Current Status and Future Opportunities in Lung Precision Medicine Research with a Focus on Biomarkers. An American Thoracic Society/National Heart, Lung, and Blood Institute Research Statement.

Am J Respir Crit Care Med. 2018 Dec 15;198(12):e116-e136

Authors: Wu AC, Kiley JP, Noel PJ, Amur S, Burchard EG, Clancy JP, Galanter J, Inada M, Jones TK, Kropski JA, Loyd JE, Nogee LM, Raby BA, Rogers AJ, Schwartz DA, Sin DD, Spira A, Weiss ST, Young LR, Himes BE

Abstract
BACKGROUND: Thousands of biomarker tests are either available or under development for lung diseases. In many cases, adoption of these tests into clinical practice is outpacing the generation and evaluation of sufficient data to determine clinical utility and ability to improve health outcomes. There is a need for a systematically organized report that provides guidance on how to understand and evaluate use of biomarker tests for lung diseases.
METHODS: We assembled a diverse group of clinicians and researchers from the American Thoracic Society and leaders from the National Heart, Lung, and Blood Institute with expertise in various aspects of precision medicine to review the current status of biomarker tests in lung diseases. Experts summarized existing biomarker tests that are available for lung cancer, pulmonary arterial hypertension, idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, sepsis, acute respiratory distress syndrome, cystic fibrosis, and other rare lung diseases. The group identified knowledge gaps that future research studies can address to efficiently translate biomarker tests into clinical practice, assess their cost-effectiveness, and ensure they apply to diverse, real-life populations.
RESULTS: We found that the status of biomarker tests in lung diseases is highly variable depending on the disease. Nevertheless, biomarker tests in lung diseases show great promise in improving clinical care. To efficiently translate biomarkers into tests used widely in clinical practice, researchers need to address specific clinical unmet needs, secure support for biomarker discovery efforts, conduct analytical and clinical validation studies, ensure tests have clinical utility, and facilitate appropriate adoption into routine clinical practice.
CONCLUSIONS: Although progress has been made toward implementation of precision medicine for lung diseases in clinical practice in certain settings, additional studies focused on addressing specific unmet clinical needs are required to evaluate the clinical utility of biomarkers; ensure their generalizability to diverse, real-life populations; and determine their cost-effectiveness.

PMID: 30640517 [PubMed - in process]

Transnasal Humidified Rapid-Insufflation Ventilatory Exchange for Deep Sedation in a Lung Transplant Candidate With Severe Cystic Fibrosis: A Case Report.

A A Pract. 2019 Jan 10;:

Authors: You-Ten KE, Zasso FB

Abstract
Transnasal humidified rapid-insufflation ventilatory exchange is a recently described technique for safer management of difficult airways and a novel ventilation technique under anesthesia. Its full potential in patient safety and benefits are still being investigated. We describe the use of transnasal humidified rapid-insufflation ventilatory exchange for deep sedation during dental extractions in a patient with severe cystic fibrosis as a precondition for lung transplantation. Patient wanted to have the procedure under general anesthesia with intubation due to extreme anxiety. However, we advocated deep IV sedation with transnasal humidified rapid-insufflation ventilatory exchange. Oxygenation was maintained without airway obstruction and pulmonary complications during the entire procedure of 110 minutes.

PMID: 30640278 [PubMed - as supplied by publisher]

Assessment of adherence and asthma medication ratio (AMR) for a once-daily and twice-daily inhaled corticosteroid/long acting beta agonist (ICS/LABA) for asthma.

J Allergy Clin Immunol Pract. 2019 Jan 09;:

Authors: Stanford RH, Averell C, Parker ED, Blauer-Peterson C, Reinsch TK, Buikema AR

