Funding Opportunity PAR-17-268 from the NIH Guide for Grants and Contracts. The purpose of this funding opportunity announcement is to provide time and support for the applicant to develop plans for the design and execution of clinical trials that are highly relevant to the NIGMS mission. Activities supported by a planning grant could include development of a Manual of Procedures, creation of a Data Safety and Monitoring Board charter, development of data handling and statistical analysis plans, establishment of recruitment sites, preparation of preliminary submissions for regulatory approvals, development of training materials, and other tasks essential to a trial. Following funding and successful completion of a planning grant, an application for a clinical trial that is highly relevant to the institute's mission may be submitted to NIGMS via an appropriate clinical trial funding opportunity announcement.

Funding Opportunity PAR-17-270 from the NIH Guide for Grants and Contracts. The NIDDK Central Repositories house valuable samples and data from numerous major clinical studies. This FOA allows investigators to apply for access to non-renewable samples from one or more of these studies. Information about the samples available can be found at www.niddkrepository.org. Applicants must provide information from the NIDDK Central Repositories documenting sample availability.

Funding Opportunity PAR-17-265 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to encourage research applications to develop and test the effectiveness and implementation of family navigator models designed to promote early access, engagement and coordination of mental health treatment and services for children and adolescents who are experiencing early symptoms of mental health problems. For the purposes of this FOA, NIMH defines a family navigator model as a health care professional or paraprofessional whose role is to deploy a set of strategies designed to rapidly engage youth and families in needed treatment and services, work closely with the family and other involved treatment and service providers to optimize care and monitor the trajectory of mental health symptoms and outcomes over time. Applicants are encouraged to develop and test the navigator models ability to promote early access, engagement and coordination of mental health treatment and services for children and adolescents as soon as symptoms are detected. Of interest are navigator models that coordinate needed care strategies, determine the personalized match to the level of needed service amount, frequency and intensity, and harness novel technologies to track and monitor the trajectory of clinical, functional and behavioral progress toward achieving intended services outcomes.

Funding Opportunity PAR-17-266 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to encourage research applications to develop and pilot test the effectiveness and implementation of family navigator models designed to promote early access, engagement and coordination of mental health treatment and services for children and adolescents who are experiencing early symptoms of mental health problems. For the purposes of this FOA, NIMH defines a family navigator model as a health care professional or paraprofessional whose role is to deploy a set of strategies designed to rapidly engage youth and families in needed treatment and services, work closely with the family and other involved treatment and service providers to optimize care and monitor the trajectory of mental health symptoms and outcomes over time. Applicants are encouraged to develop and pilot test the navigator models ability to promote early access, engagement and coordination of mental health treatment and services for children and adolescents as soon as symptoms are detected. Of interest are navigator models that coordinate needed care strategies, determine the personalized match to the level of needed service amount, frequency and intensity, and harness novel technologies to track and monitor the trajectory of clinical, functional and behavioral progress toward achieving intended services outcomes.

Notice NOT-RM-17-029 from the NIH Guide for Grants and Contracts

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

Notice NOT-GM-17-008 from the NIH Guide for Grants and Contracts

Notice NOT-OD-17-064 from the NIH Guide for Grants and Contracts

21 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2017/05/02

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Related Articles

In silico drug repurposing of FDA-approved drugs to predict new inhibitors for drug resistant T315I mutant and wild-type BCR-ABL1: A virtual screening and molecular dynamics study.

J Mol Graph Model. 2017 Apr 13;74:234-240

Authors: Sohraby F, Bagheri M, Aliyar M, Aryapour H

Abstract
The BCR-ABL fusion gene is one of the major causes of 95% of Chronic Myeloid Leukemia (CML). While, BCR-ABL protein is currently being used as a major target to treat CML. Although, current FDA-approved drugs such as; Imatinib and Nilotinib have stupendously improved the patients 5-year's survival rates, the drug resistance has dramatically reduced their effects. So, more accurate and effective alternative treatments are crucially needed. To address this issue, we screened the FDA-approved drugs by virtual screening and binding free energy calculations to identify new inhibitors for the wild-type and T315I gatekeeper mutant ABL1. It was invigorating to identify that chlorohexidine, paromomycin and deferoxamine could inhibit the wild-type ABL1, while chlorohexidine and ritonavir could inhibit the T315I mutant ABL1. The applications of these newly identified drugs are not just an effortless hypothesis in drug discovery. These drugs can be evaluated in phase 2 clinical trials after a simple kinase selectivity assay.

