Cystic Fibrosis
Functional correction of CFTR mutations in human airway epithelial cells using adenine base editors
Nucleic Acids Res. 2021 Sep 14:gkab788. doi: 10.1093/nar/gkab788. Online ahead of print.
ABSTRACT
Mutations in the CFTR gene that lead to premature stop codons or splicing defects cause cystic fibrosis (CF) and are not amenable to treatment by small-molecule modulators. Here, we investigate the use of adenine base editor (ABE) ribonucleoproteins (RNPs) that convert A•T to G•C base pairs as a therapeutic strategy for three CF-causing mutations. Using ABE RNPs, we corrected in human airway epithelial cells premature stop codon mutations (R553X and W1282X) and a splice-site mutation (3849 + 10 kb C > T). Following ABE delivery, DNA sequencing revealed correction of these pathogenic mutations at efficiencies that reached 38-82% with minimal bystander edits or indels. This range of editing was sufficient to attain functional correction of CFTR-dependent anion channel activity in primary epithelial cells from CF patients and in a CF patient-derived cell line. These results demonstrate the utility of base editor RNPs to repair CFTR mutations that are not currently treatable with approved therapeutics.
PMID:34520545 | DOI:10.1093/nar/gkab788
Gender differences in non-cystic fibrosis bronchiectasis severity and bacterial load: the potential role of hormones
Ther Adv Respir Dis. 2021 Jan-Dec;15:17534666211035311. doi: 10.1177/17534666211035311.
ABSTRACT
Non cystic-fibrosis bronchiectasis (NCFB) is a complex chronic respiratory disease, characterised by excessive sputum production and abnormal permanent dilation of bronchi. Mucus accumulation leads to recurrent bacterial infections and increased bacterial load, causing vicious cycles of structural damage and decreased lung function. Respiratory physiotherapy management of NCFB includes airway clearance techniques and use of nebulised, hypertonic saline. Despite advances in treatment, a consistent relationship has been observed between gender and disease occurrence, with a higher prevalence amongst females. Furthermore, NCFB presents most aggressively amongst post-menopausal females, a group likely exposed to higher levels of progesterone (P4) over a longer period of time. The effects of gender-specific hormones on bacterial load and physiotherapy management of people living with NCFB remain unknown. The aim of this narrative review was to discuss the potential influence of gender specific hormones on NCFB disease progression and influence on physiotherapy, medical management and future research. SCOPUS and PUBMED electronic databases were used to conduct searches for relevant studies using specific inclusion and exclusion criteria. Secondary inclusion of relevant literature was obtained from primary paper references. Previous literature suggests that P4 may impair Cilia Beat Frequency (CBF) in airway epithelium. Reduction in CBF may further reduce ability to expectorate amongst individuals with NCFB, increasing bacterial load and likelihood of exacerbations, negatively impacting on disease progression. Furthermore, coadministration of Estrogen has been suggested to offer opposing effects to that of P4 only. These findings question whether hormonal levels may be monitored, controlled and optimised within management and treatment of females with NCFB to improve airway clearance, reduce exacerbations and improve quality of life. Larger scale, long-term trials are required to further explore the effects of gender specific hormones on NCFB and the viability of treatment with hormone replacement therapy.The reviews of this paper are available via the supplemental material section.
PMID:34520299 | DOI:10.1177/17534666211035311
Correction to "Discovery of GLPG2451, a Novel Once Daily Potentiator for the Treatment of Cystic Fibrosis"
J Med Chem. 2021 Sep 14. doi: 10.1021/acs.jmedchem.1c01537. Online ahead of print.
NO ABSTRACT
PMID:34520202 | DOI:10.1021/acs.jmedchem.1c01537
Mucolytic bacteria: prevalence in various pathological diseases
World J Microbiol Biotechnol. 2021 Sep 14;37(10):176. doi: 10.1007/s11274-021-03145-9.