Abstract
BACKGROUND: While efficacy and safety of fluticasone furoate/vilanterol (FF/VI) and budesonide/formoterol (BUD/F) have been demonstrated in clinical studies, real-world comparisons of utilization has not been performed.
OBJECTIVE: Compare similar asthma patients initiating FF/VI or BUD/F on measures of adherence, persistence, and the asthma medication ratio (AMR).
METHODS: This was a retrospective cohort study of commercial and Medicare Advantage with Part D enrollees initiating FF/VI or BUD/F for asthma. Adult patients (≥18 years), at least 15-months (12-months pre- and 3-months post-index) continuous enrollment, and ≥1 asthma diagnosis code were eligible for the study. Patients with a history of fixed-dose ICS/LABA and other respiratory disorders (COPD, cystic fibrosis, acute respiratory failure) in the baseline period were excluded. Propensity-score matching (PSM) was used to balance cohorts on baseline characteristics. Logistic regression and Cox-proportional hazard models were used to assess differences.
RESULTS: Total of 9,951 patients met all criteria. After PSM, 1,725 patients were matched in each cohort. Subjects that initiated FF/VI had significantly higher mean proportion of days covered (PDC) (p<0.001), had 86% greater odds of PDC≥0.80 (adjusted OR: 1.86; 95% CI:1.51-2.30), 26% lower risk of discontinuation (adjusted HR: 0.74, 95% CI: 0.69-0.79), and 36% greater odds of an AMR ≥0.50 (adjusted OR: 1.36, 95% CI: 1.23-1.50) compared with BUD/F.
CONCLUSIONS: Adherence and treatment persistence were low in both cohorts, however, patients initiating once-daily FF/VI were more likely to be adherent, have an AMR ≥0.5, and were less likely to discontinue therapy compared with patients initiating twice-daily BUD/F. (GSK Study HO1617302/206482).

PMID: 30639604 [PubMed - as supplied by publisher]

Defective CFTR promotes intestinal proliferation via inhibition of the hedgehog pathway during cystic fibrosis.

Cancer Lett. 2019 Jan 10;:

Authors: Liu K, Wang X, Zou C, Zhang J, Chen H, Tsang L, Yu MK, Chung YW, Wang J, Dai Y, Liu Y, Zhang X

Abstract
Hyperproliferation occurs in a variety of tissues and organs during cystic fibrosis (CF). However, the associated molecular mechanisms remain elusive. We investigated the molecular link between cystic fibrosis transmembrane conductance regulator (CFTR) defects and hyperproliferation, and showed that the length of the entire gastrointestinal tract was longer and the intestinal crypts were deeper in CF mice compared to those in wild-type animals. PCNA expression increased in CF mouse intestines and CFTR-knockdown cells. Villin1, an intestinal differentiation marker, was downregulated in CF mice. Ihh and Gli1 were significantly downregulated, whereas TCF4 was activated in CF mouse intestines and CFTR-knockdown Caco2 cells. Importantly, β-catenin activators rescued Gli1 suppression, suggesting that hedgehog signaling might be mediated by the Wnt/β-catenin pathway in the absence of functional CFTR. Moreover, PCNA positivity in the crypts of CF mice was alleviated by LiCl, which activates Wnt/β-catenin signaling. Further, a strong positive correlation was observed between the expression of CFTR and Ihh in intestines. Our study revealed a previously unidentified role of CFTR in regulating hedgehog signaling through β-catenin, providing novel insights into the physiological function of CFTR and CF-related diseases.

PMID: 30639531 [PubMed - as supplied by publisher]

Macrophage polarization: reaching across the aisle?

J Allergy Clin Immunol. 2019 Jan 08;:

Authors: Bosco MC

Abstract
Macrophage polarization may influence the pathogenesis of many human diseases; however the transcriptional program regulating this process remains poorly characterized. Gharib et al.1 highlight the high diversity of M1-to-M2 re-polarization exerted by distinct M2 stimuli via transcriptome-based pathway analysis and provide a new approach to phenotype human macrophages in clinically relevant disease states such as cystic fibrosis and asthma.

PMID: 30639344 [PubMed - as supplied by publisher]

Systemic levels of anti-PAD4 autoantibodies correlate with airway obstruction in cystic fibrosis.

