Glucose Fluctuations are Not Modulated by the Proportion of Calories from Macronutrients or Spontaneous Total Energy Expenditure in Adults with Cystic Fibrosis.

Can J Diabetes. 2016 Jul 7;

Authors: Ziai S, Coriati A, St-Pierre D, Chabot K, Desjardins K, Leroux C, Richter MV, Rabasa-Lhoret R

Abstract
OBJECTIVES: To determine the modifiable factors affecting glucose variability in people with cystic fibrosis (CF). CF-related diabetes (CFRD) is the most common complication of CF, and its presence increases morbidity and mortality in patients. Patients with CF (with and without CFRD) have potentially harmful glucose fluctuations and glucose excursions when compared to healthy adults. Carbohydrate intake and exercise have been shown to affect glycemia. Therefore, our hypothesis was that the proportion of energy from carbohydrates and total energy expenditure (TEE) would influence glucose fluctuations in adults with CF.
METHODS: A cross-sectional study involved 36 patients with CF, in whom continuous glucose monitoring systems were installed. Glucose fluctuations were then quantified using 3 indexes: mean amplitude of glucose excursions, standard deviation and coefficient of variation. Patients filled out a 3-day food diary to quantify energy intake and the proportions of calories from carbohydrates, fats and proteins, and they wore Sensewear Armbands to estimate spontaneous TEE and footsteps walked. Glucose tolerance status was determined using oral glucose tolerance tests.
RESULTS: Patients with CF with normal and impaired glucose tolerance had fewer glucose fluctuations than patients with CFRD (p<0.05). However, linear regression models used to determine whether nutrition or energy expenditure affects glucose fluctuations demonstrated that energy, the proportion of carbohydrates, of fat and of protein, TEE or the number of footsteps walked did not affect glucose fluctuation indexes (p>0.05).
CONCLUSIONS: TEE and the proportion of energy from carbohydrates did not affect glucose fluctuations in adults with CF.

PMID: 27397678 [PubMed - as supplied by publisher]

Changes in lipid raft proteome upon TNF-α stimulation of cystic fibrosis cells.

J Proteomics. 2016 Jul 7;

Authors: Chhuon C, Pranke I, Borot F, Tondelier D, Lipecka J, Fritsch J, Chanson M, Edelman A, Ollero M, Guerrera IC

Abstract
We have previously shown (i) that the cystic fibrosis transmembrane regulator (CFTR) locates to lipid raft-like microdomains of epithelial cells upon TNF-α proinflammatory stimulation; and (ii) that TNF-α increases the membrane localization and the channel function of F508del-mutated CFTR. In the present work, we hypothesized that CFTR mutations modify the proteome of lipid rafts in the same proinflammatory conditions. We prepared lipid rafts from HeLa cells transfected with either wild-type or F508del-CFTR and incubated for 10min with 100U/mL of TNF-α. Proteins were extracted, trypsin digested, and peptides analyzed by high resolution MS. Proteins were quantified by a stable isotope labeling with aminoacids in cell culture approach. Out of the 22 proteins differentially recruited in lipid rafts after proinflammatory exposure, 17 were increased in F508del cells with respect to wild-type, including two G-protein coupled receptors, three anion transporters, and one cell surface mucin. In both HeLa and bronchial epithelial cells we confirmed that G-protein coupled receptor 5A relocates to lipid rafts along with F508del-CFTR after TNF-α treatment. These results could enlighten the cross-talk between CFTR and TNF-α and its impact on the cell response to proinflammatory challenge.
BIOLOGICAL SIGNIFICANCE: CFTR mutations are at the origin of cystic fibrosis. The latter disease is characterized, among other symptoms, by a defective management of infection and inflammation in the airways. Short exposure to the proinflammatory cytokine TNF-α targets mutated CFTR to the plasma membrane and increases its chloride channel activity. The results hereby presented show a substantial modification of the lipid raft proteome in the same conditions, and may enlighten the effect of this cytokine and the role of CFTR in the cell response to inflammation.

