Insulin secretion abnormalities in patients with cystic fibrosis.

J Cyst Fibros. 2016 Jun 8;

Authors: Schnyder MA, Benden C, Faulenbach M, Schmid C

PMID: 27289198 [PubMed - as supplied by publisher]

Bioelectrical impedance in young patients with cystic fibrosis: Validation of a specific equation and clinical relevance.

J Cyst Fibros. 2016 Jun 8;

Authors: Charatsi AM, Dusser P, Freund R, Maruani G, Rossin H, Boulier A, Le Bourgeois M, Chedevergne F, de Blic J, Letourneur A, Casimir G, Jais JP, Sermet-Gaudelus I

Abstract
BACKGROUND: Body composition (BC) analysis based on bioelectrical impedance analysis (BIA) provides conflicting results. The purpose of the study was to validate an equation specific for young patients with cystic fibrosis (CF), describe their BC and investigate its association with lung function.
METHODS: Fifty-four young CF patients were evaluated by BIA and dual X-ray absorptiometry (DXA). An empirically derived CF-specific equation for fat-free mass (FFM) estimation by BIA was elaborated after stepwise multivariate regression and the agreement between BIA and DXA was assessed by Bland-Altman plots. The association between BC and lung function was investigated by regression analysis.
RESULTS: The mean difference between the BIA and DXA assessment was close to zero. A total of 22.5% of patients (n=9) presented a FFM z-score≤-2. They had a worse pulmonary function and diaphragmatic impairment. Among these 9 patients, 7 had a normal BMI z-score>-1.
CONCLUSIONS: BIA, based on a CF-specific equation, is a reliable method for BC assessment and allows the identification of patients at risk of nutritional degradation and bad respiratory prognosis.

PMID: 27289197 [PubMed - as supplied by publisher]

Nutritional status of children with clinical conditions.

Clin Nutr. 2016 May 26;

Authors: Murphy AJ, Hill RJ, Buntain H, White M, Brookes D, Davies PS

Abstract
BACKGROUND & AIMS: Nutritional status is an important consideration in many pediatric clinical conditions. This paper aimed to examine and compare the nutritional status, represented by body cell mass (BCM), of children with cancer, Crohn's disease (CD), cystic fibrosis (CF) and anorexia nervosa (AN).
METHODS: Anthropometry was measured and BCM was calculated from whole body potassium-40 counting in 259 children being treated for clinical conditions (n = 66 cancer; n = 59 AN; n = 75 CF; n = 59 CD) and 108 healthy children. BCM was adjusted for height (BCMI) and expressed as a Z-score relative to laboratory reference data.
RESULTS: The CD (-0.80 ± 1.61; p = 0.0001) and AN (-1.13 ± 0.99; p = 0.0001) groups had significantly lower BMI Z-score than the healthy control (0.13 ± 0.75), cancer (0.50 ± 1.40) and CF groups (-0.09 ± 0.95). The cancer (-1.16 ± 1.60; p = 0.0001), CD (-1.13 ± 1.36; p = 0.0001) and AN (-0.97 ± 1.18; p = 0.0001) groups had significantly reduced BCM compared to the healthy control (0.07 ± 0.93) and CF group (0.31 ± 1.08). According to BCMI Z-score, 42.4% of patients with cancer, 41.7% of the patients with CD, 27.1% of patients with AN, and 4.0% of patients with CF were considered malnourished.
CONCLUSIONS: This study demonstrates that children undergoing treatment for clinical conditions may have alterations in BCM, independent of BMI. Children with cancer, CD and AN all had a high prevalence of malnutrition. Assessment of body composition, not just body size, is vital to understand nutritional status in children with clinical conditions.

PMID: 27289162 [PubMed - as supplied by publisher]

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

"Cystic Fibrosis"

These pubmed results were generated on 2016/06/12

PubMed comprises more than 24 million 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.

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis.

