Proteomic profiling identifies novel circulating markers associated with bronchiectasis in cystic fibrosis.

Proteomics Clin Appl. 2017 Apr 28;:

Authors: DeBoer EM, Kroehl M, Wagner BD, Accurso F, Harris JK, Lynch DA, Sagel SD, Deterding RR

Abstract
PURPOSE: Evaluate bronchiectasis change over one year in children with cystic fibrosis (CF) and find blood proteins associated with bronchiectasis.
EXPERIMENTAL DESIGN: Pilot study of CF children who had chest computed tomography (CT) scans and blood collected during times of clinical stability. Blood plasma was analyzed for 1129 proteins using SOMAmer(®) , the SOMAscan proteomics platform. Bronchiectasis was measured on two CT scans collected 1 year apart. Spearman's rank estimated the correlations between outcomes. Clinical relevance was defined as |r| > 0.40.
RESULTS: There were 26 children included: mean age 11.3 years (SD 2.4 years), mean Brody Bronchiectasis score 0.65 (SD 0.83), mean airway count 14.3 (SD 5.7) per CT slice. Brody bronchiectasis change over 1 year ranged from -1.0 to 1.9 and airway count change over one year ranged from -7.7 to 13.5 airways per slice. Proteins related to inflammation and extracellular matrix degradation were associated with cross-sectional and longitudinal structural changes.
CONCLUSIONS AND CLINICAL RELEVANCE: Imaging outcomes were more strongly correlated with circulating proteins than age or spirometry values. The unique SOMAscan(TM) proteomic platform identifies several novel proteins in blood that are associated with bronchiectasis and that may serve as clinically useful biomarkers in children with CF. This article is protected by copyright. All rights reserved.

PMID: 28452194 [PubMed - as supplied by publisher]

Computation of ancestry scores with mixed families and unrelated individuals.

Biometrics. 2017 Apr 27;:

Authors: Zhou YH, Marron JS, Wright FA

Abstract
The issue of robustness to family relationships in computing genotype ancestry scores such as eigenvector projections has received increased attention in genetic association, and is particularly challenging when sets of both unrelated individuals and closely related family members are included. The current standard is to compute loadings (left singular vectors) using unrelated individuals and to compute projected scores for remaining family members. However, projected ancestry scores from this approach suffer from shrinkage toward zero. We consider two main novel strategies: (i) matrix substitution based on decomposition of a target family-orthogonalized covariance matrix, and (ii) using family-averaged data to obtain loadings. We illustrate the performance via simulations, including resampling from 1000 Genomes Project data, and analysis of a cystic fibrosis dataset. The matrix substitution approach has similar performance to the current standard, but is simple and uses only a genotype covariance matrix, while the family-average method shows superior performance. Our approaches are accompanied by novel ancillary approaches that provide considerable insight, including individual-specific eigenvalue scree plots.

PMID: 28452052 [PubMed - as supplied by publisher]

Neutrophil extracellular trap release driven by bacterial motility: Relevance to cystic fibrosis lung disease.

Commun Integr Biol. 2017;10(2):e1296610

Authors: Rada B

Abstract
Neutrophil extracellular trap (NET) formation represents a unique effector function of neutrophils (PMN). The mechanism of NET release in response to bacteria is largely unknown. We studied the process by which Pseudomonas aeruginosa, an opportunistic pathogen, interacts with primary PMNs, and found that flagellar swimming motility of the bacterium is essential for inducing NET extrusion. Cystic fibrosis (CF) lung disease is associated with P. aeruginosa infection and PMN-dominated inflammation. Although NETs are abundant in CF airways, the main factors triggering NET release in CF remain unclear. Our study implicates that motile P. aeruginosa is a strong NET-inducer in CF. In early stages of CF lung disease flagellated, motile isolates of P. aeruginosa are characteristic and their interactions with PMNs could lead to NET formation. In chronic CF, P. aeruginosa down-regulates its flagellum expression to avoid recognition by the immune system and forms biofilms. Flagellated bacteria, however, are released from biofilms and could interact with PMNs to form NETs. Although flagellated forms likely represent only a small fraction of the total P. aeruginosa load in chronic CF, NET release induced by them could have a significant impact on inflammation and lung function since flagellated forms trigger the most robust response of the immune system including PMNs. Overall, we speculate that NET formation driven by motile P. aeruginosa could be a novel, significant contributor to pathogenesis at both, early and late stages of CF lung disease.

