Notice NOT-DA-17-032 from the NIH Guide for Grants and Contracts

Notice NOT-DA-17-031 from the NIH Guide for Grants and Contracts

Notice NOT-DA-17-033 from the NIH Guide for Grants and Contracts

Notice NOT-AG-17-007 from the NIH Guide for Grants and Contracts

Notice NOT-DA-17-030 from the NIH Guide for Grants and Contracts

Notice NOT-TR-17-016 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-AR-18-002 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) solicits applications that propose to conduct time-sensitive mechanistic ancillary studies related to the NIAMS mission in conjunction with privately or publicly funded, ongoing interventional clinical trials. The ongoing parent project has to be an interventional clinical trial that can provide a cohort of well-characterized patients, infrastructure, data, and biological samples. Applications submitted in response to this FOA will undergo an accelerated review and award process. The objective of this FOA is to provide a flexible mechanism to leverage established resources and maximize the return on existing investments in parent projects. Successful ancillary studies will enhance the scientific content and value of the parent projects, improve the research communitys understanding of a disease or organ system in the NIAMS portfolio, and thus may identify novel targets for diagnosis, treatment, and prevention of disease.

Funding Opportunity RFA-AR-18-003 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) solicits applications that propose to conduct time-sensitive mechanistic ancillary studies related to the NIAMS mission in conjunction with privately or publicly funded, ongoing interventional clinical trials. The ongoing parent project has to be an interventional clinical trial that can provide a cohort of well-characterized patients, infrastructure, data, and biological samples. Applications submitted in response to this FOA will undergo an accelerated review and award process. The objective of this FOA is to provide a flexible mechanism to leverage established resources and maximize the return on existing investments in parent projects. Successful ancillary studies will enhance the scientific content and value of the parent projects, improve the research communitys understanding of a disease or organ system in the NIAMS portfolio, and thus may identify novel targets for diagnosis, treatment, and prevention of disease.

Notice NOT-HL-17-511 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-MH-18-300 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites research grant applications studying mechanisms of HIV-1 persistence in myeloid cells and strategies to target this reservoir in the central nervous system. Basic and translational research in domestic and international settings are of interest. Multidisciplinary research teams and collaborative alliances are encouraged but not required. RFA-MH-18-300 uses the R01 grant mechanism while RFA-MH-18-301 uses the R21 mechanism. High risk/high payoff projects that lack preliminary data or utilize existing data may be most appropriate for the R21 mechanism, while applicants with preliminary data may wish to apply using the R01 mechanism.

Funding Opportunity RFA-MH-18-301 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites research grant applications studying mechanisms of HIV-1 persistence in myeloid cells and strategies to target this reservoir in the central nervous system. Basic and translational research in domestic and international settings are of interest. Multidisciplinary research teams and collaborative alliances are encouraged but not required. RFA-MH-18-300 uses the R01 grant mechanism while RFA-MH-18-301 uses the R21 mechanism. High risk/high payoff projects that lack preliminary data or utilize existing data may be most appropriate for the R21 mechanism, while applicants with preliminary data may wish to apply using the R01 mechanism.

Funding Opportunity RFA-HD-18-010 from the NIH Guide for Grants and Contracts. This funding opportunity announcement (FOA) invites applications from institutions/organizations willing to participate with the NICHD as the Data Coordinating Center (DCC) under a cooperative agreement in an ongoing multi-center research network designed to perform observational and interventional clinical studies, using common protocols, to improve outcomes for neonates.

Rapid evidence review of the comparative effectiveness, harms, and cost-effectiveness of pharmacogenomics-guided antidepressant treatment versus usual care for major depressive disorder.

Psychopharmacology (Berl). 2017 Apr 29;:

Authors: Peterson K, Dieperink E, Anderson J, Boundy E, Ferguson L, Helfand M

Abstract
OBJECTIVE: This study aims to conduct an evidence review of the effectiveness, harms, and cost-effectiveness of pharmacogenomics-guided antidepressant treatment for major depressive disorder.
METHODS: We searched MEDLINE®, the Cochrane Central Registry of Controlled Trials, and PsycINFO through February 2017. We used prespecified criteria to select studies, abstract data, and rate internal validity and strength of the evidence (PROSPERO number CRD42016036358).
RESULTS: We included two randomized trials (RCT), five controlled cohort studies, and six modeling studies of mostly women in their mid-40s with few comorbidities. CNSDose (ABCB1, ABCC1, CYP2C19, CYP2D6, UGT1A1) is the only pharmacogenomics test that significantly improved remission (one additional remitting patient in 12 weeks per three genotyped, 95% CI 1.7 to 3.5) and reduced intolerability in an RCT. ABCB1 genotyping leads to one additional remitting patient in 5 weeks per three genotyped (95% CI 3 to 20), but tolerability was not reported. In an RCT, GeneSight (CYP2D6, CYPC19, CYP1A2, SLC6A4, HTR2A) did not statistically significantly improve remission, and evidence is inconclusive about its tolerability. Evidence is generally low strength because RCTs were few and underpowered. Cost-effectiveness is unclear due to lack of directly observed cost-effectiveness outcomes. We found no studies that evaluated whether pharmacogenomics shortens time to optimal treatment, whether improvements were due to switches to genetically congruent medication, or whether effectiveness varies based on test and patient characteristics.
CONCLUSIONS: Certain pharmacogenomics tools show promise of improving short-term remission rates in women in their mid-40s with few comorbidities. But, important evidence limitations preclude recommending their widespread use and indicate a need for further research.

PMID: 28456840 [PubMed - as supplied by publisher]

Association of regulatory TPH2 polymorphisms with higher reduction in depressive symptoms in children and adolescents treated with fluoxetine.

Prog Neuropsychopharmacol Biol Psychiatry. 2017 Apr 26;:

Authors: Gassó P, Rodríguez N, Boloc D, Blázquez A, Torres T, Gortat A, Plana MT, Lafuente A, Mas S, Lázaro L

Abstract
Genetic variability related to the brain serotonergic system has a significant impact on both the susceptibility to psychiatric disorders, such as major depressive disorder (MDD), and the response to antidepressant drugs, such as fluoxetine. TPH2 is one of the most important serotonergic candidate genes in selective serotonin reuptake inhibitors (SSRIs) pharmacogenetic studies. The aim of the present study was to evaluate the influence of regulatory polymorphisms that are specifically located in human TPH2 transcription factor binding sites (TFBSs), and therefore could be functional by altering gene expression, on clinical improvement in children and adolescents treated with fluoxetine. The selection of SNPs was also based on their linkage disequilibrium with TPH2 rs4570625, a genetic variant with questionable functionality, which was previously associated with clinical response in our pediatric population. A total of 83 children and adolescents were clinically evaluated 12weeks after initiating antidepressant treatment with fluoxetine for the first time. Clinical improvement was assessed by reductions in depressive symptoms measured using the Children's Depression Inventory (CDI) scale. The polymorphisms rs11179002, rs60032326 and rs34517220 were, for the first time in the literature, significantly associated with higher clinical improvement. The strongest association was found for rs34517220. In particular, minor allele homozygotes showed higher score reductions on the CDI scale compared with the major allele carriers. Interestingly, this polymorphism is located in a human TPH2 TFBS for two relevant transcription factors in the serotoninergic neurons, Foxa1 and Foxa2, which together with the high level of significance found for this SNP, could indicate that rs34517220 is in fact the crucial functional genetic variant related to the fluoxetine response. These results provide new evidence for the role of regulatory genetic variants that could modulate human TPH2 expression in the SSRI antidepressant response.

PMID: 28456685 [PubMed - as supplied by publisher]

Novel Oxytocin Receptor Variants in Laboring Women Requiring High Doses of Oxytocin.

Am J Obstet Gynecol. 2017 Apr 26;:

Authors: Reinl EL, Goodwin ZA, Raghuraman N, Lee GY, Jo EY, Gezahegn BM, Pillai MK, Cahill AG, de Guzman Strong C, England SK