ABSTRACT
All mucins are highly glycosylated and a key constituent of the mucus layer that is vigilant against pathogens in many organ systems of animals and humans. The viscous layer is organized in bilayers, i.e., an outer layer that is loosely arranged, variable in thickness, home to the commensal microbiota that grows in the complex environment, and an innermost layer that is stratified, non-aspirated, firmly adherent to the epithelial cells and devoid of any microorganisms. The O-glycosylation moiety represents the site of adhesion for pathogens and due to the increase of motility, mucolytic activity, and upregulation of virulence factors, some microorganisms can circumvent the component of the mucus layer and cause disruption in organ homeostasis. A dysbiotic microbiome, defective mucus barrier, and altered immune response often result in various diseases. In this review, paramount emphasis is given to the role played by the bacterial species directly or indirectly involved in mucin degradation, alteration in mucus secretion or its composition or mucin gene expression, which instigates many diseases in the digestive, respiratory, and other organ systems. A systematic view can help better understand the etiology of some complex disorders such as cystic fibrosis, ulcerative colitis and expand our knowledge about mucin degraders to develop new therapeutic approaches to correct ill effects caused by these mucin-dwelling pathogens.
PMID:34519941 | DOI:10.1007/s11274-021-03145-9
Assessment of hepatic involvement by two-dimensional shear wave elastography in paediatric patients with cystic fibrosis
J Paediatr Child Health. 2021 Sep 14. doi: 10.1111/jpc.15741. Online ahead of print.
ABSTRACT
AIM: This study aimed to investigate parenchymal changes in the liver in paediatric patients with cystic fibrosis (CF) and to analyse diagnostic performance of two-dimensional shear wave elastography (2D-SWE) for the detection of hepatic involvement.
METHODS: Patients with CF treated and followed at our centre were evaluated prospectively. All patients underwent liver tissue stiffness (TS) measurements by 2D-SWE, in addition to routine clinical assessments, laboratory work-up and abdominal ultrasound imaging. Data from patients with CF were compared with healthy control subjects.
RESULTS: This study included 39 patients with CF and 37 healthy controls. Patients had a mean body weight of 29.9 (16.6-55) kg, mean age of 9 (5-17) years, mean height of 130 (107-172) cm and a mean body mass index of 16.1 (12.8-21.4) kg/m2 . Average SWE values of the liver were 1.02 (0.70-1.60) m/s in patients with CF (n = 39) and 0.89 (0.60-1.35) m/s in healthy controls (n = 37). Cystic fibrosis patients had significantly increased tissue stifness by liver elastography compared to controls (P = 0.005).
CONCLUSION: Parenchymal liver changes may occur early in cystic fibrosis, which cannot be detected by conventional ultrasonography but may be demonstrated by 2D-SWE. Based on this cross-sectional study, 2D-SWE may be a promising, simple and non-invasive modality for objective monitoring of patients with cystic fibrosis who require lifelong follow-up, by providing numerical data for tissue stiffness early in the disease.
PMID:34519139 | DOI:10.1111/jpc.15741
Novel detection of specific bacterial quorum sensing molecules in saliva: Potential non-invasive biomarkers for pulmonary Pseudomonas aeruginosa in cystic fibrosis
J Cyst Fibros. 2021 Sep 10:S1569-1993(21)01371-0. doi: 10.1016/j.jcf.2021.08.030. Online ahead of print.
ABSTRACT
Pseudomonas aeruginosa produces specific signalling molecules, 2-alkyl-4-quinolones (AQs) that are detectable in the sputum of adults with cystic fibrosis (CF) and who have pulmonary infection with this opportunistic pathogen. This study aimed to determine whether AQs could be detected in saliva of patients with CF and known infection with Pseudomonas aeruginosa. Saliva and sputum samples were obtained from 89 adults with CF and analyzed using liquid chromatography-tandem mass spectrometry. AQs were detected in 39/89 (43.8%) saliva samples and 70/77(90.9%) sputum samples. Salivary AQs had a sensitivity of 50% (95%CI; 37.8; 62.2), specificity of 100% (95%CI; 47.8; 100), when compared to a molecular microbiological measure of P. aeruginosa in sputum as measured using polymerase chain reaction. Specific AQs produced by P. aeruginosa can be detected in the saliva and warrant investigation as potential non-invasive biomarkers of pulmonary P. aeruginosa.
PMID:34518117 | DOI:10.1016/j.jcf.2021.08.030
GRASP55 regulates intra-Golgi localization of glycosylation enzymes to control glycosphingolipid biosynthesis
EMBO J. 2021 Sep 13:e107766. doi: 10.15252/embj.2021107766. Online ahead of print.
