Notice NOT-NS-18-017 from the NIH Guide for Grants and Contracts

Notice NOT-OD-18-150 from the NIH Guide for Grants and Contracts

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

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pharmacogenomics

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"systems biology"

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Funding Opportunity RFA-CA-18-020 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to support research projects designed to solve specific problems and paradoxes in cancer research identified by the National Cancer Institute (NCI) Provocative Questions initiative. These problems and paradoxes phrased as questions are not intended to represent the full range of NCI's priorities in cancer research. Rather, they are meant to challenge cancer researchers to think about and elucidate specific problems in key areas of cancer research that are deemed important but have not received sufficient attention. Some of these "Provocative Questions" (PQs) stem from intriguing but older, neglected observations that have never been adequately explored. Other PQs are built on more recent findings that are perplexing or paradoxical, revealing important gaps in current knowledge. Finally, some PQs reflect problems that traditionally have been thought to be intractable but that now may be open to investigations using new strategies and recent technical advances. The current issuance of the PQ Initiative includes an updated set of 12 PQs. Each research project proposed in response to this FOA must be focused on addressing one particular research problem defined by one specific PQ selected from the list. Projects proposed to address specific PQs may use strategies that incorporate ideas and approaches from multiple disciplines, as appropriate. Transdisciplinary projects are encouraged as long as they serve the scientific focus of the specific PQ chosen.

Funding Opportunity RFA-CA-18-019 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to support research projects designed to solve specific problems and paradoxes in cancer research identified by the National Cancer Institute (NCI) Provocative Questions initiative. These problems and paradoxes phrased as questions are not intended to represent the full range of NCI's priorities in cancer research. Rather, they are meant to challenge cancer researchers to think about and elucidate specific problems in key areas of cancer research that are deemed important but have not received sufficient attention. Some of these "Provocative Questions" (PQs) stem from intriguing but older, neglected observations that have never been adequately explored. Other PQs are built on more recent findings that are perplexing or paradoxical, revealing important gaps in current knowledge. Finally, some PQs reflect problems that traditionally have been thought to be intractable but that now may be open to investigations using new strategies and recent technical advances. The current issuance of the PQ Initiative includes an updated set of 12 PQs. Each research project proposed in response to this FOA must be focused on addressing one particular research problem defined by one specific PQ selected from the list. Projects proposed to address specific PQs may use strategies that incorporate ideas and approaches from multiple disciplines, as appropriate. Transdisciplinary projects are encouraged as long as they serve the scientific focus of the specific PQ chosen.

Notice NOT-DA-18-009 from the NIH Guide for Grants and Contracts

Notice NOT-AT-18-008 from the NIH Guide for Grants and Contracts

In silico identification of potent small molecule inhibitors targeting epidermal growth factor receptor 1.

J Cancer Res Ther. 2018 Jan;14(1):18-23

Authors: Shi Z, Chen J, Guo X, Cheng L, Guo X, Yu T

Abstract
Background: The receptor tyrosine kinase of the epidermal growth factor receptor (EGFR, ErbB) family played an important role in multisignaling pathways, which controlled numerous biological activities including proliferation, differentiation, apoptosis, etc. EGFR abnormalities have been associated with a variety of human tumors, which was a well-characterized target for cancer treatment. It was known to all that drug repositioning has been considered as a useful tool to accelerate the process of drug development.
Materials and Methods: Herein, a total of 1408 small molecule drugs approved by the Food and Drug Administration (FDA) were employed to identify potential EGFR inhibitors by a series of bioinformatics approaches, including virtual screening and molecular dynamics (MD) simulations.
Results: According to the docking score, five small molecules were chosed for further MD simulations. Following the 5 ns MD simulations, ZINC03830276 (Benzonatate) were finally recognized as "new use" of FDA-approved EGFR-targeting drug.
Conclusions: Our findings suggested that the small molecule ZINC03830276 (Benzonatate) could be a promising EGFR inhibitor candidate and may also provide new ideas for designing more potent EGFR inhibitors for the future study.

PMID: 29516953 [PubMed - in process]

Low Molecular Weight Chitosan-Coated PLGA Nanoparticles for Pulmonary Delivery of Tobramycin for Cystic Fibrosis.