Proc Natl Acad Sci U S A. 2016 Jun 10;

Authors: Malcomson B, Wilson H, Veglia E, Thillaiyampalam G, Barsden R, Donegan S, El Banna A, Elborn JS, Ennis M, Kelly C, Zhang SD, Schock BC

Abstract
Cystic fibrosis (CF) lung disease is characterized by chronic and exaggerated inflammation in the airways. Despite recent developments to therapeutically overcome the underlying functional defect in the cystic fibrosis transmembrane conductance regulator, there is still an unmet need to also normalize the inflammatory response. The prolonged and heightened inflammatory response in CF is, in part, mediated by a lack of intrinsic down-regulation of the proinflammatory NF-κB pathway. We have previously identified reduced expression of the NF-κB down-regulator A20 in CF as a key target to normalize the inflammatory response. Here, we have used publicly available gene array expression data together with a statistically significant connections' map (sscMap) to successfully predict drugs already licensed for the use in humans to induce A20 mRNA and protein expression and thereby reduce inflammation. The effect of the predicted drugs on A20 and NF-κB(p65) expression (mRNA) as well as proinflammatory cytokine release (IL-8) in the presence and absence of bacterial LPS was shown in bronchial epithelial cells lines (16HBE14o-, CFBE41o-) and in primary nasal epithelial cells from patients with CF (Phe508del homozygous) and non-CF controls. Additionally, the specificity of the drug action on A20 was confirmed using cell lines with tnfαip3 (A20) knockdown (siRNA). We also show that the A20-inducing effect of ikarugamycin and quercetin is lower in CF-derived airway epithelial cells than in non-CF cells.

PMID: 27286825 [PubMed - as supplied by publisher]

RareVariantVis: new tool for visualization of causative variants in rare monogenic disorders using whole genome sequencing data.

Bioinformatics. 2016 Jun 10;

Authors: Stokowy T, Garbulowski M, Fiskerstrand T, Holdhus R, Labun K, Sztromwasser P, Gilissen C, Hoischen A, Houge G, Petersen K, Jonassen I, Steen VM

Abstract
MOTIVATION: The search for causative genetic variants in rare diseases of presumed monogenic inheritance has been boosted by the implementation of whole exome (WES) and whole genome (WGS) sequencing. In many cases, WGS seems to be superior to WES, but the analysis and visualization of the vast amounts of data is demanding.
RESULTS: To aid this challenge, we have developed a new tool - RareVariantVis - for analysis of genome sequence data (including non-coding regions) for both germ line and somatic variants. It visualizes variants along their respective chromosomes, providing information about exact chromosomal position, zygosity and frequency, with point-and-click information regarding dbSNP IDs, gene association and variant inheritance. Rare variants as well as de novo variants can be flagged in different colors. We show the performance of the RareVariantVis tool in the Genome in a Bottle WGS data set.
AVAILABILITY: https://www.bioconductor.org/packages/3.3/bioc/html/RareVariantVis.html CONTACT: tomasz.stokowy@k2.uib.no SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 27288501 [PubMed - as supplied by publisher]

A giant adrenal myelolipoma in a beta-thalassemia major patient: Does ineffective erythropoiesis play a role?

Am J Hematol. 2016 Jun 10;

Authors: Motta I, Boiocchi L, Delbini P, Migone De Amicis M, Cassinerio E, Dondossola D, Rossi G, Cappellini MD

PMID: 27288248 [PubMed - as supplied by publisher]

Identification of genetic variants in pharmacokinetic genes associated with Ewing Sarcoma treatment outcome.

Ann Oncol. 2016 Jun 10;

Authors: Ruiz-Pinto S, Pita G, Patiño-García A, García-Miguel P, Alonso J, Pérez-Martínez A, Sastre A, Gómez-Mariano G, Lissat A, Scotlandi K, Serra M, Ladenstein R, Lapouble E, Pierron G, Kontny U, Picci P, Kovar H, Delattre O, González-Neira A