PMID: 28458002 [PubMed - as supplied by publisher]

Related Articles

Repurposing Treprostinil for Enhancing Hematopoietic Progenitor Cell Transplantation.

Mol Pharmacol. 2016 Jun;89(6):630-44

Authors: Kazemi Z, Bergmayr C, Prchal-Murphy M, Javaheri T, Themanns M, Pham HT, Strohmaier W, Sexl V, Freissmuth M, Zebedin-Brandl E

Abstract
Activation of Gs-coupled receptors enhances engraftment of hematopoietic stem and progenitor cells (HSPCs). We tested the hypothesis that treprostinil, a prostacyclin analog approved for the treatment of pulmonary hypertension, can be repurposed to improve hematopoietic stem cell transplantation. Murine and human HSPCs were isolated from bone marrow and umbilical cord blood, respectively. Prostanoid receptor agonists and the combination thereof with forskolin were tested for their capacity to stimulate [(3)H]cAMP accumulation in HSPCs. Three independent approaches were employed to verify the ability of agonist-activated HSPCs to reconstitute the bone marrow in lethally irradiated recipient mice. The underlying mechanism was explored in cellular migration assays and by blocking C-X-C motif chemokine receptor 4 (CXCR4). Among several prostanoid agonists tested in combination with forskolin, treprostinil was most efficacious in raising intracellular cAMP levels in murine and human HPSCs. Injection of murine and human HSPCs, which had been pretreated with treprostinil and forskolin, enhanced survival of lethally irradiated recipient mice. Survival was further improved if recipient mice were subcutaneously administered treprostinil (0.15 mg kg(-1) 8 h(-1)) for 10 days. This regimen also reduced the number of HSPCs required to rescue lethally irradiated mice. Enhanced survival of recipient mice was causally related to treprostinil-enhanced CXCR4-dependent migration of HSPCs. Treprostinil stimulates the engraftment of human and murine hematopoietic stem cells without impairing their capacity for self-renewal. The investigated dose range corresponds to the dose approved for human use. Hence, these findings may be readily translated into a clinical application.

PMID: 26989084 [PubMed - indexed for MEDLINE]

Related Articles

[A rare pulmonary tumor: Primary carcinosarcoma of the lung].

Rev Pneumol Clin. 2016 Dec;72(6):381-384

Authors: Mjid M, Toujani S, Blibech H, Hedhli A, Ouahchi Y, Haouet S, Cherif J, Beji M

PMID: 27789162 [PubMed - indexed for MEDLINE]

Related Articles

[Azygos vein aneurysm: An unusual and rare diagnostic].

Rev Pneumol Clin. 2016 May;72(3):217-9

Authors: Alberti N, Petitpierre F, Crombe A, Bernard S, Sironneau S

PMID: 27133177 [PubMed - indexed for MEDLINE]

An American Thoracic Society/National Heart, Lung, and Blood Institute Workshop Report: Addressing Respiratory Health Equality in the United States.

Ann Am Thorac Soc. 2017 May;14(5):814-826

Authors: Celedón JC, Burchard EG, Schraufnagel D, Castillo-Salgado C, Schenker M, Balmes J, Neptune E, Cummings KJ, Holguin F, Riekert KA, Wisnivesky JP, Garcia JGN, Roman J, Kittles R, Ortega VE, Redline S, Mathias R, Thomas A, Samet J, Ford JG, American Thoracic Society and the National Heart, Lung, and Blood Institute