Pharmaceuticals (Basel). 2018 Mar 08;11(1):

Authors: Al-Nemrawi NK, Alshraiedeh NH, Zayed AL, Altaani BM

Abstract
(1) Background: Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with Tobramycin were prepared using a solvent-evaporation method. (2) Methods: The NPs were coated with low molecular weight chitosan (LMWC) to enhance the mucoadhesiveness of PLGA-NPs. The following w/w ratios of tobramycin to LMWC were prepared: control (0:0.50), F₀ (1:0.25), F₀.₅ (1:0.5), and F₁ (1:1). (3) Results: The results showed that the size of the particles increased from 220.7 nm to 575.77 nm as the concentration of LMWC used in the formulation increased. The surface charge was also affected by the amount of LMWC, where uncoated-PLGA nanoparticles had negative charges (-2.8 mV), while coated-PLGA NPs had positive charges (+33.47 to +50.13 mV). SEM confirmed the size and the spherical homogeneous morphology of the NPs. Coating the NPs with LMWC enhanced the mucoadhesive properties of the NPs and sustained the tobramycin release over two days. Finally, all NPs had antimicrobial activity that increased as the amount of LMWC increased. (4) Conclusion: In conclusion, the formulation of mucoadhesive, controlled-release, tobramycin-LMWC-PLGA nanoparticles for the treatment of P. aeruginosa in cystic fibrosis patients is possible, and their properties could be controlled by controlling the concentration of LMWC.

PMID: 29517998 [PubMed]

Disease-modifying genetic factors in cystic fibrosis.

Curr Opin Pulm Med. 2018 Mar 06;:

Authors: Marson FAL

Abstract
PURPOSE OF REVIEW: To compile data from the past 10 years regarding the role of modifying genes in cystic fibrosis (CF).
RECENT FINDINGS: CF is a model disease for understanding of the action of modifying genes. Although it is a monogenic (CFTR) autosomal recessive disease, CF presents with wide phenotypic variability. In CF, variability occurs with different intensity among patients by each organ, being organ-specific, resulting from the mutual interaction of environmental and genetic factors, including CFTR mutations and various other genes, most of which are associated with inflammatory processes. In individuals, using precision medicine, gene modification studies have revealed individualized responses to drugs depending on particular CFTR mutations and modifying genes, most of which are alternative ion channels.
SUMMARY: Studies of modifying genes in CF allow: understanding of clinical variability among patients with the same CFTR genotype; evaluation of precision medicine; understanding of environmental and genetic effects at the organ level; understanding the involvement of genetic variants in inflammatory responses; improvements in genetic counseling; understanding the involvement of genetic variants in inflammatory responses in lung diseases, such as asthma; and understanding the individuality of the person with the disease.

PMID: 29517584 [PubMed - as supplied by publisher]

DEVELOPMENT OF A POLARIZED PANCREATIC DUCTULAR CELL EPITHELIA FOR PHYSIOLOGICAL STUDIES.

J Appl Physiol (1985). 2018 Mar 08;:

Authors: O'Malley Y, Rotti PG, Thornell IM, Vanegas Calderón OG, Febres-Aldana C, Durham K, Yao J, Li X, Zhu Z, Norris AW, Zabner J, Engelhardt JF, Uc A