ABSTRACT
The Golgi apparatus, the main glycosylation station of the cell, consists of a stack of discontinuous cisternae. Glycosylation enzymes are usually concentrated in one or two specific cisternae along the cis-trans axis of the organelle. How such compartmentalized localization of enzymes is achieved and how it contributes to glycosylation are not clear. Here, we show that the Golgi matrix protein GRASP55 directs the compartmentalized localization of key enzymes involved in glycosphingolipid (GSL) biosynthesis. GRASP55 binds to these enzymes and prevents their entry into COPI-based retrograde transport vesicles, thus concentrating them in the trans-Golgi. In genome-edited cells lacking GRASP55, or in cells expressing mutant enzymes without GRASP55 binding sites, these enzymes relocate to the cis-Golgi, which affects glycosphingolipid biosynthesis by changing flux across metabolic branch points. These findings reveal a mechanism by which a matrix protein regulates polarized localization of glycosylation enzymes in the Golgi and controls competition in glycan biosynthesis.
PMID:34516001 | DOI:10.15252/embj.2021107766
Association of Quality of Life Measures and Otolaryngologic Care in Cystic Fibrosis Patients
Ann Otol Rhinol Laryngol. 2021 Sep 11:34894211045636. doi: 10.1177/00034894211045636. Online ahead of print.
ABSTRACT
OBJECTIVES: Appropriate management of chronic rhinosinusitis (CRS) among patients with cystic fibrosis (CF) is important in improving quality of life. Otolaryngologists play a critical role in reducing CRS symptom burden. This study seeks to evaluate the role of patient-reported quality-of-life measures in guiding interventions for CF-related sinus disease.
METHODS: We performed a prospective, cross-sectional study of 105 patients presenting to a CF-accredited clinic between July and September 2018. Demographic data and sinus surgery history were collected, in addition to Sino-Nasal Outcome Test (SNOT-22) and Questionnaire of Olfactory Disorders (QOD-NS) scores. Statistical analysis was conducted using correlation and non-parametric Mann-Whitney U tests.
RESULTS: Baseline well-care visits accounted for 71.4% of all clinical evaluations. Prior otolaryngology intervention was noted in 69 (66%) patients, where the majority of these patients (63/69; 91%) underwent endoscopic sinus surgery (ESS). Patients with a history of otolaryngology intervention had an average SNOT-22 score of 33.2 (SD = 20.6) compared to 24.9 (SD = 18.5) for patients without prior intervention (P = .048). The average QOD-NS score was 5.5 (SD = 6.4) among patients referred to otolaryngologists and 3.1 (SD = 5.7) for non-referred patients (P = .012). SNOT-22 and QOD-NS scores were modestly correlated (R of .43).
CONCLUSION: CF patients with symptoms resulting in worse quality-of-life assessments were more likely to have established coordinated care with an otolaryngologist. Further validation of the utility of SNOT-22 and QOD-NS questionnaires as care coordination metrics is necessary in the CF population.
PMID:34514873 | DOI:10.1177/00034894211045636
Mechanistic analysis and significance of sphingomyelinase-mediated decreases in transepithelial CFTR currents in nHBEs
Physiol Rep. 2021 Sep;9(17):e15023. doi: 10.14814/phy2.15023.
ABSTRACT
Loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) causes cystic fibrosis (CF). In the lungs, this manifests as immune cell infiltration and bacterial infections, leading to tissue destruction. Previous work has determined that acute bacterial sphingomyelinase (SMase) decreases CFTR function in bronchial epithelial cells from individuals without CF (nHBEs) and with CF (cfHBEs, homozygous ΔF508-CFTR mutation). This study focuses on exploring the mechanisms underlying this effect. SMase increased the abundance of dihydroceramides, a result mimicked by blockade of ceramidase enzyme using ceranib-1, which also decreased CFTR function. The SMase-mediated inhibitory mechanism did not involve the reduction of cellular CFTR abundance or removal of CFTR from the apical surface, nor did it involve the activation of 5' adenosine monophosphate-activated protein kinase. In order to determine the pathological relevance of these sphingolipid imbalances, we evaluated the sphingolipid profiles of cfHBEs and cfHNEs (nasal) as compared to non-CF controls. Sphingomyelins, ceramides, and dihydroceramides were largely increased in CF cells. Correction of ΔF508-CFTR trafficking with VX445 + VX661 decreased some sphingomyelins and all ceramides, but exacerbated increases in dihydroceramides. Additional treatment with the CFTR potentiator VX770 did not affect these changes, suggesting rescue of misfolded CFTR was sufficient. We furthermore determined that cfHBEs express more acid-SMase protein than nHBEs. Lastly, we determined that airway-like neutrophils, which are increased in the CF lung, secrete acid-SMase. Identifying the mechanism of SMase-mediated inhibition of CFTR will be important, given the imbalance of sphingolipids in CF cells and the secretion of acid-SMase from cell types relevant to CF.
