Genetic predisposition in pancreatitis.

Curr Opin Pediatr. 2018 10;30(5):660-664

Authors: Gonska T

Abstract
PURPOSE OF REVIEW: Genetic mutations are the primary cause for acute recurrent (ARP) and chronic pancreatitis in children. Further, our medical approach for many diseases is changing from a one-drug therapy to more individualized therapeutic strategies. In respect to the therapeutic management of ARP/chronic pancreatitis, this entails an understanding of the individual, mainly genetic, risk factors that led to pancreatitis disease.
RECENT FINDINGS: New pancreatitis-associated genes are continuously emerging from increasingly large genetic cohort studies. Furthermore, newer research findings demonstrate that multiple genetic and nongenetic factors are required to increase the individual risk for developing ARP/chronic pancreatitis. Last, there is new exciting development towards targeted pancreatitis therapy in the future.
SUMMARY: This review introduces the current concept of ARP/chronic pancreatitis as a complex disease caused by multiple genetic and nongenetic factors. This warrants careful evaluation of these patients and ideally consultation of a pancreas expert to help understand individual genetic risk profiles and to provide more effective patient consultation.

PMID: 30015686 [PubMed - indexed for MEDLINE]

Pseudomonas aeruginosa eradication therapy and risk of acquiring Aspergillus in young children with cystic fibrosis.

Thorax. 2019 Jun 15;:

Authors: Harun SN, Holford NHG, Grimwood K, Wainwright CE, Hennig S, Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) study group

Abstract
BACKGROUND: While Aspergillus detection rates in adults, adolescents and older children with cystic fibrosis (CF) have increased, the risk of acquiring this fungal pathogen in young children is unknown.
AIM: To determine the risk and explanatory factors of acquiring Aspergillus in children with CF by age 5 years.
METHODS: Cross-sectional analysis of clinical, bronchoalveolar lavage and treatment data from the Australasian Cystic Fibrosis Bronchoalveolar Lavage study was used to identify predictive factors for detecting Aspergillus at age 5 years. A parametric repeated time-to-event model quantitatively described the risk and factors associated with acquiring Aspergillus and Pseudomonas aeruginosa from birth until age 5 years.
RESULTS: Cross-sectional analysis found that the number of P. aeruginosa eradication courses increased the odds of detecting Aspergillus at age 5 years (OR 1.61, 95% CI 1.23 to 2.12). The median (IQR) age for the first P. aeruginosa positive culture was 2.38 (1.32-3.79) years and 3.69 (1.68-4.74) years for the first Aspergillus positive culture. The risk of P. aeruginosa and Aspergillus events changes with time after the first year of study entry. It also decreases for P. aeruginosa after completing P. aeruginosa eradication (HR 0.15, 95% CI 0.00 to 0.79), but increases for Aspergillus events (HR 2.75, 95% CI 1.45 to 5.41). The risk of acquiring both types of events increases after having had a previous event.
CONCLUSION: In young children with CF, completing P. aeruginosa eradication therapy and previous Aspergillus events are associated with increased risk of acquiring Aspergillus.

PMID: 31203197 [PubMed - as supplied by publisher]

Proteomic Profiling to Identify Blood Biomarkers Predictive of Response to Azithromycin in Children and Adolescents with Cystic Fibrosis.

Chest. 2019 Jun 12;:

Authors: Dong K, Singh A, Ng RT, Sin DD, Tebbutt SJ, Ratjen F, Quon BS

Abstract
BACKGROUND: Azithromycin reduces pulmonary exacerbation (PEx) risk in cystic fibrosis (CF) but not all individuals benefit. The goal of this study was to discover blood protein biomarkers predictive of clinical response to azithromycin treatment in CF children and adolescents.
METHODS: Novel proteomic technologies were applied to examine 188 serum and plasma proteins from 40 CF subjects randomized to azithromycin in the AZ0004 trial. Early change in blood protein levels from day 0 to day 28 of treatment were examined in relation to changes in FEV1 % predicted (ppFEV1) and weight by day 28 and 168, and to predict PEx risk by day 168.
RESULTS: Early change in the levels of 15 plasma proteins following 28 days of azithromycin significantly correlated with changes in ppFEV1 from day 0 to day 28 (q-value < 0.10) but this was not sustained to day 168. Early change in serum calprotectin levels following 28 days of azithromycin was predictive of PEx risk by day 168 of treatment (AUC = 0.76, 95% CI: 0.57-0.95). Based on a calprotectin cut-off to maximize test sensitivity (88%) and specificity (68%), 40% of subjects who had a calprotectin reduction less than the cut-off experienced at least one PEx compared to only 8% of subjects with calprotectin reduction greater than the cut-off.
CONCLUSIONS: Early change in blood protein biomarkers following azithromycin treatment are associated with short but not longer-term changes in lung function. Early change in serum calprotectin is predictive of response to azithromycin in terms of modifying PEx risk.