PMID: 28451056 [PubMed - in process]

Lessons from the lower airway microbiome in early CF.

Thorax. 2017 Apr 27;:

Authors: Hoppe JE, Zemanick ET

PMID: 28450530 [PubMed - as supplied by publisher]

Cystic fibrosis: current therapeutic targets and future approaches.

J Transl Med. 2017 Apr 27;15(1):84

Authors: Rafeeq MM, Murad HAS

Abstract
OBJECTIVES: Study of currently approved drugs and exploration of future clinical development pipeline therapeutics for cystic fibrosis, and possible limitations in their use.
METHODS: Extensive literature search using individual and a combination of key words related to cystic fibrosis therapeutics.
KEY FINDINGS: Cystic fibrosis is an autosomal recessive disorder due to mutations in CFTR gene leading to abnormality of chloride channels in mucus and sweat producing cells. Respiratory system and GIT are primarily involved but eventually multiple organs are affected leading to life threatening complications. Management requires drug therapy, extensive physiotherapy and nutritional support. Previously, the focus was on symptomatic improvement and complication prevention but recently the protein rectifiers are being studied which are claimed to correct underlying structural and functional abnormalities. Some improvement is observed by the corrector drugs. Other promising approaches are gene therapy, targeting of cellular interactomes, and newer drugs for symptomatic improvement.
CONCLUSIONS: The treatment has a long way to go as most of the existing therapeutics is for older children. Other limiting factors include mutation class, genetic profile, drug interactions, adverse effects, and cost. Novel approaches like gene transfer/gene editing, disease modeling and search for alternative targets are warranted.

PMID: 28449677 [PubMed - in process]

Erratum to: The altered gut microbiota in adults with cystic fibrosis.

BMC Microbiol. 2017 Apr 27;17(1):102

Authors: Burke DG, Fouhy F, Harrison MJ, Rea MC, Cotter PD, O'Sullivan O, Stanton C, Hill C, Shanahan F, Plant BJ, Ross RP

PMID: 28449644 [PubMed - in process]

Unusual Pulmonary Arterial Filling Defect caused by Systemic to Pulmonary Shunt in the Setting of Chronic Lung Disease Demonstrated by Dynamic 4D CTA.

J Radiol Case Rep. 2015 Nov;9(11):17-23

Authors: Ansari-Gilani K, Gilkeson RC, Hsiao EM, Rajiah P

Abstract
Even though pulmonary embolism is by far the most common cause of filling defect in the pulmonary arterial system, other less common etiologies should be considered especially in the setting of atypical clinical scenario or unusual imaging findings. Unusual pattern of filling defect in the pulmonary artery in the setting of chronic inflammatory/fibrotic parenchymal lung disease should raise the concern for systemic to pulmonary artery shunt. This diagnosis is typically made by conventional angiography. Dynamic 4D CT angiography however can be a safe, noninvasive and effective alternative tool for making such a diagnosis. It has the added value of multiplanar reconstruction capabilities and providing detailed anatomy which can be vital for interventional radiologists when planning their approach for possible intervention. We present 2 cases of such shunts, and illustrate the demonstration of these shunts by using dynamic 4D CT angiography.

PMID: 27252791 [PubMed - indexed for MEDLINE]

Research Review: Childhood chronic physical illness and adult emotional health - a systematic review and meta-analysis.