PMID: 27397611 [PubMed - as supplied by publisher]

Mortality on the Waiting List for Lung Transplantation in Patients with Idiopathic Pulmonary Fibrosis: A Single-Centre Experience.

Lung. 2015 Oct;193(5):677-81

Authors: Bennett D, Fossi A, Bargagli E, Refini RM, Pieroni M, Luzzi L, Ghiribelli C, Paladini P, Voltolini L, Rottoli P

Abstract
PURPOSE: Lung transplantation (LTX) is nowadays accepted as a treatment option for selected patients with end-stage pulmonary disease. Idiopathic pulmonary fibrosis (IPF) is characterized by the radiological and histologic appearance of usual interstitial pneumonia. It is associated with a poor prognosis, and LTX is considered an effective treatment to significantly modify the natural history of this disease. The aim of the present study was to analyse mortality during the waiting list in IPF patients at a single institution.
METHODS: A retrospective analysis on IPF patients (n = 90) referred to our Lung Transplant Program in the period 2001-2014 was performed focusing on patients' characteristics and associated risk factors.
RESULTS: Diagnosis of IPF was associated with high mortality on the waiting list with respect to other diagnosis (p < 0.05). No differences in demographic, clinical, radiological data and time spent on the waiting list were observed between IPF patients who underwent to LTX or lost on the waiting list. Patients who died showed significant higher levels of pCO2 and needed higher flows of O2-therapy on effort (p < 0.05). Pulmonary function tests failed to predict mortality and no other medical conditions were associated with survival.
CONCLUSIONS: Patients newly diagnosed with IPF, especially in small to medium lung transplant volume centres and in Countries where a long waiting list is expected, should be immediately referred to transplantation, delay results in increased mortality. Early identification of IPF patients with a rapid progressive phenotype is strongly needed.

PMID: 26216722 [PubMed - indexed for MEDLINE]

Pulmonary varix: A case report.

Rev Port Cardiol. 2016 Jul 6;

Authors: Haddad J, Badran A, Pavão R, de Padua AI, Lago I, Marin Neto JA

Abstract
The authors report a case of multiple pulmonary varices, a rare disease characterized by aneurysmatic venous dilatations, which can be present at any age and without gender predominance, occurring in isolation or associated with obstruction of the pulmonary veins. This condition usually manifests as a lung mass with variable clinical consequences.

PMID: 27395560 [PubMed - as supplied by publisher]

Salivary Gland. Photon beam and particle radiotherapy: Present and future.

Oral Oncol. 2016 Jul 6;

Authors: Orlandi E, Iacovelli NA, Bonora M, Cavallo A, Fossati P

Abstract
Salivary gland cancers (SGCs) are rare diseases and their treatment depends upon histology, stage and site of origin. Radical surgery is the mainstay of treatment but radiotherapy (RT) plays a key role in both the postoperative and the inoperable setting, as well as in recurrent disease. In the absence of prospective randomized trials, a wide retrospective literature suggests postoperative RT (PORT) in patients with high risk pathological features. SGCs, and adenoid cystic carcinoma (ACC) in particular, are known to be radio-resistant tumors and should therefore respond well to particle beam therapy. Recently, excellent outcome has been reported with radical carbon ion RT (CIRT) in particular for ACC. Both modern photon- and hadron-based treatments are effective and are characterized by a favourable toxicity profile. But it is not clear whether one modality is superior to the other for disease control, due to the differences in patients' selection, techniques, fractionation schedules and outcome measurements among clinical experiences. In this paper, we review the role of photon and particle RT for malignant SGCs, discussing the difference between modalities in terms of biological and technical characteristics. RT dose and target volumes for different histologies (ACC versus non-ACC) have also been taken into consideration.