PMID: 31201785 [PubMed - as supplied by publisher]

Mucosal-associated invariant T cells: new players in CF lung disease?

Inflamm Res. 2019 Jun 14;:

Authors: Anil N

Abstract
The past decade has witnessed a surge in research centered around exploring the role of the enigmatic innate immune-like lymphocyte MAIT cell in human disease. Recent evidence has led to the elucidation of its role as a potent defender at mucosal surfaces including lungs due to its capacity to mount a formidable immediate response to bacterial pathogens. MAIT cells have a unique attribute of recognizing microbial ligands in conjunction with non-classical MHC-related protein MR1. Recent studies have demonstrated their contribution in the pathogenesis of chronic pulmonary disorders including asthma and chronic obstructive pulmonary disease. Several cellular players including innate immune cells are active contributors in the immune imbalance present in cystic fibrosis(CF) lung. This immune dysregulation serves as a central pivot in disease pathogenesis, responsible for causing immense structural damage in the CF lung. The present review focuses on understanding the role of MAIT cells in CF lung disease. Future studies directed at understanding the possible relationship between MAIT cells and regulatory T cells (Tregs) in CF lung disease could unravel a holistic picture where a combination of antimicrobial effects of MAIT cells and anti-inflammatory effects of Tregs could be exploited in synergy to alleviate the rapid deterioration of lung function in CF lung disease due to the underlying complex interplay between persistent infection and inflammation.

PMID: 31201438 [PubMed - as supplied by publisher]

Domain-interface dynamics of CFTR revealed by stabilizing nanobodies.

Nat Commun. 2019 Jun 14;10(1):2636

Authors: Sigoillot M, Overtus M, Grodecka M, Scholl D, Garcia-Pino A, Laeremans T, He L, Pardon E, Hildebrandt E, Urbatsch I, Steyaert J, Riordan JR, Govaerts C

Abstract
The leading cause of cystic fibrosis (CF) is the deletion of phenylalanine 508 (F508del) in the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR). The mutation affects the thermodynamic stability of the domain and the integrity of the interface between NBD1 and the transmembrane domain leading to its clearance by the quality control system. Here, we develop nanobodies targeting NBD1 of human CFTR and demonstrate their ability to stabilize both isolated NBD1 and full-length protein. Crystal structures of NBD1-nanobody complexes provide an atomic description of the epitopes and reveal the molecular basis for stabilization. Furthermore, our data uncover a conformation of CFTR, involving detachment of NBD1 from the transmembrane domain, which contrast with the compact assembly observed in cryo-EM structures. This unexpected interface rearrangement is likely to have major relevance for CF pathogenesis but also for the normal function of CFTR and other ABC proteins.

PMID: 31201318 [PubMed - in process]

Enhancing intrinsic motivation for physical activity among adolescents with cystic fibrosis: a qualitative study of the views of healthcare professionals.

BMJ Open. 2019 Jun 14;9(6):e028996

Authors: Denford S, Mackintosh KA, McNarry MA, Barker AR, Williams CA, Youth Activity Unlimited – A Strategic Research Centre of the UK Cystic Fibrosis Trust

Abstract
OBJECTIVE: To explore the views of healthcare professionals from cystic fibrosis (CF) multidisciplinary teams (MDT) on physical activity for adolescents with CF, the specific strategies used for physical activity promotion and associated challenges.
DESIGN: In this exploratory study, in-depth qualitative interviews were conducted with 15 healthcare professionals from CF MDTs to explore their views surrounding physical activity promotion for adolescents with CF.
PARTICIPANTS: Eleven physiotherapists (nine female), two consultants (both male) and two dieticians (both female) provided written informed consent and participated in the study.
SETTING: CF clinics in the UK.
RESULTS: While healthcare professionals highlighted the importance of physical activity in the management of CF, they noted that very few patients were motivated solely by (CF or general) health reasons. Healthcare professionals discussed the need for physical activity to be an enjoyable and routine part of their life, undertaken with significant others, outside the clinic whenever possible. Adopted approaches for physical activity promotion focused on providing individualised recommendations that suit the patients' individual needs and goals and enhance intrinsic motivation for physical activity.
CONCLUSION: Our research offers valuable information for those seeking to develop interventions to promote physical activity among adolescents with CF. Specifically, intervention developers should focus on developing individualised interventions that focus on enhancing intrinsic motivation and support the integration of physical activity into everyday life.

