Pharmaceuticals (Basel). 2021 Nov 13;14(11):1157. doi: 10.3390/ph14111157.

ABSTRACT

Many bacteriophages are obligate killers of bacteria. That this property could be medically useful was first recognized over one hundred years ago, with 2021 being the 100-year anniversary of the first clinical phage therapy publication. Here we consider modern use of phages in clinical settings. Our aim is to answer one question: do phages serve as effective anti-bacterial infection agents when used clinically? An important emphasis of our analyses is on whether phage therapy-associated anti-bacterial infection efficacy can be reasonably distinguished from that associated with often coadministered antibiotics. We find that about half of 70 human phage treatment reports-published in English thus far in the 2000s-are suggestive of phage-mediated anti-bacterial infection efficacy. Two of these are randomized, double-blinded, infection-treatment studies while 14 of those studies, in our opinion, provide superior evidence of a phage role in observed treatment successes. Roughly three-quarters of these potentially phage-mediated outcomes are based on microbiological as well as clinical results, with the rest based on clinical success. Since many of these phage treatments are of infections for which antibiotic therapy had not been successful, their collective effectiveness is suggestive of a valid utility in employing phages to treat otherwise difficult-to-cure bacterial infections.

PMID:34832939 | DOI:10.3390/ph14111157

Pathogens. 2021 Oct 21;10(11):1363. doi: 10.3390/pathogens10111363.

ABSTRACT

The colonization of Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), has a detrimental effect on the respiratory care of pediatric patients with cystic fibrosis (CF). In addition to being resistant to multiple antibiotics, S. aureus also has the ability to form biofilms, which makes the infection more difficult to treat and eradicate. In this study, we examined the ability of S. aureus strains isolated from pediatric patients with CF to form biofilms. We screened a transposon mutant library of MRSA and identified a putative cobalt transporter ATP binding domain (cbiO) that is required for biofilm formation. We discovered that deleting cbiO creating a cbiO null mutant in CFSa36 (an MRSA strain isolated from a patient with cystic fibrosis) significantly hinders the ability of CFSa36 to form biofilm. The complementation of cbiO restored the ability of the cbiO deletion mutant to generate biofilm. Interestingly, we revealed that incorporating extra copper ions to the chemically defined medium (CDM) complemented the function of cbiO for biofilm formation in a dose-dependent manner, while the addition of extra iron ions in CDM enhanced the effect of cbiO null mutation on biofilm formation. In addition, neither the addition of certain extra amounts of copper ions nor iron ions in CDM had an impact on bacterial growth. Taken together, our findings suggest that cbiO mediates biofilm formation by affecting the transportation of copper ions in the MRSA CFSa36 strain. This study provides new insights into the molecular basis of biofilm formation by S. aureus.

PMID:34832519 | DOI:10.3390/pathogens10111363

Membranes (Basel). 2021 Oct 22;11(11):804. doi: 10.3390/membranes11110804.

ABSTRACT

Cystic fibrosis is a hereditary disease that mainly affects secretory organs in humans. It is caused by mutations in the gene encoding CFTR with the most common phenylalanine deletion at position 508. CFTR is an anion channel mainly conducting Cl- across the apical membranes of many different epithelial cells, the impairment of which causes dysregulation of epithelial fluid secretion and thickening of the mucus. This, in turn, leads to the dysfunction of organs such as the lungs, pancreas, kidney and liver. The CFTR protein is mainly localized in the plasma membrane; however, there is a growing body of evidence that it is also present in the intracellular organelles such as the endosomes, lysosomes, phagosomes and mitochondria. Dysfunction of the CFTR protein affects not only the ion transport across the epithelial tissues, but also has an impact on the proper functioning of the intracellular compartments. The review aims to provide a summary of the present state of knowledge regarding CFTR localization and function in intracellular compartments, the physiological role of this localization and the consequences of protein dysfunction at cellular, epithelial and organ levels. An in-depth understanding of intracellular processes involved in CFTR impairment may reveal novel opportunities in pharmacological agents of cystic fibrosis.

PMID:34832033 | DOI:10.3390/membranes11110804

Int J Environ Res Public Health. 2021 Nov 10;18(22):11776. doi: 10.3390/ijerph182211776.