PMID: 27394087 [PubMed - as supplied by publisher]

Lung clearance index in adults and children with cystic fibrosis.

Chest. 2016 Jul 6;

Authors: O'Neill K, Tunney MM, Johnston E, Rowan S, Downey DG, Rendall J, Reid A, Bradbury I, Elborn JS, Bradley JM

Abstract
BACKGROUND: Lung clearance index (LCI) has good clinimetric properties and an acceptable feasibility profile as a surrogate endpoint in Cystic Fibrosis (CF). Although most studies to date have been in children, increasing numbers of adults with CF also have normal spirometry. Further study of LCI as an endpoint in CF adults is required. Therefore, the purpose of this study was to determine the clinimetric properties of LCI over the complete age range of people with CF.
METHODS: Clinically stable adults and children with CF and age matched healthy controls were recruited.
RESULTS: LCI and spirometry data for 110 CF subjects and 61 controls were collected at a stable visit. CF Questionnaire-Revised (CFQ-R) was completed by 80/110 CF subjects. Fifty-six CF subjects completed a second stable visit. The LCI CV% was 4.1% in adults and 6.3% in children with CF. The coefficient of repeatability of LCI was 1.2 in adults and 1.3 in children. In both adults and children, LCI (AUC(ROC)=0.93 and 0.84) had greater combined sensitivity and specificity to discriminate between people with CF and controls compared to FEV1 (AUC(ROC)=0.88 and 0.60) and FEF25-75 (AUC(ROC)=0.87 and 0.68). LCI correlated significantly with the CFQ-R treatment burden in adults (r=-0.37; p<0.01) and children (r=-0.50; p<0.01). Washout tests were successful in 90% of CF subjects and were perceived as comfortable and easy to perform in both adults and children.
CONCLUSIONS: These data support the use of LCI as a surrogate outcome measure in CF clinical trials in adults as well as children.

PMID: 27395423 [PubMed - as supplied by publisher]

Long-Term Pulmonal Therapy of Cystic Fibrosis-Patients with Amitriptyline.

Cell Physiol Biochem. 2016 Jul 11;39(2):565-572

Authors: Adams C, Icheva V, Deppisch C, Lauer J, Herrmann G, Graepler-Mainka U, Heyder S, Gulbins E, Riethmueller J

Abstract
BACKGROUND/AIMS: Several recent clinical studies revealed an accumulation of ceramide in bronchial epithelial cells of patients with cystic fibrosis (CF). Degradation of ceramide concentrations in lungs of CF patients employing the functional acid sphingomyelinase inhibitor amitriptyline revealed a benefit in lung function, weight and exacerbation rates.
METHODS: To test for a beneficial effect of amitriptyline in vivo, we performed two phase II randomised, double-blind, placebo-controlled studies. CF patients were treated with 25 mg amitriptyline twice daily, i.e. a total dose of 50 mg/d. After those two studies part of the patients used amitriptyline in an off-lable-use for routine treatment. These patients were observed after one, two and three years after continuous use of amitriptyline and were matched with those patients who were not treated. These patients were used as a control group.
RESULTS: After one year of treatment, forced expiratory volume in 1 sec predicted (FEV1) increased significantly by 7.6±7.0%, p=<0.001, and weight increased by 2.1±2.3kg, p=<0.001 in the amitriptyline population (n=20), whereas FEV1 decreased significantly in the control group by 1.8±3.3%, p=0.010, and weight increased by 1.1±2.7kg, p=0.010 (n=14). After two years of treatment, FEV1 increased significantly by 5.6±10.3%, p=0.009, and weight increased by 3.6±2.9kg, p=<0.001 in the amitriptyline population (n=12). In contrast, FEV1 decreased in the control group by 2.1±3.7%, p=0.051 and weight increased by only 0.4±2.9kg, p=0.31 (n=10). After three years of treatment, FEV1 increased significantly by 7.7±8%, p=0.050, and weight increased by 7.3±3.8kg, p=0.016, in the amitriptyline population (n=5), whereas FEV1 decreased in the control group by 1.0±1.3%, p=0.075 and weight increased by 0.4±1.5kg, p=0.29 (n=5).
CONCLUSION: Amitriptyline significantly increases FEV1, reduces ceramide in lung cells and increases weight of CF patients.

