Reading-induced shifts of perceptual speech representations in auditory cortex.

Sci Rep. 2017 Jul 11;7(1):5143

Authors: Bonte M, Correia JM, Keetels M, Vroomen J, Formisano E

Abstract
Learning to read requires the formation of efficient neural associations between written and spoken language. Whether these associations influence the auditory cortical representation of speech remains unknown. Here we address this question by combining multivariate functional MRI analysis and a newly-developed 'text-based recalibration' paradigm. In this paradigm, the pairing of visual text and ambiguous speech sounds shifts (i.e. recalibrates) the perceptual interpretation of the ambiguous sounds in subsequent auditory-only trials. We show that it is possible to retrieve the text-induced perceptual interpretation from fMRI activity patterns in the posterior superior temporal cortex. Furthermore, this auditory cortical region showed significant functional connectivity with the inferior parietal lobe (IPL) during the pairing of text with ambiguous speech. Our findings indicate that reading-related audiovisual mappings can adjust the auditory cortical representation of speech in typically reading adults. Additionally, they suggest the involvement of the IPL in audiovisual and/or higher-order perceptual processes leading to this adjustment. When applied in typical and dyslexic readers of different ages, our text-based recalibration paradigm may reveal relevant aspects of perceptual learning and plasticity during successful and failing reading development.

PMID: 28698606 [PubMed - in process]

Proteomics and metabolomics in ageing research: from biomarkers to systems biology.

Essays Biochem. 2017 Jul 15;61(3):379-388

Authors: Hoffman JM, Lyu Y, Pletcher SD, Promislow DEL

Abstract
Age is the single greatest risk factor for a wide range of diseases, and as the mean age of human populations grows steadily older, the impact of this risk factor grows as well. Laboratory studies on the basic biology of ageing have shed light on numerous genetic pathways that have strong effects on lifespan. However, we still do not know the degree to which the pathways that affect ageing in the lab also influence variation in rates of ageing and age-related disease in human populations. Similarly, despite considerable effort, we have yet to identify reliable and reproducible 'biomarkers', which are predictors of one's biological as opposed to chronological age. One challenge lies in the enormous mechanistic distance between genotype and downstream ageing phenotypes. Here, we consider the power of studying 'endophenotypes' in the context of ageing. Endophenotypes are the various molecular domains that exist at intermediate levels of organization between the genotype and phenotype. We focus our attention specifically on proteins and metabolites. Proteomic and metabolomic profiling has the potential to help identify the underlying causal mechanisms that link genotype to phenotype. We present a brief review of proteomics and metabolomics in ageing research with a focus on the potential of a systems biology and network-centric perspective in geroscience. While network analyses to study ageing utilizing proteomics and metabolomics are in their infancy, they may be the powerful model needed to discover underlying biological processes that influence natural variation in ageing, age-related disease, and longevity.

PMID: 28698311 [PubMed - in process]

Systems modelling ageing: from single senescent cells to simple multi-cellular models.

Essays Biochem. 2017 Jul 15;61(3):369-377

Authors: Martinez Guimera A, Welsh C, Dalle Pezze P, Fullard N, Nelson G, Roger MF, Przyborski SA, Shanley DP

Abstract
Systems modelling has been successfully used to investigate several key molecular mechanisms of ageing. Modelling frameworks to allow integration of models and methods to enhance confidence in models are now well established. In this article, we discuss these issues and work through the process of building an integrated model for cellular senescence as a single cell and in a simple tissue context.

PMID: 28698310 [PubMed - in process]

On the Origin of Reverse Transcriptase-Using CRISPR-Cas Systems and Their Hyperdiverse, Enigmatic Spacer Repertoires.

