Funding Opportunity RFA-DK-17-025 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages applications from institutions/organizations proposing original research addressing barriers that limit progress toward effective open- and closed-loop glucose control systems. Proposed research should tackle important obstacles at the level of sensing, hormone formulation and delivery, self-management decision support systems, and/or design of automated controllers/algorithms able to manage an integrated platform. This research may contribute to development of affordable and user friendly technologies to improve glucose control in patients with type 1 diabetes.

Notice NOT-FD-18-005 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-DA-19-003 from the NIH Guide for Grants and Contracts. This initiative will support projects that exploit Omics assays to address outstanding questions regarding molecular regulation of persistent HIV (e.g. latency or reservoirs) in the context of chronic substance use or substance use disorder (SUD).

Funding Opportunity RFA-DK-17-031 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages applications from institutions/organizations proposing original research aimed at the characterization and discovery of neoantigens and neoepitopes in type 1 diabetes. These include the characterization of the humoral and cell mediated autoimmune responses elicited by these neoepitopes and neoantigens and their role in the etiology and pathophysiology of type 1 diabetes. These studies should be integrated with the present knowledge of established epitopes and antigens (e.g. autoantibodies for insulin, GAD65, IA-2, and ZnT8T).

Funding Opportunity RFA-DK-18-003 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages applications from institutions/organizations proposing research on the use of current and emerging technologies for monitoring of blood glucose levels to capture the relationship between blood glucose excursions, perception of wellbeing, and cognitive status in people with type 1 diabetes (T1D). This information will inform the design of more effective interventions that may improve patient reported outcomes (PROs), including quality of life measures, and validate glycemic measures that may serve as outcomes in clinical trials to improve glucose management in T1D.

Funding Opportunity RFA-DK-17-021 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) requests applications to explore human pancreatic tissues for the discovery of early biomarkers of T1D pathogenesis, the description of specific signaling or processing pathways that may contribute to the asymptomatic phase of T1D, the development of clinical diagnostic tools for the detection and staging of early T1D in at-risk or recently-diagnosed individuals, and/or the identification of therapeutic targets for the development of preventative or early treatment strategies. Successful applicants will join the Consortium on Beta Cell Death and Survival (CBDS), whose mission is to better define and detect the mechanisms of beta cell stress and destruction central to the development of T1D in humans, with the long-term goal of detecting beta cell destruction and protecting the residual beta cell mass in T1D patients as early as possible in the disease process, and of preventing the progression to autoimmunity. The CBDS is part of a collaborative research framework, the Human Islet Research Network (HIRN, https://hirnetwork.org), whose overall mission is to support innovative and collaborative translational research to understand how human beta cells are lost in T1D, and to find innovative strategies to protect and replace functional beta cell mass in humans. This FOA will only support studies with a primary focus on increasing our understanding of human disease biology (as opposed to rodent or other animal models). This FOA will not accept applications proposing a clinical trial.

Funding Opportunity RFA-DK-17-022 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites cooperative agreement applications that will contribute to a higher resolution understanding of the physical and functional organization of the human islet tissue environment by describing the composition (cellular and molecular) and function of important components of the pancreatic islet and peri-islet tissue architecture, the cell-cell relationships and means of communications used by cell types and cell subtypes within the pancreatic tissue ecosystem, and/or the contribution of adjacent (including acinar, ductal, lymphatic) and neighboring (intestinal, mesenteric and adipose) tissues to islet cell function and dysfunction. Successful projects will integrate the Human Pancreas Analysis Consortium (HPAC), that will consist of the research teams funded in response to this FOA with the Human Pancreas Analysis Program (HPAP), a resource-generation program that was funded in 2016 in response to RFA-DK-15-027. HPAC will become the fifth consortium of the Human Islet Research Network (HIRN, https://hirnetwork.org/ ). HIRN's overall mission is to support innovative and collaborative translational research to understand how human beta cells are lost in T1D, and to find innovative strategies to protect and replace functional beta cell mass in humans. This FOA will only support studies with a primary focus on increasing our understanding of human tissue structure and function, and human disease biology (as opposed to rodent or other animal models). This FOA is not intended to support the conduct of a clinical trial.