PMID: 27395380 [PubMed - as supplied by publisher]

Electronic patient records, past, present and future.

Paediatr Respir Rev. 2016 Jun 15;

Authors: Peckham D

Abstract
The health informatics revolution was spear-headed in the 1980s by pioneers in primary care who worked in an opportune environment and were able to successfully implement electronic patient records (EPR) as far back as the 1990s. Although the ambitious and costly National Programme for IT failed to deliver an integrated EPR, the project achieved the creation of the Spine, the N3 Network, choose and book, picture archiving, communication systems and standards which have allowed integration. Real change is taking place within the NHS with the launch of exciting new projects focusing on true integration and secure data flows across primary, community and secondary care. These changes have been brought about by the realisation that linking "best in class" is more likely to secure a successful cost-effective national integrated EPR.

PMID: 27394677 [PubMed - as supplied by publisher]

Lumacaftor/Ivacaftor: A Review in Cystic Fibrosis.

Drugs. 2016 Jul 9;

Authors: Deeks ED

Abstract
Lumacaftor/ivacaftor (Orkambi™) is a fixed-dose tablet containing a corrector (lumacaftor) and potentiator (ivacaftor) of the cystic fibrosis transmembrane conductance regulator (CFTR) and is the first therapy approved to treat the underlying cause of cystic fibrosis in patients (aged ≥12 years) homozygous for the most common CFTR mutation, F508del. Lumacaftor improves the processing of F508del CFTR and its transport to the cell surface, while ivacaftor increases the channel's open probability and transport of chloride. In two 24-week trials in the approved patient population (TRAFFIC and TRANSPORT), lumacaftor 400 mg plus ivacaftor 250 mg, administered every 12 h in combination with standard therapy, was associated with an ≈3 % statistically significant improvement in lung function relative to placebo (as measured by the percent predicted forced expiratory volume in 1 s). Lumacaftor plus ivacaftor did not significantly improve respiratory symptoms, although reduced pulmonary exacerbations to a clinically meaningful extent and, in one trial (TRANSPORT), significantly improved body mass index (BMI). In an ongoing extension of these studies (PROGRESS), lumacaftor plus ivacaftor provided clinical benefit over a further 72 weeks of treatment. Lumacaftor plus ivacaftor had an acceptable tolerability profile, with the most common adverse events being respiratory or gastrointestinal in nature. Thus, lumacaftor/ivacaftor expands the treatment options available for patients with cystic fibrosis homozygous for the F508del-CFTR mutation, although its precise place in clinical practice remains to be determined.

PMID: 27394157 [PubMed - as supplied by publisher]

10 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 2016/07/10

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.

High-Throughput Screening for Identification of Blood-Brain Barrier Integrity Enhancers: A Drug Repurposing Opportunity to Rectify Vascular Amyloid Toxicity.

J Alzheimers Dis. 2016 Jul 6;

Authors: Qosa H, Mohamed LA, Al Rihani SB, Batarseh YS, Duong QV, Keller JN, Kaddoumi A