PMID: 31201192 [PubMed - in process]

Identification of a novel large deletion and other copy number variations in the CFTR gene in patients with Cystic Fibrosis from a multiethnic population.

Mol Genet Genomic Med. 2019 Jun 14;:e645

Authors: Martins RDS, Campos Junior M, Dos Santos Moreira A, Marques Zembrzuski V, da Fonseca ACP, Abreu GM, Cabello PH, de Cabello GMK

Abstract
BACKGROUND: Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). There are over 2000 different pathogenic and non-pathogenic variants described in association with a broad clinical heterogeneity. The most common types of mutations in this gene are single nucleotide substitutions or small deletions and insertions. However, large rearrangements, such as large duplications or deletions, are also a possible cause of CF; these variations are rarely tested in routine screenings, and much of them remain unidentified in some populations, especially those with high ethnic heterogeneity.
METHODS: The present study utilized the Multiplex Ligation-dependent Probe Amplification (MLPA) technique for the detection of duplications and deletions in 165 CF patients from the Rio de Janeiro State (Brazil), which after extensive mutational screening, still exhibited one or two unidentified CF alleles.
RESULTS: Five patients with alterations in MLPA signals were detected. After validation, we identified three copy number variations, one large duplication (CFTRdup2-3) and two large deletions (CFTRdel25-26 and CFTRdel25-27-CTTNBP2). Two detected deletions were not validated. They were false positives caused by a small deletion of 18 base pairs (232del18) and a point mutation (S168L) in the probe binding site.
CONCLUSION: Our results highlight the importance of screening for large rearrangements in CF cases with no or only one CFTR mutation defined.

PMID: 31199594 [PubMed - as supplied by publisher]

Effect of Including Important Clinical Variables on Accuracy of the Lung Allocation Score for Cystic Fibrosis and Chronic Obstructive Pulmonary Disease.

Am J Respir Crit Care Med. 2019 Jun 14;:

Authors: Lehr CJ, Skeans M, Dasenbrook EC, Fink A, Fernandez G, Faro A, Valapour M

Abstract
RATIONALE: Clinical variables associated with shortened survival in advanced-stage cystic fibrosis (CF) patients are not included in the lung allocation score (LAS).
OBJECTIVE: Identify variables associated with waitlist and posttransplant mortality for CF lung transplant candidates using a novel database; analyze the impact of including new CF-specific variables in the LAS.
METHODS: A deterministic matching algorithm identified patients from the Scientific Registry of Transplant Recipients and the Cystic Fibrosis Foundation Patient Registry. LAS waitlist and posttransplant survival models were recalculated using CF-specific variables. This multi-center, retrospective, population-based study of lung transplant waitlist candidates aged ≥ 12 years, January 1, 2011-December 31, 2014, included 9043 patients on the lung transplant waiting list and 6110 lung transplant recipients, 2011-2014, 1020 and 677 with CF, respectively.
MEASUREMENTS AND MAIN RESULTS: Measured outcomes were changes in LAS and lung allocation rank. For CF candidates, any Burkholderia sp. (hazard ratio 2.8, 95% confidence interval 1.2-6.6), 29-42 days hospitalized (2.8, 1.3-5.9), massive hemoptysis (2.1, 1.1-3.9), and relative drop in FEV1 ≥ 30% over 12 months (1.7, 1.0-2.8) increased waitlist mortality risk; pulmonary exacerbation time 15-28 days (1.8, 1.1-2.9) increased posttransplant mortality risk. A relative drop in FEV1 of ≥ 10% in chronic obstructive pulmonary disease (COPD) candidates was associated with increased waitlist mortality risk (2.6, 1.2-5.4). Variability in LAS score and rank increased in CF patients. Priority for transplant increased for COPD candidates. Access did not change for other diagnosis groups.
CONCLUSIONS: Adding CF-specific variables improved discrimination among waitlisted CF candidates, and benefitted COPD candidates.

PMID: 31199166 [PubMed - as supplied by publisher]

Airway regeneration using iPS cell-derived airway epithelial cells with Cl- channel function.

