Feasibility and Acceptability of a Telephone-Based Chaplaincy Intervention to Decrease Parental Spiritual Struggle.

J Relig Health. 2019 Oct 04;:

Authors: Betz J, Szczesniak R, Lewis K, Pestian T, Bennethum AS, McBride J, Grossoehme DH

Abstract
Spiritual struggles (SSs) are distressing spiritual thoughts associated with poorer health outcomes. This study's purpose was to test feasibility, acceptability, and fidelity of an intervention to decrease SS of parents of children with CF. Parents screening positive for SS were enrolled and were randomized to intervention or attention-control condition. Intervention focused on intra-, inter-, and divine SS. Mixed linear modeling examined between-group differences. We present analyses of N = 23, and participants all showed decreased levels of SS. Acceptability was high; feasibility was higher in the intervention arm. GuideSS_CF is acceptable and feasible and warrants development as a potentially efficacious intervention.

PMID: 31584149 [PubMed - as supplied by publisher]

Ceftazidime plasma concentration in a patient with cystic fibrosis treated with ceftazidime/avibactam plus trimethoprim/sulfametoxazole for Bulkholderia cepacia reacutization.

J Chemother. 2019 Oct 04;:1-3

Authors: Saffioti C, Barco S, Cangemi G, Mesini A, Casciaro R, Cresta F, Castellani C, Bandettini R, Morelli P, Castagnola E

PMID: 31583970 [PubMed - as supplied by publisher]

Approaching two decades of cystic fibrosis research in Qatar: a historical perspective and future directions.

Multidiscip Respir Med. 2019;14:29

Authors: Hammoudeh S, Gadelhak W, AbdulWahab A, Al-Langawi M, Janahi IA

Abstract
Cystic fibrosis (CF) is a genetic disease caused by a defect of CF transmembrane conductance regulator (CFTR) gene. CF affects multiple systems, predominantly with respiratory involvement. In Qatar, researchers have been exploring various aspects of the disease for almost 20 years. PubMed and Google Scholar were reviewed for articles related to CF in Qatar. The first publication appeared in the year 2000. Since then, several studies have been conducted on CF patients in Qatar considering a variety of topics. The presence of the CFTR I1234V mutation in a certain Arab tribe stands out as a distinguishing characteristic of CF patients in Qatar when compared to the larger Arab region or even worldwide. We aim here to summarize the existing CF research conducted in Qatar over the years as well as to introduce topics for future research.

PMID: 31583102 [PubMed]

The renoprotective effect of concomitant fosfomycin in the treatment of pulmonary exacerbations in cystic fibrosis.

Clin Kidney J. 2019 Oct;12(5):652-658

Authors: Al-Aloul M, Nazareth D, Walshaw M

Abstract
Background: Fosfomycin, effective in Cystic Fibrosis (CF), competes with aminoglycosides at renal binding sites and may therefore afford a renoprotective effect when used in combination therapy. We explored this by using markers of acute renal tubular damage [N-acetyl-β-d-glucose-aminidase (NAG), alanine amino-peptidase (AAP) and β2-microglobulin].
Methods: Using a prospective randomized crossover trial design, at an acute pulmonary exacerbation, 18 adult CF patients received either 14 days of intravenous (IV) tobramycin or IV tobramycin and IV fosfomycin, both in combination with a second IV antibiotic (colomycin).
Results: Urinary NAG (P = 0.003) and AAP (P = 0.03) following treatment with concomitant fosfomycin were lower than those after treatment with tobramycin and colomycin alone. Fosfomycin attenuated the total 24-h urinary protein leak (P = 0.0001). The 14-day improvements in all surrogate markers of exacerbation resolution (FEV1% predicted, FVC, white cell count and C-reactive protein) were similar for both treatment regimens.
Conclusion: The addition of fosfomycin reduces acute renal injury caused by IV aminoglycoside therapy in CF pulmonary exacerbations.

PMID: 31583092 [PubMed]

Adiponectin Expression Is Modulated by Long-Term Physical Activity in Adult Patients Affected by Cystic Fibrosis.