Abstract
The blood-brain barrier (BBB) is a dynamic interface that maintains brain homeostasis and protects it from free entry of chemicals, toxins, and drugs. The barrier function of the BBB is maintained mainly by capillary endothelial cells that physically separate brain from blood. Several neurological diseases, such as Alzheimer's disease (AD), are known to disrupt BBB integrity. In this study, a high-throughput screening (HTS) was developed to identify drugs that rectify/protect BBB integrity from vascular amyloid toxicity associated with AD progression. Assessing Lucifer Yellow permeation across in-vitro BBB model composed from mouse brain endothelial cells (bEnd3) grown on 96-well plate inserts was used to screen 1280 compounds of Sigma LOPAC®1280 library for modulators of bEnd3 monolayer integrity. HTS identified 62 compounds as disruptors, and 50 compounds as enhancers of the endothelial barrier integrity. From these 50 enhancers, 7 FDA approved drugs were identified with EC50 values ranging from 0.76-4.56 μM. Of these 7 drugs, 5 were able to protect bEnd3-based BBB model integrity against amyloid toxicity. Furthermore, to test the translational potential to humans, the 7 drugs were tested for their ability to rectify the disruptive effect of Aβ in the human endothelial cell line hCMEC/D3. Only 3 (etodolac, granisetron, and beclomethasone) out of the 5 effective drugs in the bEnd3-based BBB model demonstrated a promising effect to protect the hCMEC/D3-based BBB model integrity. These drugs are compelling candidates for repurposing as therapeutic agents that could rectify dysfunctional BBB associated with AD.

PMID: 27392852 [PubMed - as supplied by publisher]

Developing a Data Element Repository to Support EHR-driven Phenotype Algorithm Authoring and Execution.

J Biomed Inform. 2016 Jul 5;

Authors: Jiang G, Kiefer RC, Rasmussen LV, Solbrig HR, Mo H, Pacheco JA, Xu J, Montague E, Thompson WK, Denny JC, Chute CG, Pathak J

Abstract
The Quality Data Model (QDM) is an information model developed by the National Quality Forum for representing electronic health record (EHR)-based electronic clinical quality measures (eCQMs). In conjunction with the HL7 Health Quality Measures Format (HQMF), QDM contains core elements that make it a promising model for representing EHR-driven phenotype algorithms for clinical research. However, the current QDM specification is available only as descriptive documents suitable for human readability and interpretation, but not for machine consumption. The objective of the present study is to develop and evaluate a data element repository (DER) for providing machine-readable QDM data element service APIs to support phenotype algorithm authoring and execution. We used the ISO/IEC 11179 metadata standard to capture the structure for each data element, and leverage Semantic Web technologies to facilitate semantic representation of these metadata. We observed there are a number of underspecified areas in the QDM, including the lack of model constraints and pre-defined value sets. We propose a harmonization with the models developed in HL7 Fast Healthcare Interoperability Resources (FHIR) and Clinical Information Modeling Initiatives (CIMI) to enhance the QDM specification and enable the extensibility and better coverage of the DER. We also compared the DER with the existing QDM implementation utilized within the Measure Authoring Tool (MAT) to demonstrate the scalability and extensibility of our DER-based approach.

PMID: 27392645 [PubMed - as supplied by publisher]

NeuroRDF: semantic integration of highly curated data to prioritize biomarker candidates in Alzheimer's disease.