Channels (Austin). 2019 Dec;13(1):227-234

Authors: Yoshie S, Omori K, Hazama A

Abstract
induced pluripotent stem (iPS) cells can be differentiated into various cell types, including airway epithelial cells, since they have the capacity for self-renewal and pluripotency. Thus, airway epithelial cells generated from iPS cells are expected to be potent candidates for use in airway regeneration and the treatment of airway diseases such as cystic fibrosis (CF). Recently, it was reported that iPS cells can be differentiated into airway epithelial cells according to the airway developmental process. These studies demonstrate that airway epithelial cells generated from iPS cells are equivalent to their in vivo counterparts. However, it has not been evaluated in detail whether these cells exhibit physiological functions and are fully mature. Airway epithelial cells adequately control water volume on the airway surface via the function of Cl- channels. Reasonable environments on the airway surface cause ciliary movement with a constant rhythm and maintain airway clearance. Therefore, the generation of functional airway epithelial cells/tissues with Cl- channel function from iPS cells will be indispensable for cell/tissue replacement therapy, the development of a reliable airway disease model, and the treatment of airway disease. This review highlights the generation of functional airway epithelial cells from iPS cells and discusses the remaining challenges to the generation of functional airway epithelial cells for airway regeneration and the treatment of airway disease.

PMID: 31198082 [PubMed - in process]

Fair subject selection in cystic fibrosis trials.

J Cyst Fibros. 2019 Jun 10;:

Authors: Strassle C

PMID: 31196671 [PubMed - as supplied by publisher]

Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries.

J Cyst Fibros. 2019 Jun 10;:

Authors: Volkova N, Moy K, Evans J, Campbell D, Tian S, Simard C, Higgins M, Konstan MW, Sawicki GS, Elbert A, Charman SC, Marshall BC, Bilton D

Abstract
BACKGROUND: Ivacaftor is the first in a class of drugs, CFTR modulators, that target the underlying defect in cystic fibrosis (CF). This long-term observational safety study evaluated CF disease progression in patients treated with ivacaftor in a real-world setting for up to 5 years.
METHODS: Data from existing US and UK CF patient registries were used to assess longitudinal patterns in lung function, nutritional status, pulmonary exacerbations and hospitalizations, CF-related diabetes (CFRD), and Pseudomonas aeruginosa in ivacaftor-treated vs untreated comparator cohorts matched by age, sex, and disease severity.
RESULTS: US analyses included 635 ivacaftor-treated patients and 1874 comparators followed for 5 years from year 1 of market availability (2012-2016). Evaluation of outcome patterns from pretreatment baseline (2011) through year 5 (2016), showed that relative to comparators, ivacaftor-treated patients had better preserved lung function (mean change in percent predicted FEV1, -0.7 percentage points with ivacaftor vs -8.3 percentage points in comparators) and improved nutritional status (mean body mass index change +2.4 kg/m2 with ivacaftor vs +1.6 kg/m2 in comparators). US patients treated with ivacaftor had significantly lower frequencies of exacerbations and hospitalizations in each of the 5 years of follow-up relative to pretreatment baseline and comparators. Favorable trends in CFRD and P. aeruginosa prevalence were also observed. Findings from the smaller UK registry were directionally similar to and consistent with US findings.
CONCLUSIONS: This observational study represents the largest longitudinal analysis of patients treated with ivacaftor in a real-world setting. The findings support disease modification by CFTR modulation with ivacaftor.

PMID: 31196670 [PubMed - as supplied by publisher]

Roles of volume-regulatory anion channels, VSOR and Maxi-Cl, in apoptosis, cisplatin resistance, necrosis, ischemic cell death, stroke and myocardial infarction.

Curr Top Membr. 2019;83:205-283

Authors: Okada Y, Numata T, Sato-Numata K, Sabirov RZ, Liu H, Mori SI, Morishima S