Mediators Inflamm. 2019;2019:2153934

Authors: Polito R, Nigro E, Elce A, Monaco ML, Iacotucci P, Carnovale V, Comegna M, Gelzo M, Zarrilli F, Corso G, Castaldo G, Daniele A

Abstract
Cystic fibrosis (CF) is a genetic disease characterized by progressive decline of lung function and chronic airway inflammation. Adipose tissue, through adiponectin and leptin, exerts several effects on energy metabolism and inflammatory processes. This study evaluated the levels of adiponectin and leptin in adult healthy subjects, in patients with CF and their correlation with long-term physical activity. CF patients were divided into two groups (sedentary versus active) based on their regular physical activity over 3 years. Anthropometric and serum biochemical profiles of CF patients and controls were evaluated and compared. Total serum adiponectin and leptin levels were measured by ELISA; adiponectin oligomeric profiles were analysed by western blot. Adiponectin levels were significantly higher while leptin levels were lower in patients with CF than in healthy controls. Furthermore, adiponectin was significantly lower in active compared to sedentary CF (p = 0.047), while leptin was slightly increased in active compared to sedentary CF. In addition, C-reactive protein levels were significantly lower in active than in sedentary CF patients (p = 0.048). Interestingly, only in the active group adiponectin levels were inversely correlated with forced expiratory volume (FEV) 1% decrease/year and FEV1% decrease. Moreover, adiponectin levels negatively correlated with lipid profiles. Our findings indicated that regular, long-term physical activity in CF improves respiratory function, metabolism, and inflammation status. These improvements in patients' conditions are associated with immunometabolic processes involving adiponectin, leptin, and C-reactive protein. Therefore, we propose that both adipokines may be a useful biomarker in the evaluation of metabolic and inflammatory status in patients with CF.

PMID: 31582896 [PubMed - in process]

Of Slide Rules and Stethoscopes: AI and the Future of Doctoring.

Hastings Cent Rep. 2019 Sep;49(5):3

Authors: Truog RD

Abstract
Historically, the practice of medicine has been a physically intimate endeavor. Physicians have used their hands to palpate and reveal the secrets hidden within the body. Smelling the breath for the ketosis of diabetes or tasting the skin for the saltiness of cystic fibrosis were among the physician's essential practices. Today, perhaps the most defining characteristic of a brilliant clinician is the ability to synthesize many images-from electrocardiograms, ultrasounds, CT scans, and so forth-into a coherent picture that can guide our diagnosis and treatment. Yet this is rapidly becoming a Sisyphean task. Just as we are about to drown in a deluge of data, AI is throwing us a life preserver, to save not only our patients but ourselves. But where will AI take us?

PMID: 31581326 [PubMed - in process]

Increased expression of anion transporter SLC26A9 delays diabetes onset in cystic fibrosis.

J Clin Invest. 2019 Oct 03;:

Authors: Lam AN, Aksit MA, Vecchio-Pagan B, Shelton CA, Osorio DL, Anzmann AF, Goff LA, Whitcomb DC, Blackman SM, Cutting GR

Abstract
Diabetes is a common complication of cystic fibrosis (CF) that affects approximately 20% of adolescents and 40% to 50% of adults with CF. The age-at-onset of CF-related diabetes (marked by clinical diagnosis and treatment initiation) is an important measure of the disease process. DNA variants associated with age-at-onset of CFRD reside in and near SLC26A9. Deep sequencing of the SLC26A9 gene in 762 individuals with CF revealed that two common DNA haplotypes formed by the risk variants account for the association with diabetes (high risk, P-value: 4.34E-3; low risk, P-value: 1.14E-3). Single-cell RNA (scRNA) sequencing indicated that SLC26A9 is predominantly expressed in pancreatic ductal cells, and frequently co-expressed with CFTR along with transcription factors that have binding sites 5' of SLC26A9. These findings replicated upon re-analysis of scRNA data from 4 independent studies. DNA fragments derived from the 5' region of SLC26A9 bearing variants from the low risk haplotype generated 12% to 20% higher levels of expression in PANC-1 and CFPAC-1 cells compared to the high risk haplotype (P-values: 2.00E-3 to 5.15E-9). Taken together, our findings indicate that an increase in SLC26A9 expression in ductal cells of the pancreas delays the age-at-onset of diabetes, thereby suggesting a CFTR-agnostic treatment for a major complication of CF.

PMID: 31581148 [PubMed - as supplied by publisher]

Antioxidant supplementation for lung disease in cystic fibrosis.