J Child Psychol Psychiatry. 2017 Apr 27;:

Authors: Secinti E, Thompson EJ, Richards M, Gaysina D

Abstract
BACKGROUND: Childhood chronic physical illness is associated with a greater vulnerability for emotional problems (i.e. depression and anxiety) in childhood. However, little is known about life-long effects of childhood chronic physical illness on mental health. The present study aims to systematically review evidence for associations between eight chronic physical illnesses with childhood onset (arthritis, asthma, cancer, chronic renal failure, congenital heart disease, cystic fibrosis, type 1 diabetes, and epilepsy) and adult emotional problems.
METHODS: A database search of MEDLINE, PsycARTICLES, PsycINFO, and ScienceDirect was undertaken, and random effects meta-analyses were used to synthesise evidence from eligible studies.
RESULTS: In total, 37 studies were eligible for the systematic review (n = 45,733) and of these, 34 studies were included in the meta-analyses (n = 45,358). There were overall associations between childhood chronic physical illness and adult depression (OR = 1.31; 95% CI [1.12, 1.54]) and anxiety (OR = 1.47; 95% CI [1.13, 1.92]). Separate meta-analyses for childhood asthma, type 1 diabetes and cancer were also conducted, with cancer being significantly associated with adult depression (OR = 1.19; 95% CI [1.00, 1.42]).
CONCLUSIONS: The effects of childhood chronic physical illness on the risk of emotional problems persist beyond childhood and adolescence. Mental health prevention and intervention strategies targeting children with chronic physical illnesses can have long-term benefits.

PMID: 28449285 [PubMed - as supplied by publisher]

Combination of Correctors Rescues CFTR Transmembrane-Domain Mutants by Mitigating their Interactions with Proteostasis.

Cell Physiol Biochem. 2017 Apr 25;41(6):2194-2210

Authors: Lopes-Pacheco M, Boinot C, Sabirzhanova I, Rapino D, Cebotaru L

Abstract
BACKGROUND/AIMS: Premature degradation of mutated cystic fibrosis transmembrane conductance regulator (CFTR) protein causes cystic fibrosis (CF), the commonest Mendelian disease in Caucasians. Despite recent advances in precision medicines for CF patients, many CFTR mutants have not been characterized and the effects of these new therapeutic approaches are still unclear for those mutants.
METHODS: Cells transfected or stably expressing four CFTR transmembrane-domain mutants (G85E, E92K, L1077P, and M1101K) were used to: 1) characterize the mutants according to their protein expression, thermal sensitivity, and degradation pathways; 2) evaluate the effects of correctors in rescuing them; and 3) explore the effects of correctors on CFTR interactions with proteostasis components.
RESULTS: All four mutants exhibited lower protein expression than did wild type-CFTR, and they were degraded by proteasomes and aggresomes. At low temperature, only cells expressing the mutants L1077P and M1101K exhibited increased CFTR maturation. Co-administration of C4 and C18 showed the greatest effect, restoring functional expression and partial stability of CFTR bearing E92K, L1077P, or M1101K at the cell surface. However, this treatment was inefficient in rectifying the defect of CFTR bearing G85E. Correctors rescued CFTR mutants by reducing their interactions with proteostasis components associated with protein retention in the endoplasmic reticulum and ubiquitination.
CONCLUSION: Co-administration of C4 and C18 rescued CFTR transmembrane-domain mutants by remodeling the CFTR interactome.

PMID: 28448979 [PubMed - as supplied by publisher]

A commensal streptococcus hijacks a Pseudomonas aeruginosa exopolysaccharide to promote biofilm formation.

PLoS Pathog. 2017 Apr;13(4):e1006300

Authors: Scoffield JA, Duan D, Zhu F, Wu H

Abstract
Pseudomonas aeruginosa causes devastating chronic pulmonary infections in cystic fibrosis (CF) patients. Although the CF airway is inhabited by diverse species of microorganisms interlaced within a biofilm, many studies focus on the sole contribution of P. aeruginosa pathogenesis in CF morbidity. More recently, oral commensal streptococci have been identified as cohabitants of the CF lung, but few studies have explored the role these bacteria play within the CF biofilm. We examined the interaction between P. aeruginosa and oral commensal streptococci within a dual species biofilm. Here we report that the CF P. aeruginosa isolate, FRD1, enhances biofilm formation and colonization of Drosophila melanogaster by the oral commensal Streptococcus parasanguinis. Moreover, production of the P. aeruginosa exopolysaccharide, alginate, is required for the promotion of S. parasanguinis biofilm formation and colonization. However, P. aeruginosa is not promoted in the dual species biofilm. Furthermore, we show that the streptococcal adhesin, BapA1, mediates alginate-dependent enhancement of the S. parasanguinis biofilm in vitro, and BapA1 along with another adhesin, Fap1, are required for the in vivo colonization of S. parasanguinis in the presence of FRD1. Taken together, our study highlights a new association between streptococcal adhesins and P. aeruginosa alginate, and reveals a mechanism by which S. parasanguinis potentially colonizes the CF lung and interferes with the pathogenesis of P. aeruginosa.