MBio. 2017 Jul 11;8(4):

Authors: Silas S, Makarova KS, Shmakov S, Páez-Espino D, Mohr G, Liu Y, Davison M, Roux S, Krishnamurthy SR, Fu BXH, Hansen LL, Wang D, Sullivan MB, Millard A, Clokie MR, Bhaya D, Lambowitz AM, Kyrpides NC, Koonin EV, Fire AZ

Abstract
Cas1 integrase is the key enzyme of the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas adaptation module that mediates acquisition of spacers derived from foreign DNA by CRISPR arrays. In diverse bacteria, the cas1 gene is fused (or adjacent) to a gene encoding a reverse transcriptase (RT) related to group II intron RTs. An RT-Cas1 fusion protein has been recently shown to enable acquisition of CRISPR spacers from RNA. Phylogenetic analysis of the CRISPR-associated RTs demonstrates monophyly of the RT-Cas1 fusion, and coevolution of the RT and Cas1 domains. Nearly all such RTs are present within type III CRISPR-Cas loci, but their phylogeny does not parallel the CRISPR-Cas type classification, indicating that RT-Cas1 is an autonomous functional module that is disseminated by horizontal gene transfer and can function with diverse type III systems. To compare the sequence pools sampled by RT-Cas1-associated and RT-lacking CRISPR-Cas systems, we obtained samples of a commercially grown cyanobacterium-Arthrospira platensis Sequencing of the CRISPR arrays uncovered a highly diverse population of spacers. Spacer diversity was particularly striking for the RT-Cas1-containing type III-B system, where no saturation was evident even with millions of sequences analyzed. In contrast, analysis of the RT-lacking type III-D system yielded a highly diverse pool but reached a point where fewer novel spacers were recovered as sequencing depth was increased. Matches could be identified for a small fraction of the non-RT-Cas1-associated spacers, and for only a single RT-Cas1-associated spacer. Thus, the principal source(s) of the spacers, particularly the hypervariable spacer repertoire of the RT-associated arrays, remains unknown.IMPORTANCE While the majority of CRISPR-Cas immune systems adapt to foreign genetic elements by capturing segments of invasive DNA, some systems carry reverse transcriptases (RTs) that enable adaptation to RNA molecules. From analysis of available bacterial sequence data, we find evidence that RT-based RNA adaptation machinery has been able to join with CRISPR-Cas immune systems in many, diverse bacterial species. To investigate whether the abilities to adapt to DNA and RNA molecules are utilized for defense against distinct classes of invaders in nature, we sequenced CRISPR arrays from samples of commercial-scale open-air cultures of Arthrospira platensis, a cyanobacterium that contains both RT-lacking and RT-containing CRISPR-Cas systems. We uncovered a diverse pool of naturally occurring immune memories, with the RT-lacking locus acquiring a number of segments matching known viral or bacterial genes, while the RT-containing locus has acquired spacers from a distinct sequence pool for which the source remains enigmatic.

PMID: 28698278 [PubMed - in process]

Bioinformatics in the Plant Genomic and Phenomic Domain: The German Contribution to Resources, Services and Perspectives.

J Biotechnol. 2017 Jul 08;:

Authors: Schmutzer T, Bolger ME, Rudd S, Chen J, Gundlach H, Arend D, Oppermann M, Weise S, Lange M, Spannagl M, Usadel B, Mayer KFX, Scholz U

Abstract
Plant genetic resources are a substantial opportunity for plant breeding, preservation and maintenance of biological diversity. As part of the German Network for Bioinformatics Infrastructure (de.NBI) the German Crop BioGreenformatics Network (GCBN) focuses mainly on crop plants and provides both data and software infrastructure which are tailored to the needs of the plant research community. Our mission and key objectives include: (1) provision of transparent access to germplasm seeds, (2) the delivery of improved workflows for plant gene annotation, and (3) implementation of bioinformatics services that link genotypes and phenotypes. This review introduces the GCBN's spectrum of web-services and integrated data resources that address common research problems in the plant genomics community.

PMID: 28698099 [PubMed - as supplied by publisher]

Efficacy and safety of micafungin versus extensive azoles in the prevention and treatment of invasive fungal infections for neutropenia patients with hematological malignancies: A meta-analysis of randomized controlled trials.