Abstract
Two types of anion channels are directly activated by osmotic swelling and are involved in the regulatory volume decrease (RVD) in most types of mammalian cells, and they include the volume-sensitive outwardly rectifying anion channel (VSOR), also called the volume-regulated anion channel (VRAC), and the large-conductance maxi-anion channel (Maxi-Cl). In cardiomyocytes, a splice variant of cystic fibrosis transmembrane conductance regulator anion channel (cardiac CFTR) participates in the RVD mechanism under β-adrenergic stimulation. VSOR and Maxi-Cl are also involved in facilitation of the RVD process by releasing extracellular autocrine/paracrine signals, glutamate and ATP. Apoptotic cell death starts with cell shrinkage, called the apoptotic volume decrease (AVD), which is also caused by activation of VSOR. Since VSOR is implicated not only in the AVD induction but also in the uptake of an anti-cancer drug, cisplatin, downregulation of VSOR activity is causatively involved in acquisition of cisplatin resistance in cancer cells. Necrotic cell death exhibits persistent cell swelling, called the necrotic volume increase (NVI), which is coupled to RVD dysfunction due to impaired VSOR function. Acidotoxic and lactacidosis-induced necrotic cell death is induced both by glutamate release mediated by astroglial VSOR and Maxi-Cl and by exaggerated Cl- influx mediated by neuronal VSOR under prolonged depolarization caused by activation of ionotropic glutamate receptor (iGluR) cation channels. Both VSOR and Maxi-Cl are elaborately involved, in a manner as double-edged swords, in ischemia- and ischemia-reperfusion-induced apoptotic or necrotic cell death in cerebral and myocardial cells by mediating not only Cl- transport but also release of glutamate and/or ATP. Cardiac CFTR exerts a protective action against ischemia(-reperfusion)-induced cardiac injury, called myocardial infarction (MI), which is largely necrotic. Cardiac Maxi-Cl activity may participate in protection against ischemia(-reperfusion) injury by mediating ATP release.

PMID: 31196606 [PubMed - in process]

A non-randomised single centre cohort study, comparing standard and modified bowel preparations, in adults with cystic fibrosis requiring colonoscopy.

BMC Gastroenterol. 2019 Jun 13;19(1):89

Authors: Matson AG, Bunting JP, Kaul A, Smith DJ, Stonestreet J, Herd K, Hodgson RS, Bell SC

Abstract
BACKGROUND: Adults with cystic fibrosis (CF) have been reported to be at five to ten-fold risk (25 to 30 fold risk after solid organ transplant) of colorectal cancer (CRC) than the general population. Limited publications to date have reported on practical aspects of achieving adequate colonic cleanse producing good visualisation. In this study, we compared two bowel preparation regimens, standard bowel preparation and a modified CF bowel preparation.
METHODS: A non-randomised study of adults with CF attending a single centre, requiring colonoscopy investigation were selected. Between 2001 and 2015, 485 adults with CF attended the clinic; 70 adults with CF had an initial colonoscopy procedure. After five exclusions, standard bowel preparation was prescribed for 27 patients, and modified CF bowel preparation for 38 patients. Demographic and clinical data were collected for all consenting patients.
RESULTS: There was a significant difference between modified CF bowel preparation group and standard bowel preparation group in bowel visualisation outcomes, with the modified CF bowel preparation group having a higher proportion of "excellent/good" GI visualisation cleanse (50.0% versus 25.9%) and lower rates of "poor" visualisation cleanse (10.5% versus 44.5%) than standard bowel preparation (p = 0.006). Rates of "fair" GI cleanse visualisation were similar between the two groups (39.4% versus 29.6%) (Additional file 1: Table S1). Detection rates of adenomatous polyps at initial colonoscopy was higher in modified CF bowel preparation cohort than with standard preparation group (50.0% versus 18.5%, p < 0.01). Positive adenomatous polyp detection rate in patient's age > 40 years of age was higher (62.5%) than those < 40 years of age (24.3%) (p = 0.003). Colonic adenocarcinoma diagnosis was similar in both groups.
CONCLUSION: This study primarily highlights that standard colonoscopy bowel preparation is often inadequate in patients with CF, and that colonic lavage using modified CF bowel preparation is required to obtain good colonic visualisation. A higher rate of polyps in patients over 40 years of age (versus less than 40 years) was evident. These results support adults with CF considered for colonoscopy screening at 40 years of age, or prior to this if symptomatic; which is earlier than CRC screening in the non-CF Australian population.

PMID: 31195989 [PubMed - in process]

Chronic rhino-sinusitis treatment in children with cystic fibrosis: A cross-sectional survey of pediatric pulmonologists and otolaryngologists.