Abstract
Health disparities related to race, ethnicity, and socioeconomic status persist and are commonly encountered by practitioners of pediatric and adult pulmonary, critical care, and sleep medicine in the United States. To address such disparities and thus progress toward equality in respiratory health, the American Thoracic Society and the National Heart, Lung, and Blood Institute convened a workshop in May of 2015. The workshop participants addressed health disparities by focusing on six topics, each of which concluded with a panel discussion that proposed recommendations for research on racial, ethnic, and socioeconomic disparities in pulmonary, critical care, and sleep medicine. Such recommendations address best practices to advance research on respiratory health disparities (e.g., characterize broad ethnic groups into subgroups known to differ with regard to a disease of interest), risk factors for respiratory health disparities (e.g., study the impact of new tobacco or nicotine products on respiratory diseases in minority populations), addressing equity in access to healthcare and quality of care (e.g., conduct longitudinal studies of the impact of the Affordable Care Act on respiratory and sleep disorders), the impact of personalized medicine on disparities research (e.g., implement large studies of pharmacogenetics in minority populations), improving design and methodology for research studies in respiratory health disparities (e.g., use study designs that reduce participants' burden and foster trust by engaging participants as decision-makers), and achieving equity in the pulmonary, critical care, and sleep medicine workforce (e.g., develop and maintain robust mentoring programs for junior faculty, including local and external mentors). Addressing these research needs should advance efforts to reduce, and potentially eliminate, respiratory, sleep, and critical care disparities in the United States.

PMID: 28459618 [PubMed - in process]

Related Articles

Pharmacogenetic testing revisited: 5' nuclease real-time polymerase chain reaction test panels for genotyping CYP2D6 and CYP2C19.

Pharmgenomics Pers Med. 2017;10:115-128

Authors: Larsen JB, Rasmussen JB

Abstract
Due to their involvement in the metabolization of commonly prescribed psychopharmaceutical drugs, the cytochrome oxidase genes CYP2D6 and CYP2C19 are extensive targets for pharmacogenetic testing. The existence of common allelic variants allows the prediction of a metabolic phenotype based on a genotype result, hereby supplying a clinical tool for optimizing prescription and minimizing adverse effects. In this study, we present the development of two 5' nuclease real-time polymerase chain reaction (PCR) test panels, capable of detecting eight of the most clinically relevant alleles of the CYP2D6 gene (*2, *3, *4, *6, *9, *10, 17, *41) and the three most common nonfunctional alleles of CYP2C19 (*2, *3, *4). The assays have been thoroughly validated using a large collection of reference samples, by parallel testing and by DNA sequencing. The reanalysis of reference samples provided the calculation of the frequency of the CYP2D6*4K allele in a population, not previously reported. Furthermore, original test results from CYP2D6*41, generated based on the presence of the 2850T and the lack of the -1584G single-nucleotide polymorphism (SNP), were compared with genotyping based on the current acknowledged founder SNP 2988G of this allele. These results indicate that up to 17.7% of the patients originally tested as carriers of the CYP2D6*41 allele may have had an incorrect phenotypic result assigned. The two 5' nuclease real-time PCR test panels have subsequently been optimized for use in the clinical laboratory, using a standard real-time PCR instrument and software.

PMID: 28458572 [PubMed - in process]

Related Articles

Antidepressant Pharmacogenetics.

Am J Psychiatry. 2017 May 01;174(5):417-418

Authors: Singh AB, Bousman CA

PMID: 28457163 [PubMed - in process]

Related Articles

Cross-Talk between Alternatively Spliced UGT1A Isoforms and Colon Cancer Cell Metabolism.

Mol Pharmacol. 2017 Mar;91(3):167-177

Authors: Audet-Delage Y, Rouleau M, Rouleau M, Roberge J, Miard S, Picard F, Têtu B, Guillemette C

Abstract
Alternative splicing at the human glucuronosyltransferase 1 gene locus (UGT1) produces alternate isoforms UGT1A_i2s that control glucuronidation activity through protein-protein interactions. Here, we hypothesized that UGT1A_i2s function as a complex protein network connecting other metabolic pathways with an influence on cancer cell metabolism. This is based on a pathway enrichment analysis of proteomic data that identified several high-confidence candidate interaction proteins of UGT1A_i2 proteins in human tissues-namely, the rate-limiting enzyme of glycolysis pyruvate kinase (PKM), which plays a critical role in cancer cell metabolism and tumor growth. The partnership of UGT1A_i2 and PKM2 was confirmed by coimmunoprecipitation in the HT115 colon cancer cells and was supported by a partial colocalization of these two proteins. In support of a functional role for this partnership, depletion of UGT1A_i2 proteins in HT115 cells enforced the Warburg effect, with a higher glycolytic rate at the expense of mitochondrial respiration, and led to lactate accumulation. Untargeted metabolomics further revealed a significantly altered cellular content of 58 metabolites, including many intermediates derived from the glycolysis and tricarboxylic acid cycle pathways. These metabolic changes were associated with a greater migration potential. The potential relevance of our observations is supported by the down-regulation of UGT1A_i2 mRNA in colon tumors compared with normal tissues. Alternate UGT1A variants may thus be part of the expanding compendium of metabolic pathways involved in cancer biology directly contributing to the oncogenic phenotype of colon cancer cells. Findings uncover new aspects of UGT functions diverging from their transferase activity.