J Biomed Semantics. 2016;7(1):45

Authors: Iyappan A, Kawalia SB, Raschka T, Hofmann-Apitius M, Senger P

Abstract
BACKGROUND: Neurodegenerative diseases are incurable and debilitating indications with huge social and economic impact, where much is still to be learnt about the underlying molecular events. Mechanistic disease models could offer a knowledge framework to help decipher the complex interactions that occur at molecular and cellular levels. This motivates the need for the development of an approach integrating highly curated and heterogeneous data into a disease model of different regulatory data layers. Although several disease models exist, they often do not consider the quality of underlying data. Moreover, even with the current advancements in semantic web technology, we still do not have cure for complex diseases like Alzheimer's disease. One of the key reasons accountable for this could be the increasing gap between generated data and the derived knowledge.
RESULTS: In this paper, we describe an approach, called as NeuroRDF, to develop an integrative framework for modeling curated knowledge in the area of complex neurodegenerative diseases. The core of this strategy lies in the usage of well curated and context specific data for integration into one single semantic web-based framework, RDF. This increases the probability of the derived knowledge to be novel and reliable in a specific disease context. This infrastructure integrates highly curated data from databases (Bind, IntAct, etc.), literature (PubMed), and gene expression resources (such as GEO and ArrayExpress). We illustrate the effectiveness of our approach by asking real-world biomedical questions that link these resources to prioritize the plausible biomarker candidates. Among the 13 prioritized candidate genes, we identified MIF to be a potential emerging candidate due to its role as a pro-inflammatory cytokine. We additionally report on the effort and challenges faced during generation of such an indication-specific knowledge base comprising of curated and quality-controlled data.
CONCLUSION: Although many alternative approaches have been proposed and practiced for modeling diseases, the semantic web technology is a flexible and well established solution for harmonized aggregation. The benefit of this work, to use high quality and context specific data, becomes apparent in speculating previously unattended biomarker candidates around a well-known mechanism, further leveraged for experimental investigations.

PMID: 27392431 [PubMed - as supplied by publisher]

Chronic Rhinosinusitis in Patients with Cystic Fibrosis.

J Allergy Clin Immunol Pract. 2016 Jul-Aug;4(4):605-612

Authors: Hamilos DL

Abstract
Chronic rhinosinusitis (CRS) is highly prevalent in patients with cystic fibrosis (CF) and accounts for significant morbidity and contribution to CF lung disease. Mutations of the cystic fibrosis transmembrane regulator gene occur with increased prevalence in patients with CRS without CF, suggesting some contribution to CRS pathophysiology. Nasal polyps (NPs) occur with increased prevalence in patients with CF of all ages and have a more neutrophilic appearance with fewer eosinophils and increased submucosal glandular elements in comparison to NPs from patients without CF. Mainstays of medical treatment include isotonic saline irrigations and topical intranasal glucocorticoids, with some evidence that topical intranasal glucocorticoids reduce NP size. Although inhaled hypertonic saline (7%) has been widely studied as a mucolytic agent for CF lung disease, there are no reports of its use in CF CRS. Mucolytics have also not been studied as a treatment for CRS in CF, and most evidence does not support their use for CF lung disease. Nasally nebulized dornase alfa (recombinant human deoxyribonuclease) following sinus surgery shows promise for treatment. Other unproven therapies include addition of baby shampoo to isotonic saline to potentially thin mucus and help prevent biofilm formation. There are no data to support the use of low-dose oral macrolide antibiotics or the use of prophylactic oral antibiotics for CRS in patients with CF. However, there is some support for the use of topical antibiotics, including colistimethate sodium or tobramycin, administered as a sinus irrigation or antral lavage in patients following sinus surgery when susceptible bacteria are cultured. Key components of CF sinus surgical management include extensive surgery to ensure that the maxillary, frontal, sphenoid, and ethmoid sinuses are all widely opened with smoothing of bony overhangs to prevent mucus retention and bacterial recolonization, postoperative meticulous daily nasal irrigations, and appropriate use of culture-directed topical antibiotics. There are no data yet on whether CF-targeted therapies, including ivacaftor or ivacaftor combined with lumacaftor, have an impact on CF CRS.

PMID: 27393775 [PubMed - as supplied by publisher]

Predictors of Hospital Readmission in Patients Receiving Outpatient Parenteral Antimicrobial Therapy.

Pharmacotherapy. 2016 Jul 9;