Cochrane Database Syst Rev. 2019 Oct 03;10:CD007020

Authors: Ciofu O, Smith S, Lykkesfeldt J

Abstract
BACKGROUND: Airway infection leads to progressive damage of the lungs in cystic fibrosis (CF) and oxidative stress has been implicated in the etiology. Supplementation of antioxidant micronutrients (vitamin E, vitamin C, beta-carotene and selenium) or N-acetylcysteine (NAC) as a source of glutathione, may therefore potentially help maintain an oxidant-antioxidant balance. Glutathione or NAC can also be inhaled and if administered in this way can also have a mucolytic effect besides the antioxidant effect. Current literature suggests a relationship between oxidative status and lung function. This is an update of a previously published review.
OBJECTIVES: To synthesise existing knowledge on the effect of antioxidants such as vitamin C, vitamin E, beta-carotene, selenium and glutathione (or NAC as precursor of glutathione) on lung function through inflammatory and oxidative stress markers in people with CF.
SEARCH METHODS: The Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register and PubMed were searched using detailed search strategies. We contacted authors of included studies and checked reference lists of these studies for additional, potentially relevant studies. We also searched online trials registries.Last search of Cystic Fibrosis Trials Register: 08 January 2019.
SELECTION CRITERIA: Randomised and quasi-randomised controlled studies comparing antioxidants as listed above (individually or in combination) in more than a single administration to placebo or standard care in people with CF.
DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, extracted data and assessed the risk of bias in the included studies. We contacted study investigators to obtain missing information. If meta-analysed, studies were subgrouped according to supplement, method of administration and the duration of supplementation. We assessed the quality of the evidence using GRADE.
MAIN RESULTS: One quasi-randomised and 19 randomised controlled studies (924 children and adults) were included; 16 studies (n = 639) analysed oral antioxidant supplementation and four analysed inhaled supplements (n = 285). Only one of the 20 included studies was judged to be free of bias.Oral supplements versus controlThe change from baseline in forced expiratory volume in one second (FEV1) % predicted at three months and six months was only reported for the comparison of NAC to control. Four studies (125 participants) reported at three months; we are uncertain whether NAC improved FEV1 % predicted as the quality of the evidence was very low, mean difference (MD) 2.83% (95% confidence interval (CI) -2.16 to 7.83). However, at six months two studies (109 participants) showed that NAC probably increased FEV1 % predicted from baseline (moderate-quality evidence), MD 4.38% (95% CI 0.89 to 7.87). A study of a combined vitamin and selenium supplement (46 participants) reported a greater change from baseline in FEV1 % predicted in the control group at two months, MD -4.30% (95% CI -5.64 to -2.96). One study (61 participants) found that NAC probably makes little or no difference in the change from baseline in quality of life (QoL) at six months (moderate-quality evidence), standardised mean difference (SMD) -0.03 (95% CI -0.53 to 0.47), but the two-month combined vitamin and selenium study reported a small difference in QoL in favour of the control group, SMD -0.66 (95% CI -1.26 to -0.07). The NAC study reported on the change from baseline in body mass index (BMI) (62 participants) and similarly found that NAC probably made no difference between groups (moderate-quality evidence). One study (69 participants) found that a mixed vitamin and mineral supplement may lead to a slightly lower risk of pulmonary exacerbation at six months than a multivitamin supplement (low-quality evidence). Nine studies (366 participants) provided information on adverse events, but did not find any clear and consistent evidence of differences between treatment or control groups with the quality of the evidence ranging from low to moderate. Studies of β-carotene and vitamin E consistently reported greater plasma levels of the respective antioxidants.Inhaled supplements versus controlTwo studies (258 participants) showed inhaled glutathione probably improves FEV1 % predicted at three months, MD 3.50% (95% CI 1.38 to 5.62), but not at six months compared to placebo, MD 2.30% (95% CI -0.12 to 4.71) (moderate-quality evidence). The same studies additionally reported an improvement in FEV1 L in the treated group compared to placebo at both three and six months. One study (153 participants) reported inhaled glutathione probably made little or no difference to the change in QoL from baseline, MD 0.80 (95% CI -1.63 to 3.23) (moderate-quality evidence). No study reported on the change from baseline in BMI at six months, but one study (16 participants) reported at two months and a further study (105 participants) at 12 months; neither study found any difference at either time point. One study (153 participants) reported no difference in the time to the first pulmonary exacerbation at six months. Two studies (223 participants) reported treatment may make little or no difference in adverse events (low-quality evidence), a further study (153 participants) reported that the number of serious adverse events were similar across groups.
AUTHORS' CONCLUSIONS: With regards to micronutrients, there does not appear to be a positive treatment effect of antioxidant micronutrients on clinical end-points; however, oral supplementation with glutathione showed some benefit to lung function and nutritional status. Based on the available evidence, inhaled and oral glutathione appear to improve lung function, while oral administration decreases oxidative stress; however, due to the very intensive antibiotic treatment and other concurrent treatments that people with CF take, the beneficial effect of antioxidants remains difficult to assess in those with chronic infection without a very large population sample and a long-term study period. Further studies, especially in very young children, using outcome measures such as lung clearance index and the bronchiectasis scores derived from chest scans, with improved focus on study design variables (such as dose levels and timing), and elucidating clear biological pathways by which oxidative stress is involved in CF, are necessary before a firm conclusion regarding effects of antioxidants supplementation can be drawn. The benefit of antioxidants in people with CF who receive CFTR modulators therapies should also be assessed in the future.