ABSTRACT

Improvements in the survival and clinical outcomes of cystic fibrosis (CF) patients raised questions about their workforce participation and capacity to work. One hundred and ninety-six outpatients, attending the Adult CF Center of an Italian University Hospital, were enrolled between May 2020 and March 2021. The patients' personal and clinical characteristics, employment status, and profession were assessed. The Cystic Fibrosis Questionnaire-Revised and the work ability index (WAI) were employed to assess CF health-related quality of life and the employee's perception of their ability to work, respectively. Among the enrolled patients, 98 (50%) were employed. The non-working subjects were significantly younger (mean age ± standard deviation: 30 ± 10 vs. 37 ± 10 years) and were diagnosed with CF significantly earlier (9 ± 13 vs. 17 ± 18 years) than the employed subjects. The vast majority of CF workers (82.6%) were employed in tertiary professions. A general good work ability perception was determined in the employed population. Aging and being employed for >15 years could significantly predict a reduction in work ability, while a better quality of life was a positive predictor for its enhancement. Although further research is necessary, these results may introduce interdisciplinary CF healthcare management that includes a work function assessment, formal career counseling, and job guidance to support the personal, social and professional lives of CF patients.

PMID:34831532 | DOI:10.3390/ijerph182211776

Cells. 2021 Nov 22;10(11):3260. doi: 10.3390/cells10113260.

ABSTRACT

Defective CFTR biogenesis and activity in cystic fibrosis airways leads to airway dehydration and impaired mucociliary clearance, resulting in chronic airway infection and inflammation. Most cystic fibrosis patients have at least one copy of the F508del CFTR mutation, which results in a protein retained in the endoplasmic reticulum and degraded by the proteosomal pathway. CFTR modulators, e.g., correctors, promote the transfer of F508del to the apical membrane, while potentiators increase CFTR activity. Corrector and potentiator double therapies modestly improve lung function, whereas triple therapies with two correctors and one potentiator indicate improved outcomes. Enhanced F508del rescue by CFTR modulators is achieved by exposing F508del/F508del primary cultures of human bronchial epithelia to relevant inflammatory stimuli, i.e., supernatant from mucopurulent material or bronchoalveolar lavage fluid from human cystic fibrosis airways. Inflammation enhances the biochemical and functional rescue of F508del by double or triple CFTR modulator therapy and overcomes abrogation of CFTR correction by chronic VX-770 treatment in vitro. Furthermore, the impact of inflammation on clinical outcomes linked to CFTR rescue has been recently suggested. This review discusses these data and possible mechanisms for airway inflammation-enhanced F508del rescue. Expanding the understanding of how airway inflammation improves CFTR rescue may benefit cystic fibrosis patients.

PMID:34831482 | DOI:10.3390/cells10113260

Cells. 2021 Nov 10;10(11):3107. doi: 10.3390/cells10113107.

ABSTRACT

The mucus obstructing the airways of Cystic Fibrosis (CF) patients is a yield stress fluid. Linear and non-linear rheological analyses of CF sputa can provide relevant biophysical markers, which could be used for the management of this disease. Sputa were collected from CF patients either without any induction or following an aerosol treatment with the recombinant human DNAse (rhDNAse, Pulmozyme®). Several sample preparations were considered and multiple measurements were performed in order to assess both the repeatability and the robustness of the rheological measurements. The linear and non-linear rheological properties of all CF sputa were characterized. While no correlation between oscillatory shear linear viscoelastic properties and clinical data was observed, the steady shear flow data showed that the apparent yield stress of sputum from CF patients previously treated with rhDNAse was approximately one decade lower than that of non-treated CF patients. Similar results were obtained with sputa from non-induced CF patients subjected ex vivo to a Pulmozyme® aerosol treatment. The results demonstrate that the apparent yield stress of patient sputa is a relevant predictive/prognostic biomarker in CF patients and could help in the development of new mucolytic agents.

PMID:34831330 | DOI:10.3390/cells10113107

Cells. 2021 Nov 2;10(11):2980. doi: 10.3390/cells10112980.

ABSTRACT

In cystic fibrosis (CF), p.Phe508del is the most frequent mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. The p.Phe508del-CFTR protein is retained in the ER and rapidly degraded. This retention likely triggers an atypical Unfolded Protein Response (UPR) involving ATF6, which reduces the expression of p.Phe508del-CFTR. There are still some debates on the role of the UPR in CF: could it be triggered by the accumulation of misfolded CFTR proteins in the endoplasmic reticulum as was proposed for the most common CFTR mutation p.Phe508del? Or, is it the consequence of inflammation and infection that occur in the disease? In this review, we summarize recent findings on UPR in CF and show how infection, inflammation and UPR act together in CF. We propose to rethink their respective role in CF and to consider them as a whole.