PLoS One. 2017;12(7):e0180050

Authors: Lee CH, Lin JC, Ho CL, Sun M, Yen WT, Lin C

Abstract
BACKGROUND: Current studies that compare the efficacy and safety of micafungin (MCFG) with that of triazoles for the prophylaxis and treatment of invasive fungal infections (IFIs) demonstrate a lack of sufficient evidence and yield conflicting results. To compare the efficacy and safety of MCFG and triazoles in the prevention and treatment of IFIs, we conducted a meta-analysis and trial sequential analysis (TSA).
METHODS: For the meta-analysis, we systematically searched the databases of PubMed, Embase and Cochrane Central Register of Controlled Trials and relevant database articles for randomized controlled studies published through November 2016. Comparative studies of the efficacy and safety of MCFG versus triazoles in the prevention and treatment of IFIs were selected. Meta-analysis was performed by R software with the "metafor" package. Pooled results were expressed as risk ratios (RRs) with corresponding 95% confidence intervals (CI). TSA was adopted to assess the studies' power with TSA version 0.9 beta.
RESULTS: Nine current studies were included in the meta-analysis (1049 cases and 959 controls). Pooled trial comparisons indicated that MCFG does have significantly higher treatment success rates (RR = 1.13; 95% CI, 1.02-1.25; p = 0.0205) and reduces the number of overall IFIs (RR = 0.75; 95% CI, 0.61-0.92; p = 0.0056). However, MCFG demonstrates no difference in all-cause mortality (RR = 0.76; 95% CI, 0.52-1.12, p = 0.1624). For the safety evaluation, MCFG had a significantly lower incidence of severe adverse events (AEs) (RR = 0.45; 95% CI, 0.25-0.83; p = 0.0105), hepatic impairment (RR = 0.70; 95% CI, 0.50-0.97; p = 0.0363) and premature discontinuation (RR = 0.51; 95% CI, 0.34-0.76, p = 0.0010). Meta-regression analysis disclosed the correction of mean age and treatment success rates (P < 0.0001). Meanwhile, TSA demonstrated sufficient power to show efficacy.
CONCLUSIONS: The treatment success rate of MCFG is superior to that of triazoles for the prophylaxis and treatment of IFIs, and correction of the mean patient age demonstrates that efficacy increases as patient age decreases. MCFG appears to be well-tolerated with manageable side effects and lower withdrawal rates. However, additional clinical trials should be conducted on specific drug-related mortality and AEs to gather sufficient evidence on these matters.

PMID: 28700646 [PubMed - in process]

ExCNVSS: A Noise-Robust Method for Copy Number Variation Detection in Whole Exome Sequencing Data.

Biomed Res Int. 2017;2017:9631282

Authors: Kong J, Shin J, Won J, Lee K, Lee U, Yoon J

Abstract
Copy number variations (CNVs) are structural variants associated with human diseases. Recent studies verified that disease-related genes are based on the extraction of rare de novo and transmitted CNVs from exome sequencing data. The need for more efficient and accurate methods has increased, which still remains a challenging problem due to coverage biases, as well as the sparse, small-sized, and noncontinuous nature of exome sequencing. In this study, we developed a new CNV detection method, ExCNVSS, based on read coverage depth evaluation and scale-space filtering to resolve these problems. We also developed the method ExCNVSS_noRatio, which is a version of ExCNVSS, for applying to cases with an input of test data only without the need to consider the availability of a matched control. To evaluate the performance of our method, we tested it with 11 different simulated data sets and 10 real HapMap samples' data. The results demonstrated that ExCNVSS outperformed three other state-of-the-art methods and that our method corrected for coverage biases and detected all-sized CNVs even without matched control data.

PMID: 28698882 [PubMed - in process]

Payer coverage policies for multigene tests.

Nat Biotechnol. 2017 Jul 12;35(7):614-617

Authors: Phillips KA, Deverka PA, Trosman JR, Douglas MP, Chambers JD, Weldon CB, Dervan AP

PMID: 28700544 [PubMed - in process]

Personalizing antiplatelet prescribing using genetics for patients undergoing percutaneous coronary intervention.

Expert Rev Cardiovasc Ther. 2017 Jul 12;:

Authors: Cavallari LH

Abstract
INTRODUCTION: Clopidogrel is commonly prescribed with aspirin to reduce the risk for adverse cardiovascular events after percutaneous coronary intervention (PCI). However, there is significant inter-patient variability in clopidogrel response. The CYP2C19 enzyme is involved in the biotransformation of clopidogrel to its pharmacologically active form, and variation in the CYP2C19 gene contributes to clopidogrel response variability. Areas covered. This article describes the impact of CYP2C19 genotype on clopidogrel pharmacokinetics, pharmacodynamics, and effectiveness. Examples of clinical implementation of CYP2C19 genotyping-guided antiplatelet therapy for patients undergoing PCI are also described as are emerging outcomes data with this treatment approach. Expert commentary. A large clinical trial evaluating outcomes with CYP2C19 genotype-guided antiplatelet therapy after PCI is on-going. In the meantime, data from pragmatic and observational studies and smaller trials support improved outcomes with genotyping after PCI and use of alternative antiplatelet therapy in patients with a CYP2C19 genotype associated with reduced clopidogrel effectiveness.