J Cyst Fibros. 2019 Jan 09;:

Authors: Yadav R, Yoo DG, Kahlenberg JM, Bridges SL, Oni O, Huang H, Stecenko A, Rada B

Abstract
Cystic fibrosis (CF) airway disease is characterized by the long-term presence of neutrophil granulocytes. Formation of neutrophil extracellular traps (NETs) and/or autoantibodies directed against extracellular components of NETs are possible contributors to neutrophil-mediated lung damage in CF. The goal of this study was to measure their levels in CF adults compared to healthy controls and subjects with rheumatologic diseases known to develop NET-related autoantibodies and pathologies, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Sera were analyzed from the following number of subjects: 37 CF, 23 healthy controls (HC), 20 RA, and 21 SLE. CF had elevated serum myeloperoxidase (MPO) concentrations (347.5±56.1 ng/ml, mean+/-S.E.M., p = .0132) compared to HC (144.5±14.6 ng/ml) but not of neutrophil elastase (NE) complexed with alpha-1-antitrypsin, cell-free DNA or NE-DNA complexes. The peptidylarginine deiminase 4 (PAD4) enzyme is required for NET formation and associated DNA release in neutrophils. Serum levels of anti-PAD4 antibodies (Ab) were elevated in CF (p = .0147) compared to HC and showed an inverse correlation with a measure of lung function, FEV1% predicted (r = -0.5020, p = .015), as did MPO levels (r = -0.4801, p = .0026). Anti-PAD4 Ab levels in CF sera associated with lung infection by P. aeruginosa, but not that by S. aureus, age, sex, CF-related diabetes or the presence of musculoskeletal pain. Serum levels of anti-citrullinated protein Abs (ACPAs) and anti-nucleosome Abs were not elevated in CF compared to HC (p = .7498, p = .0678). In summary, adult CF subjects develop an autoimmune response against NET components that correlates with worsening lung disease.

PMID: 30638826 [PubMed - as supplied by publisher]

High airborne level of Aspergillus fumigatus and presence of azole-resistant TR34/L98H isolates in the home of a cystic fibrosis patient harbouring chronic colonisation with azole-resistant H285Y A. fumigatus.

J Cyst Fibros. 2019 Jan 09;:

Authors: Paluch M, Lejeune S, Hecquet E, Prévotat A, Deschildre A, Fréalle E

Abstract
Azole-resistant Aspergillus fumigatus (ARAF) has been reported in the domestic environment of patients at risk for aspergillosis. Here, we assessed the mother's and father's homes of an 18-year-old cystic fibrosis patient harbouring chronic colonisation with H285Y CYP51A azole-resistant isolate, in order to explore the link between environmental exposure and ARAF infection. In one dwelling, a very high overall contamination level was found (710-7.240 CFU/m3), with a predominance of A. fumigatus (640-6.490 CFU/m3), and ARAF showing the TR34/L98H mutation was isolated. Mycological follow-up of the patient showed the persistence of H285Y isolates, but no acquisition of TR34/L98H isolates was observed. This could be due to the low proportion of TR34/L98H isolates (<3%), or the establishment of preventative measures and dwelling remediation taken after the environmental investigation. Our data underlines the value of an environmental assessment to establish preventative measures and limit the risk of A. fumigatus exposure and ARAF acquisition.

PMID: 30638825 [PubMed - as supplied by publisher]

A EAACI Drug Allergy Interest Group survey on how European allergy specialists deal with β-lactam allergy.

Allergy. 2019 Jan 14;:

Authors: Torres MJ, Celik G, Whitaker P, Atanaskovic-Markovic M, Barbaud A, Bircher A, Blanca M, Brockow K, Caubet JC, Cernadas J, Chiriac A, Demoly P, Garvey LH, Merk H, Mosbech H, Nakonechna A, Romano A

Abstract
An accurate diagnosis of β-lactam (BL) allergy can reduce patient morbidity and mortality. Our aim is to investigate the availability of BL reagents, their use, and test procedures in different parts of Europe, as well as any differences in the diagnostic workups for evaluating subjects with BL hypersensitivity. A survey was emailed to all members of the EAACI Drug Allergy Interest Group (DAIG) between February-April 2016, the questionnaire was meant to study the management of suspected BL hypersensitivity.The questionnaire was emailed to 82 DAIG centres and answered by 57. Amoxicillin alone or combined to clavulanic acid the most commonly involved BL except in the Danish centre, where penicillin V was the most frequently suspected BL. All centres performed an allergy workup in subjects with histories of hypersensitivity to BL; 53 centres (93%) followed DAIG guidelines, 2 national guidelines, and 2 local guidelines. However, there were deviations from DAIG recommendations concerning allergy tests, especially drug provocation tests. A significant heterogeneity exists in current practice not only among countries, but also among centres within the same country. This suggests the need to re-evaluate, update, and standardise protocols on the management of patients with suspected BL allergy. This article is protected by copyright. All rights reserved.