PMID: 31580490 [PubMed - as supplied by publisher]

Lying in Wait: Modeling the Control of Bacterial Infections via Antibiotic-Induced Proviruses.

mSystems. 2019 Oct 01;4(5):

Authors: Clifton SM, Kim T, Chandrashekhar JH, O'Toole GA, Rapti Z, Whitaker RJ

Abstract
Most bacteria and archaea are infected by latent viruses that change their physiology and responses to environmental stress. We use a population model of the bacterium-phage relationship to examine the role that latent phage play in the bacterial population over time in response to antibiotic treatment. We demonstrate that the stress induced by antibiotic administration, even if bacteria are resistant to killing by antibiotics, is sufficient to control the infection under certain conditions. This work expands the breadth of understanding of phage-antibiotic synergy to include both temperate and chronic viruses persisting in their latent form in bacterial populations.IMPORTANCE Antibiotic resistance is a growing concern for management of common bacterial infections. Here, we show that antibiotics can be effective at subinhibitory levels when bacteria carry latent phage. Our findings suggest that specific treatment strategies based on the identification of latent viruses in individual bacterial strains may be an effective personalized medicine approach to antibiotic stewardship.

PMID: 31575664 [PubMed]

Medical Deferred Action - Living on Borrowed Time.

N Engl J Med. 2019 Oct 02;:

Authors: Ganapathi L, Caldas A, Miranda J, Köhler JR, Visner G, Sawicki G

PMID: 31577869 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa Quorum Sensing Molecule Alters Skeletal Muscle Protein Homeostasis by Perturbing the Antioxidant Defense System.

MBio. 2019 Oct 01;10(5):

Authors: Bandyopadhaya A, Tzika AA, Rahme LG

Abstract
Skeletal muscle function is compromised in many illnesses, including chronic infections. The Pseudomonas aeruginosa quorum sensing (QS) signal, 2-amino acetophenone (2-AA), is produced during acute and chronic infections and excreted in human tissues, including the lungs of cystic fibrosis patients. We have shown that 2-AA facilitates pathogen persistence, likely via its ability to promote the formation of bacterial persister cells, and that it acts as an interkingdom immunomodulatory signal that epigenetically reprograms innate immune functions. Moreover, 2-AA compromises muscle contractility and impacts the expression of genes involved in reactive oxygen species (ROS) homeostasis in skeletal muscle and in mitochondrial functions. Here, we elucidate the molecular mechanisms of 2-AA's impairment of skeletal muscle function and ROS homeostasis. Murine in vivo and differentiated C2C12 myotube cell studies showed that 2-AA promotes ROS generation in skeletal muscle via the modulation of xanthine oxidase (XO) activity, NAD(P)H oxidase2 (NOX2) protein level, and the activity of antioxidant enzymes. ROS accumulation triggers the activity of AMP-activated protein kinase (AMPK), likely upstream of the observed locations of induction of ubiquitin ligases Muscle RING Finger 1 (MuRF1) and Muscle Atrophy F-box (MAFbx), and induces autophagy-related proteins. The protein-level perturbation in skeletal muscle of silent mating type information regulation 2 homolog 1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1), and uncoupling protein 3 (UCP3) is rescued by the antioxidant N-acetyl-l-cysteine (NAC). Together, these results unveil a novel form of action of a QS bacterial molecule and provide molecular insights into the 2-AA-mediated skeletal muscle dysfunction caused by P. aeruginosa IMPORTANCE Pseudomonas aeruginosa, a bacterium that is resistant to treatment, causes serious acute, persistent, and relapsing infections in humans. There is increasing evidence that bacterial excreted small molecules play a critical role during infection. We have shown that a quorum sensing (QS)-regulated excreted small molecule, 2-AA, which is abundantly produced by P. aeruginosa, promotes persistent infections, dampens host inflammation, and triggers mitochondrial dysfunction in skeletal muscle. QS is a cell-to-cell communication system utilized by bacteria to promote collective behaviors. The significance of our study in identifying a mechanism that leads to skeletal muscle dysfunction, via the action of a QS molecule, is that it may open new avenues in the control of muscle loss as a result of infection and sepsis. Given that QS is a common characteristic of prokaryotes, it is possible that 2-AA-like molecules promoting similar effects may exist in other pathogens.