PMID:34831204 | DOI:10.3390/cells10112980

Cells. 2021 Oct 24;10(11):2867. doi: 10.3390/cells10112867.

ABSTRACT

Cystic fibrosis (CF) is the most common of rare hereditary diseases in Caucasians, and it is estimated to affect 75,000 patients globally. CF is a complex disease due to the multiplicity of mutations found in the CF transmembrane conductance regulator (CFTR) gene causing the CFTR protein to become dysfunctional. Correctors and potentiators have demonstrated good clinical outcomes for patients with specific gene mutations; however, there are still patients for whom those treatments are not suitable and require alternative CFTR-independent strategies. Although CFTR is the main chloride channel in the lungs, others could, e.g., anoctamin-1 (ANO1 or TMEM16A), compensate for the deficiency of CFTR. This review summarizes the current knowledge on calcium-activated chloride channel (CaCC) ANO1 and presents ANO1 as an exciting target in CF.

PMID:34831090 | DOI:10.3390/cells10112867

Cells. 2021 Oct 22;10(11):2844. doi: 10.3390/cells10112844.

ABSTRACT

Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in a gene encoding a protein called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). The CFTR protein is known to acts as a chloride (Cl-) channel expressed in the exocrine glands of several body systems where it also regulates other ion channels, including the epithelial sodium (Na+) channel (ENaC) that plays a key role in salt absorption. This function is crucial to the osmotic balance of the mucus and its viscosity. However, the pathophysiology of CF is more challenging than a mere dysregulation of epithelial ion transport, mainly resulting in impaired mucociliary clearance (MCC) with consecutive bronchiectasis and in exocrine pancreatic insufficiency. This review shows that the CFTR protein is not just a chloride channel. For a long time, research in CF has focused on abnormal Cl- and Na+ transport. Yet, the CFTR protein also regulates numerous other pathways, such as the transport of HCO3-, glutathione and thiocyanate, immune cells, and the metabolism of lipids. It influences the pH homeostasis of airway surface liquid and thus the MCC as well as innate immunity leading to chronic infection and inflammation, all of which are considered as key pathophysiological characteristics of CF.

PMID:34831067 | DOI:10.3390/cells10112844

Cancers (Basel). 2021 Nov 15;13(22):5710. doi: 10.3390/cancers13225710.

ABSTRACT

Metastasis contributes to the poor prognosis of colorectal cancer, the causative factor of which is not fully understood. Previously, we found that miR-125b (Accession number: MIMAT0000423) contributed to cetuximab resistance in colorectal cancer (CRC). In this study, we identified a novel mechanism by which miR-125b enhances metastasis by targeting cystic fibrosis transmembrane conductance regulator (CFTR) and the tight junction-associated adaptor cingulin (CGN) in CRC. We found that miR-125b expression was upregulated in primary CRC tumors and metastatic sites compared with adjacent normal tissues. Overexpression of miR-125b in CRC cells enhanced migration capacity, while knockdown of miR-125b decreased migration and invasion. RNA-sequencing (RNA-seq) and dual-luciferase reporter assays identified CFTR and CGN as the target genes of miR-125b, and the inhibitory impact of CFTR and CGN on metastasis was further verified both in vitro and in vivo. Moreover, we found that miR-125b facilitated the epithelial-mesenchymal transition (EMT) process and the expression and secretion of urokinase plasminogen activator (uPA) by targeting CFTR and enhanced the Ras Homolog Family Member A (RhoA)/Rho Kinase (ROCK) pathway activity by targeting CGN. Together, these findings suggest miR-125b as a key functional molecule in CRC and a promising biomarker for the diagnosis and treatment of CRC.

PMID:34830864 | DOI:10.3390/cancers13225710

J Clin Med. 2021 Nov 13;10(22):5280. doi: 10.3390/jcm10225280.

ABSTRACT

This review reports on methods used to evaluate airway clearance techniques (ACT) in adults with CF and examined data for evidence of any effect. Sixty-eight studies described ACT in adequate detail and were included in this review. Frequently reported outcomes were sputum expectoration (72%) and spirometric lung function (60%). Compared with cough alone, following any ACT, there was a trend for greater sputum wet weight, however FEV1 was not different. The mean (95% CI) within-group effect for sputum wet weight following any ACT was 12.43 g (9.28 to 15.58) (n = 30 studies) and for FEV1 was 0.03 L (-0.17 to 0.24) (n = 14 studies). Meta-regression demonstrated that, when compared with cough alone, greater sputum wet weight was reported in groups that received additional ACT by between 2.45 and 3.94 g (F3,66 = 2.97, p = 0.04). These data suggest the addition of ACT to cough alone may optimise sputum clearance; however, FEV1 lacked sensitivity to detect this change. Importantly, this review highlights the lack of appropriate measures to assess ACT efficacy.

