Notice NOT-DA-17-012 from the NIH Guide for Grants and Contracts

Notice NOT-DA-17-011 from the NIH Guide for Grants and Contracts

Notice NOT-DA-17-010 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-17-227 from the NIH Guide for Grants and Contracts. This FOA encourages exploratory and developmental research applications for research on hearing health care in adults in support of improving access and affordability. Further research is needed to strengthen the evidence base with a goal of delivering better hearing health care outcomes in adults.

Notice NOT-HS-17-010 from the NIH Guide for Grants and Contracts

30 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 2017/03/18

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Related Articles

Clinical Impact of Pharmacogenetic-Guided Treatment for Patients Exhibiting Neuropsychiatric Disorders: A Randomized Controlled Trial.

Prim Care Companion CNS Disord. 2017 Mar 16;19(2):

Authors: Olson MC, Maciel A, Gariepy JF, Cullors A, Saldivar JS, Taylor D, Centeno J, Garces JA, Vaishnavi S

Abstract
Objective: Pharmacogenetic testing holds promise as a personalized medicine tool by permitting individualization of pharmacotherapy in accordance with genes influencing therapeutic response, side effects, and adverse events. The authors evaluated the effect on outcomes for patients diagnosed with neuropsychiatric disorders of pharmacogenetics (PGx)-guided treatment compared to usual standard of care.
Methods: This was a prospective, randomized study of 237 patients at an outpatient community-based psychiatric practice conducted between April 2015 and October 2015. Baseline patient assessments and a buccal swab were collected for pharmacogenetic testing at study initiation. For the experimental group, PGx results were provided to the clinicians as guides to treatment. Control subjects were treated according to the usual standard of care with no clinician reference to their PGx results. Neuropsychiatric Questionnaire (NPQ) and Symbol Digit Coding Test (SDC) scores and adverse drug events, hospitalizations, and medication information were collected at 30, 60, and 90 days.
Results: More than half (53%) of patients in the control group reported at least 1 adverse drug event compared to 28% of patients with PGx-guided medication management (P = .001). NPQ and SDC scores improved for both groups, but no statistical difference in efficacy as measured by these assessments was observed within the 90-day observation period.
Conclusions: Pharmacogenetic testing may facilitate psychiatric drug therapy with greater tolerability and similar efficacy compared to standard of care.
Trial Registration: ClinicalTrials.gov Identifier: NCT02411123​​.

PMID: 28314093 [PubMed - in process]

Related Articles

Impact of the CYP2C19 genotype on voriconazole exposure in adults with invasive fungal infections.

Pharmacogenet Genomics. 2017 Mar 16;:

Authors: Hamadeh IS, Klinker KP, Borgert SJ, Richards AI, Li W, Mangal N, Hiemenz JW, Schmidt S, Langaee TY, Peloquin CA, Johnson JA, Cavallari LH

Abstract
OBJECTIVES: Voriconazole, a first-line agent for the treatment of invasive fungal infections (IFIs), is metabolized by CYP2C19. A significant proportion of patients fail to achieve therapeutic trough concentrations with standard weight-based voriconazole dosing, placing them at increased risk for treatment failure, which can be life threatening. We sought to test the association between the CYP2C19 genotype and subtherapeutic voriconazole concentrations in adults with IFIs.
PATIENT AND METHODS: Adults receiving weight-based voriconazole dosing for the treatment of IFIs were genotyped for the CYP2C19*2, *3, and *17 polymorphisms, and CYP2C19 metabolizer phenotypes were inferred. Steady-state voriconazole trough plasma concentrations and the prevalence of subtherapeutic troughs (<2 mg/l) were compared between patients with the CYP2C19*17/*17 (ultrarapid metabolizer, UM) or *1/*17 (rapid metabolizer, RM) genotype versus those with other genotypes. Logistic regression, adjusting for clinical factors, was performed to estimate the odds of subtherapeutic concentrations.
RESULTS: Of 70 patients included (mean age 52.5±18 years), 39% were RMs or UMs. Compared with patients with the other phenotypes, RMs/UMs had a lower steady-state trough concentration (4.26±2.2 vs. 2.86±2.3, P=0.0093) and a higher prevalence of subtherapeutic troughs (16 vs. 52%, P=0.0028), with an odds ratio of 5.6 (95% confidence interval: 1.64-19.24, P=0.0044).
CONCLUSION: Our findings indicate that adults with the CYP2C19 RM or UM phenotype are more likely to have subtherapeutic concentrations with weight-based voriconazole dosing. These results corroborate previous findings in children and support the potential clinical utility of CYP2C19 genotype-guided voriconazole dosing to avoid underexposure in RMs and UMs.