PMID: 28049773 [PubMed - indexed for MEDLINE]

Related Articles

Prediction of early weight gain during psychotropic treatment using a combinatorial model with clinical and genetic markers.

Pharmacogenet Genomics. 2016 Dec;26(12):547-557

Authors: Vandenberghe F, Saigí-Morgui N, Delacrétaz A, Quteineh L, Crettol S, Ansermot N, Gholam-Rezaee M, von Gunten A, Conus P, Eap CB

Abstract
BACKGROUND: Psychotropic drugs can induce significant (>5%) weight gain (WG) already after 1 month of treatment, which is a good predictor for major WG at 3 and 12 months. The large interindividual variability of drug-induced WG can be explained in part by genetic and clinical factors.
AIM: The aim of this study was to determine whether extensive analysis of genes, in addition to clinical factors, can improve prediction of patients at risk for more than 5% WG at 1 month of treatment.
METHODS: Data were obtained from a 1-year naturalistic longitudinal study, with weight monitoring during weight-inducing psychotropic treatment. A total of 248 Caucasian psychiatric patients, with at least baseline and 1-month weight measures, and with compliance ascertained were included. Results were tested for replication in a second cohort including 32 patients.
RESULTS: Age and baseline BMI were associated significantly with strong WG. The area under the curve (AUC) of the final model including genetic (18 genes) and clinical variables was significantly greater than that of the model including clinical variables only (AUCfinal: 0.92, AUCclinical: 0.75, P<0.0001). Predicted accuracy increased by 17% with genetic markers (Accuracyfinal: 87%), indicating that six patients must be genotyped to avoid one misclassified patient. The validity of the final model was confirmed in a replication cohort. Patients predicted before treatment as having more than 5% WG after 1 month of treatment had 4.4% more WG over 1 year than patients predicted to have up to 5% WG (P≤0.0001).
CONCLUSION: These results may help to implement genetic testing before starting psychotropic drug treatment to identify patients at risk of important WG.

PMID: 27741037 [PubMed - indexed for MEDLINE]

Related Articles

Influence of the CYP3A4/5 genetic score and ABCB1 polymorphisms on tacrolimus exposure and renal function in Brazilian kidney transplant patients.

Pharmacogenet Genomics. 2016 Oct;26(10):462-72

Authors: Genvigir FD, Salgado PC, Felipe CR, Luo EY, Alves C, Cerda A, Tedesco-Silva H, Medina-Pestana JO, Oliveira N, Rodrigues AC, Doi SQ, Hirata MH, Hirata RD

Abstract
BACKGROUND: Polymorphisms in genes encoding transport proteins and metabolizing enzymes involved in tacrolimus (TAC) disposition may be important sources of individual variability during treatment.
OBJECTIVE: The aim of this study was to investigate the effect of combined CYP3A4 and CYP3A5 variants, using a CYP3A4/5 genetic score, and ABCB1 polymorphisms on therapeutic TAC monitoring and their relationship with clinical outcomes.
MATERIAL AND METHODS: Brazilian kidney transplant recipients (n=151), who received TAC over 3 months after transplantation, were genotyped for CYP3A4 rs2242480 (g.20230G>A), CYP3A5 rs15524 (g.31611C>T) and rs776746 (g.6986A>G), ABCB1 rs1128503 (c.1236C>T), rs1045642 (c.3435C>T), and rs2032582 (c.2677G>T/A) polymorphisms.
RESULTS: Frequencies of CYP3A4 g.20230A, CYP3A5 g.31611C, and g.6986A were 0.37, 0.26, and 0.28, respectively. These alleles were associated with TAC rapid metabolization and were used for CYP3A4/5 genetic score construction. A higher CYP3A4/5 genetic score was associated with higher TAC dose and lower concentrations for dose administered (Co/D, P<0.05). Ninety days after transplantation, the presence of two or more rapid metabolization alleles contributed toward 27.7% of Co/D variability and was associated with a lower estimated glomerular filtration rate values (P<0.05). For ABCB1, the frequencies of c.1236T, c.3435T, and c.2677T/A alleles were 0.42, 0.42, and 0.33/0.04. At 30 days after transplantation, patients carrying ABCB1 c.1236TT+c.3435TT+(c.2677TT+TA) genotypes had higher TAC Co/D than those with common or heterozygous genotypes (P<0.05).
CONCLUSION: The results show the impact of the CYP3A4/5 genetic score on TAC exposure and renal function in Brazilian patients. Furthermore, ABCB1 polymorphisms, in a combined analysis, influenced TAC Co/D at 30 days after transplantation.