PMID: 28699807 [PubMed - as supplied by publisher]

Pharmacogenomics Implementation: Considerations for Selecting a Reference Laboratory.

Pharmacotherapy. 2017 Jul 12;:

Authors: Vo TT, Bell GC, Owusu Obeng A, Hicks JK, Dunnenberger HM

Abstract
One of the initial steps for implementing pharmacogenomics into routine patient care is selecting an appropriate clinical laboratory to perform the testing. With the rapid advances in genotyping technologies, many clinical laboratories are now performing pharmacogenomic testing. Selection of a reference laboratory depends on whether a particular genotype assay is already performed by an internal healthcare organization laboratory or only available externally. Other factors for consideration are coverage of genomic variants important for your patient population, technical support, and cost. In some instances, the decision to select a particular reference laboratory may be the responsibility of the clinician who is recommending genomic interrogation. There is limited guidance describing the laboratory characteristics to consider when selecting a reference laboratory. We provide practical considerations for selecting a clinical laboratory for pharmacogenomic testing broadly categorized into 4 domains: (1) pharmacogene and variant selection, (2) logistics, (3) reporting of results, and (4) test costs along with reimbursement. This article is protected by copyright. All rights reserved.

PMID: 28699700 [PubMed - as supplied by publisher]

Review of Opioid Pharmacogenetics and Considerations for Pain Management.

Pharmacotherapy. 2017 Jul 12;:

Authors: Owusu Obeng A, Hamadeh I, Smith M

Abstract
Opioid analgesics are the standards of care for the treatment of moderate to severe nociceptive pain, particularly in the setting of cancer and surgery. Their analgesic properties mainly emanate from stimulation of the μ receptors, which are encoded by the OPRM1 gene. Hepatic metabolism represents the major route of elimination, which, for some opioids, namely codeine and tramadol, is necessary for their bioactivation into more potent analgesics. The highly polymorphic nature of the genes coding for phase I and phase II enzymes (pharmacokinetics genes) that are involved in the metabolism and bioactivation of opioids suggests a potential interindividual variation in their disposition and, most likely, response. In fact, such an association has been substantiated in several pharmacokinetic studies described in this review, in which drug exposure and/or metabolism differed significantly based on the presence of polymorphisms in these pharmacokinetics genes. Furthermore, in some studies, the observed variability in drug exposure translated into differences in the incidence of opioid-related adverse effects, particularly nausea, vomiting, constipation, and respiratory depression. Although the influence of polymorphisms in pharmacokinetics genes, as well as pharmacodynamics genes (OPRM1 and COMT) on response to opioids has been a subject of intense research, the results have been somehow conflicting, with some evidence insinuating for a potential role for OPRM1. The Clinical Pharmacogenetics Implementation Consortium guidelines provide CYP2D6-guided therapeutic recommendations to individualize treatment with tramadol and codeine. However, implementation guidelines for other opioids, which are more commonly used in real-world settings for pain management, are currently lacking. Hence, further studies are warranted to bridge this gap in our knowledge base and ultimately ascertain the role of pharmacogenetic markers as predictors of response to opioid analgesics. This article is protected by copyright. All rights reserved.

PMID: 28699646 [PubMed - as supplied by publisher]

Pharmacogenetics and Pharmacogenomics of Targeted Therapeutics in Chronic Myeloid Leukemia.

Mol Diagn Ther. 2017 Jul 11;:

Authors: Nath A, Wang J, Stephanie Huang R

Abstract
The advent of targeted therapeutics has greatly improved outcomes of chronic myeloid leukemia (CML) patients. Despite increased efficacy and better clinical responses over cytotoxic chemotherapies, many patients receiving targeted drugs exhibit a poor initial response, develop drug resistance, or undergo relapse after initial success. This inter-individual variation in response has heightened the interest in studying pharmacogenetics and pharmacogenomics (PGx) of cancer drugs. In this review, we discuss the influence of various germline and somatic factors on targeted drug response in CML. Specifically, we examine the role of genetic variants in drug metabolism genes, i.e. CYP3A family genes, and drug transporters, i.e. ABC and SLC family genes. Additionally, we focus on acquired somatic variations in BCR-ABL1, and the potential role played by additional downstream signaling pathways, in conferring resistance to targeted drugs in CML. This review highlights the importance of PGx of targeted therapeutics and its potential application to improving treatment decisions and patient outcomes.