Notice NOT-HD-18-003 from the NIH Guide for Grants and Contracts

11 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 2018/02/15

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.

36 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 2018/02/15

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.

Implementing pharmacogenomics decision support across seven European countries: The Ubiquitous Pharmacogenomics (U-PGx) project.

J Am Med Inform Assoc. 2018 Feb 09;:

Authors: Blagec K, Koopmann R, Crommentuijn-van Rhenen M, Holsappel I, van der Wouden CH, Konta L, Xu H, Steinberger D, Just E, Swen JJ, Guchelaar HJ, Samwald M

Abstract
Clinical pharmacogenomics (PGx) has the potential to make pharmacotherapy safer and more effective by utilizing genetic patient data for drug dosing and selection. However, widespread adoption of PGx depends on its successful integration into routine clinical care through clinical decision support tools, which is often hampered by insufficient or fragmented infrastructures. This paper describes the setup and implementation of a unique multimodal, multilingual clinical decision support intervention consisting of digital, paper-, and mobile-based tools that are deployed across implementation sites in seven European countries participating in the Ubiquitous PGx (U-PGx) project.

PMID: 29444243 [PubMed - as supplied by publisher]

Polymorphisms of drug-metabolizing enzyme CYP2E1 in Chinese Uygur population.

Medicine (Baltimore). 2018 Feb;97(7):e9970

Authors: Zhu L, He Y, Niu F, Yan M, Li J, Yuan D, Jin T

Abstract
Pharmacogenetics is the genetic basis of pharmacokinetics, genetic testing, and clinical management in diseases. Evaluation about genetic alterations of drug metabolizing enzymes in human genome contributes toward understanding the interindividual and interethnic variability for clinical response to potential toxicants. CYP2E1 gene encodes a drug-metabolizing enzyme that metabolizes mostly small, polar molecules, including toxic laboratory chemicals. The aim of this study was to investigate CYP2E1 polymorphisms and gene profile in a Chinese Uygur population. Frequencies for the CYP2E1 mutated alleles and genotypes were screened in 100 unrelated random healthy Uygur volunteers. PCR and direct sequencing revealed a total of 32 polymorphisms, of which 5 novel mutations were presented. Rs 943975 was the most common single nucleotide polymorphism (SNP). The allele frequencies of CYP2E11A, 4, 7A, and 7C were 65.5, 2, 19.5, and 13%, respectively. The most common genotype combinations were CYP2C191A/1A (43%) and 1A/7C (24%). Functional prediction for 2 nonsynonymous mutations G173S and V179I was performed using MutationTaster, sorting intolerant from tolerant, and PolyPhen-2. The observations of the present study give rise to useful information on CYP2E1 polymorphisms in Chinese Uygur individuals. The results suggest important clinical implications for the use of medications metabolized by CYP2E1 among Uygurs.

PMID: 29443789 [PubMed - in process]

Improving decision making on DPYD and UGT1A1*28 patients' profiling with an innovative reimbursement strategy.

Pharmacogenomics. 2018 Feb 14;:

Authors: Roncato R, Cecchin E, Toffoli G

PMID: 29441806 [PubMed - as supplied by publisher]

Related Articles

Genetic polymorphisms of HTR2C, LEP and LEPR on metabolic syndromes in patients treated with atypical antipsychotic drugs.