Authors: Means L, Bleasdale S, Sikka M, Gross AE

Abstract
STUDY OBJECTIVE: Outpatient parenteral antimicrobial therapy (OPAT) is increasingly used and unfortunately, readmissions during OPAT are common. The purpose of this study was to identify predictors of hospital readmission among patients receiving OPAT.
DESIGN: Retrospective cohort study.
SETTING: Large, academic, tertiary-care hospital.
PATIENTS: A total of 216 adults who were discharged and received OPAT through a peripherally inserted central catheter for at least 2 days for treatment of an active infection, excluding patients with cystic fibrosis, between January 2012 and August 2013; of these patients, 43 had hospital readmissions and 173 did not.
MEASUREMENTS AND MAIN RESULTS: The median age of all study patients was 56 years. Common infections included bone and joint (32%), genital/urinary tract (16%), endocarditis (14%), central nervous system (9.7%), and pneumonia (9.7%). For the 43 patients (20%) who had readmissions, reasons for readmission were infection recurrence or progression (33%), adverse drug reactions (24%), central catheter-associated issues (16%), or non-OPAT-related reasons (27%). In the multivariate analysis, patients assigned to a primary care physician were less likely to be readmitted (odds ratio [OR] 0.286, 95% confidence interval [CI] 0.115-0.711), whereas factors independently associated with an increased readmission rate included previous hospital admission in the past 12 months (OR 2.588, 95% CI 1.159-5.778), medical history of malignant lymphoma (OR 25.172, 95% CI 2.311-272.209), and increased planned OPAT duration (OR 1.058, 95% CI 1.034-1.082).
CONCLUSION: Readmissions while patients received OPAT were common. Therefore, proactive interventions including primary care physician assignment to facilitate follow-up and communication should be implemented to decrease the risk of readmission, particularly in the identified high-risk populations. This article is protected by copyright. All rights reserved.

PMID: 27393717 [PubMed - as supplied by publisher]

Selection on metabolic pathway function in the presence of mutation-selection-drift balance leads to rate-limiting steps that are not evolutionarily stable.

Biol Direct. 2016;11(1):31

Authors: Orlenko A, Teufel AI, Chi PB, Liberles DA

Abstract
BACKGROUND: While commonly assumed in the biochemistry community that the control of metabolic pathways is thought to be critical to cellular function, it is unclear if metabolic pathways generally have evolutionarily stable rate limiting (flux controlling) steps.
RESULTS: A set of evolutionary simulations using a kinetic model of a metabolic pathway was performed under different conditions to evaluate the evolutionary stability of rate limiting steps. Simulations used combinations of selection for steady state flux, selection against the cost of molecular biosynthesis, and selection against the accumulation of high concentrations of a deleterious intermediate. Two mutational regimes were used, one with mutations that on average were neutral to molecular phenotype and a second with a preponderance of activity-destroying mutations. The evolutionary stability of rate limiting steps was low in all simulations with non-neutral mutational processes. Clustering of parameter co-evolution showed divergent inter-molecular evolutionary patterns under different evolutionary regimes.
CONCLUSIONS: This study provides a null model for pathway evolution when compensatory processes dominate with potential applications to predicting pathway functional change. This result also suggests a possible mechanism in which studies in statistical genetics that aim to associate a genotype to a phenotype assuming independent action of variants may be mis-specified through a mis-characterization of the link between individual gene function and pathway function. A better understanding of the genotype-phenotype map has potential applications in differentiating between compensatory changes and directional selection on pathways as well as detecting SNPs and fixed differences that might have phenotypic effects.
REVIEWERS: This article was reviewed by Arne Elofsson, David Ardell, and Shamil Sunyaev.

PMID: 27393343 [PubMed - as supplied by publisher]

12 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 2016/07/09

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 2016/07/09

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.

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

"Systems Biology"[Title/Abstract] AND ("2005/01/01"[PDAT] : "3000"[PDAT])

These pubmed results were generated on 2016/07/09

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.

Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity.

Nat Commun. 2016;7:10787

Authors: Sant'Anna R, Gallego P, Robinson LZ, Pereira-Henriques A, Ferreira N, Pinheiro F, Esperante S, Pallares I, Huertas O, Almeida MR, Reixach N, Insa R, Velazquez-Campoy A, Reverter D, Reig N, Ventura S

Abstract
Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson's disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists.

PMID: 26902880 [PubMed - indexed for MEDLINE]