PMID: 28698977 [PubMed - as supplied by publisher]

Bacterial Community Profile of the Gut Microbiota Differs between Hypercholesterolemic Subjects and Controls.

Biomed Res Int. 2017;2017:8127814

Authors: Rebolledo C, Cuevas A, Zambrano T, Acuña JJ, Jorquera MA, Saavedra K, Martínez C, Lanas F, Serón P, Salazar LA, Saavedra N

Abstract
The role of gut microbiota in the development of metabolic illnesses has been abundantly demonstrated. Recent studies suggest that gut microbiota alterations may also be related to the development of hypercholesterolemia. Therefore, we aimed to assess differences in the gut bacterial community profiles between hypercholesterolemic subjects and controls. Thirty cases diagnosed with hypercholesterolemia and 27 normocholesterolemic controls were included. A fasting whole blood sample was obtained to determine the lipid profile. In parallel, stool samples were collected and total DNA was isolated to assess the bacterial community profiles by denaturing gradient gel electrophoresis (DGGE). In addition, the Richness, Shannon-Weaver, and Simpson indexes were used to evaluate the richness and diversity of bacterial communities. As expected, serum concentrations of total cholesterol, triglycerides, and LDL-cholesterol were significantly higher in the cases compared with controls. Moreover, DGGE analysis showed a lower richness and diversity of bacterial communities in hypercholesterolemic subjects. In conclusion, our results showed differences in the profiles of bacterial communities between hypercholesterolemic subjects and controls, suggesting a possible role of the gut microbiota in the development of hypercholesterolemia.

PMID: 28698878 [PubMed - in process]

Gene-gene and gene-environment interactions influence platinum-based chemotherapy response and toxicity in non-small cell lung cancer patients.

Sci Rep. 2017 Jul 11;7(1):5082

Authors: Cui JJ, Wang LY, Zhu T, Gong WJ, Zhou HH, Liu ZQ, Yin JY

Abstract
Platinum-based chemotherapy is a major therapeutic regimen of lung cancer. Various single nucleotide polymorphisms (SNPs) reported were associated with platinum-based chemotherapy response and drug toxicity. However, neither of the studies explored this association from SNP-SNP interaction perspective nor taking into effects of SNP-environment consideration simultaneously. We genotyped 504 polymorphisms and explore the association of gene-gene and gene-environment interactions with platinum-based chemotherapy response and toxicity in 490 NSCLC patients. 16 SNPs were found significantly associated with platinum-based chemotherapy, and they were picked out as study object in the validation cohort. We recruited 788 patients in the validation cohort. We found that HSPD1 rs17730989-SUMF1 rs2633851 interaction was associated with platinum-based chemotherapy-induced hematologic toxicity (adjusted OR = 0.233, P = 0.018). In addition, the combined effect of ABCG2 rs2231142-CES5A rs3859104 was significantly associated with overall toxicity (adjusted OR = 8.044, P = 4.350 × 10(-5)). Besides, the model of ARHGAP26 rs3776332-ERCC6 rs2228528-SLC2A1 rs4658-histology was associated with platinum-based chemotherapeutic response. Gene-gene and gene-environment interactions have been identified to contribute to chemotherapy sensitivity and toxicity. They can potentially predict drug response and toxicity of platinum-based chemotherapy in NSCLC patients.

PMID: 28698656 [PubMed - in process]

V-J combinations of T-cell receptor predict responses to erythropoietin in end-stage renal disease patients.