PMID: 28306618 [PubMed - as supplied by publisher]

Related Articles

[Genetic tests for controlling treatment with antidepressants].

Nervenarzt. 2017 Mar 16;:

Authors: Bschor T, Baethge C, Hiemke C, Müller-Oerlinghausen B

Abstract
In clinical practice, there is a need for a more individualized selection of antidepressants and adequate dosage. The investigation of pharmacokinetically relevant genes is a promising approach to assist this selection. In the past 2 years, two commercially available tests have been subject of advertisement, a test from Stada, which analyses variants of the cytochrome P450 isoenzymes CYP2D6 and CYP2C19 and a test from HMNC Brain Health, which analyses variants of the ABCB1 gene. The costs for both kits are not covered by the statutory health insurance and it is therefore proposed that the patients are invoiced directly in the form of individual healthcare payment. The companies claim that by applying the tests antidepressant treatment failure can be avoided and that patients will respond faster to the antidepressant used. These claims are not based on appropriate clinical trials, which are either lacking or reveal conflicting results. Hence, the routine use of these tests is not recommended. In accordance with the German S3 Guideline for unipolar depression, therapeutic drug monitoring (TDM) of serum levels should be carried out in cases of non-response to an antidepressant with adequate dosage and duration. As a rule the costs for TDM are covered by the statutory health insurance. Cytochrome P450 genotyping is only indicated when the serum level is not within the expected range and other reasons to explain this discrepancy are excluded. Many laboratories provide these analyses and in individual cases the costs are reimbursed by the statutory health insurance. Further research should be carried out to investigate the importance of the ABCB1 gene for the treatment with antidepressants.

PMID: 28303314 [PubMed - as supplied by publisher]

Related Articles

A prospective study to assess the association between genotype, phenotype and Prakriti in individuals on phenytoin monotherapy.

J Ayurveda Integr Med. 2017 Mar 14;:

Authors: Thaker SJ, Gandhe PP, Godbole CJ, Bendkhale SR, Mali NB, Thatte UM, Gogtay NJ

Abstract
BACKGROUND: Genetic polymorphisms in drug metabolizing enzymes (DMEs) impart distinct drug metabolizing capacity and a unique phenotype to an individual. Phenytoin has large inter-individual variability in metabolism due to polymorphisms in CYP2C9 and CYP2C19. As per Ayurveda, Prakriti imparts a unique phenotype to an individual.
OBJECTIVE: To assess whether Prakriti can substitute phenotyping [therapeutic drug monitoring (TDM)] and genotyping in individualizing therapy with phenytoin in epilepsy patients.
METHODS AND MATERIALS: This was a cross-sectional study conducted over a period of three years. Prakriti was assessed using standardized and validated software. Polymorphisms in CYP2C9 and CYP2C19 were assessed using Polymerase Chain Reaction (PCR)-Restriction fragment length polymorphism (PCR-RFLP). Plasma concentrations of phenytoin (phenotype) were determined using reverse phase-high performance liquid chromatography (RF-HPLC).
RESULTS: Total 351 patients were enrolled for the study. Kapha vata (KV) (39%) was the predominantly observed Prakriti followed by vata kapha (VK) (20.8%) and vata pitta (VP) (8.83%) among the patients. The CYP2C9 and CYP2C19 genotype distributions were in accordance with Hardy-Weinberg equilibrium. There was no association between Prakriti and genotypes and Prakriti and phenotype (p > 0.05 each). Patients with CYP2C9 *1/*3 genotype were thrice more likely to have toxic plasma concentrations of phenytoin as compared to those with wild-type genotype (*1/*1) (Adjusted odds ratio - 3.36; 95% C.I. 1.61, 7.01). However, no such association was observed between polymorphisms of CYP2C19 and phenotype.
CONCLUSIONS: We did not find any association between Prakriti and either phenotype or genotypes suggesting that Prakriti assessment would be of limited utility in individualizing phenytoin therapy in epilepsy patients.

PMID: 28302415 [PubMed - as supplied by publisher]

Related Articles

Drug Metabolism in Preclinical Drug Development: A Survey of the Discovery Process, Toxicology, and Computational Tools.

Curr Drug Metab. 2017 Mar 15;:

Authors: Issa NT, Wathieu H, Ojo A, Byers SW, Dakshanamurthy S

Abstract
Increased R & D spending and high failure rates exist in drug development, due in part to inadequate prediction of drug metabolism and its consequences in the human body. Hence, there is a need for computational methods to supplement and complement current biological assessment strategies. In this review, we provide an overview of drug metabolism in pharmacology, and discuss the current in vitro and in vivo strategies for assessing drug metabolism in preclinical drug development. We highlight computational tools available to the scientific community for the in silico prediction of drug metabolism, and examine how these tools have been implemented to produce drug-target signatures relevant to metabolic routes. Computational workflows that assess drug metabolism and its toxicological and pharmacokinetic effects, such as by applying the adverse outcome pathway framework for risk assessment, may improve the efficiency and speed of preclinical drug development.