PMID:34830562 | DOI:10.3390/jcm10225280

Int J Mol Sci. 2021 Nov 22;22(22):12561. doi: 10.3390/ijms222212561.

ABSTRACT

The opportunistic pathogen Pseudomonas aeruginosa is a significant cause of infection in immunocompromised individuals, cystic fibrosis patients, and burn victims. To benefit its survival, the bacterium adapt to either a motile or sessile lifestyle when infecting the host. The motile bacterium has an often activated type III secretion system (T3SS), which is virulent to the host, whereas the sessile bacterium harbors an active T6SS and lives in biofilms. Regulatory pathways involving Gac-Rsm or secondary messengers such as c-di-GMP determine which lifestyle is favorable for P. aeruginosa. Here, we introduce the RNA binding protein RtcB as a modulator of the switch between motile and sessile bacterial lifestyles. Using the wild-type P. aeruginosa PAO1, and a retS mutant PAO1(∆retS) in which T3SS is repressed and T6SS active, we show that deleting rtcB led to simultaneous expression of T3SS and T6SS in both PAO1(∆rtcB) and PAO1(∆rtcB∆retS). The deletion of rtcB also increased biofilm formation in PAO1(∆rtcB) and restored the motility of PAO1(∆rtcB∆retS). RNA-sequencing data suggested RtcB as a global modulator affecting multiple virulence factors, including bacterial secretion systems. Competitive killing and infection assays showed that the three T6SS systems (H1, H2, and H3) in PAO1(∆rtcB) were activated into a functional syringe, and could compete with Escherichia coli and effectively infect lettuce. Western blotting and RT-PCR results showed that RtcB probably exerted its function through RsmA in PAO1(∆rtcB∆retS). Quantification of c-di-GMP showed an elevated intracellular levels in PAO1(∆rtcB), which likely drove the switch between T6SS and T3SS, and contributed to the altered phenotypes and characteristics observed. Our data demonstrate a pivotal role of RtcB in the virulence of P. aeruginosa by controlling multiple virulence determinants, such as biofilm formation, motility, pyocyanin production, T3SS, and T6SS secretion systems towards eukaryotic and prokaryotic cells. These findings suggest RtcB as a potential target for controlling P. aeruginosa colonization, establishment, and pathogenicity.

PMID:34830443 | DOI:10.3390/ijms222212561

Int J Mol Sci. 2021 Nov 10;22(22):12169. doi: 10.3390/ijms222212169.

ABSTRACT

Cystic fibrosis (CF) disease leads to altered lung and gut microbiomes compared to healthy subjects. The magnitude of this dysbiosis is influenced by organ-specific microenvironmental conditions at different stages of the disease. However, how this gut-lung dysbiosis is influenced by Pseudomonas aeruginosa chronic infection is unclear. To test the relationship between CFTR dysfunction and gut-lung microbiome under chronic infection, we established a model of P. aeruginosa infection in wild-type (WT) and gut-corrected CF mice. Using 16S ribosomal RNA gene, we compared lung, stool, and gut microbiota of C57Bl/6 Cftr tm1UNCTgN(FABPCFTR) or WT mice at the naïve state or infected with P. aeruginosa. P. aeruginosa infection influences murine health significantly changing body weight both in CF and WT mice. Both stool and gut microbiota revealed significantly higher values of alpha diversity in WT mice than in CF mice, while lung microbiota showed similar values. Infection with P. aeruginosa did not changed the diversity of the stool and gut microbiota, while a drop of diversity of the lung microbiota was observed compared to non-infected mice. However, the taxonomic composition of gut microbiota was shown to be influenced by P. aeruginosa infection in CF mice but not in WT mice. This finding indicates that P. aeruginosa chronic infection has a major impact on microbiota diversity and composition in the lung. In the gut, CFTR genotype and P. aeruginosa infection affected the overall diversity and taxonomic microbiota composition, respectively. Overall, our results suggest a cross-talk between lung and gut microbiota in relation to P. aeruginosa chronic infection and CFTR mutation.