Int J Pediatr Otorhinolaryngol. 2019 Jun 01;124:139-142

Authors: Lowery AS, Gallant JN, Woodworth BA, Brown RF, Sawicki GS, Shannon CN, Virgin FW

Abstract
OBJECTIVES: Children with cystic fibrosis (CF) have a high incidence of chronic rhinosinusitis (CRS); however, no clinical care guidelines currently exist for the management of CRS in these patients. As a result, there is variation in the treatment of CRS in children, especially when it comes to the frequency of surgery for nasal polyposis.
METHODS: A 28-question survey was sent to pediatric otolaryngologists (POs) and pulmonologists (PPs) who care for pediatric CF patients. Questions assessed the level of agreement that practitioners had with various approaches to CRS care in pediatric CF patients.
RESULTS: Responses from 114 POs and 50 PPs were included in our final analysis. Each group demonstrated significantly different approaches to the medical and surgical management of CRS in pediatric CF patients. POs prefer multi-modal approach while PPs prefer single-modal approaches. With respect to medical management, PPs incline towards IV antibiotics while POs tend toward oral steroids.
CONCLUSION: POs and PPs strongly agree that CRS has an impact on overall disease state and quality of life of pediatric CF patients. However, POs and PPs significantly differ in their approach to treating CRS, demonstrating a potential need for clinical care guidelines for the management these common sequelae of CF.

PMID: 31195306 [PubMed - as supplied by publisher]

Antibiotic therapy for chronic infection with Burkholderia cepacia complex in people with cystic fibrosis.

Cochrane Database Syst Rev. 2019 Jun 13;6:CD013079

Authors: Frost F, Shaw M, Nazareth D

Abstract
BACKGROUND: Cystic fibrosis (CF) a life-limiting inherited disease affecting a number of organs, but classically associated with chronic lung infection and progressive loss of lung function. Chronic infection by Burkholderia cepacia complex (BCC) is associated with increased morbidity and mortality and therefore represents a significant challenge to clinicians treating people with CF. This review examines the current evidence for long-term antibiotic therapy in people with CF and chronic BCC infection.
OBJECTIVES: The objective of this review is to assess the effects of long-term oral and inhaled antibiotic therapy targeted against chronic BCC lung infections in people with CF. The primary objective is to assess the efficacy of treatments in terms of improvements in lung function and reductions in exacerbation rate. Secondary objectives include quantifying adverse events, mortality and changes in quality of life associated with treatment.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched online trial registries and the reference lists of relevant articles and reviews.Date of last search: 29 May 2019.
SELECTION CRITERIA: Randomised controlled trials (RCTs) of long-term antibiotic therapy in people with CF and chronic BCC infection.
DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and assessed the quality of the evidence using GRADE.
MAIN RESULTS: We included one RCT (100 participants) which lasted 52 weeks comparing continuous inhaled aztreonam lysine (AZLI) and placebo in a double-blind RCT for 24 weeks, followed by a 24-week open-label extension and a four-week follow-up period. The average participant age was 26.3 years, 61% were male and average lung function was 56.5% predicted.Treatment with AZLI for 24 weeks was not associated with improvement in forced expiratory volume in one second (FEV1), mean difference 0.91% (95% confidence interval (CI) -3.15 to 4.97) (moderate-quality evidence). The median time to the next exacerbation was 75 days in the AZLI group compared to 51 days in the placebo group, but the difference was not significant (P = 0.27) (moderate-quality evidence). Similarly, the number of participants hospitalised for respiratory exacerbations showed no difference between groups, risk ratio (RR) 0.88 (95% CI 0.53 to 1.45) (moderate-quality evidence). Overall adverse events were similar between groups, RR 1.08 (95% CI 0.98 to 1.19) (moderate-quality evidence). There were no significant differences between treatment groups in relation to mortality (moderate-quality evidence), quality of life or sputum density.In relation to methodological quality, the overall risk of bias in the study was assessed to be unclear to low risk.
AUTHORS' CONCLUSIONS: We found insufficient evidence from the literature to determine an effective strategy for antibiotic therapy for treating chronic BCC infection.

PMID: 31194880 [PubMed - as supplied by publisher]

Exercise capacity in patients with cystic fibrosis vs. non-cystic fibrosis bronchiectasis.