J Pharm Pharmacol. 2018 Feb 13;:

Authors: Puangpetch A, Unaharassamee W, Jiratjintana N, Koomdee N, Sukasem C

Abstract
OBJECTIVE: Single nucleotide polymorphisms in serotonin 2C receptor (HTR2C), leptin (LEP), and leptin receptor (LEPR) genes are reportedly associated with the presence of metabolic syndrome (MS). We investigated whether HTR2C:rs518147 (-697G/C), rs12836771 (A/G), LEP: rs7799039 (-2548G/A) and LEPR:rs1137101 (668A/G) are related to MS in psychotic disorder patients treated with atypical antipsychotics.
METHODS: A cross-sectional study including 200 patients was conducted; genetic polymorphisms in HTR2C (rs518147 and rs12836771), LEP (rs7799039) and LEPR (rs1137101) were genotyped. The presence of MS was evaluated according to the 2005 International Diabetes Federation (IDF) Asia criteria. The associations of genetic factors with the presence of MS are analysed.
KEY FINDINGS: Two SNPs in the HTR2C gene but not LEP and LEPR were associated with the presence of MS after adjustment for the combination of atypical antipsychotics. With respect to the effect of gender after treatment with risperidone and clozapine was statistically significant. Moreover, genotype combinations had no effect on MS.
CONCLUSIONS: Therefore, HTR2C genetic variants may be involved in the susceptibility to MS in patients treated with atypical antipsychotics. Additionally, there was a gender effect in the presence of MS. No effect of LEP or LEPR polymorphisms or the combination of HTR2C-LEP and HTR2C-LEPR was observed for the presence of MS.

PMID: 29441581 [PubMed - as supplied by publisher]

Related Articles

Evaluation of alteration in hepatic and intestinal BCRP function in vivo due to ABCG2 c.421C>A polymorphism based on PBPK analysis of rosuvastatin.

Drug Metab Dispos. 2018 Feb 12;:

Authors: Futatsugi A, Toshimoto K, Yoshikado T, Sugiyama Y, Kato Y

Abstract
Polymorphism c.421C>A in ABCG2 gene is thought to reduce the activity of breast cancer resistance protein (BCRP), a xenobiotic transporter, although it is not clear which organ(s) contributes to the polymorphism-associated pharmacokinetic change. The aim of the present study was to quantitatively estimate the influence of c.421C>A on intestinal and hepatic BCRP activity, using a physiologically based pharmacokinetic (PBPK) model of rosuvastatin developed from clinical data and several in vitro studies. Simultaneous fitting of clinical data for orally and intravenously administered rosuvastatin, obtained in human subjects without genotype information was first performed with the PBPK model to estimate intrinsic clearance for hepatic elementary process. The fraction of BCRP activity in 421CA and 421AA (fca and faa values, respectively) with respect to that in 421CC subjects was then estimated based on extended clearance concepts and simultaneous fitting to oral administration data for the three genotypes (421CC, 421CA, and 421AA). On the assumption that c.421C>A affects both intestinal and hepatic BCRP, clinical data in each genotype were well reproduced by the model, and the estimated terminal half-life was compatible with the observed values. The assumption that c.421C>A only affects either intestinal or hepatic BCRP gave poorer agreement with observed values. The faa values obtained on the former assumption were 0.48-0.54. Thus, PBPK model analysis enabled quantitative evaluation of alteration in BCRP activity due to c.421C>A, and BCRP activity in 421AA was estimated as half that in 421CC.

PMID: 29440178 [PubMed - as supplied by publisher]

Related Articles

A review of ustekinumab in the treatment of psoriatic arthritis.

Immunotherapy. 2018 Feb 14;:

Authors: Roberts J, O'Rielly DD, Rahman P

Abstract
Psoriatic arthritis is an inflammatory arthritis associated with psoriasis. The IL-23/IL-17 axis is an important pathway in the development of psoriatic disease. Ustekinumab is a fully human monoclonal IgG1 antibody that binds to the p40 subunit of IL-12 and IL-23, which, in turn, inhibits downstream signaling pathways. PSUMMIT-1 and PSUMMIT-2 are two pivotal Phase III trials demonstrating global improvement in primary and secondary outcomes including inhibition of radiographic progression. Therapeutic benefit of ustekinumab for synovitis appears independent of previous disease modifying antirheumatic disease or anti-TNF exposure. At present, the data support the use of ustekinumab in the treatment of psoriatic arthritis after the failure of NSAIDs and conventional disease modifying antirheumatic diseases as an alternative to, or after failure of an anti-TNF agent.