Abstract
BACKGROUND: Despite the effectiveness of current treatment protocols for Ewing sarcoma (ES), many patients still experience relapse, and survival following recurrence is less than 15%. We aimed to identify genetic variants that predict treatment outcome in children diagnosed with ES.
PATIENTS AND METHODS: We carried out a pharmacogenetic study of 384 single nucleotide polymorphisms (SNPs) in 24 key transport or metabolism genes relevant to drugs used to treat in pediatric patients (<30 years) with histologically confirmed ES. We studied the association of genotypes with tumor response and overall survival (OS) in a discovery cohort of 106 Spanish children, with replication in a second cohort of 389 pediatric patients from across Europe.
RESULTS: We identified associations with OS (P<0.05) for three SNPs in the Spanish cohort that were replicated in the European cohort. The strongest association observed was with rs7190447, located in the ATP-binding cassette sub-family C member 6 (ABCC6) gene (discovery: HR=14.30, 95%CI=1.53-134, P=0.020; replication: HR=9.28, 95%CI=2.20-39.2, P=0.0024) and its correlated SNP rs7192303, which was predicted to have a plausible regulatory function. We also replicated associations with rs4148737 in the ATP-binding cassette sub-family B member 1 (ABCB1) gene (discovery: HR=2.96, 95%CI=1.08-8.10, P=0.034; replication: HR=1.60, 95%CI=1.05-2.44, P=0.029), which we have previously found to be associated with poorer OS in pediatric osteosarcoma patients, and rs11188147 in cytochrome P450 family 2 subfamily C member 8 gene (CYP2C8) (discovery : HR=2.49, 95%CI=1.06-5.87, P=0.037; replication: HR=1.77, 95%CI=1.06-2.96, P=0.030), an enzyme involved in the oxidative metabolism of the ES chemotherapeutic agents cyclophosphamide and ifosfamide. None of the associations with tumor response were replicated.
CONCLUSION: Using an integrated pathway-based approach we identified polymorphisms in ABCC6, ABCB1 and CYP2C8 associated with OS. These associations were replicated in a large independent cohort, highlighting the importance of pharmacokinetic genes as prognostic markers in ES.

PMID: 27287205 [PubMed - as supplied by publisher]

The Story of Angioedema: from Quincke to Bradykinin.

Clin Rev Allergy Immunol. 2016 Jun 10;

Authors: Reshef A, Kidon M, Leibovich I

Abstract
The term "swelling" has been used in the old scriptures to illustrate a change of normal figure and, as such, an expression of illness. It should be noted that in ancient times, human diseases were very often regarded a punishment from God. Hence, it is not surprising that one of the oldest tests for infidelity involved swelling as an inflicted punishment. The great Greek physician Hippocrates (377-460 BC), considered one of the most outstanding figures in the history of medicine and "Father of the Western Medicine," already used the term oídēma to describe swelling of organs. It took many centuries later until the first description of angioedema as a distinct medical entity was minted by Quinke in 1882. The historical progression in angioedema research has been characterized by intermittent "leaps" in interest and scientific achievements. As an example, it took 75 years from the accurate description of hereditary angioedema (HAE) by Osler (1888), until a group of researchers headed by Donaldson (1963) disclosed the central role of C1 inhibitor in angioedema pathophysiology. What followed was a result of a collective effort by many researchers and scientific groups who were able to elucidate the intricate connections between the implicated biochemical pathways. Still, scientific progress was hardly translated into effective therapy, and another 45 years had to elapse until the renewed interest in HAE was boosted by studies on the efficacy and safety of novel therapies about 10 years ago. In the twenty-first century, HAE ceased to be an "orphan disease" and its future is far more optimistic. It is better managed now by specialized angioedema centers, harmonized clinical guidelines, educational programs, laboratory services, and continued basic and clinical research. Patient associations worldwide are offering support and guidance, and governments and healthcare systems are gradually addressing patient and family needs.

PMID: 27287037 [PubMed - as supplied by publisher]

Advances in the integration of transcriptional regulatory information into genome-scale metabolic models.