PMID: 28302026 [PubMed - as supplied by publisher]

Related Articles

A possible role for HLA-DRB1*04:06 in statin-related myopathy in Japanese patients.

Drug Metab Pharmacokinet. 2016 Dec;31(6):467-470

Authors: Sai K, Kajinami K, Akao H, Iwadare M, Sato-Ishida R, Kawai Y, Takeda K, Tanimoto T, Yamano T, Akasaka T, Ishida T, Hirata KI, Saku K, Yagi S, Soeki T, Sata M, Ueno M, Miyazaki S, Shiraki A, Oyama JI, Node K, Sugamura K, Ogawa H, Kurose K, Maekawa K, Matsuzawa Y, Imatoh T, Hasegawa R, Japanese Pharmacogenomics Data Science Consortium, Saito Y

Abstract
Statin-related myopathy (SRM) is a clinically important adverse reaction. Recent pharmacogenetic research, mainly in non-Asian populations, have indicated clinical relevance of some of genetic biomarkers to SRM, but predictive markers for SRM in Asian populations including Japanese has not yet been established. This study was aimed to identify clinically important genetic markers associated with SRM in Japanese patients. Allele frequencies of the three reported candidate markers - SLCO1B1 rs4149056, RYR2 rs2819742, and GATM rs9806699 - and carrier frequencies of HLA types were compared between patients with SRM patients (n = 52) and healthy Japanese subjects (n = 2878 or 86 (for rs9806699) as controls). No significant association of RYR2, SLCO1B1, and GATM variants with SRM were observed in our Japanese patients, but a significant association was detected for HLA-DRB1*04:06 with SRM (odds ratio: 3.19; 95% confidence interval: 1.53-6.66). This study suggested that HLA-DRB1*04:06 might be associated with SRM onset in a Japanese population. Further studies are required to validate these results.

PMID: 27839692 [PubMed - indexed for MEDLINE]

Related Articles

Developmental regulation of CYP3A4 and CYP3A7 in Chinese Han population.

Drug Metab Pharmacokinet. 2016 Dec;31(6):433-444

Authors: He H, Nie YL, Li JF, Meng XG, Yang WH, Chen YL, Wang SJ, Ma X, Kan QC, Zhang LR

Abstract
CYP3A4 and CYP3A7 are generally served as the major adult and fetal liver forms, respectively, and exhibited a developmental switch during liver maturation. The objective of this study was to explore the potential mechanisms associated with the developmental switch of CYP3A4 and CYP3A7 in the Chinese Han population. We analyzed CYP3A4/7, nuclear receptors, and epigenetic modifications in human liver samples. We found that the expression levels of CYP3A4 mRNA in adults were significantly higher than the levels in fetus. In contrast, CYP3A7 mRNA expression reached a maximal level at an estimated gestational age of 25 weeks and then substantially decreased during the first year after birth. We also found that the expression level of hepatocyte nuclear factor 4 alpha (HNF4A) was most associated with CYP3A4 expression in adult liver; whereas the expression level of glucocorticoid receptor (GR) was intensively correlated with CYP3A7 expression in fetal liver. Furthermore, we illustrated the dynamic changes of H3K4me2 and H3K27me3 in the developmental switch of CYP3A7 and CYP3A4. In summary, our data suggested that HNF4A and GR, and epigenetic changes of H3K4me2 and H3K27me3 are associated with the ontogenic expressions of CYP3A4/3A7 in the livers of the Chinese Han population.

PMID: 27727071 [PubMed - indexed for MEDLINE]

Related Articles

Targeting DNA Damage Response in the Radio(Chemo)therapy of Non-Small Cell Lung Cancer.