PLoS One. 2019;14(6):e0217491

Authors: Bar-Yoseph R, Ilivitzki A, Cooper DM, Gur M, Mainzer G, Hakim F, Livnat G, Schnapp Z, Shalloufeh G, Zucker-Toledano M, Subar Y, Bentur L

Abstract
BACKGROUND: Bronchiectasis is associated with morbidity, low exercise capacity and poor quality of life. There is a paucity of data on exercise capacity using cardiopulmonary exercise test (CPET) in non-cystic fibrosis (CF) bronchiectasis. Our aim was to compare exercise capacity using CPET in CF and non-CF bronchiectasis patients.
METHODS: Cross-sectional retrospective/prospective controlled study assessing CPET using cycle ergometer. Exercise parameters and computed tomography (CT) findings were compared. Results: Hundred two patients with bronchiectasis and 88 controls were evaluated; 49 CF (age 19.7 ± 9.7 y/o, FEV1%predicted 70.9 ± 20.5%) and 53 non-CF (18.6 ± 10.6 y/o, FEV1%predicted 68.7 ± 21.5%). Peak oxygen uptake (peak [Formula: see text]) was similar and relatively preserved in both groups (CF 1915.5±702.0; non-CF 1740±568; control 2111.0±748.3 mL/min). Breathing limitation was found in the two groups vs. control; low breathing reserve (49% in CF; 43% non-CF; 5% control) and increased [Formula: see text] (CF 31.4±4.1, non-CF 31.7±4.1 and control 27.2 ± 2.8). Oxygen pulse was lower in the non-CF; whereas a linear relationship between peak [Formula: see text] vs. FEV1 and vs. FVC was found only for CF. CT score correlated with [Formula: see text] and negatively correlated with [Formula: see text] and post exercise oxygen saturation (SpO2).
CONCLUSIONS: CPET parameters may differ between CF and non-CF bronchiectasis. However, normal exercise capacity may be found unrelated to the etiology of the bronchiectasis. Anatomical changes in CT are associated with functional finding of increased [Formula: see text] and decreased SpO2. Larger longitudinal studies including cardiac assessment are needed to better study exercise capacity in different etiologies of non-CF bronchiectasis.
TRIAL REGISTRATION: ClinicalTrials.gov, registration number: NCT03147651.

PMID: 31194748 [PubMed - in process]

Delivering on the promise of gene editing for cystic fibrosis.

Genes Dis. 2019 Jun;6(2):97-108

Authors: Hodges CA, Conlon RA

Abstract
In this review, we describe a path for translation of gene editing into therapy for cystic fibrosis (CF). Cystic fibrosis results from mutations in the CFTR gene, with one allele predominant in patient populations. This simple, genetic etiology makes gene editing appealing for treatment of this disease. There already have been success in applying this approach to cystic fibrosis in cell and animal models, although these advances have been modest in comparison to advances for other disease. Less than six years after its first demonstration in animals, CRISPR/Cas gene editing is in early clinical trials for several disorders. Most clinical trials, thus far, attempt to edit genes in cells of the blood lineages. The advantage of the blood is that the stem cells are known, can be isolated, edited, selected, expanded, and returned to the body. The likely next trials will be in the liver, which is accessible to many delivery methods. For cystic fibrosis, the biggest hurdle is to deliver editors to other, less accessible organs. We outline a path by which delivery can be improved. The translation of new therapies doesn't occur in isolation, and the development of gene editors is occurring as advances in gene therapy and small molecule therapeutics are being made. The advances made in gene therapy may help develop delivery vehicles for gene editing, although major improvements are needed. Conversely, the approval of effective small molecule therapies for many patients with cystic fibrosis will raise the bar for translation of gene editing.

PMID: 31193992 [PubMed]

CFTR Expression Analysis for Subtyping of Human Pancreatic Cancer Organoids.

Stem Cells Int. 2019;2019:1024614

Authors: Hennig A, Wolf L, Jahnke B, Polster H, Seidlitz T, Werner K, Aust DE, Hampe J, Distler M, Weitz J, Stange DE, Welsch T

Abstract
Background: Organoid cultures of human pancreatic ductal adenocarcinoma (PDAC) have become a promising tool for tumor subtyping and individualized chemosensitivity testing. PDACs have recently been grouped into different molecular subtypes with clinical impact based on cytokeratin-81 (KRT81) and hepatocyte nuclear factor 1A (HNF1A). However, a suitable antibody for HNF1A is currently unavailable. The present study is aimed at establishing subtyping in PDAC organoids using an alternative marker.
Methods: A PDAC organoid biobank was generated from human primary tumor samples containing 22 lines. Immunofluorescence staining was established and done for 10 organoid lines for cystic fibrosis transmembrane conductance regulator (CFTR) and KRT81. Quantitative real-time PCR (qPCR) was performed for CFTR and HNF1A. A chemotherapeutic drug response analysis was done using gemcitabine, 5-FU, oxaliplatin, and irinotecan.
Results: A biobank of patient-derived PDAC organoids was established. The efficiency was 71% (22/31) with 68% for surgical resections and 83% for fine needle aspirations. Organoids could be categorized into the established quasimesenchymal, exocrine-like, and classical subtypes based on KRT81 and CFTR immunoreactivity. CFTR protein expression was confirmed on the transcript level. CFTR and HNF1A transcript expression levels positively correlated (n = 10; r = 0.927; p = 0.001). PDAC subtypes of the primary tumors and the corresponding organoid lines were identical for most of the cases analyzed (6/7). Treatment with chemotherapeutic drugs revealed tendencies but no significant differences regarding drug responses.
Conclusions: Human PDAC organoids can be classified into known subtypes based on KRT81 and CFTR immunoreactivity. CFTR and HNF1A mRNA levels correlated well. Furthermore, subtype-specific immunoreactivity matched well between PDAC organoids and the respective primary tumor tissue. Subtyping of human PDACs using CFTR might constitute an alternative to HNF1A and should be further investigated.