PMID: 30637768 [PubMed - as supplied by publisher]

Increasing Wellness Through Physical Activity in Children With Chronic Disease and Disability.

Curr Sports Med Rep. 2018 Dec;17(12):425-432

Authors: Coleman N, Nemeth BA, LeBlanc CMA

Abstract
Children with chronic medical conditions face many challenges when considering sport participation. Compared with their healthy counterparts, they are often discouraged from physical activity or sports participation because of real or perceived limitations imposed by their condition. Prescribed exercise should be based on the demands of the sport, the effect of the disease on performance, and the potential for exercise-induced acute or chronic worsening of the illness or disability. This article will focus on several examples of chronic medical conditions and the clinician's role in providing advice about sport participation.

PMID: 30531459 [PubMed - indexed for MEDLINE]

Dynamic changes in nitric oxide synthase expression are involved in seawater acclimation of rainbow trout Oncorhynchus mykiss.

Am J Physiol Regul Integr Comp Physiol. 2018 04 01;314(4):R552-R562

Authors: Gerber L, Jensen FB, Madsen SS

Abstract
Recent research has shown that nitric oxide (NO) produced by nitric oxide synthases (NOS) is an inhibitor of ion transporter activity and a modulator of epithelial ion transport in fish, but little is known on changes in the NOS/NO system during osmotic stress. We hypothesized that the NOS/NO system responds to salinity changes as an integrated part of the acclimation process. Expression and localization of nos1/Nos1 and nos2/Nos2 were investigated in gill, kidney, and intestine of freshwater (FW)- and seawater (SW)-transferred trout using quantitative PCR, Western blotting, and immunohistochemistry, along with expressional changes of major ion transporters in the gill. The classical branchial ion transporters showed expected expressional changes upon SW transfer, there among a rapid decrease in Slc26a6 mRNA, coding a branchial Cl-/[Formula: see text] exchanger. There was a major downregulation of nos1/ nos2/Nos2 expression in the gill during SW acclimation. A significant decrease in plasma nitrite supported an overall decreased Nos activity and NO production. In the middle intestine, Nos1 was upregulated during SW acclimation, whereas no changes in nos/Nos expression were observed in the posterior intestine and the kidney. Nos1 was localized along the longitudinal axis of the gill filament, beneath smooth muscle fibers of the intestine wall and in blood vessel walls of the kidney. Nos2 was localized within the epithelium adjacent to the gill filament axis and in hematopoietic tissues of the kidney. We conclude that downregulation of branchial NOS is integrated to the SW acclimation process likely to avoid the inhibitory effects of NO on active ion extrusion.

PMID: 29351430 [PubMed - indexed for MEDLINE]

Protein stability and degradation in health and disease.

Adv Protein Chem Struct Biol. 2019;114:61-83

Authors: Clausen L, Abildgaard AB, Gersing SK, Stein A, Lindorff-Larsen K, Hartmann-Petersen R

Abstract
The cellular proteome performs highly varied functions to sustain life. Since most of these functions require proteins to fold properly, they can be impaired by mutations that affect protein structure, leading to diseases such as Alzheimer's disease, cystic fibrosis, and Lynch syndrome. The cell has evolved an intricate protein quality control (PQC) system that includes degradation pathways and a multitude of molecular chaperones and co-chaperones, all working together to catalyze the refolding or removal of aberrant proteins. Thus, the PQC system limits the harmful consequences of dysfunctional proteins, including those arising from disease-causing mutations. This complex system is still not fully understood. In particular the structural and sequence motifs that, when exposed, trigger degradation of misfolded proteins are currently under investigation. Moreover, several attempts are being made to activate or inhibit parts of the PQC system as a treatment for diseases. Here, we briefly review the present knowledge on the PQC system and list current strategies that are employed to exploit the system in disease treatment.