Int J Mol Sci. 2016 May 31;17(6):

Authors: Li L, Zhu T, Gao YF, Zheng W, Wang CJ, Xiao L, Huang MS, Yin JY, Zhou HH, Liu ZQ

Abstract
Lung cancer is the leading cause of cancer death worldwide due to its high incidence and mortality. As the most common lung cancer, non-small cell lung cancer (NSCLC) is a terrible threat to human health. Despite improvements in diagnosis and combined treatments including surgical resection, radiotherapy and chemotherapy, the overall survival for NSCLC patients still remains poor. DNA damage is considered to be the primary cause of lung cancer development and is normally recognized and repaired by the intrinsic DNA damage response machinery. The role of DNA repair pathways in radio(chemo)therapy-resistant cancers has become an area of significant interest in the clinical setting. Meanwhile, some studies have proved that genetic and epigenetic factors can alter the DNA damage response and repair, which results in changes of the radiation and chemotherapy curative effect in NSCLC. In this review, we focus on the effect of genetic polymorphisms and epigenetic factors such as miRNA regulation and lncRNA regulation participating in DNA damage repair in response to radio(chemo)therapy in NSCLC. These may provide novel information on the radio(chemo)therapy of NSCLC based on the individual DNA damage response.

PMID: 27258253 [PubMed - indexed for MEDLINE]

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

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2017/03/18

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Related Articles

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi.

PLoS Negl Trop Dis. 2017 Mar 17;11(3):e0005472

Authors: Reigada C, Valera-Vera EA, Sayé M, Errasti AE, Avila CC, Miranda MR, Pereira CA

Abstract
Polyamines are essential compounds to all living organisms and in the specific case of Trypanosoma cruzi, the causative agent of Chagas disease, they are exclusively obtained through transport processes since this parasite is auxotrophic for polyamines. Previous works reported that retinol acetate inhibits Leishmania growth and decreases its intracellular polyamine concentration. The present work describes a combined strategy of drug repositioning by virtual screening followed by in vitro assays to find drugs able to inhibit TcPAT12, the only polyamine transporter described in T. cruzi. After a screening of 3000 FDA-approved drugs, 7 retinoids with medical use were retrieved and used for molecular docking assays with TcPAT12. From the docked molecules, isotretinoin, a well-known drug used for acne treatment, showed the best interaction score with TcPAT12 and was selected for further in vitro studies. Isotretinoin inhibited the polyamine transport, as well as other amino acid transporters from the same protein family (TcAAAP), with calculated IC50 values in the range of 4.6-10.3 μM. It also showed a strong inhibition of trypomastigote burst from infected cells, with calculated IC50 of 130 nM (SI = 920) being significantly less effective on the epimastigote stage (IC50 = 30.6 μM). The effect of isotretinoin on the parasites plasma membrane permeability and on mammalian cell viability was tested, and no change was observed. Autophagosomes and apoptotic bodies were detected as part of the mechanisms of isotretinoin-induced death indicating that the inhibition of transporters by isotretinoin causes nutrient starvation that triggers autophagic and apoptotic processes. In conclusion, isotretinoin is a promising trypanocidal drug since it is a multi-target inhibitor of essential metabolites transporters, in addition to being an FDA-approved drug largely used in humans, which could reduce significantly the requirements for its possible application in the treatment of Chagas disease.

PMID: 28306713 [PubMed - as supplied by publisher]

Related Articles

Innovative approach for self-management and social welfare of children with cystic fibrosis in Europe: development, validation and implementation of an mHealth tool (MyCyFAPP).

BMJ Open. 2017 Mar 16;7(3):e014931

Authors: Calvo-Lerma J, Martinez-Jimenez CP, Lázaro-Ramos JP, Andrés A, Crespo-Escobar P, Stav E, Schauber C, Pannese L, Hulst JM, Suárez L, Colombo C, Barreto C, de Boeck K, Ribes-Koninckx C, MyCyFAPP

Abstract
INTRODUCTION: For the optimal management of children with cystic fibrosis, there are currently no efficient tools for the precise adjustment of pancreatic enzyme replacement therapy, either for advice on appropriate dietary intake or for achieving an optimal nutrition status. Therefore, we aim to develop a mobile application that ensures a successful nutritional therapy in children with cystic fibrosis.
METHODS AND ANALYSIS: A multidisciplinary team of 12 partners coordinate their efforts in 9 work packages that cover the entire so-called 'from laboratory to market' approach by means of an original and innovative co-design process. A cohort of 200 patients with cystic fibrosis aged 1-17 years are enrolled. We will develop an innovative, clinically tested mobile health application for patients and health professionals involved in cystic fibrosis management. The mobile application integrates the research knowledge and innovative tools for maximising self-management with the aim of leading to a better nutritional status, quality of life and disease prognosis. Bringing together different and complementary areas of knowledge is fundamental for tackling complex challenges in disease treatment, such as optimal nutrition and pancreatic enzyme replacement therapy in cystic fibrosis. Patients are expected to benefit the most from the outcomes of this innovative project.
ETHICS AND DISSEMINATION: The project is approved by the Ethics Committee of the coordinating organisation, Hospital Universitari La Fe (Ref: 2014/0484). Scientific findings will be disseminated via journals and conferences addressed to clinicians, food scientists, information and communications technology experts and patients. The specific dissemination working group within the project will address the wide audience communication through the website (http://www.mycyfapp.eu), the social networks and the newsletter.