PMID: 31575771 [PubMed - in process]

A Humanized Yeast Phenomic Model of Deoxycytidine Kinase to Predict Genetic Buffering of Nucleoside Analog Cytotoxicity.

Genes (Basel). 2019 Sep 30;10(10):

Authors: Santos SM, Icyuz M, Pound I, William D, Guo J, McKinney BA, Niederweis M, Rodgers J, Iv JLH

Abstract
Knowledge about synthetic lethality can be applied to enhance the efficacy of anticancer therapies in individual patients harboring genetic alterations in their cancer that specifically render it vulnerable. We investigated the potential for high-resolution phenomic analysis in yeast to predict such genetic vulnerabilities by systematic, comprehensive, and quantitative assessment of drug-gene interaction for gemcitabine and cytarabine, substrates of deoxycytidine kinase that have similar molecular structures yet distinct antitumor efficacy. Human deoxycytidine kinase (dCK) was conditionally expressed in the Saccharomyces cerevisiae genomic library of knockout and knockdown (YKO/KD) strains, to globally and quantitatively characterize differential drug-gene interaction for gemcitabine and cytarabine. Pathway enrichment analysis revealed that autophagy, histone modification, chromatin remodeling, and apoptosis-related processes influence gemcitabine specifically, while drug-gene interaction specific to cytarabine was less enriched in gene ontology. Processes having influence over both drugs were DNA repair and integrity checkpoints and vesicle transport and fusion. Non-gene ontology (GO)-enriched genes were also informative. Yeast phenomic and cancer cell line pharmacogenomics data were integrated to identify yeast-human homologs with correlated differential gene expression and drug efficacy, thus providing a unique resource to predict whether differential gene expression observed in cancer genetic profiles are causal in tumor-specific responses to cytotoxic agents.

PMID: 31575041 [PubMed - in process]

Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases 2017. An Official American Thoracic Society Workshop Report.

Am J Respir Cell Mol Biol. 2019 Oct;61(4):429-439

Authors: Ryan AL, Ikonomou L, Atarod S, Bölükbas DA, Collins J, Freishtat R, Hawkins F, Gilpin SE, Uhl FE, Uriarte JJ, Weiss DJ, Wagner DE

Abstract
The University of Vermont Larner College of Medicine, in collaboration with the National Heart, Lung, and Blood Institute (NHLBI), the Alpha-1 Foundation, the American Thoracic Society, the Cystic Fibrosis Foundation, the European Respiratory Society, the International Society for Cell & Gene Therapy, and the Pulmonary Fibrosis Foundation, convened a workshop titled "Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases" from July 24 through 27, 2017, at the University of Vermont, Burlington, Vermont. The conference objectives were to review and discuss current understanding of the following topics: 1) stem and progenitor cell biology and the role that they play in endogenous repair or as cell therapies after lung injury, 2) the emerging role of extracellular vesicles as potential therapies, 3) ex vivo bioengineering of lung and airway tissue, and 4) progress in induced pluripotent stem cell protocols for deriving lung cell types and applications in disease modeling. All of these topics are research areas in which significant and exciting progress has been made over the past few years. In addition, issues surrounding the ethics and regulation of cell therapies worldwide were discussed, with a special emphasis on combating the growing problem of unproven cell interventions being administered to patients with lung diseases. Finally, future research directions were discussed, and opportunities for both basic and translational research were identified.

PMID: 31573338 [PubMed - in process]

Efficacy and safety of oral sildenafil in cystic fibrosis children with mild to moderate lung disease.