PMID: 30635086 [PubMed - in process]

Activated PMN Exosomes: Pathogenic Entities Causing Matrix Destruction and Disease in the Lung.

Cell. 2019 Jan 10;176(1-2):113-126.e15

Authors: Genschmer KR, Russell DW, Lal C, Szul T, Bratcher PE, Noerager BD, Abdul Roda M, Xu X, Rezonzew G, Viera L, Dobosh BS, Margaroli C, Abdalla TH, King RW, McNicholas CM, Wells JM, Dransfield MT, Tirouvanziam R, Gaggar A, Blalock JE

Abstract
Here, we describe a novel pathogenic entity, the activated PMN (polymorphonuclear leukocyte, i.e., neutrophil)-derived exosome. These CD63+/CD66b+ nanovesicles acquire surface-bound neutrophil elastase (NE) during PMN degranulation, NE being oriented in a configuration resistant to α1-antitrypsin (α1AT). These exosomes bind and degrade extracellular matrix (ECM) via the integrin Mac-1 and NE, respectively, causing the hallmarks of chronic obstructive pulmonary disease (COPD). Due to both ECM targeting and α1AT resistance, exosomal NE is far more potent than free NE. Importantly, such PMN-derived exosomes exist in clinical specimens from subjects with COPD but not healthy controls and are capable of transferring a COPD-like phenotype from humans to mice in an NE-driven manner. Similar findings were observed for another neutrophil-driven disease of ECM remodeling (bronchopulmonary dysplasia [BPD]). These findings reveal an unappreciated role for exosomes in the pathogenesis of disorders of ECM homeostasis such as COPD and BPD, providing a critical mechanism for proteolytic damage.

PMID: 30633902 [PubMed - in process]

Widespread alterations of the peripheral blood innate immune cell profile in cystic fibrosis reflect lung pathology and may inform patient management.

Immunol Cell Biol. 2019 Jan 11;:

Authors: Mulcahy EM, Cooley MA, McGuire H, Asad S, Fazekas de St Groth B, Beggs SA, Roddam LF

Abstract
Cystic fibrosis (CF) is caused by mutations to the CF transmembrane conductance regulator (CFTR) gene. The CFTR is known to be expressed on multiple immune cell subtypes, dendritic cells (DCs), monocytes/macrophages, neutrophils and lymphocytes. We hypothesised that lack of CFTR expression on peripheral blood innate immune cells would result in an altered cell profile in the periphery and that this profile would reflect lung pathology. We performed a flow cytometric phenotypic investigation of innate immune cell proportions in peripheral blood collected from 17 CF patients and 15 age-matched healthy controls. We observed significant differences between CF patients and controls in the relative proportions of NK cells, monocytes and their subsets, with significant correlations observed between proportions of NK and monocyte cell subsets and lung function (FEV1% predicted) in CF patients. This study demonstrates the widespread nature of immune dysregulation in CF and provides a basis for identification of potential therapeutic targets. Modulation of the distinct CF-related immune cell phenotype identified could also be an important biomarker for evaluating CFTR-targeted drug efficacy. This article is protected by copyright. All rights reserved.

PMID: 30633378 [PubMed - as supplied by publisher]

Transient Exocrine Pancreatic Insufficiency in Children: An Existing Entity?

J Pediatr Gastroenterol Nutr. 2019 Jan 08;:

Authors: Garah J, Rosen I, Shaoul R

Abstract
OBJECTIVES: Pancreatic insufficiency in children is usually associated with diseases such as cystic fibrosis, Shwachman-Diamond syndrome, or chronic pancreatitis. Fecal elastase-1 is a reliable laboratory test for the diagnosis of exocrine pancreatic insufficiency (EPI). Transient pancreatic insufficiency has been rarely described and data on this entity are lacking in the medical literature. In this retrospective study we report 17 cases of transient pancreatic insufficiency presented mainly with failure to thrive and/or diarrhea.
METHODS: We followed 43 children (age range 1 month-18 years) with low fecal elastase-1 in our institution between the years 2009 and 2017. We followed growth and laboratory results (particularly, complete blood count, albumin, transaminases, celiac serology, sweat test, and fat-soluble vitamins). Elastase levels <200 mg/g were considered as pancreatic insufficiency.
RESULTS: Twenty-six were excluded due to missing data, a comorbidity or being syndromatic. Enrolled children (17) were all otherwise healthy.The median age at diagnosis was 3 years (range 0.2-15 years), 11 girls and 6 boys. Their main presenting symptoms were failure to thrive and/or diarrhea. Median fecal elastase-1 levels were 71 mg/g (range 18-160). Median time for normalization was 6 months (range 1-48 months). Abdominal sonography, celiac serology, and sweat test were normal for all patients. Most patients were treated with pancreatic enzymes until resolution.
CONCLUSIONS: Transient EPI without clear etiology should be in the differential diagnosis of EPI after ruling out known etiologies. The resolving course pattern may be attributed to an unidentified infectious agent. Further studies to assess the etiology are mandated.

PMID: 30633105 [PubMed - as supplied by publisher]

Transcriptional profiling of Pseudomonas aeruginosa and Staphylococcus aureus during in vitro co-culture.

BMC Genomics. 2019 Jan 10;20(1):30

Authors: Tognon M, Köhler T, Luscher A, van Delden C

Abstract
BACKGROUND: Co-colonization by Pseudomonas aeruginosa and Staphylococcus aureus is frequent in cystic fibrosis patients. Polymicrobial infections involve both detrimental and beneficial interactions between different bacterial species. Such interactions potentially indirectly impact the human host through virulence, antibiosis and immunomodulation.
RESULTS: Here we explored the responses triggered by the encounter of these two pathogens to identify early processes that are important for survival when facing a potential competitor. Transcriptional profiles of both bacteria were obtained after 3 h co-culture and compared to the respective mono-culture using RNAseq. Global responses in both bacteria included competition for nitrogen sources, amino acids and increased tRNA levels. Both organisms also induced lysogenic mechanisms related to prophage induction (S. aureus) and R- and F- pyocin synthesis (P. aeruginosa), possibly as a response to stress resulting from nutrient limitation or cell damage. Specific responses in S. aureus included increased expression of de novo and salvation pathways for purine and pyrimidine synthesis, a switch to glucose fermentation, and decreased expression of major virulence factors and global regulators.
CONCLUSIONS: Taken together, transcriptomic data indicate that early responses between P. aeruginosa and S. aureus involve competition for resources and metabolic adaptations, rather than the expression of bacteria- or host-directed virulence factors.

PMID: 30630428 [PubMed - in process]

Case 40-2018: A 47-Year-Old Woman with Recurrent Sinusitis, Cough, and Bronchiectasis.

N Engl J Med. 2018 Dec 27;379(26):2558-2565

Authors: Mojica JE, Richards CJ, Husseini JS, Hariri LP

PMID: 30586519 [PubMed - indexed for MEDLINE]

The respiratory delivery of high dose dry powders.

Int J Pharm. 2018 Oct 25;550(1-2):486-487

Authors: Das SC, Stewart PJ, Tucker IG

PMID: 30245068 [PubMed - indexed for MEDLINE]

A Comparison between Two Pathophysiologically Different yet Microbiologically Similar Lung Diseases: Cystic Fibrosis and Chronic Obstructive Pulmonary Disease.

Int J Respir Pulm Med. 2018;5(2):

Authors: Fenker DE, McDaniel CT, Panmanee W, Panos RJ, Sorscher EJ, Sabusap C, Clancy JP, Hassett DJ

Abstract
Cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) are chronic pulmonary diseases that affect ~70,000 and 251 million individuals worldwide, respectively. Although these two diseases have distinctly different pathophysiologies, both cause chronic respiratory insufficiency that erodes quality of life and causes significant morbidity and eventually death. In both CF and COPD, the respiratory microbiome plays a major contributing role in disease progression and morbidity. Pulmonary pathogens can differ dramatically during various stages of each disease and frequently cause acute worsening of lung function due to disease exacerbation. Despite some similarities, outcome and timing/type of exacerbation can also be quite different between CF and COPD. Given these clinical distinctions, both patients and physicians should be aware of emerging therapeutic options currently being offered or in development for the treatment of lung infections in individuals with CF and COPD. Although interventions are available that prolong life and mitigate morbidity, neither disorder is curable. Both acute and chronic pulmonary infections contribute to an inexorable downward course and may trigger exacerbations, culminating in loss of lung function or respiratory failure. Knowledge of the pulmonary pathogens causing these infections, their clinical presentation, consequences, and management are, therefore, critical. In this review, we compare and contrast CF and COPD, including underlying causes, general outcomes, features of the lung microbiome, and potential treatment strategies.