PMID: 28302638 [PubMed - in process]

Related Articles

Immunomodulatory effects of pidotimod in adults with community-acquired pneumonia undergoing standard antibiotic therapy.

Pulm Pharmacol Ther. 2017 Mar 13;:

Authors: Trabattoni D, Clerici M, Centanni S, Mantero M, Garziano M, Blasi F

Abstract
The morbidity and mortality of community-acquired pneumonia (CAP) are still elevated and two aspects seem to contribute to a worse outcome: an uncontrolled inflammatory reaction and an inadequate immune response. Adjuvants, including corticosteroids and intravenous immunoglobulins, have been proposed to counterbalance these effects but their efficacy is only partial. We examined the immunomodulatory activity of Pidotimod (PDT), a synthetic dipeptide molecule in adult patients hospitalized for CAP. Sixteen patients with a diagnosis of CAP and a PSI score III or IV and/or a CURB-65 0-2 were randomized to receive either levofloxacin 500 mg b.i.d. alone or levofloxacin plus PDT (800mg, 2 daily doses). Blood samples were drawn at baseline (T0), before initiation of therapy, as well as 3 (T3), and 5 (T5) days after initiation of therapy. Immunologic and clinical parameters were analyzed at each time point. Supplementation of antibiotic therapy with PDT resulted in an upregulation of antimicrobial and of immunomodulatory proteins as well as in an increased percentage of Toll like receptor (TLR)2- and TLR4, and of CD80- and CD86-expressing immune cells. Notably, Pidotimod supplementation was also associated with a robust reduction of TNFα-producing immune cells. No significant differences were observed in clinical parameters. These results confirm that supplementation of antibiotic therapy with Pidotimod in patients with CAP results in a potentially beneficial modulation of innate immunity.

PMID: 28302543 [PubMed - as supplied by publisher]

Related Articles

The CF-CARES primary palliative care model: A CF-specific structured assessment of symptoms, distress, and coping.

J Cyst Fibros. 2017 Mar 14;:

Authors: Friedman D, Linnemann RW, Altstein LL, Islam S, Bach KT, Lamb C, Volpe J, Doolittle C, St John A, O'Malley PJ, Sawicki GS, Georgiopoulos AM, Yonker LM, Moskowitz SM

Abstract
BACKGROUND: Current palliative care tools do not address distressing chronic symptoms that are most relevant to cystic fibrosis.
METHODS: A CF-specific structured assessment based on a primary palliative care framework was administered to 41 adolescents and adults with CF. Descriptive and correlational analyses were conducted.
RESULTS: Patients reported numerous physical and psychological symptoms (mean of 10 per patient), with psychological symptoms rated as more distressing. Anxiety (34%) and depression (44%) were prevalent and correlated with distress attributable to physical symptoms and difficulty with CF self-management, but did not correlate with disease severity.
CONCLUSIONS: Individuals with CF, regardless of disease severity, face challenges managing symptom burden. Frequently reported symptoms are not consistently associated with distress, suggesting the importance of individualized evaluation. The CF-CARES (Coping, goal Assessment, and Relief from Evolving CF Symptoms) primary palliative care assessment model provides a framework for patients experiencing chronic symptoms to explore interventional options with their clinicians.

PMID: 28302366 [PubMed - as supplied by publisher]

Related Articles

Pseudomonas aeruginosa biofilm, a programmed bacterial life for fitness.

J Microbiol Biotechnol. 2017 Mar 17;:

Authors: Lee K, Yoon SS

Abstract
Biofilm is a community of microbes that typically inhabits on surfaces and is encased in an extracellular matrix. Biofilms display very dissimilar characteristics to their planktonic counterparts. Biofilms are ubiquitous in the environments and influence our life tremendously in both positive and negative ways. Pseudomonas aeruginosa is a bacterium, known to produce robust biofilms. P. aeruginosa biofilms cause severe problems in immunocompromised patients including those with cystic fibrosis or wound infection. Moreover, the unique biofilm properties further complicates the eradication of the biofilm infection and leading to the development of chronic infections. In this review, we discuss a history of biofilm research and general characteristics of bacterial biofilms. Then, distinct features pertaining to each stage of P. aeruginosa biofilm development are highlighted. Furthermore, infections caused by biofilms of its own or in association with other bacterial species (i.e., multi-species biofilms) are discussed in detail.

PMID: 28301918 [PubMed - as supplied by publisher]