Pediatr Pulmonol. 2019 Sep 30;:

Authors: Reisi M, Modaresi MR, Aghaii Z, Mirlohi SH, Rafiemanesh H, Azizi G, Sayedi SJ

Abstract
BACKGROUND: Airway inflammation due to chronic infection is the leading cause of respiratory failure and death in most of patients with cystic fibrosis (CF). There is some evidence about anti-inflammatory activity of phosphodiesterase inhibitors in adult patients with CF. This study was designed to evaluate the efficacy, safety, and tolerability of sildenafil (a phosphodiesterase inhibitor drug) in children with CF.
METHOD: This uncontrolled before-after study was conducted on 20 children with CF (mean age 14 ± 2.8 years, 50% male) with mild to moderate lung disease who were referred to CF clinic of Imam Hossein hospital in Isfahan, Iran. The patients received oral sildenafil (1 mg/kg p.o tid for 3 months). Changes in spirometric values, maximal exercise capacity, and patient-reported health by using the cystic fibrosis questionnaire-revised (CFQ-R) were evaluated before and after treatment.
RESULT: CFQ-R (69.54 ± 4.6 vs 76.90 ± 5.4; P < .001) and exercise duration (401 ± 45.6 vs 497 ± 60.1 second; P < .01) increased following sildenafil therapy. In contrast, the forced expiratory value (FEV1; 84.60 ± 13.67 vs 78.40 ± 12.95; P < .001) and FEF25-75 (77.80 ± 27.33 vs 69.20 ± 21.91; P = .004) showed significant decreases. However, the mean of FEV1 /forced vital capacity did not change significantly during the study (P = .682).
CONCLUSIONS: Although sildenafil can improve the quality of life and exercise capacities in CF children, it significantly decreases lung function. So, administration of this drug for CF children should be reconsidered.

PMID: 31571429 [PubMed - as supplied by publisher]

ABC Family Transporters.

Adv Exp Med Biol. 2019;1141:13-100

Authors: Liu X

Abstract
The transport of specific molecules across lipid membranes is an essential function of all living organisms. The processes are usually mediated by specific transporters. One of the largest transporter families is the ATP-binding cassette (ABC) family. More than 40 ABC transporters have been identified in human, which are divided into 7 subfamilies (ABCA to ABCG) based on their gene structure, amino acid sequence, domain organization, and phylogenetic analysis. Of them, at least 11 ABC transporters including P-glycoprotein (P-GP/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs), and breast cancer resistance protein (BCRP/ABCG2) are involved in multidrug resistance (MDR) development. These ABC transporters are expressed in various tissues such as the liver, intestine, kidney, and brain, playing important roles in absorption, distribution, and excretion of drugs. Some ABC transporters are also involved in diverse cellular processes such as maintenance of osmotic homeostasis, antigen processing, cell division, immunity, cholesterol, and lipid trafficking. Several human diseases such as cystic fibrosis, sitosterolemia, Tangier disease, intrahepatic cholestasis, and retinal degeneration are associated with mutations in corresponding transporters. This chapter will describe function and expression of several ABC transporters (such as P-GP, BCRP, and MRPs), their substrates and inhibitors, as well as their clinical significance.

PMID: 31571164 [PubMed - in process]

The C-terminal dimerization domain of the respiratory mucin MUC5B functions in mucin stability and intracellular packaging before secretion.

J Biol Chem. 2019 Sep 30;:

Authors: Ridley C, Lockhart-Cairns MP, Collins RF, Jowitt TA, Subramani DB, Kesimer M, Baldock C, Thornton DJ

Abstract
Mucin 5B (MUC5B) has an essential role in mucociliary clearance that protects the pulmonary airways. Accordingly, knowledge of MUC5B structure and its interactions with itself and other proteins is critical to better understand airway mucus biology and improve the management of lung diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). The role of an N-terminal multimerization domain in the supramolecular organization of MUC5B has been previously described, but less is known about its C-terminal dimerization domain. Here, using cryogenic electron microscopy (cryo-EM) and small-angle X-ray scattering (SAXS) analyses of recombinant disulfide-linked dimeric MUC5B dimerization domain we identified an asymmetric, elongated twisted structure, with a double globular base. We found that the dimerization domain is more resistant to disruption than the multimerization domain suggesting the twisted structure of the dimerization domain confers additional stability to MUC5B polymers. Size-exclusion chromatography-multi-angle light scattering (SEC-MALS), SPR-based biophysical analyses and microscale thermophoresis of the dimerization domain disclosed no further assembly, but did reveal reversible, calcium-dependent interactions between the dimerization and multimerization domains that were most active at acidic pH, suggesting that these domains have a role in MUC5B intragranular organization. In summary, our results suggest a role for the C-terminal dimerization domain of MUC5B in compaction of mucin chains during granular packaging via interactions with the N-terminal multimerization domain. Our findings further suggest that the less stable multimerization domain provides a potential target for mucin depolymerization to remove mucus plugs in COPD and other lung pathologies.