PMID: 28448633 [PubMed - in process]

Little Cigars are More Toxic than Cigarettes and Uniquely Change the Airway Gene and Protein Expression.

Sci Rep. 2017 Apr 27;7:46239

Authors: Ghosh A, Abdelwahab SH, Reeber SL, Reidel B, Marklew AJ, Garrison AJ, Lee S, Dang H, Herring AH, Glish GL, Kesimer M, Tarran R

Abstract
Little cigars (LCs) are regulated differently than cigarettes, allowing them to be potentially targeted at youth/young adults. We exposed human bronchial epithelial cultures (HBECs) to air or whole tobacco smoke from cigarettes vs. LCs. Chronic smoke exposure increased the number of dead cells, lactate dehydrogenase release, and interleukin-8 (IL-8) secretion and decreased apical cilia, cystic fibrosis transmembrane conductance regulator (CFTR) protein levels, and transepithelial resistance. These adverse effects were significantly greater in LC-exposed HBECs than cigarette exposed cultures. LC-exposure also elicited unique gene expression changes and altered the proteomic profiles of airway apical secretions compared to cigarette-exposed HBECs. Gas chromatography-mass spectrometry (GC-MS) analysis indicated that LCs produced more chemicals than cigarettes, suggesting that the increased chemical load of LCs may be the cause of the greater toxicity. This is the first study of the biological effects of LCs on pulmonary epithelia and our observations strongly suggest that LCs pose a more severe danger to human health than cigarettes.

PMID: 28447619 [PubMed - in process]

Proprotein Convertase Subtilisin/Kexin type 9 affects insulin but not lipid metabolism in cystic fibrosis.

Clin Invest Med. 2017 Apr 26;40(2):E59-E65

Authors: Coriati A, Arslanian E, Bouvet GF, Prat A, Seidah NG, Rabasa-Lhoret R, Berthiaume Y

Abstract
PURPOSE: Cystic Fibrosis (CF) is the most common genetic disorder and, with improved survival, glucose abnormalities have emerged as a major comorbidity. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulator of plasma LDL-cholesterol homeostasis, is associated with lipid and glucose metabolism in healthy individuals. Here we report on the link between PCSK9 and markers of metabolism in CF.
METHODS: Cross-sectional analysis was performed on CF patients (≥ 18 years, N=94) from the Montreal Cohort, without known diabetes, and on healthy individuals (N=19). The levels of PCSK9 and lipid markers were quantified and all subjects underwent a 2 h oral glucose tolerance test.
RESULTS: No significant differences in PCSK9 levels were found between healthy individuals and patients with CF, or between the groups with different degrees of glucose tolerance. No association was found between PCSK9 and markers of lipid metabolism; however, a positive correlation was found between PCSK9 and total insulin secretion and a negative one with insulin sensitivity in CF patients who had normal glucose tolerance.
CONCLUSION: Circulating levels of PCSK9 in the CF population are comparable to those in the healthy population. There are no associations between PCSK9 levels and either glucose or lipid homeostasis parameters. Nevertheless, a statistically significant link was observed between PCSK9 and markers of insulin homeostasis, solely in CF patients who presented normal glucose tolerance. Further exploration of the relationship between PCSK9 and insulin homeostasis in CF patients with normal glucose tolerance is warranted.

PMID: 28447578 [PubMed - in process]

Ecology of the Human Opportunistic Black Yeast Exophiala dermatitidis Indicates Preference for Human-Made Habitats.