Biosystems. 2016 Jun 7;

Authors: Vivek-Ananth RP, Samal A

Abstract
A major goal of systems biology is to build predictive computational models of cellular metabolism. Availability of complete genome sequences and wealth of legacy biochemical information has led to the reconstruction of genome-scale metabolic networks in the last 15 years for several organisms across the three domains of life. Due to paucity of information on kinetic parameters associated with metabolic reactions, the constraint-based modelling approach, flux balance analysis (FBA), has proved to be a vital alternative to investigate the capabilities of reconstructed metabolic networks. In parallel, advent of high-throughput technologies has led to the generation of massive amounts of omics data on transcriptional regulation comprising mRNA transcript levels and genome-wide binding profile of transcriptional regulators. A frontier area in metabolic systems biology has been the development of methods to integrate the available transcriptional regulatory information into constraint-based models of reconstructed metabolic networks in order to increase the predictive capabilities of computational models and understand the regulation of cellular metabolism. Here, we review the existing methods to integrate transcriptional regulatory information into constraint-based models of metabolic networks.

PMID: 27287878 [PubMed - as supplied by publisher]

Metabolic characterization of the natural progression of chronic hepatitis B.

Genome Med. 2016;8(1):64

Authors: Schoeman JC, Hou J, Harms AC, Vreeken RJ, Berger R, Hankemeier T, Boonstra A

Abstract
BACKGROUND: Worldwide, over 350 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing progressive liver diseases. The confinement of HBV replication to the liver, which also acts as the central hub for metabolic and nutritional regulation, emphasizes the interlinked nature of host metabolism and the disease. Still, the metabolic processes operational during the distinct clinical phases of a chronic HBV infection-immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis phases-remains unexplored.
METHODS: To investigate this, we conducted a targeted metabolomics approach on serum to determine the metabolic progression over the clinical phases of chronic HBV infection, using patient samples grouped based on their HBV DNA, alanine aminotransferase, and HBeAg serum levels.
RESULTS: Our data illustrate the strength of metabolomics to provide insight into the metabolic dysregulation experienced during chronic HBV. The immune tolerant phase is characterized by the speculated viral hijacking of the glycerol-3-phosphate-NADH shuttle, explaining the reduced glycerophospholipid and increased plasmalogen species, indicating a strong link to HBV replication. The persisting impairment of the choline glycerophospholipids, even during the inactive carrier phase with minimal HBV activity, alludes to possible metabolic imprinting effects. The progression of chronic HBV is associated with increased concentrations of very long chain triglycerides together with citrulline and ornithine, reflective of a dysregulated urea cycle peaking in the HBV envelope antigen-negative phase.
CONCLUSIONS: The work presented here will aid in future studies to (i) validate and understand the implication of these metabolic changes using a thorough systems biology approach, (ii) monitor and predict disease severity, as well as (iii) determine the therapeutic value of the glycerol-3-phosphate-NADH shuttle.

PMID: 27286979 [PubMed - as supplied by publisher]

Metabolic processes of Methanococcus maripaludis and potential applications.

Microb Cell Fact. 2016;15(1):107

Authors: Goyal N, Zhou Z, Karimi IA

Abstract
Methanococcus maripaludis is a rapidly growing, fully sequenced, genetically tractable model organism among hydrogenotrophic methanogens. It has the ability to convert CO2 and H2 into a useful cleaner energy fuel (CH4). In fact, this conversion enhances in the presence of free nitrogen as the sole nitrogen source due to prolonged cell growth. Given the global importance of GHG emissions and climate change, diazotrophy can be attractive for carbon capture and utilization applications from appropriately treated flue gases, where surplus hydrogen is available from renewable electricity sources. In addition, M. maripaludis can be engineered to produce other useful products such as terpenoids, hydrogen, methanol, etc. M. maripaludis with its unique abilities has the potential to be a workhorse like Escherichia coli and S. cerevisiae for fundamental and experimental biotechnology studies. More than 100 experimental studies have explored different specific aspects of the biochemistry and genetics of CO2 and N2 fixation by M. maripaludis. Its genome-scale metabolic model (iMM518) also exists to study genetic perturbations and complex biological interactions. However, a comprehensive review describing its cell structure, metabolic processes, and methanogenesis is still lacking in the literature. This review fills this crucial gap. Specifically, it integrates distributed information from the literature to provide a complete and detailed view for metabolic processes such as acetyl-CoA synthesis, pyruvate synthesis, glycolysis/gluconeogenesis, reductive tricarboxylic acid (RTCA) cycle, non-oxidative pentose phosphate pathway (NOPPP), nitrogen metabolism, amino acid metabolism, and nucleotide biosynthesis. It discusses energy production via methanogenesis and its relation to metabolism. Furthermore, it reviews taxonomy, cell structure, culture/storage conditions, molecular biology tools, genome-scale models, and potential industrial and environmental applications. Through the discussion, it develops new insights and hypotheses from experimental and modeling observations, and identifies opportunities for further research and applications.