PMID: 31570524 [PubMed - as supplied by publisher]

Pharmacological reversal of renal cysts from secretion to absorption suggests a potential therapeutic strategy for managing polycystic kidney disease.

J Biol Chem. 2019 Sep 30;:

Authors: Yanda MK, Cha B, Cebotaru C, Cebotaru L

Abstract
Autosomal-dominant polycystic kidney disease (ADPKD) induces a secretory phenotype, resulting in multiple fluid-filled cysts. We have previously demonstrated that VX-809, a corrector of the cystic fibrosis transmembrane conductance regulator (CFTR), reduces cyst growth. Here, we show that in normal mice, CFTR is located within the cells and also at the apical and basolateral membranes. However, in polycystic kidney disease 1 (PKD1)-knockout mice, CFTR was located at the plasma membrane, consistent with its role in cAMP-dependent fluid secretion. In cystic mice, VX-809 treatment increased CFTR levels at the apical membrane and reduced its association with the endoplasmic reticulum. Surprisingly, VX-809 treatment significantly increased CFTR's co-localization with the basolateral membrane in cystic mice. Na+/H+ exchanger 3 (NHE3) is present in PKD1-knockout and normal mice and in proximal tubule-derived, cultured PKD1-knockout cells. VX-809 increased the expression, activity, and apical plasma membrane localization of NHE3. Co-localization of epithelial sodium channel (ENaC) with the plasma membrane was reduced in cysts in PKD1-knockout mice, consistent with an inability of the cysts to absorb fluid. Interestingly, in the cystic mice, VX-809 treatment increased ENaC levels at the apical plasma membrane consistent with fluid absorption. Thus, VX-809 treatment of pkd1-null mouse kidneys significantly affected CFTR, NHE3, and ENaC, altering the cyst phenotype from one poised toward fluid secretion toward one more favorable for absorption. VX-809 also altered the location of CFTR but not of NHE3 or ENaC in normal mice. Given that VX-809 administration is safe, it may have potential utility for treating patients with ADPKD.

PMID: 31570523 [PubMed - as supplied by publisher]

Bridging the Gap between Scientific Advancement and Real-World Application: Pediatric Genetic Counseling for Common Syndromes and Single-Gene Disorders.

Cold Spring Harb Perspect Med. 2019 Sep 30;:

Authors: McGlynn JA, Langfelder-Schwind E

Abstract
Screening and diagnostic testing for single-gene disorders and common syndromes in the pediatric setting frequently generate data that are challenging to interpret, and the ability to diagnose genetic conditions has outpaced the development of successful treatments or cures. Genetic testing is now integrated purposefully into a variety of primary and specialty care clinics, creating an increased requirement for genetic literacy among providers and patients, as well as a growing need to incorporate genetic counseling services into mainstream clinical practice. The practice of pediatric genetic counseling encompasses a unique combination of skills and training designed to address the evolving psychological, social, educational, medical, and reproductive concerns of patients and their families, which complements the multidisciplinary services of physicians, nurses, and other allied health professionals caring for patients with pediatric-onset genetic conditions. The potential range of genetic counseling needs in the pediatric setting transcends the diagnostic period. The sustained nature of pediatric care presents opportunities for development of trusting and longstanding professional relationships that permit the evolving genetic counseling needs of patients and families to be met. A discussion of cystic fibrosis, a common autosomal recessive single-gene disorder with an increasingly broad clinical spectrum and genotype-phenotype variability, serves as a useful case study to illustrate the current and emerging genetic counseling practices, goals, and challenges impacting patients and their families.

PMID: 31570386 [PubMed - as supplied by publisher]

Clinical care for cystic fibrosis: preparing for the future now.

Lancet Respir Med. 2019 Sep 27;:

Authors: Konstan MW, Flume PA

PMID: 31570320 [PubMed - as supplied by publisher]

Progress in understanding the molecular pathology and microbiology of cystic fibrosis.

Lancet Respir Med. 2019 Sep 27;:

Authors: Tümmler B

PMID: 31570319 [PubMed - as supplied by publisher]