23.  Glut4 Storage Vesicles without Glut4: Transcriptional Regulation of Insulin-Dependent Vesicular Traffic 
Molecular and Cellular Biology  2004;24(16):7151-7162.
Two families of transcription factors that play a major role in the development of adipocytes are the CCAAT/enhancer-binding proteins (C/EBPs) and the peroxisome proliferator-activated receptors (PPARs), in particular PPARγ. Ectopic expression of either C/EBPα or PPARγ in NIH 3T3 fibroblasts results in the conversion of these cells to adipocyte-like cells replete with fat droplets. NIH 3T3 cells ectopically expressing C/EBPα (NIH-C/EBPα) differentiate into adipocytes and exhibit insulin-stimulated glucose uptake, whereas NIH 3T3 cells ectopically expressing PPARγ (NIH-PPARγ) differentiate but do not exhibit any insulin-stimulated glucose uptake, nor do they express any C/EBPα. The reason for the lack of insulin-responsive glucose uptake in the NIH-PPARγ cells is their virtual lack of the insulin-responsive glucose transporter, Glut4. The NIH-PPARγ cells express functionally active components of the insulin receptor-signaling pathway (the insulin receptor, IRS-1, phosphatidylinositol 3-kinase, and Akt2) at levels comparable to those in responsive cell lines. They also express components of the insulin-sensitive vesicular transport machinery, namely, VAMP2, syntaxin-4, and IRAP, the last of these being the other marker of insulin-regulated vesicular traffic along with Glut4. Interestingly, the NIH-PPARγ cells show normal insulin-dependent translocation of IRAP and form an insulin-responsive vesicular compartment as assessed by cell surface biotinylation and sucrose velocity gradient analysis, respectively. Moreover, expression of a Glut4-myc construct in the NIH-PPARγ cells results in its insulin-dependent translocation to the plasma membrane as assessed by immunofluorescence and Western blot analysis. Based on these data, we conclude that major role of C/EBPα in the context of the NIH-PPARγ cells is to regulate Glut4 expression. The differentiated cells possess a large insulin-sensitive vesicular compartment with negligible Glut4, and Glut4 translocation can be reconstituted on expression of this transporter.
doi:10.1128/MCB.24.16.7151-7162.2004
PMCID: PMC479711  PMID: 15282314
24.  The Impact of National Institutes of Health Funding on U.S. Cardiovascular Disease Research 
PLoS ONE  2009;4(7):e6425.
Background
Intense interest surrounds the recent expansion of US National Institutes of Health (NIH) budgets as part of economic stimulus legislation. However, the relationship between NIH funding and cardiovascular disease research is poorly understood, making the likely impact of this policy change unclear.
Methods
The National Library of Medicine's PubMed database was searched for articles published from 1996 to 2006, originating from U.S. institutions, and containing the phrases “cardiolog,” “cardiovascular,” or “cardiac,” in the first author's department. Research methodology, journal of publication, journal impact factor, and receipt of NIH funding were recorded. Differences in means and trends were tested with t-tests and linear regression, respectively, with P≤0.05 for significance.
Results
Of 117,643 world cardiovascular articles, 36,684 (31.2%) originated from the U.S., of which 10,293 (28.1%) received NIH funding. The NIH funded 40.1% of U.S. basic science articles, 20.3% of overall clinical trials, 18.1% of randomized-controlled, and 12.2% of multicenter clinical trials. NIH-funded and total articles grew significantly (65 articles/year, P<0.001 and 218 articles/year, P<0.001, respectively). The proportion of articles receiving NIH funding was stable, but grew significantly for basic science and clinical trials (0.87%/year, P<0.001 and 0.67%/year, P = 0.029, respectively). NIH-funded articles had greater journal impact factors than non NIH-funded articles (5.76 vs. 3.71, P<0.001).
Conclusions
NIH influence on U.S. cardiovascular research expanded in the past decade, during the period of NIH budget doubling. A substantial fraction of research is now directly funded and thus likely sensitive to budget fluctuations, particularly in basic science research. NIH funding predicts greater journal impact.
doi:10.1371/journal.pone.0006425
PMCID: PMC2713403  PMID: 19641617
25.  Pharmacological studies with a nonpeptidic, delta-opioid (-)-(1R,5R,9R)-5,9-Dimethyl-2’-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((-)-NIH 11082) 
European journal of pharmacology  2007;566(1-3):88-93.
In the search for a selective delta-opioid receptor agonist, (-)-(1R,5R,9R)-5,9-dimethyl-2’-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((-)-NIH 11082) and the (+)-enantiomer were synthesized and tested. (-)-NIH 11082 displayed antinociceptive activity in the paraphenylquinone test (PPQ test) in male ICR mice [ED50 = 1.9 (0.7 – 5.3) mg/kg, s.c.] and showed little, if any, activity in the tail-flick and hot-plate assays. The (+)-enantiomer was essentially inactive indicating stereoselectivity. Opioid receptor subtype characterization studies indicated that naltrindole, a delta-opioid receptor antagonist, was potent versus the ED80 of (-)-NIH 11082 in the PPQ test [AD50 = 0.75 (0.26 – 2.20) mg/kg, s.c]. beta-Funaltrexamine and nor-binaltorphimine, selective mu- and kappa-receptor antagonists, respectively, were inactive versus the ED80 of (-)-NIH 11082. In rats with inflammation-induced pain, (-)-NIH 11082 produced antihyperalgesic effects that were attenuated by naltrindole. In morphine-dependent rhesus monkeys of both sexes, (-)-NIH 11082 neither substituted for morphine nor exacerbated withdrawal signs in the dose range of 4.0 to 32.0 mg/kg, s.c. Neither convulsions nor other overt behavioral signs were observed in any of the species tested. The results indicate that (-)-NIH 11082 has delta-opioid receptor properties.
doi:10.1016/j.ejphar.2007.03.008
PMCID: PMC2994320  PMID: 17434480
Selective delta opioid; (-)-(1R,5R,9R)-5,9-Dimethyl-2’-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((-)-NIH 11082); antinociception; antihyperalgesia; mouse; rat; rhesus monkey

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