PMID: 31191661 [PubMed]

Cystic Fibrosis-Related Diabetes: Pathophysiology and Therapeutic Challenges.

Clin Med Insights Endocrinol Diabetes. 2019;12:1179551419851770

Authors: Kelsey R, Manderson Koivula FN, McClenaghan NH, Kelly C

Abstract
Cystic fibrosis-related diabetes (CFRD) is among the most common extrapulmonary co-morbidity associated with cystic fibrosis (CF), affecting an estimated 50% of adults with the condition. Cystic fibrosis is prevalent in 1 in every 2500 Caucasian live births and is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Mutated CFTR leads to dehydrated epithelial surfaces and a build-up of mucus in a variety of tissues including the lungs and pancreas. The leading cause of mortality in CF is repeated respiratory bacterial infections, which prompts a decline in lung function. Co-morbid diabetes promotes bacterial colonisation of the airways and exacerbates the deterioration in respiratory health. Cystic fibrosis-related diabetes is associated with a 6-fold higher mortality rate compared with those with CF alone. The management of CFRD adds a further burden for the patient and creates new therapeutic challenges for the clinical team. Several proposed hypotheses on how CFRD develops have emerged, including exocrine-driven fibrosis and destruction of the entire pancreas and contrasting theories on the direct or indirect impact of CFTR mutation on islet function. The current review outlines recent data on the impact of CFTR on endocrine pancreatic function and discusses the use of conventional diabetic therapies and new CFTR-correcting drugs on the treatment of CFRD.

PMID: 31191067 [PubMed]

Overexpression of miRNA-25-3p inhibits Notch1 signaling and TGF-β-induced collagen expression in hepatic stellate cells.

Sci Rep. 2019 Jun 12;9(1):8541

Authors: Genz B, Coleman MA, Irvine KM, Kutasovic JR, Miranda M, Gratte FD, Tirnitz-Parker JEE, Olynyk JK, Calvopina DA, Weis A, Cloonan N, Robinson H, Hill MM, Al-Ejeh F, Ramm GA

Abstract
During chronic liver injury hepatic stellate cells (HSCs), the principal source of extracellular matrix in the fibrotic liver, transdifferentiate into pro-fibrotic myofibroblast-like cells - a process potentially regulated by microRNAs (miRNAs). Recently, we found serum miRNA-25-3p (miR-25) levels were upregulated in children with Cystic Fibrosis (CF) without liver disease, compared to children with CF-associated liver disease and healthy individuals. Here we examine the role of miR-25 in HSC biology. MiR-25 was detected in the human HSC cell line LX-2 and in primary murine HSCs, and increased with culture-induced activation. Transient overexpression of miR-25 inhibited TGF-β and its type 1 receptor (TGFBR1) mRNA expression, TGF-β-induced Smad2 phosphorylation and subsequent collagen1α1 induction in LX-2 cells. Pull-down experiments with biotinylated miR-25 revealed Notch signaling (co-)activators ADAM-17 and FKBP14 as miR-25 targets in HSCs. NanoString analysis confirmed miR-25 regulation of Notch- and Wnt-signaling pathways. Expression of Notch signaling pathway components and endogenous Notch1 signaling was downregulated in miR-25 overexpressing LX-2 cells, as were components of Wnt signaling such as Wnt5a. We propose that miR-25 acts as a negative feedback anti-fibrotic control during HSC activation by reducing the reactivity of HSCs to TGF-β-induced collagen expression and modulating the cross-talk between Notch, Wnt and TGF-β signaling.

PMID: 31189969 [PubMed - in process]