J Biomed Sci. 2017 Jul 11;24(1):43

Authors: Wong HS, Chang CM, Kao CC, Hsu YW, Liu X, Chang WC, Wu MS, Chang WC

Abstract
BACKGROUND: Anemia is common among end-stage renal disease (ESRD) patients who undergone hemodialysis. The total reduction of red blood cell (RBC) count is associated with poor prognosis in these patients. Although erythropoietin (EPO) has been used as an effective treatment for ESRD patients with anemia, a large number of patients still present poor responses to EPO treatment.
METHODS: We measured T-cell receptor sequencing profiles, including length of complementarity-deteremining region 3 (CDR3), intra- and inter-group (EPO resistant vs. responsive) clonotype diversity, V(D)J usage profiles and V-J combinations from ESRD patients and to investigate the correlation between these features and EPO treatment efficacy.
RESULTS: Our results revealed statistical significance in the top 3 ~ 15 most abundant joint distributions of Vβ/Jβ among the two groups, suggesting the importance of V or J gene utilization in the EPO response of ESRD patients.
CONCLUSIONS: In summary, we provided evidence addressing the potential correlation between the immune repertoire and EPO response in ESRD patients.
TRIAL REGISTRATION: TMU-JIRB 201309026. Registered 16 October 2013.

PMID: 28697735 [PubMed - in process]

FDA deems in vitro data on mutations sufficient to expand cystic fibrosis drug label.

Nat Biotechnol. 2017 Jul 12;35(7):606

Authors: Ratner M

PMID: 28700545 [PubMed - in process]

D-methionine interferes with non-typeable Haemophilus influenzae peptidoglycan synthesis during growth and biofilm formation.

Microbiology. 2017 Jul 12;:

Authors: Dawe H, Berger E, Sihlbom C, Angus EM, Howlin RP, Laver JR, Tebruegge M, Hall-Stoodley L, Stoodley P, Faust SN, Allan RN

Abstract
Non-typeable Haemophilus influenzae (NTHi) is an opportunistic pathogen that plays a major role in a number of respiratory tract infections, including otitis media, cystic fibrosis and chronic obstructive pulmonary disease. Biofilm formation has been implicated in both NTHi colonization and disease, and is responsible for the increased tolerance of this pathogen towards antibiotic treatment. Targeting metabolic pathways that are important in NTHi biofilm formation represents a potential strategy to combat this antibiotic recalcitrance. A previous investigation demonstrated increased expression of a putative d-methionine uptake protein following exposure of NTHi biofilms to the ubiquitous signalling molecule, nitric oxide. We therefore hypothesized that treatment with exogenous d-methionine would impact on NTHi biofilm formation and increase antibiotic sensitivity. Treatment of NTHi during the process of biofilm formation resulted in a reduction in biofilm viability, increased biomass, changes in the overall biofilm architecture and the adoption of an amorphous cellular morphology. Quantitative proteomic analyses identified 124 proteins that were differentially expressed following d-methionine treatment, of which 51 (41 %) were involved in metabolic and transport processes. Nine proteins involved in peptidoglycan synthesis and cell division showed significantly increased expression. Furthermore, d-methionine treatment augmented the efficacy of azithromycin treatment and highlighted the potential of d-methionine as an adjunctive therapeutic approach for NTHi biofilm-associated infections.

PMID: 28699879 [PubMed - as supplied by publisher]

Estimating Direct Cost of Cystic Fibrosis Care Using Irish Registry Healthcare Resource Utilisation Data, 2008-2012.

Pharmacoeconomics. 2017 Jul 11;:

Authors: Jackson AD, Jackson AL, Fletcher G, Doyle G, Harrington M, Zhou S, Cullinane F, Gallagher C, McKone E