PMID:34514718 | DOI:10.14814/phy2.15023
Antimicrobial activity of ceftazidime/avibactam, ceftolozane/tazobactam and comparator agents against Pseudomonas aeruginosa from cystic fibrosis patients
JAC Antimicrob Resist. 2021 Sep 4;3(3):dlab126. doi: 10.1093/jacamr/dlab126. eCollection 2021 Sep.
ABSTRACT
OBJECTIVES: To evaluate the antimicrobial susceptibility patterns of Pseudomonas aeruginosa isolates collected from the lower respiratory tract of cystic fibrosis (CF) patients.
METHODS: We susceptibility tested 273 contemporary P. aeruginosa isolates from 39 hospitals worldwide (17 countries) by the reference broth microdilution method.
RESULTS: Ceftazidime/avibactam [MIC50/90, 2/8 mg/L; 96.0% susceptible (S)] was the most active agent, followed by ceftolozane/tazobactam (MIC50/90, 1/4 mg/L; 90.5% S), ceftazidime (MIC50/90, 2/>32 mg/L; 80.6% S), piperacillin/tazobactam (MIC50/90, 4/128 mg/L; 80.2% S) and tobramycin (MIC50/90, 2/>16 mg/L; 76.6% S). Ceftazidime/avibactam retained activity against P. aeruginosa isolates non-susceptible to meropenem (86.5% S to ceftazidime/avibactam), piperacillin/tazobactam (85.2% S to ceftazidime/avibactam) or ceftazidime (79.2% S to ceftazidime/avibactam). MDR phenotype was observed among 36.3% of isolates, and 88.9% and 73.7% of MDR isolates were susceptible to ceftazidime/avibactam and ceftolozane/tazobactam, respectively. Against isolates non-susceptible to meropenem, piperacillin/tazobactam and ceftazidime, susceptibility rates were 78.9% for ceftazidime/avibactam and 47.4% for ceftolozane/tazobactam. Ceftazidime/avibactam was active against 65.4% of ceftolozane/tazobactam-non-susceptible isolates and ceftolozane/tazobactam was active against 18.2% of ceftazidime/avibactam-non-susceptible isolates.
CONCLUSIONS: Ceftazidime/avibactam and ceftolozane/tazobactam exhibited potent and broad-spectrum activity against P. aeruginosa isolated from CF patients worldwide, but higher susceptibility rates for ceftazidime/avibactam compared with ceftolozane/tazobactam were observed among the resistant subsets. Ceftazidime/avibactam and ceftolozane/tazobactam represent valuable options to treat CF pulmonary exacerbations caused by P. aeruginosa.
PMID:34514403 | PMC:PMC8417452 | DOI:10.1093/jacamr/dlab126
An Innovative Protocol for Metaproteomic Analyses of Microbial Pathogens in Cystic Fibrosis Sputum
Front Cell Infect Microbiol. 2021 Aug 27;11:724569. doi: 10.3389/fcimb.2021.724569. eCollection 2021.
ABSTRACT
Hallmarks of cystic fibrosis (CF) are increased viscosity of mucus and impaired mucociliary clearance within the airways due to mutations of the cystic fibrosis conductance regulator gene. This facilitates the colonization of the lung by microbial pathogens and the concomitant establishment of chronic infections leading to tissue damage, reduced lung function, and decreased life expectancy. Although the interplay between key CF pathogens plays a major role during disease progression, the pathophysiology of the microbial community in CF lungs remains poorly understood. Particular challenges in the analysis of the microbial population present in CF sputum is (I) the inhomogeneous, viscous, and slimy consistence of CF sputum, and (II) the high number of human proteins masking comparably low abundant microbial proteins. To address these challenges, we used 21 CF sputum samples to develop a reliable, reproducible and widely applicable protocol for sputum processing, microbial enrichment, cell disruption, protein extraction and subsequent metaproteomic analyses. As a proof of concept, we selected three sputum samples for detailed metaproteome analyses and complemented and validated metaproteome data by 16S sequencing, metabolomic as well as microscopic analyses. Applying our protocol, the number of bacterial proteins/protein groups increased from 199-425 to 392-868 in enriched samples compared to nonenriched controls. These early microbial metaproteome data suggest that the arginine deiminase pathway and multiple proteases and peptidases identified from various bacterial genera could so far be underappreciated in their contribution to the CF pathophysiology. By providing a standardized and effective protocol for sputum processing and microbial enrichment, our study represents an important basis for future studies investigating the physiology of microbial pathogens in CF in vivo - an important prerequisite for the development of novel antimicrobial therapies to combat chronic recurrent airway infection in CF.