PMID: 29439608 [PubMed - as supplied by publisher]

Related Articles

NAT2 slow acetylator associated with anti-tuberculosis drug-induced liver injury in Thai patients.

Int J Tuberc Lung Dis. 2016 Oct;20(10):1364-1369

Authors: Wattanapokayakit S, Mushiroda T, Yanai H, Wichukchinda N, Chuchottawon C, Nedsuwan S, Rojanawiwat A, Denjanta S, Kantima T, Wongyai J, Suwankesawong W, Rungapiromnan W, Kidkeukarun R, Bamrungram W, Chaiwong A, Suvichapanich S, Mahasirimongkol S, Tokunaga K

Abstract
BACKGROUND: Anti-tuberculosis drug-induced liver injury (AT-DILI) is one of the most common forms of drug-induced liver injury (DILI) in high tuberculosis (TB) burden countries. Among anti-tuberculosis drugs, isoniazid is the main cause of hepatotoxicity in patients with AT-DILI.
OBJECTIVE: To investigate the association of AT-DILI with N-acetyltransferase 2 (NAT2) genotype status in Thai TB patients.
METHODS: We enrolled 53 patients diagnosed with AT-DILI and 85 patients who tolerated anti-tuberculosis treatment as controls. Acetylator status was determined based on the inferred NAT2 haplotypes from four common single-nucleotide polymorphisms (SNPs) in Thais using Sanger sequencing.
RESULTS: Phenotype frequencies of the NAT2 acetylator in AT-DILI patients were respectively 71.7%, 22.6% and 5.7% for slow, intermediate and rapid acetylators. Among slow, intermediate, and rapid acetylators in treatment tolerant controls, phenotype frequencies were respectively 22.4%, 62.4% and 15.3%. Slow NAT2 acetylators demonstrated a significant association with risk of AT-DILI. The odds ratio of comparing slow NAT2 acetylator in DILI patients and tolerance was 8.80 (95%CI 4.01-19.31, P = 1.53 × 10-8).
CONCLUSIONS: Slow acetylator status in the NAT2 genotype is a significant risk factor for DILI in Thai patients with TB. This evidence provides confirmatory data in support of the role of NAT2 in AT-DILI in the Thai population.

PMID: 27725049 [PubMed - indexed for MEDLINE]

Proceedings of the 2017 WAO Symposium on Hot Topics in Allergy: Pediatric & Regulatory Aspects: Rome, Italy/Vatican City. 27-29 April 2017.