PMID: 27286964 [PubMed - as supplied by publisher]

Comparative genome-scale modelling of Staphylococcus aureus strains identifies strain-specific metabolic capabilities linked to pathogenicity.

Proc Natl Acad Sci U S A. 2016 Jun 10;

Authors: Bosi E, Monk JM, Aziz RK, Fondi M, Nizet V, Palsson BØ

Abstract
Staphylococcus aureus is a preeminent bacterial pathogen capable of colonizing diverse ecological niches within its human host. We describe here the pangenome of S. aureus based on analysis of genome sequences from 64 strains of S. aureus spanning a range of ecological niches, host types, and antibiotic resistance profiles. Based on this set, S. aureus is expected to have an open pangenome composed of 7,411 genes and a core genome composed of 1,441 genes. Metabolism was highly conserved in this core genome; however, differences were identified in amino acid and nucleotide biosynthesis pathways between the strains. Genome-scale models (GEMs) of metabolism were constructed for the 64 strains of S. aureus These GEMs enabled a systems approach to characterizing the core metabolic and panmetabolic capabilities of the S. aureus species. All models were predicted to be auxotrophic for the vitamins niacin (vitamin B3) and thiamin (vitamin B1), whereas strain-specific auxotrophies were predicted for riboflavin (vitamin B2), guanosine, leucine, methionine, and cysteine, among others. GEMs were used to systematically analyze growth capabilities in more than 300 different growth-supporting environments. The results identified metabolic capabilities linked to pathogenic traits and virulence acquisitions. Such traits can be used to differentiate strains responsible for mild vs. severe infections and preference for hosts (e.g., animals vs. humans). Genome-scale analysis of multiple strains of a species can thus be used to identify metabolic determinants of virulence and increase our understanding of why certain strains of this deadly pathogen have spread rapidly throughout the world.

PMID: 27286824 [PubMed - as supplied by publisher]

The microbiome during pregnancy and early postnatal life.

Semin Fetal Neonatal Med. 2016 Jun 7;

Authors: Neu J

Abstract
We are changing our concept that the newborn infant emerges from a sterile environment. In-utero colonization may have major impacts on the developing mammal in terms of development of immunity and metabolism that, with epigenetic modifications, will lead to diseases in later life. In addition, the microbial profile that develops during and after birth depends on mode of delivery, type of feeding (human milk versus formula) and various other environmental factors to which the newborn is exposed. The goal of this review is to clarify that the microbiome in the maternal fetal unit as well as the immediate changes that occur as new microbes are acquired postnatally play major roles in subsequent health and disease. Rapidly developing technologies for multi-omic analyses and systems biology are shifting paradigms in both scientific knowledge and clinical care.

PMID: 27286643 [PubMed - as supplied by publisher]

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

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/06/11

PubMed comprises more than 24 million 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.

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

"Cystic Fibrosis"

These pubmed results were generated on 2016/06/11

PubMed comprises more than 24 million 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.

PDNAsite: Identification of DNA-binding Site from Protein Sequence by Incorporating Spatial and Sequence Context.