PMID:34513734 | PMC:PMC8432295 | DOI:10.3389/fcimb.2021.724569
Paradoxical Reactions to Midazolam in a Term Parturient After Intravenous Sedation During Cesarean Section
Cureus. 2021 Sep 3;13(9):e17678. doi: 10.7759/cureus.17678. eCollection 2021 Sep.
ABSTRACT
Propofol and midazolam are commonly used drugs in procedural sedation. Midazolam is widely used for its five principal pharmacologic effects: anxiolysis, sedation and hypnosis, anticonvulsant actions, spinal cord-mediated skeletal muscle relaxation, and anterograde amnesia. Increased talkativeness, emotional release, excitement, and excessive movement are the common paradoxical reactions to all kinds of benzodiazepines, which are reported since the introduction of chlordiazepoxide (Librium), the first benzodiazepine in 1955. In the United States, sedation with a combination of midazolam with opioids accounts for approximately 75% of routine procedural sedations. Most cases are distinctive. However, some data indicate that these reactions are due to serotonin imbalance, a central cholinergic effect, or a reflection of genetically determined variability in benzodiazepine receptor density or affinity (isoreceptors) throughout the brain. The idea of isoreceptors is comparable to that of isoenzymes like genetic variants of pseudocholinesterase. We report a case in which midazolam administration resulted in paradoxical reactions, which manifested as profound delirium with extrapyramidal symptoms after cessation of propofol sedation in a term parturient during cesarean section. This case report describes paradoxical reactions to benzodiazepines in a term parturient promptly reversed with a small dose of flumazenil. Even though paradoxical reactions to benzodiazepines have low prevalence and are not life-threatening, they have to be treated promptly with flumazenil. Therefore, anesthesiologists performing procedural sedation should be aware of untoward reactions and be prepared to manage them promptly.
PMID:34513535 | PMC:PMC8415540 | DOI:10.7759/cureus.17678
Cardiovascular System Involvement in Cystic Fibrosis
Cureus. 2021 Jul 29;13(7):e16723. doi: 10.7759/cureus.16723. eCollection 2021 Jul.
ABSTRACT
Cystic fibrosis (CF) is an autosomal recessive disease primarily affecting the respiratory system and gastrointestinal system. The life expectancy of patients with CF has significantly improved due to medical advancement and the effective use of screening techniques. However, new challenges have emerged. Particularly those involving cardiovascular pathology. This study aims to provide a better understanding of the different mechanisms that cause cardiovascular complications in patients with CF, which would help find an efficient treatment that not only prolongs survival but also improves their quality of life. This study extensively reviews different theories such as right ventricular hypertrophy due to lung pathology, ventricular interdependence, the association of nutritional deficiencies and severe cystic fibrosis transmembrane conductance regulator (CFTR) genotypes with myocardial fibrosis, effects of hypoxia, recurrent infections, and systemic inflammation of the heart and blood vessels that explain the direct or indirect involvement of the cardiovascular system in CF. For this review, 258 articles were retrieved from PubMed and Google Scholar. Out of which, a total of 12 high-quality articles were selected using appropriate quality assessment tools and preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The result of this study suggests that early detection of cardiovascular dysfunction can improve the survival rate of the patient. Furthermore, this study could aid future researchers in the exploration of various best screening modality techniques for the early detection of cardiovascular dysfunction.
PMID:34513358 | PMC:PMC8405250 | DOI:10.7759/cureus.16723
ABCC7/CFTR Expression Is Associated with the Clinical Course of Ulcerative Colitis Patients
Gastroenterol Res Pract. 2021 Aug 31;2021:5536563. doi: 10.1155/2021/5536563. eCollection 2021.