World Allergy Organ J. 2017;10(Suppl 2):39

Authors: Traina G, Valluzzi RL, Fierro V, Riccardi C, Artesani MC, De Vuono A, Fiocchi A, Martelli AG, Ríos LA, Alcocer CR, Navarrete E, Del Rio Navarro BE, Gonzalez V, Velasco B, Perez Aviles HJ, Fernandez RJ, Pozo FC, Farhan AJ, Arshad H, Hussain A, Sharikadze O, Okhotnikova O, Alcover J, Rodriguez D, Pineda F, Dalal I, Weinbrand-Goichberg J, Benor S, Rottem M, Kivity S, Sato S, Yanagida N, Ebisawa M, Umanets T, Pineda F, Antipkin Y, Barzylovich V, Lapshyn V, Umanets T, Umanets M, Yuriev S, Pineda F, Rodriguez D, Alcover J, Bekir S, Pincock T, Vieira Hernandez A, Capriles Hulett A, Sánchez Borges M, Fabiano F, Albarran C, Goyal R, Gupta S, Gaurav G, Luskin AT, Griffin NM, Wagelie-Steffen A, Trzaskoma BL, Limb SL, Busse WW, Zeiger RS, Gonzalez-Reyes E, Casale TB, Chipps BE, Sugizaki C, Goto F, Sato S, Yanagida N, Ebisawa M, Yamaide A, Mitsunaga K, Tomiita M, Hoshioka A, Shimojo N, Pop LL, Ciucǎ IM, Tǎmaş L, Lazarescu M, Pienar C, Yamaide F, Fikri B, Sato H, Shimojo N, Okishima N, Kobayashi M, Takai M, Nishigata K, Yoda R, Oana YT, Kajiwara C, Shimodaira M, Suzuki T, Iizawa H, Kamijo K, Karmakar B, Bhattacharya SG, Blohlávková S, Kopelentová E, Víšek P, Štádler J, Šetinová I, Novobílská J, Lundelin K, Salminen S, Isolauri E, Pitt T, Flanders T, Peñalver M, Martínez P, Lluch M, Malet A, Nam YH, Jin HJ, Lee SK, Kulalert P, Sritipsukho P, Pathumanond J, Baynova K, Labella M, De Aramburu T, Prados M, Haanpää L, Aarnio J, Nermes M, Af Ursin P, Kaljonen A, Isolauri E, Bala N, Bhagwat K, Hindley J, Chapman M, Baalasubramanian S, Besednjak-Kocijančič L, SenGupta K, Bhattacharya SG, Chipps BE, Antonova E, Kong AM, Iqbal A, Teague WG, Chipps BE, Antonova E, Trzaskoma B, Ortiz B, Paknis B, Iqbal A, Rosen K, Szefler S, Alblooshi A, Al-Hammadi S, Vega A, Gutiérrez-Rivas R, Alonso AM, Beitia JM, Belén Mateo M, Cárdenas R, García-Domínguez JJ, Pitchon Dos Reis R, Gonçalves Alvim C, Andrade C, Reis A, Ribeiro H, Panaitescu Bunu C, Marusciac L, Paralescu S, Tamas P, Panitescu Bunu C, Marusciac L, Paralescu S, Tamas P, Martí Guadaño E, Escobar Bolaños C, Martí José N, Pau Casanovas P, Biarnés Rib G, Castells M, de Vicente Jiménez T, Mennini M, Riccardi C, De Angelis P, Rea F, Malamisura M, Tambucci R, Fiocchi A, Dall'Oglio L, Mennini M, Del Chierico F, Napolitano T, Reddel S, Vernocchi P, D'Ambrosio A, Putignani L, Artesani MC, Dahdah L, Fierro V, Banzato C, Echeverría Zudaire LA, Plaza AM, Bosque García M, Íbero M, Mazzina O, Fierro V, Marzano V, Riccardi C, Mazzina O, Dahdah L, Mennini M, Artesani MC, Mazzina O, Pecora V, Koch P, Valluzzi RL, Fierro V, Fiocchi A, Pecora V, Valentini D, Mennini M, Dahdah L, Mazzina O, Santamaria F, Valluzzi R, Mukherjee A, Kandhare A, Bodhankar S

PMID: 29444193 [PubMed]

Airway ciliary dysfunction and respiratory symptoms in patients with transposition of the great arteries.