Abstract
Pancreatic ductular epithelial cells comprise the majority of duct cells in pancreas, control cystic fibrosis transmembrane conductance regulator (CFTR)-dependent bicarbonate [HCO3-] secretion, but are difficult to grow as a polarized monolayer. Using NIH-3T3-J2 fibroblast feeder cells and a Rho-associated kinase inhibitor, we produced well-differentiated and polarized porcine pancreatic ductular epithelial cells. Cells grown on semipermeable filters at air-liquid interface (ALI) developed typical epithelial cell morphology and stable transepithelial resistance (TER), expressed epithelial cell markers (zona occludens-1 and beta catenin), duct cell markers (SOX-9 and CFTR), but no acinar (amylase) or islet cell (chromogranin) markers. Polarized cells were studied in Ussing chambers bathed in Krebs Ringer [HCO3-] solution, at 37oC gassed with 5% CO2 to measure short circuit currents (Isc). Ratiometric measurement of extracellular pH was performed using fluorescent SNARF-conjugated dextran at 5% CO2. Cells demonstrated a baseline Isc (12.2+3.2 μA/cm2) that increased significantly in response to apical forskolin/IBMX (∆Isc: 35.4{plus minus}3.8, p<0.001) or basolateral secretin (∆Isc: 31.4{plus minus}2.5 μA/cm2, p<0.001), both of which increase cellular levels of cAMP. Subsequent addition of apical GlyH-101, a CFTR inhibitor decreased the current (∆Isc: 20.4{plus minus}3.8, p<0.01). Extracellular pH and bicarbonate concentration increased significantly after forskolin/IBMX (pH: 7.18{plus minus}0.23 vs 7.53{plus minus}0.19; [HCO3-] in mM 14.5{plus minus}5.9 vs 31.8{plus minus}13.4, p<0.05 for both). We demonstrate the development of a polarized pancreatic ductular epithelial cell epithelia with CFTR-dependent bicarbonate secretion in response to secretin and cAMP. This model is highly relevant as porcine pancreas physiology is very similar to humans and pancreatic damage in cystic fibrosis pig model recapitulates that of humans.

PMID: 29517421 [PubMed - as supplied by publisher]

In vitro activity of seven hospital biocides against Mycobacterium abscessus: Implications for patients with cystic fibrosis.

Int J Mycobacteriol. 2018 Jan-Mar;7(1):45-47

Authors: Caskey S, Moore JE, Rendall JC

Abstract
Background: Mycobacterium abscessus pulmonary infection has recently emerged as a significant pathogen in patients with cystic fibrosis (CF) and is associated with significant morbidity and accelerated pulmonary decline. There is a paucity of data describing the activity of hospital biocides against this organism.
Methods: M. abscessus isolates (n = 13) were recovered from CF and non-CF respiratory specimens. Seven commonly employed hospital biocides with generic ingredients as follows: acetone, propan-2-ol, diethylene glycol, 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one, chlorine dioxide, 4% chlorhexidine, alcohol, and disodium carbonate, compound with hydrogen peroxide, 10% sodium hypochlorite were assayed for their biocidal activity against M. abscessus. Fresh cultures of M. abscessus were exposed to biocide in liquid medium as per manufacturers' instruction and were immediately plated following the completion of the contact period. The mean concentration of M. abscessus plated was 9.82 × 106 colony-forming units (range: 1.63 × 105-1.12 × 108). In addition, the remaining bacteria/biocide solution was enriched nonselectively in Mueller Hinton broth (37°C/1 week) and then plated.
Results: All M. abscessus isolates survived in alkyl dimethyl benzyl ammonium chloride, 5-chloro-2-methyl-2H-isothiazol-3-one (EC No. 247-500-7) and 2-methyl-2H-isothiazol-3-one, 4% Chlorhexidine™, O-phenylphenol and Sodium Lauryl Sulfate™ and disodium carbonate, compound with hydrogen peroxide. One out of 13 M. abscessus cultures was killed by Chlorine Dioxide™ and one by Sodium Dichloroisocyanurate™, representing a 5-log kill. Two isolates were killed by Alcohol™ again representing a 5 log kill. Following enrichment, O-phenylphenol and Sodium Lauryl Sulfate™ showed the greatest biocidal activity with 11/13 isolates, whereas 2/13 cultures were killed by sodium dichloroisocyanurate™. All other biocide/culture combinations yielded growth.
Conclusion: These data indicate that M. abscessus may persist after exposure to several common hospital biocides. Further work is urgently needed to define unequivocal biocide contact treatments to prevent cross-infection with this mycobacterial species in this patient population and thus ensure effective infection control and prevention.

PMID: 29516885 [PubMed - in process]

Related Articles

Exploring the need for Transition Readiness Scales within Cystic Fibrosis Services: A Qualitative Descriptive Study.