ABSTRACT
Inflammatory bowel disease includes ulcerative colitis (UC) and Crohn's disease (CD) of unknown etiology. The expression of ATP-binding cassette (ABC) family proteins has been associated with drug resistance and development of UC. The cystic fibrosis transmembrane conductance regulator (CFTR) or also known as ABCC7 is involved in the inflammatory chronic response. The aim of this study was to evaluate the role of ABCC7/CFTR in UC patients and normal controls without inflammation. This is an exploratory, observational, and cross-sectional study that included a total of 62 patients with UC and normal controls. Gene expression of CFTR was measured by RT-PCR, and protein expression of CFTR was determined by western blot analysis. We found a significant downregulation of the CFTR gene expression in patients with active UC compared to normal controls without inflammation (P < 0.004); even the gene expression of CFTR was decreased in remission UC patients compared to normal controls without inflammation (P = 0.04). The CFTR gene expression was associated with the clinical course of UC and the protein expression of CFTR was decreased in active UC patients compared to normal controls without inflammation suggesting that this molecule might play a role in the inflammation in UC patients.
PMID:34512749 | PMC:PMC8426104 | DOI:10.1155/2021/5536563
Traditional Chinese Medicine is an Alternative Therapeutic Option for Treatment of <em>Pseudomonas aeruginosa</em> Infections
Front Pharmacol. 2021 Aug 27;12:737252. doi: 10.3389/fphar.2021.737252. eCollection 2021.
ABSTRACT
Pseudomonas aeruginosa is an opportunistic pathogen causing life-threatening infections in cystic fibrosis patients and immunocompromised individuals, and it is a leading cause of nosocomial infections associated with significant morbidity and mortality. Treatment of P. aeruginosa infections is challenging due to the antibiotic resistance to most of the conventional antibiotics. Development of alternative therapeutic options is urgently demanded for the patients who have antibiotic-resistant infections. Traditional Chinese medicine (TCM) has a clinical history of thousands of years for prevention and treatment of infectious diseases in China, taking advantages of improving clinical outcomes, producing less side effects, inhibiting pathogen, and modulating host immunity. Recent research has revealed a variety of natural products derived from TCM showing significant antimicrobial effects on antibiotic-resistant strains of P. aeruginosa alone or combined with antibiotics in vitro or in animal models, suggesting that TCM is a promising complementary and alternative therapeutic approach for treatment of chronic P. aeruginosa infections. This review summarizes the recent findings attempting to dissect the mechanisms of TCM combating P. aeruginosa infections and highlights the molecular targets of TCM on P. aeruginosa and host.
PMID:34512364 | PMC:PMC8429605 | DOI:10.3389/fphar.2021.737252
Serological biomarkers for the diagnosis of Mycobacterium abscessus infections in cystic fibrosis patients
J Cyst Fibros. 2021 Sep 9:S1569-1993(21)01360-6. doi: 10.1016/j.jcf.2021.08.019. Online ahead of print.
ABSTRACT
BACKGROUND: Culture conditions sometimes make it difficult to detect non-tuberculous mycobacteria (NTM), particularly Mycobacterium abscessus, an emerging cystic fibrosis (CF) pathogen. The diagnosis of NTM positive cases not detected by classical culture methods might benefit from the development of a serological assay.
METHODS: As part of a diagnostic accuracy study, a total of 173 sera CF-patients, including 33 patients with M. abscessus positive cultures, and 31 non-CF healthy controls (HC) were evaluated. Four M. abscessus antigens were used separately, comprising two surface extracts (Interphase (INP) and a TLR2 positive extract (TLR2eF)) and two recombinant proteins (rMAB_2545c and rMAB_0555 also known as the phospholipase C (rPLC)).
RESULTS: TLR2eF and rPLC were the most efficient antigens to discriminate NTM-culture positive CF-patients from NTM-culture negative CF-patients. The best clinical values were obtained for the detection of M. abscessus-culture positive CF-patients; with sensitivities for the TLR2eF and rPLC of 81.2% (95% CI:65.7-92.3%) and 87.9% (95% CI:71.9-95.6%) respectively, and specificities of 88.9% (95% CI:85.3-94.8%) and 84.8% (95% CI:80.6-91.5%) respectively. When considering as positive all sera, giving a positive response in at least one of the two tests, and, as negative, all sera negative for both tests, we obtained a sensitivity of 93.9% and a specificity of 80.7% for the detection of M. abscessus-culture positive CF-patients.
CONCLUSION: High antibody titers against TLR2eF and rPLC were obtained in M. abscessus-culture positive CF-patients, allowing us to consider these serological markers as potential tools in the detection of CF-patients infected with M. abscessus.