PLoS One. 2018;13(2):e0191605

Authors: Zahid M, Bais A, Tian X, Devine W, Lee DM, Yau C, Sonnenberg D, Beerman L, Khalifa O, Lo CW

Abstract
BACKGROUND: Our prior work on congenital heart disease (CHD) with heterotaxy, a birth defect involving randomized left-right patterning, has shown an association of a high prevalence of airway ciliary dysfunction (CD; 18/43 or 42%) with increased respiratory symptoms. Furthermore, heterotaxy patients with ciliary dysfunction were shown to have more postsurgical pulmonary morbidities. These findings are likely a reflection of the common role of motile cilia in both airway clearance and left-right patterning. As CHD comprising transposition of the great arteries (TGA) is commonly thought to involve disturbance of left-right patterning, especially L-TGA with left-right ventricular inversion, we hypothesize CHD patients with transposition of great arteries (TGA) may have high prevalence of airway CD with increased respiratory symptoms.
METHODS AND RESULTS: We recruited 75 CHD patients with isolated TGA, 28% L and 72% D-TGA. Patients were assessed using two tests typically used for evaluating airway ciliary dysfunction in patients with primary ciliary dyskinesia (PCD), a recessive sinopulmonary disease caused by respiratory ciliary dysfunction. This entailed the measurement of nasal nitric oxide (nNO), which is typically low with PCD. We also obtained nasal scrapes and conducted videomicroscopy to assess respiratory ciliary motion (CM). We observed low nNO in 29% of the patients, and abnormal CM in 57%, with 22% showing both low nNO and abnormal CM. No difference was observed for the prevalence of either low nNO or abnormal ciliary motion between patients with D vs. L-TGA. Respiratory symptoms were increased with abnormal CM, but not low nNO. Sequencing analysis showed no compound heterozygous or homozygous mutations in 39 genes known to cause PCD, nor in CFTR, gene causing cystic fibrosis. As both are recessive disorders, these results indicate TGA patients with ciliary dysfunction do not have PCD or cystic fibrosis (which can cause low nNO or abnormal ciliary motion).
CONCLUSIONS: TGA patients have high prevalence of abnormal CM and low nNO, but ciliary dysfunction was not correlated with TGA type. Differing from PCD, respiratory symptoms were increased with abnormal CM, but not low nNO. Together with the negative findings from exome sequencing analysis, this would suggest TGA patients with ciliary dysfunction do not have PCD but nevertheless may suffer from milder airway clearance deficiency. Further studies are needed to investigate whether such ciliary dysfunction is associated with increased postsurgical complications as previously observed in CHD patients with heterotaxy.

PMID: 29444099 [PubMed - in process]

Prognostic significance of pulmonary hypertension in patients with cystic fibrosis: A systematic review and meta-analysis.

Medicine (Baltimore). 2018 Feb;97(7):e9708

Authors: Li D, Wang B, Wang H, Liu Q

Abstract
BACKGROUND AND OBJECTIVE: Pulmonary hypertension (PH) is frequently found in advanced parenchymal lung diseases like cystic fibrosis (CF), but the role played by PH in the clinical outcome of CF patients remains unclear. The aim of this study is to determine the influence of PH on survival in the CF population by meta-analysis.
METHODS: Publications addressing the associations between PH and overall survival (OS) or other clinical characteristics in CF patients were selected from electronic databases. Odds ratios (ORs) or mean differences (MDs) were used to estimate the association between PH and the clinical characteristics. The hazard ratios (HRs) with 95% confidence interval (CI) were abstracted or calculated to evaluate the association between PH and CF survival outcome. Subgroup analyses were also conducted.
RESULTS: Seven studies including 2141 CF patients who met the inclusion criteria were included in our meta-analysis. With respect to clinical features, PH was significantly associated with lower PaO2 (P < .001), higher PaCO2 (P = .02), lower forced expiratory volume in 1 second percent (P < .001) and lower forced vital capacity percent (P < .001). However, PH had no significant impact on CF patients' OS (HR = 1.29, 95% CI 0.81 to 2.06, P = .283). Furthermore, subgroup analyses also showed no evidence of prognostic role of PH in CF patients (all P values >.05).
CONCLUSIONS: Our findings suggest that the presence of PH was strongly correlated with worse blood-gas parameters and worse lung function, but surprisingly had no significant prognostic value on survival among CF patients. Further large-scale and prospective studies are needed to confirm these findings.

PMID: 29443734 [PubMed - in process]