PMID: 30627668 [PubMed]

Reappraisal of Frequency of Common Cystic Fibrosis Transmembrane Conductance Regulator Gene Mutations in Iranian Cystic Fibrosis Patients.

Tanaffos. 2018 Feb;17(2):73-81

Authors: Khalilzadeh S, Hassanzad M, PourAbdollah Toutkaboni M, Tashayoie Nejad S, Sheikholeslami FM, Velayati AA

Abstract
Background: Cystic Fibrosis (CF) is a life-threatening recessive genetic disorder resulting from mutations in the gene encoding the fibrosis transmembrane conductance regulator protein (CFTR). The CF clinical phenotype shows wide variation ranging from severe disease in early childhood in those homozygous for the p.Phe508del mutation to absence of the vas deferens in otherwise healthy men homozygous for the p.Arg117His mutation.
Materials and Methods: DNA was extracted from whole blood from 62 patients with CF. The CFTR mutation was determined by Allele-Specific PCR assay. The spearman and linear regression analysis were used to obtain the correlation between phenotype and genotype relationship.
Results: Out of total 62 patients, 35 (56.4%) were male. The mean age of the patients was 15.56 ± 6.65 years. Mutations in CFTR were detected in 64.5% of the patients. The commonest mutations were p.Phe508del (33.9%), p.Arg117His; [5T] (5.64%), p.Arg117His; [7T] (4.03%) and p.Trp1282X (5.64%). Mutations p.Ile507del (4%), p.Gly542X (4%), p.Asn1303Lys (2.42%), c.489+1G>T (1.6%), p.Gly551Asp (1.6%) and c.1585-1G>A (1.6%) were also detected. Most mutations were detected in west and south of Iran, while p.Phe508del mutation was dominant mutation (75%) in east and southeast of Iran. The study showed either an association between this mutation with severity of disease and sex or an association between p.Arg117His mutations and age at diagnosis.
Conclusion: The geographic distribution of gene mutation in Iranian cystic fibrosis patients was very heterogenic. In spite of the study that showed a correlation between p.Phe508del and severity of disease, to find any correlation between genotype and phenotype a broad and multi-centered study is recommended.

PMID: 30627177 [PubMed]

Immunologic Role of Extracellular Vesicles and Exosomes in the Pathogenesis of Cystic Fibrosis.

Tanaffos. 2018 Feb;17(2):66-72

Authors: Asef A, Mortaz E, Jamaati H, Velayati A

Abstract
Cystic Fibrosis (CF) is the most common lethal autosomal recessive disease that affects many organs including, lung, pancreas and liver. Cystic fibrosis is a monogenic disease and occurs in the white Caucasians. Massive neutrophil granulocyte influx in the airways is one of the characteristics of CF. Extracellular Vesicles (EVs), microvesicles, and exosomes are vesicles released from cells into extracellular space of the body and are able to influence other cells by different methods. They have an important role in the intracellular communication by transferring information between donor and recipients cells. Granulocytes are known as the main source of microparticles in the CF patients. Microparticles derived from neutrophils are associated with the extensive neutrophil influx into airways and aggregation at the epithelial surface of the CF patient's respiratory tract. Exosomes are found in almost all body fluids, such as urine, sputum, Bronchoalveolar Lavage (BAL), milk, Cerebrospinal Fluid (CSF), plasma and sputum. Examination of exosomes derived from CF patients may be helpful in the characterization of pathogenesis of disease in detail. In this mini review, we have summarized the role of microparticles and exosomes in pathogenesis of CF and finally discussed the feasibility of this particle in treatment approaches.

PMID: 30627176 [PubMed]