J Clin Nurs. 2018 Mar 08;:

Authors: Bourke M, Houghton C

Abstract
AIMS AND OBJECTIVES: The aim of this study was to explore health care professionals' (HCP) and patients' perceptions of the potential use of a Transition Readiness Scale (TRS) in cystic fibrosis care. This included an examination of barriers and facilitators to its implementation along with the identification of key items to include in a TRS.
BACKGROUND: Due to increasing life expectancy and improved quality of life, more adolescents with cystic fibrosis are transitioning from paediatric to adult health care. In order to assess and correctly manage this transition a more structured approach to transition is advocated. This can be achieved using a Transition Readiness Scale (TRS) to potentially identify or target areas of care in which the adolescent may have poor knowledge. These key items include education, developmental readiness taking in to account relationships, reproduction, future plans and self-management skills. Existing tools to gauge readiness concentrate mainly on education and self-care needs assessment as their key items. Currently there is no specific CF TRS in use in Ireland or internationally.
DESIGN: The study used a descriptive qualitative design.
METHODS: Data were collected using semi-structured interviews (n=8) and analysed using a thematic approach.
RESULTS: The findings identified the potential benefits of this tool and secondly the resources which need to be in place before its development and implementation in to cystic fibrosis services.
CONCLUSION: Transition Readiness Scales have substantial relevance with cystic fibrosis services emphasising the importance of establishing the necessary resources prior to its implementation. These were identified as more staff, a dedicated private space, and staff training and education.
RELEVANCE TO CLINICAL PRACTICE: Significant resources are needed to fully integrate transition readiness scales in practice. The study findings suggest multidisciplinary collaborations and patient engagement are pivotal in planning and easing the transition process for adolescents with cystic fibrosis. This article is protected by copyright. All rights reserved.

PMID: 29516552 [PubMed - as supplied by publisher]

Related Articles

Assembly 3: Basic and Translational Sciences.

Breathe (Sheff). 2018 Mar;14(1):67-68

Authors: Greene CM, Hiemstra PS

Abstract
Meet @ERStalk Assembly 3: Basic and Translational Sciences http://ow.ly/66E830hFi7U.

PMID: 29515672 [PubMed]

Related Articles

Cystic Fibrosis-Related Diabetes.

Front Endocrinol (Lausanne). 2018;9:20

Authors: Kayani K, Mohammed R, Mohiaddin H

Abstract
Cystic fibrosis (CF) is the most common autosomal recessive disorder in Caucasian populations. Individuals with CF have seen significant increases in life expectancy in the last 60 years. As a result, previously rare complications are now coming to light. The most common of these is cystic fibrosis-related diabetes (CFRD), which affects 40-50% of CF adults. CFRD significantly impacts the pulmonary function and longevity of CF patients, yet a lack of consensus on the best methods to diagnose and treat CFRD remains. We begin by reviewing our understanding of the pathogenesis of CFRD, as emerging evidence shows the cystic fibrosis transmembrane conductance regulator (CFTR) also has important roles in the release of insulin and glucagon and in the protection of β cells from oxidative stress. We then discuss how current recommended methods of CFRD diagnosis are not appropriate, as continuous glucose monitoring becomes more effective, practical, and cost-effective. Finally, we evaluate emerging treatments which have narrowed the mortality gap within the CF patient group. In the future, pharmacological potentiators and correctors directly targeting CFTR show huge promise for both CFRD and the wider CF patient groups.

PMID: 29515516 [PubMed]

Defective mitochondrial protease LonP1 can cause classical mitochondrial disease.

Hum Mol Genet. 2018 Mar 06;:

Authors: Peter B, Waddington CL, Oláhová M, Sommerville EW, Hopton S, Pyle A, Champion M, Ohlson M, Siibak T, Chrzanowska-Lightowlers ZMA, Taylor RW, Falkenberg M, Lightowlers RN

Abstract
LonP1 is a mitochondrial matrix protease whose selective substrate specificity is essential for maintaining mitochondrial homeostasis. Recessively-inherited, pathogenic defects in LonP1 have been previously reported to underlie cerebral, ocular, dental, auricular and skeletal anomalies (CODAS) syndrome, a complex multisystemic and developmental disorder. Intriguingly, although classical mitochondrial disease presentations are well-known to exhibit marked clinical heterogeneity, the skeletal and dental features associated with CODAS syndrome are pathognomonic. We have applied whole exome sequencing to a patient with congenital lactic acidosis, muscle weakness, profound deficiencies in mitochondrial oxidative phosphorylation associated with loss of mtDNA copy number and MRI abnormalities consistent with Leigh syndrome, identifying biallelic variants in the LONP1 (NM_004793.3) gene; c.1693T>C predicting p.(Tyr565His) and c.2197G>A predicting p.(Glu733Lys); no evidence of the classical skeletal or dental defects observed in CODAS syndrome patients were noted in our patient. In vitro experiments confirmed the p.(Tyr565His) LonP1 mutant alone could not bind or degrade a substrate, consistent with the predicted function of Tyr565, whilst a second missense (p.(Glu733Lys)) variant had minimal effect. Mixtures of p.(Tyr565His) mutant and wild type LonP1 retained partial protease activity but this was severely depleted when the p.(Tyr565His) mutant was mixed with the p.(Glu733Lys) mutant, data consistent with the compound heterozygosity detected in our patient. In summary, we conclude that pathogenic LONP1 variants can lead to a classical mitochondrial disease presentations associated with severe biochemical defects in oxidative phosphorylation in clinically-relevant tissues.