Sci Rep. 2016;6:27653

Authors: Zhou J, Xu R, He Y, Lu Q, Wang H, Kong B

Abstract
Protein-DNA interactions are involved in many fundamental biological processes essential for cellular function. Most of the existing computational approaches employed only the sequence context of the target residue for its prediction. In the present study, for each target residue, we applied both the spatial context and the sequence context to construct the feature space. Subsequently, Latent Semantic Analysis (LSA) was applied to remove the redundancies in the feature space. Finally, a predictor (PDNAsite) was developed through the integration of the support vector machines (SVM) classifier and ensemble learning. Results on the PDNA-62 and the PDNA-224 datasets demonstrate that features extracted from spatial context provide more information than those from sequence context and the combination of them gives more performance gain. An analysis of the number of binding sites in the spatial context of the target site indicates that the interactions between binding sites next to each other are important for protein-DNA recognition and their binding ability. The comparison between our proposed PDNAsite method and the existing methods indicate that PDNAsite outperforms most of the existing methods and is a useful tool for DNA-binding site identification. A web-server of our predictor (http://hlt.hitsz.edu.cn:8080/PDNAsite/) is made available for free public accessible to the biological research community.

PMID: 27282833 [PubMed - in process]

Virtual Pharmacist: A Platform for Pharmacogenomics.

PLoS One. 2015;10(10):e0141105

Authors: Cheng R, Leung RK, Chen Y, Pan Y, Tong Y, Li Z, Ning L, Ling XB, He J

Abstract
We present Virtual Pharmacist, a web-based platform that takes common types of high-throughput data, namely microarray SNP genotyping data, FASTQ and Variant Call Format (VCF) files as inputs, and reports potential drug responses in terms of efficacy, dosage and toxicity at one glance. Batch submission facilitates multivariate analysis or data mining of targeted groups. Individual analysis consists of a report that is readily comprehensible to patients and practioners who have basic knowledge in pharmacology, a table that summarizes variants and potential affected drug response according to the US Food and Drug Administration pharmacogenomic biomarker labeled drug list and PharmGKB, and visualization of a gene-drug-target network. Group analysis provides the distribution of the variants and potential affected drug response of a target group, a sample-gene variant count table, and a sample-drug count table. Our analysis of genomes from the 1000 Genome Project underlines the potentially differential drug responses among different human populations. Even within the same population, the findings from Watson's genome highlight the importance of personalized medicine. Virtual Pharmacist can be accessed freely at http://www.sustc-genome.org.cn/vp or installed as a local web server. The codes and documentation are available at the GitHub repository (https://github.com/VirtualPharmacist/vp). Administrators can download the source codes to customize access settings for further development.

PMID: 26496198 [PubMed - indexed for MEDLINE]

Synthetic promoter design for new microbial chassis.

Biochem Soc Trans. 2016 Jun 15;44(3):731-7

Authors: Gilman J, Love J

Abstract
The judicious choice of promoter to drive gene expression remains one of the most important considerations for synthetic biology applications. Constitutive promoter sequences isolated from nature are often used in laboratory settings or small-scale commercial production streams, but unconventional microbial chassis for new synthetic biology applications require well-characterized, robust and orthogonal promoters. This review provides an overview of the opportunities and challenges for synthetic promoter discovery and design, including molecular methodologies, such as saturation mutagenesis of flanking regions and mutagenesis by error-prone PCR, as well as the less familiar use of computational and statistical analyses for de novo promoter design.

PMID: 27284035 [PubMed - in process]

Exploring Synthetic and Systems Biology at the University of Edinburgh.

Biochem Soc Trans. 2016 Jun 15;44(3):692-5

Authors: Fletcher L, Rosser S, Elfick A

Abstract
The Centre for Synthetic and Systems Biology ('SynthSys') was originally established in 2007 as the Centre for Integrative Systems Biology, funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Engineering and Physical Sciences Research Council (EPSRC). Today, SynthSys embraces an extensive multidisciplinary community of more than 200 researchers from across the University with a common interest in synthetic and systems biology. Our research is broad and deep, addressing a diversity of scientific questions, with wide ranging impact. We bring together the power of synthetic biology and systems approaches to focus on three core thematic areas: industrial biotechnology, agriculture and the environment, and medicine and healthcare. In October 2015, we opened a newly refurbished building as a physical hub for our new U.K. Centre for Mammalian Synthetic Biology funded by the BBSRC/EPSRC/MRC as part of the U.K. Research Councils' Synthetic Biology for Growth programme.

PMID: 27284029 [PubMed - in process]