Mycopathologia. 2017 Apr 26;:

Authors: Babič MN, Zupančič J, Gunde-Cimerman N, de Hoog S, Zalar P

Abstract
Exophiala dermatitidis is an ascomycetous black yeast from the order Chaetothyriales. Its growth characteristics include the polymorphic life cycle, ability to grow at high and low temperatures, at a wide pH range, survival at high concentrations of NaCl, and survival at high UV and radioactive radiation. Exophiala dermatitidis causes deep or localized phaeohyphomycosis in immuno-compromised people worldwide and is regularly encountered in the lungs of cystic fibrosis patients. Regardless of numerous ecological studies worldwide, little is known about its natural habitat or the possible infection routes. The present review summarizes the published data on its frequency of occurrence in nature and in man-made habitats. We additionally confirmed its presence with culture-depending methods from a variety of habitats, such as glacial meltwater, mineral water, mineral-rich salt-pan mud, dishwashers, kitchens and different environments polluted with aromatic hydrocarbons. In conclusion, the frequency of its recovery was the highest in man-made indoor habitats, connected to water sources, and exposed to occasional high temperatures and oxidative stress.

PMID: 28447292 [PubMed - as supplied by publisher]

Population dynamics of Staphylococcus aureus in Cystic Fibrosis patients to determine transmission events utilizing WGS.

J Clin Microbiol. 2017 Apr 26;:

Authors: Ankrum A, Hall BG

Abstract
Strict infection control practices have been implemented for healthcare visits by Cystic Fibrosis patients in an attempt to prevent transmission of important pathogens. This study used whole genome sequencing (WGS) to determine strain relatedness and assess population dynamics of Staphylococcus aureus isolates from a cohort of CF patients as assessed by strain relatedness. 311 S. aureus isolates were collected from respiratory cultures of 115 CF patients during a 22 month study period. Whole genome sequencing was performed and using SNP analysis, phylogenetic trees were assembled to determine relatedness between isolates. MRSA phenotypes were predicted using PPFS2 and compared to the observed phenotype. The accumulation of SNPs in multiple isolates obtained over time from the same patient was examined to determine if a genomic molecular clock could be calculated.Pairs of isolates with ≤ 71 SNP differences were considered to be the "same" strain. All of the "same" strain isolates were either from the same patient or siblings pairs. There were 47 examples of patients being superinfected with an unrelated strain. Predicted MRSA phenotype was accurate in all but three isolates. Mutation rates were unable to be determined because the branching order in the phylogenetic tree was inconsistent with the order of isolation.The observation that transmissions were identified between sibling patients shows that WGS is an effective tool for determining transmission between patients. The observation that transmission only occurred between siblings suggests that Staphylococcus aureus acquisition in our CF population occurred outside the hospital environment and indicates that current infection prevention efforts appear effective.

PMID: 28446577 [PubMed - as supplied by publisher]

Prevalence and Outcomes of Achromobacter species Infections in Adults with Cystic Fibrosis: A North American Cohort Study.

J Clin Microbiol. 2017 Apr 26;:

Authors: Edwards BD, Greysson-Wong J, Somayaji R, Waddell B, Whelan FJ, Storey DG, Rabin HR, Surette MG, Parkins MD

Abstract
Introduction:Achromobacter species are now increasingly recognized in CF, with unclear epidemiology and impact.Methods: We studied a cohort of patients attending a Canadian adult CF clinic who had positive sputum cultures for Achromobacter species from 1984-2013. Infection was categorized as transient or persistent (≥50% positive cultures in one year). Those with persistent infection were matched 2:1 with age, sex, and time-matched controls without history of Achromobacter infection and mixed effects models used to assess pulmonary exacerbation(PEx) frequency and lung function decline. Isolates were retrospectively assessed from a biobank, speciated by nrdA sequencing, and genotyped using PFGE.Results: Thirty-four patients (11% of clinic), median age 24 years (IQR 20.3-29.8) developed Achromobacter infection. Ten patients (29%) developed persistent infection. Persistence did not denote permanence, as most patients ultimately cleared infection, often after years. Patients were more likely to experience PEx at incident isolation compared with prior or subsequent visits (OR 2.7[95% CI 1.2--6.7];p=0.03). Following persistent infection, there was no difference in annual lung function decline (-1.08% [95% CI -2.73-0.57] vs. -2.74% [95% CI -4.02-1.46]; p=0.12) or odds of PEx (OR 1.21 [95% CI 0.45--3.28]; p=0.70). Differential virulence amongst Achromobacter species was not observed and no cases of transmission occurred.Conclusion: We demonstrated that incident Achromobacter infection was associated with greater risk of PEx, however, neither transient nor chronic infection associated with worsened long-term prognosis. Large, multicenter studies are needed to clarify the clinical impact, natural history and transmissibility of Achromobacter.