PMID: 27434656 [PubMed - indexed for MEDLINE]

Respiratory Symptoms Items from the COPD Assessment Test Identify Ever-Smokers with Preserved Lung Function at Higher Risk for Poor Respiratory Outcomes. An Analysis of the Subpopulations and Intermediate Outcome Measures in COPD Study Cohort.

Ann Am Thorac Soc. 2017 May;14(5):636-642

Authors: Martinez CH, Murray S, Barr RG, Bleecker E, Bowler RP, Christenson SA, Comellas AP, Cooper CB, Couper D, Criner GJ, Curtis JL, Dransfield MT, Hansel NN, Hoffman EA, Kanner RE, Kleerup E, Krishnan JA, Lazarus SC, Leidy NK, O'Neal W, Martinez FJ, Paine R, Rennard SI, Tashkin DP, Woodruff PG, Han MK, Subpopulations and Intermediate Outcome Measures in COPD Study Investigators

Abstract
RATIONALE: Ever-smokers without airflow obstruction scores greater than or equal to 10 on the COPD Assessment Test (CAT) still have frequent acute respiratory disease events (exacerbation-like), impaired exercise capacity, and imaging abnormalities. Identification of these subjects could provide new opportunities for targeted interventions.
OBJECTIVES: We hypothesized that the four respiratory-related items of the CAT might be useful for identifying such individuals, with discriminative ability similar to CAT, which is an eight-item questionnaire used to assess chronic obstructive pulmonary disease impact, including nonrespiratory questions, with scores ranging from 0 to 40.
METHODS: We evaluated ever-smoker participants in the Subpopulations and Intermediate Outcomes in COPD Study without airflow obstruction (FEV1/FVC ≥0.70; FVC above the lower limit of normal). Using the area under the receiver operating characteristic curve, we compared responses to both CAT and the respiratory symptom-related CAT items (cough, phlegm, chest tightness, and breathlessness) and their associations with longitudinal exacerbations. We tested agreement between the two strategies (κ statistic), and we compared demographics, lung function, and symptoms among subjects identified as having high symptoms by each strategy.
RESULTS: Among 880 ever-smokers with normal lung function (mean age, 61 yr; 52% women) and using a CAT cutpoint greater than or equal to 10, we classified 51.8% of individuals as having high symptoms, 15.3% of whom experienced at least one exacerbation during 1-year follow-up. After testing sensitivity and specificity of different scores for the first four questions to predict any 1-year follow-up exacerbation, we selected cutpoints of 0-6 as representing a low burden of symptoms versus scores of 7 or higher as representing a high burden of symptoms for all subsequent comparisons. The four respiratory-related items with cutpoint greater than or equal to 7 selected 45.8% participants, 15.6% of whom experienced at least one exacerbation during follow-up. The two strategies largely identified the same individuals (agreement, 88.5%; κ = 0.77; P < 0.001), and the proportions of high-symptoms subjects who had severe dyspnea were similar between CAT and the first four CAT questions (25.9% and 26.8%, respectively), as were the proportions reporting impaired quality of life (66.9% and 70.5%, respectively) and short walking distance (22.4% and 23.1%, respectively). There was no difference in area under the receiver operating characteristic curve to predict 1-year follow-up exacerbations (CAT score ≥10, 0.66; vs. four respiratory items from CAT ≥7 score, 0.65; P = 0.69). Subjects identified by either method also had more depression/anxiety symptoms, poor sleep quality, and greater fatigue.
CONCLUSIONS: Four CAT items on respiratory symptoms identified high-risk symptomatic ever-smokers with preserved spirometry as well as the CAT did. These data suggest that simpler strategies can be developed to identify these high-risk individuals in primary care.

PMID: 28459622 [PubMed - in process]