Abstract
BACKGROUND: Understanding the determinants of cost of cystic fibrosis (CF) care and health outcomes may be useful for financial planning for the delivery of CF services. Registries contain information otherwise unavailable to healthcare activity/cost monitoring systems. We estimated the direct medical cost of CF care using registry data and examined how cost was affected by patient characteristics and CF gene (CF Transmembrane Conductance Regulator [CFTR]) mutation.
METHODS: Healthcare resource utilisation data (2008-2012) were obtained for CF patients enrolled with the Irish CF Registry by 2013 from linked registry and national hospitalisation database records. Mean annual hospitalisation and medication per-patient costs were estimated by demographic profile, CFTR mutation, clinical status, and CF co-morbidity, and were presented in 2014 euro values. A mixed-effects regression model was used to examine the effect of demographic, CFTR mutation, and clinical outcomes on the log10 cost of direct medical CF care.
RESULTS: Using 4261 observations from 1100 patients, we found that the median annual total cost per patient increased over the period 2008-2012 from €12,659 to €16,852, inpatient bed-day cost increased from €14,026 to €17,332, and medication cost increased from €5863 to €12,467. Homozygous F508-CFTR mutation (class II) cost was highest and milder mutation (class IV/V) cost was 49% lower. Baseline estimated cost in 2008 for a hypothetical underweight, homozygous F508del-CFTR 6-year-old female without chronic Pseudomonas aeruginosa/Staphylococcus aureus, CF-related diabetes (CFRD) or methicillin-resistant S. aureus (MRSA), and with a poor percent predicted forced expiratory volume in 1 s (ppFEV1) was €10,113, and was €21,082 in a 25-year-old with the same hypothetical profile. Chronic P. aeruginosa infection increased baseline cost by 39%, CF co-morbidity diabetes by 18%, and frequency of pulmonary exacerbation by 15%. Underweight, declining ppFEV1, chronic S. aureus colonisation, and time also influenced cost.
CONCLUSIONS: CFTR mutation is an important factor influencing the cost of CF care. Costs differ among cohorts of CF patients eligible to access new and emerging CFTR repair therapies. These findings support the evaluation of outcome-associated cost in CFTR mutation-specific CF patient groups.

PMID: 28699086 [PubMed - as supplied by publisher]

Peptide Nucleic Acids as miRNA Target Protectors for the Treatment of Cystic Fibrosis.

Molecules. 2017 Jul 08;22(7):

Authors: Zarrilli F, Amato F, Morgillo CM, Pinto B, Santarpia G, Borbone N, D'Errico S, Catalanotti B, Piccialli G, Castaldo G, Oliviero G

Abstract
Cystic Fibrosis (CF) is one of the most common life shortening conditions in Caucasians. CF is caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene which result in reduced or altered CFTR functionality. Several microRNAs (miRNAs) downregulate the expression of CFTR, thus causing or exacerbating the symptoms of CF. In this context, the design of anti-miRNA agents represents a valid functional tool, but its translation to the clinic might lead to unpredictable side effects because of the interference with the expression of other genes regulated by the same miRNAs. Herein, for the first time, is proposed the use of peptide nucleic acids (PNAs) to protect specific sequences in the 3'UTR (untranslated region) of the CFTR messenger RNA (mRNA) by action of miRNAs. Two PNAs (7 and 13 bases long) carrying the tetrapeptide Gly-SerP-SerP-Gly at their C-end, fully complementary to the 3'UTR sequence recognized by miR-509-3p, have been synthesized and the structural features of target PNA/RNA heteroduplexes have been investigated by spectroscopic and molecular dynamics studies. The co-transfection of the pLuc-CFTR-3´UTR vector with different combinations of PNAs, miR-509-3p, and controls in A549 cells demonstrated the ability of the longer PNA to rescue the luciferase activity by up to 70% of the control, thus supporting the use of suitable PNAs to counteract the reduction in the CFTR expression.

PMID: 28698463 [PubMed - in process]

Cystic fibrosis: Priorities and progress for future therapies.

Paediatr Respir Rev. 2017 Jun 12;:

Authors: Kerem E

Abstract
Significant improvement in the survival of patients with CF has been achieved in the last decades. The improved clinical status of the patients is mainly the result of a better understanding of the natural course of infection and inflammation in CF that has led to the implementation of strategies that increase the life expectancy and quality of life of the patients. These strategies include prompt diagnosis, timely and aggressive nutritional support, augmentation of MCC and improved mucous drainage, initiation of antimicrobial and anti-inflammatory therapy as soon as possible, early treatment of acute exacerbations, implementation of effective hygienic measures in and outside CF centers and prompt identification and treatment of CF-related complications. Treatment at a specialized CF center by a multidisciplinary dedicated team, including frequent visits, and periodic routine tests are essential to detect and treat early changes. Adherence to these therapies is challenging. Maintaining patients in optimal status will allow them to benefit from future treatments designed to correct or modify the basic genetic defect associated with CFTR by gene replacement therapy or pharmacological interventions currently under development. These new therapies are expected to further increase life expectancy of the patients.

PMID: 28697970 [PubMed - as supplied by publisher]