PMID: 28446570 [PubMed - as supplied by publisher]

Lung lymphoid neogenesis in cystic fibrosis: a model of adaptive responses to bacteria?

Eur Respir J. 2017 Apr;49(4):

Authors: Gohy ST, Ladjemi MZ, Pilette C

PMID: 28446564 [PubMed - in process]

Pseudomonas aeruginosa adaptation and diversification in the non-cystic fibrosis bronchiectasis lung.

Eur Respir J. 2017 Apr;49(4):

Authors: Hilliam Y, Moore MP, Lamont IL, Bilton D, Haworth CS, Foweraker J, Walshaw MJ, Williams D, Fothergill JL, De Soyza A, Winstanley C

Abstract
To characterise Pseudomonas aeruginosa populations during chronic lung infections of non-cystic fibrosis bronchiectasis patients, we used whole-genome sequencing to 1) assess the diversity of P. aeruginosa and the prevalence of multilineage infections; 2) seek evidence for cross-infection or common source acquisition; and 3) characterise P. aeruginosa adaptations.189 isolates, obtained from the sputa of 91 patients attending 16 adult bronchiectasis centres in the UK, were whole-genome sequenced.Bronchiectasis isolates were representative of the wider P. aeruginosa population. Of 24 patients from whom multiple isolates were examined, there were seven examples of multilineage infections, probably arising from multiple infection events. The number of nucleotide variants between genomes of isolates from different patients was in some cases similar to the variations observed between isolates from individual patients, implying the possible occurrence of cross-infection or common source acquisition.Our data indicate that during infections of bronchiectasis patients, P. aeruginosa populations adapt by accumulating loss-of-function mutations, leading to changes in phenotypes including different modes of iron acquisition and variations in biofilm-associated polysaccharides. The within-population diversification suggests that larger scale longitudinal surveillance studies will be required to capture cross-infection or common source acquisition events at an early stage.

PMID: 28446558 [PubMed - in process]

Bacteria-driven peribronchial lymphoid neogenesis in bronchiectasis and cystic fibrosis.

Eur Respir J. 2017 Apr;49(4):

Authors: Frija-Masson J, Martin C, Regard L, Lothe MN, Touqui L, Durand A, Lucas B, Damotte D, Alifano M, Fajac I, Burgel PR

Abstract
We aimed to characterise lymphoid neogenesis in bronchiectasis and cystic fibrosis (CF) lungs and to examine the role of bacterial infection.Lymphoid aggregates were examined using immunohistochemical staining and morphometric analysis in surgical lung sections obtained from nonsmokers and patients with bronchiectasis or CF. Sterile, Pseudomonas aeruginosa- or Staphylococcus aureus-coated agarose beads were instilled intratracheally in mice. Kinetics of lymphoid neogenesis and chemokine expression were examined over 14 days.Lymphoid aggregates were scarce in human lungs of nonsmokers, but numerous peribronchial lymphoid aggregates containing B-lymphocytes, T-lymphocytes, germinal centres and high endothelial venules were found in bronchiectasis and CF. Mouse lungs contained no lymphoid aggregate at baseline. During persistent P. aeruginosa or S. aureus airway infection peribronchial lymphoid neogenesis occurred. At day 14 after instillation, lymphoid aggregates expressed markers of tertiary lymphoid organs and the chemokines CXCL12 and CXCL13. The airway epithelium was an important site of CXCL12, CXCL13 and interleukin-17A expression, which began at day 1 after instillation.Peribronchial tertiary lymphoid organs are present in bronchiectasis and in CF, and persistent bacterial infection triggered peribronchial lymphoid neogenesis in mice. Peribronchial localisation of tertiary lymphoid organs and epithelial expression of chemokines suggest roles for airway epithelium in lymphoid neogenesis.

PMID: 28446556 [PubMed - in process]

Risk factors for persistent methicillin-resistant Staphylococcus aureus infection in cystic fibrosis.