Abstract
BACKGROUND: Although oxytocin is commonly used to augment or induce labor, it is difficult to predict its effectiveness because oxytocin dose requirements vary significantly amongst women. One possibility is that women requiring high or low doses of oxytocin have variations in the oxytocin receptor gene.
OBJECTIVES: This work aims to identify oxytocin receptor gene variants in laboring women with low and high oxytocin dosage requirements.
STUDY DESIGN: Term, nulliparous women requiring oxytocin doses of ≤4 milliunits/minute (low-dose requiring, n=83) or ≥20 milliunits/minute (high-dose requiring, n=104) for labor augmentation or induction were consented to a post-partum blood draw as a source of genomic DNA. Targeted-amplicon sequencing (coverage > 30X) with Illumina MiSeq was performed to discover variants in the coding exons of the oxytocin receptor gene. Baseline relevant clinical history, outcomes, demographics, and oxytocin receptor gene sequence variants and their allele frequencies were compared between low-dose-requiring and high-dose-requiring women. The Scale-Invariant Feature Transform algorithm was used to predict the effect of variants on oxytocin receptor function. Fisher's exact or chi-squared tests were used for categorical variables, and Student t-tests or Wilcoxon rank sum tests were used for continuous variables. A P-value < 0.05 was considered statistically significant.
RESULTS: The high-dose-requiring women had higher rates of obesity and diabetes and were more likely to have undergone labor induction and required prostaglandins. High-dose-requiring women were more likely to undergo cesarean for first stage arrest and less likely to undergo cesarean for non-reassuring fetal status. Targeted sequencing of the oxytocin receptor gene in the total cohort (n=187) revealed 30 distinct coding variants: 17 non-synonymous, 11 synonymous, and two small structural variations. One novel variant (A243T) was found in both the low- and high-dose-requiring groups. Three novel variants (Y106H, A240_A249del, and P197delfs*206) resulting in an amino acid substitution, loss of 9 amino acids, and a frameshift stop mutation, respectively, were identified only in low-dose-requiring women. Nine non-synonymous variants were unique to the high-dose-requiring group. These included three known variants (R151C, G221S, and W228C) and six novel variants not found in Ensembl or ExAC (M133V, R150L, H173R, A248V, G253R, and I266V). Of these, R150L, R151C, and H173R were predicted to damage oxytocin receptor function. There was no statistically significant association between the numbers of synonymous and non-synonymous substitutions in the patient groups.
CONCLUSIONS: Obesity, diabetes, and labor induction were associated with the requirement for high doses of oxytocin. We did not identify significant differences in the prevalence of oxytocin receptor variants between low-dose-requiring and high-dose-requiring women, but novel oxytocin receptor variants were enriched in the high-dose-requiring women. Additionally, we found three oxytocin receptor variants (two novel, one known) that were predicted to damage oxytocin receptor function and would likely increase an individual's risk for requiring a high oxytocin dose. Further investigation of oxytocin receptor variants and their effects on protein function will inform precision medicine in pregnant women.

PMID: 28456503 [PubMed - as supplied by publisher]

Increased risk of PTLD in lung transplant recipients with cystic fibrosis.

J Cyst Fibros. 2017 Apr 26;:

Authors: Lowery EM, Adams W, Grim SA, Clark NM, Edwards L, Layden JE

Abstract
BACKGROUND: Post-transplant lymphoproliferative disease (PTLD) is an important cause of morbidity and mortality following lung transplantation. Recipients with cystic fibrosis (CF) may have an increased risk of PTLD although the literature is limited to single center cohorts. Our primary aim is to examine PTLD in an adult lung transplant population by utilizing the International Society for Heart and Lung Transplantation Registry.
METHODS: We studied 30,598 adult recipients of lung transplants performed between 1999 and 2011. The primary outcome was development of and time to PTLD. In addition to indication for transplant, other predictors examined included Epstein-Barr virus (EBV) and cytomegalovirus (CMV) serostatus, gender, and age. Outcomes were assessed with univariable and multivariable Cox proportional hazard models to obtain hazard ratios (HR).
RESULTS: 17% of the cohort had a diagnosis of CF. PTLD developed in 2% of CF recipients compared to 1% for non-CF recipients (p<0.001). Compared to non-CF recipients, CF recipients had higher prevalence of EBV and CMV seronegativity and higher prevalences of high risk EBV and CMV mismatch (D+/R-). There is a significant association between CF and the development of PTLD [HR 1.66 (95% CI 1.30-2.12)]. Stratified multivariable analysis controlling for age revealed EBV negative non-CF recipients have an almost 2 fold increased risk of developing PTLD, whereas EBV negative CF recipients had an almost 6.5 fold increased risk.
CONCLUSIONS: CF recipients have a higher risk for PTLD compared to non-CF recipients. Further studies are needed to account for additional risk factors and management in this population post-transplant.

PMID: 28456611 [PubMed - as supplied by publisher]

CFTR gene mutations and polymorphism are associated with non-obstructive azoospermia: From case-control study.

Gene. 2017 Apr 26;:

Authors: Jiang L, Jin J, Wang S, Zhang F, Dai Y, Shi L, Zhang S

Abstract
A variety of experimental studies have yielded evidence that the cystic fibrosis transmembrane conductance regulator (CFTR) protein participates in the process of spermatogenesis. However, the association between CFTR gene and non-obstructive azoospermia (NOA) disease remained to be a question. First, we reviewed available data from the PubMed and Embase databases before May 2016 to find the most common mutations of CFTR gene in NOA patients. Second, an original case-control study was conducted on NOA patients (n=100) and a control group consisting of fertile males (n=100), selected from August 2015 to March 2017, to detect CFTR gene mutations and polymorphism. Peripheral blood samples from NOA patients and normal controls were analyzed for the presence of specific sequences of CFTR gene by polymerase chain reaction amplification followed by direct sequencing. From our comprehensive review, 12 case-control studies were found concerning the relation between CFTR gene mutations and polymorphism and NOA disease. Fifty-four mutations were mentioned and IVS8 poly-T, TG repeats, F508del and R117H mutations were the most common ones. Based on that, we detected IVS8 poly-T, TG repeats, F508del, R117H and M470V mutations in our case control study. We found that the T5 allele was present at a significantly higher rate in NOA patients than in the control group (5.00% versus 0.00%, p<0.01) with increased risk having NOA [Odds ratios (OR) 2.05, 95% confidence intervals (CI) 1.85-2.27]. The T5 variant was always accompanied by TG12 (10/10) and V470 allele participated in most TG12T5 haplotypes (8/10). TG12T5-V470 haplotype also enhanced risk of having NOA [OR 2.04, 95% CI 1.84-2.26]. F508del and R117H mutations were not found in either group. In conclusion, the polyvariant mutant genes of CFTR: T5 allele and TG12-T5-V470 genotype are correlated with NOA, but F508del and R117H mutations have low possibility to be associated with NOA.

PMID: 28456595 [PubMed - as supplied by publisher]

Corrigendum to "Plasma metabolomics in adults with cystic fibrosis during a pulmonary exacerbation: A pilot randomized study of high-dose vitamin D3 administration" [Metabolism vol. 70, May 2017, pages 31-41].

Metabolism. 2017 Apr 26;:

Authors: Alvarez JA, Chong EY, Walker DI, Chandler JD, Michalski ES, Grossmann RE, Uppal K, Li S, Frediani JK, Tirouvanziam R, Tran VT, Tangpricha V, Jones DP, Ziegler TR

PMID: 28456337 [PubMed - as supplied by publisher]

Whole exome sequencing of sporadic patients with Currarino Syndrome: A report of three trios.

Gene. 2017 Apr 26;:

Authors: Holm I, Spildrejorde M, Stadheim B, Eiklid KL, Samarakoon PS

Abstract
Currarino Syndrome is a rare congenital malformation syndrome described as a triad of anorectal, sacral and presacral anomalies. Currarino Syndrome is reported to be both familial and sporadic. Familial CS is today known as an autosomal dominant disorder caused by mutations in the transcription factor MNX1. The aim of this study was to look for genetic causes of Currarino Syndrome in sporadic patients after ruling out other causes, like chromosome aberrations, disease-causing variants in possible MNX1 cooperating transcription factors and aberrant methylation in the promoter of the MNX1 gene. The hypothesis was that MNX1 was affected through interactions with other transcription factors or through other regulatory elements and thereby possibly leading to abnormal function of the gene. We performed whole exome sequencing with an additional 6Mb custom made region on chromosome 7 (GRCh37/hg19, chr7:153.138.664-159.138.663) to detect regulatory elements in non-coding regions around the MNX1 gene. We did not find any variants in genes of interest shared between the patients. However, after analyzing the whole exome sequencing data with Filtus, the in-house SNV filtration program, we did find some interesting variants in possibly relevant genes that could be explaining these patients` phenotypes. The most promising genes were ETV3L, ARID5A and NCAPD3. To our knowledge this is the first report of whole exome sequencing in sporadic CS patients.

PMID: 28456592 [PubMed - as supplied by publisher]

Single Cell Restriction Enzyme-Based Analysis of Methylation at Genomic Imprinted Regions in Preimplantation Mouse Embryos.

Methods Mol Biol. 2017;1605:171-189

Authors: Ling KY, Cheow LF, Quake SR, Burkholder WF, Messerschmidt DM

Abstract
The methylation of cytosines in DNA is a fundamental epigenetic regulatory mechanism. During preimplantation development, mammalian embryos undergo extensive epigenetic reprogramming, including the global erasure of germ cell-specific DNA methylation marks, to allow for the establishment of the pluripotent state of the epiblast. However, DNA methylation marks at specific regions, such as imprinted gene regions, escape this reprogramming process, as their inheritance from germline to soma is paramount for proper development. To study the dynamics of DNA methylation marks in single blastomeres of mouse preimplantation embryos, we devised a new approach-single cell restriction enzyme analysis of methylation (SCRAM). SCRAM allows for reliable, fast, and high-throughput analysis of DNA methylation states of multiple regions of interest from single cells. In the method described below, SCRAM is specifically used to address loss of DNA methylation at genomic imprints or other highly methylated regions of interest.

PMID: 28456965 [PubMed - in process]