PMID:34511392 | DOI:10.1016/j.jcf.2021.08.019
Restoration of exocrine pancreatic function in child with lumacaftor/ivacaftor therapy in cystic fibrosis
J Cyst Fibros. 2021 Sep 9:S1569-1993(21)01373-4. doi: 10.1016/j.jcf.2021.08.032. Online ahead of print.
NO ABSTRACT
PMID:34511391 | DOI:10.1016/j.jcf.2021.08.032
Diagnosing constipation in patients with cystic fibrosis applying ESPGHAN criteria
J Cyst Fibros. 2021 Sep 9:S1569-1993(21)01362-X. doi: 10.1016/j.jcf.2021.08.021. Online ahead of print.
NO ABSTRACT
PMID:34511390 | DOI:10.1016/j.jcf.2021.08.021
Frequent contiguous pattern mining over biological sequences of protein misfolded diseases
BMC Bioinformatics. 2021 Sep 11;22(1):435. doi: 10.1186/s12859-021-04341-y.
ABSTRACT
BACKGROUND: Proteins are integral part of all living beings, which are building blocks of many amino acids. To be functionally active, amino acids chain folds up in a complex way to give each protein a unique 3D shape, where a minor error may cause misfolded structure. Genetic disorder diseases i.e. Alzheimer, Parkinson, etc. arise due to misfolding in protein sequences. Thus, identifying patterns of amino acids is important for inferring protein associated genetic diseases. Recent studies in predicting amino acids patterns focused on only simple protein misfolded disease i.e. Chromaffin Tumor, by association rule mining. However, more complex diseases are yet to be attempted. Moreover, association rules obtained by these studies were not verified by usefulness measuring tools.
RESULTS: In this work, we analyzed protein sequences associated with complex protein misfolded diseases (i.e. Sickle Cell Anemia, Breast Cancer, Cystic Fibrosis, Nephrogenic Diabetes Insipidus, and Retinitis Pigmentosa 4) by association rule mining technique and objective interestingness measuring tools. Experimental results show the effectiveness of our method.
CONCLUSION: Adopting quantitative experimental methods, this work can form more reliable, useful and strong association rules i. e. dominating patterns of amino acid of complex protein misfolded diseases. Thus, in addition to usual applications, the identified patterns can be more useful in discovering medicines for protein misfolded diseases and thereby may open up new opportunities in medical science to handle genetic disorder diseases.
PMID:34511072 | DOI:10.1186/s12859-021-04341-y
Label-free quantitative proteomics identifies unique proteomes of clinical isolates of the Liverpool Epidemic Strain of Pseudomonas aeruginosa and laboratory strain PAO1
Proteomics Clin Appl. 2021 Sep 12:e2100062. doi: 10.1002/prca.202100062. Online ahead of print.
ABSTRACT
PURPOSE: Comparative genomics and phenotypic assays have shown that antibiotic resistance profiles differ among clinical isolates of Pseudomonas aeruginosa and that genotype-phenotype associations are difficult to establish for resistance phenotypes based on these comparisons alone.
EXPERIMENTAL DESIGN: Here, we used label-free quantitative proteomics to compare two isolates of the Liverpool Epidemic Strain (LES) of P. aeruginosa, LESlike1 and LESB58, and the common laboratory strain P. aeruginosa PAO1 to more accurately predict functional differences between strains.
RESULTS: Our results show that the proteomes of the LES isolates are more similar to each other than to PAO1; however, a number of differences were observed in the abundance of proteins involved in quorum sensing, virulence, and antibiotic resistance, including in the comparison of LESlike1 and LESB58. Additionally, the proteomic data revealed a higher abundance of proteins involved in polymyxin and aminoglycoside resistance in LESlike1. Minimum inhibitory concentration assays showed that LESlike1 had up to 128-fold higher resistance to antibiotics from these classes.
CONCLUSIONS: These findings provide an example of the ability of proteomic data to complement genotypic and phenotypic studies to understand resistance in clinical isolates.
CLINICAL RELEVANCE: P. aeruginosa is a predominant pathogen in chronic lung infections in individuals with cystic fibrosis (CF). LES isolates are capable of transferring between CF patients and have been associated with increased hospital visits and antibiotic treatments. This article is protected by copyright. All rights reserved.
PMID:34510773 | DOI:10.1002/prca.202100062