J Cyst Fibros. 2017 Apr 23;:

Authors: Jennings MT, Dasenbrook EC, Lechtzin N, Boyle MP, Merlo CA

Abstract
BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as an important pathogen in cystic fibrosis (CF). Over 25% of individuals in the United States with CF are found to have MRSA in respiratory culture specimens, and persistent MRSA infection has been associated with more rapid decline in lung function and increased mortality. The objective of this study was to investigate clinical and demographic characteristics that are associated with the development of persistent MRSA infection in a CF population.
METHODS: This was a retrospective cohort study of individuals followed from 2002 to 2012 in the Cystic Fibrosis Foundation Patient Registry. A time-to-event analysis for the development of persistent MRSA infection was performed, and multivariable Cox proportional hazards models were constructed to identify risk factors for infection.
RESULTS: The study cohort included 19,434 individuals, of which 5844 would develop persistent MRSA infection. In the adjusted model, pancreatic insufficiency (HR: 1.49; 95% CI: 1.29-1.72), CF related diabetes (HR: 1.13; 95% CI: 1.05-1.20), co-infection with P. aeruginosa (HR: 1.21; 95% CI: 1.13-1.28), and number of hospitalizations/year (HR: 1.09; 95% CI: 1.06-1.12) were all associated with increased risk, whereas higher socio-economic status (HR: 0.87; 95% CI: 0.82-0.93) was associated with a lower risk. Receiving care at a CF center with increased MRSA prevalence was associated with increased risk of MRSA infection: highest quartile (HR: 2.33; 95% CI: 2.13-2.56).
CONCLUSIONS: No easily modifiable risk factors for persistent MRSA were identified in this study. However, several risk factors for patients at higher risk for persistent MRSA infection were identified, for example centers with a high baseline MRSA prevalence, and may be useful in designing center-specific MRSA infection prevention and control strategies and/or eradication protocols. Additional studies are needed in order to evaluate if attention to these risk factors can improve clinical outcomes.

PMID: 28446387 [PubMed - as supplied by publisher]

High CFTR expression in Philadelphia chromosome-positive acute leukemia protects and maintains continuous activation of BCR-ABL and related signaling pathways in combination with PP2A.

Oncotarget. 2017 Apr 11;8(15):24437-24448

Authors: Yang X, Yan T, Gong Y, Liu X, Sun H, Xu W, Wang C, Naren D, Zheng Y

Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR) is classified as an anion channel transporter of Cl- and HCO3-. Through interactions with its PDZ domain, CFTR is capable of regulating other proteins, such as protein phosphatase 2A (PP2A). The aberrant expression and mutation of CFTR have been observed in several tumor, but not in philadelphia chromosome-positive(Ph+) acute leukemia, including Ph+ B cell acute lymphoblastic leukemia(Ph+ B-ALL) and chronic myelogenous leukemia blast crisis phases (CML-BC). In this study, we demonstrated the mean expression level of CFTR in Ph+ acute leukemia cells was markedly higher than that in Ph- B-ALL and CML-chronic phase cells. CFTRinh-172, a classic CFTR inhibitor, down-regulated the expression of CFTR, p-BCR-ABL and classical Wnt/β-catenin signaling in Ph+ acute leukemia cells, while imatinib had no effect on CFTR. Importantly, reduced efficacy of CFTRinh-172 was closely associated with elevated PP2A phosphatase activity. Furthermore, we confirmed an interaction between CFTR and the PP2AA subunit in K562 cells. In addition, we demonstrated CFTR and PP2AA interact in the cytosol, resulting in PP2A complex inactivation and increased degradation of PP2A substrates via the lysosomal/proteasome pathway. In conclusion, our results showed CFTR was highly expressed in Ph+ acute leukemia, which protected and maintained the continuous activation of BCR-ABL and the canonical Wnt/β-catenin signaling pathway by decreasing PP2A phosphatase activity. According to this working model of the CFTR-PP2A-BCR-ABL axis, targeting the CFTR protein will activate PP2A and may offer a new treatment strategy for Ph+ acute leukemia, especially for patients exhibiting high levels of CFTR expression.

PMID: 28445932 [PubMed - in process]