PMID: 29518248 [PubMed - as supplied by publisher]

Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.

Genet Med. 2018 Mar 08;:

Authors: Boczonadi V, King MS, Smith AC, Olahova M, Bansagi B, Roos A, Eyassu F, Borchers C, Ramesh V, Lochmüller H, Polvikoski T, Whittaker RG, Pyle A, Griffin H, Taylor RW, Chinnery PF, Robinson AJ, Kunji ERS, Horvath R

Abstract
PurposeTo understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease.MethodsWe identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons.ResultsThe patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy. Transport assays show that the mutation renders SLC25A21 dysfunctional and 2-oxoadipate cannot be imported into the mitochondrial matrix. Computer models of central metabolism predicted that impaired transport of oxodicarboxylate disrupts the pathways of lysine and tryptophan degradation, and causes accumulation of 2-oxoadipate, pipecolic acid, and quinolinic acid, which was confirmed in the patient's urine by targeted metabolomics. Exposure to 2-oxoadipate and quinolinic acid decreased the level of mitochondrial complexes in neuronal cells (SH-SY5Y) and induced apoptosis.ConclusionMitochondrial oxodicarboxylate carrier deficiency leads to mitochondrial dysfunction and the accumulation of oxoadipate and quinolinic acid, which in turn cause toxicity in spinal motor neurons leading to spinal muscular atrophy-like disease.GENETICS in MEDICINE advance online publication, 8 March 2018; doi:10.1038/gim.2017.251.

PMID: 29517768 [PubMed - as supplied by publisher]

Related Articles

Genetic Alterations in Essential Thrombocythemia Progression to Acute Myeloid Leukemia: A Case Series and Review of the Literature.

Front Oncol. 2018;8:32

Authors: Ayres-Silva JP, Bonamino MH, Gouveia ME, Monte-Mor BCR, Coutinho DF, Daumas AH, Solza C, Braggio E, Zalcberg IR

Abstract
The genetic events associated with transformation of myeloproliferative neoplasms (MPNs) to secondary acute myeloid leukemia (sAML), particularly in the subgroup of essential thrombocythemia (ET) patients, remain incompletely understood. Deep studies using high-throughput methods might lead to a better understanding of genetic landscape of ET patients who transformed to sAML. We performed array-based comparative genomic hybridization (aCGH) and whole exome sequencing (WES) to analyze paired samples from ET and sAML phases. We investigated five patients with previous history of MPN, which four had initial diagnosis of ET (one case harboring JAK2 p.Val617Phe and the remaining three CALR type II p.Lys385fs*47), and one was diagnosed with MPN/myelodysplastic syndrome with thrombocytosis (SF3B1 p.Lys700Glu). All were homogeneously treated with hydroxyurea, but subsequently transformed to sAML (mean time of 6 years/median of 4 years to transformation). Two of them have chromosomal abnormalities, and both acquire 2p gain and 5q deletion at sAML stage. The molecular mechanisms associated with leukemic progression in MPN patients are not clear. Our WES data showed TP53 alterations recurrently observed as mutations (missense and frameshift) and monoallelic loss. On the other hand, aCGH showed novel chromosome abnormalities (+2p and del5q) potentially associated with disease progression. The results reported here add valuable information to the still fragmented molecular basis of ET to sAML evolution. Further studies are necessary to identify minimal deleted/amplified region and genes relevant to sAML transformation.

PMID: 29515972 [PubMed]