PMID:34830048 | DOI:10.3390/ijms222212169

Biomedicines. 2021 Oct 29;9(11):1573. doi: 10.3390/biomedicines9111573.

ABSTRACT

Vitamin D modulates immune responses and its deficiency has been observed in more than 60% of bronchiectasis patients. Vitamin D binding protein (DBP) is coded by the GC gene, is involved in the transport of vitamin D, and includes a number of isoforms based on single nucleotide polymorphisms (SNPs) in the coding region at rs7041 and rs4855. We evaluated the possible clinical impact of DBP polymorphisms and isoforms in an observational, cross-sectional study conducted in 116 bronchiectasis patients, who were genetically characterized for rs4588 and rs7041 SNPs. Results showed that the GC1f isoform (rs7041/rs4588 A/G) correlated with a more severe disease (18.9% vs. 6.3%, p = 0.038), a higher incidence of chronic infections (63.6% vs. 42%, p = 0.041), and a lower BACI score (0.0 (0.0, 2.5) vs. 3.0 (0.0, 3.0), p = 0.035). Moreover, blood concentration of vitamin D was higher in patients carrying GC1s (median (IQR): 20.5 (14.3, 29.7 vs. 15.8 (7.6, 22.4), p = 0.037)). Patients carrying GC1f isoform have a more severe disease, more chronic infections and lower asthmatic comorbidity in comparison to those without the GC1f isoform. Presence of the GC1s isoform (rs7041/rs4588 C/G) seems to be associated to a milder clinical phenotype with increased vitamin D levels and lower comorbidities score.

PMID:34829802 | DOI:10.3390/biomedicines9111573

Antioxidants (Basel). 2021 Nov 12;10(11):1805. doi: 10.3390/antiox10111805.

ABSTRACT

In our organism, mucous surfaces are important boundaries against the environmental milieu with defined fluxes of metabolites through these surfaces and specific rules for defense reactions. Major mucous surfaces are formed by epithelia of the respiratory system and the digestive tract. The heme peroxidases lactoperoxidase (LPO), myeloperoxidase (MPO), and eosinophil peroxidase (EPO) contribute to immune protection at epithelial surfaces and in secretions. Whereas LPO is secreted from epithelial cells and maintains microbes in surface linings on low level, MPO and EPO are released from recruited neutrophils and eosinophils, respectively, at inflamed mucous surfaces. Activated heme peroxidases are able to oxidize (pseudo)halides to hypohalous acids and hypothiocyanite. These products are involved in the defense against pathogens, but can also contribute to cell and tissue damage under pathological conditions. This review highlights the beneficial and harmful functions of LPO, MPO, and EPO at unperturbed and inflamed mucous surfaces. Among the disorders, special attention is directed to cystic fibrosis and allergic reactions.

PMID:34829676 | DOI:10.3390/antiox10111805

Diagnostics (Basel). 2021 Nov 10;11(11):2075. doi: 10.3390/diagnostics11112075.

ABSTRACT

Micro-computed tomography (micro-CT) is a promising novel medical imaging modality that allows for non-destructive volumetric imaging of surgical tissue specimens at high spatial resolution. The aim of this study is to provide a comprehensive assessment of the clinical applications of micro-CT for the tissue-based diagnosis of lung diseases. This scoping review was conducted in accordance with the PRISMA Extension for Scoping Reviews, aiming to include every clinical study reporting on micro-CT imaging of human lung tissues. A literature search yielded 570 candidate articles, out of which 37 were finally included in the review. Of the selected studies, 9 studies explored via micro-CT imaging the morphology and anatomy of normal human lung tissue; 21 studies investigated microanatomic pulmonary alterations due to obstructive or restrictive lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and cystic fibrosis; and 7 studies examined the utility of micro-CT imaging in assessing lung cancer lesions (n = 4) or in transplantation-related pulmonary alterations (n = 3). The selected studies reported that micro-CT could successfully detect several lung diseases providing three-dimensional images of greater detail and resolution than routine optical slide microscopy, and could additionally provide valuable volumetric insight in both restrictive and obstructive lung diseases. In conclusion, micro-CT-based volumetric measurements and qualitative evaluations of pulmonary tissue structures can be utilized for the clinical management of a variety of lung diseases. With micro-CT devices becoming more accessible, the technology has the potential to establish itself as a core diagnostic imaging modality in pathology and to enable integrated histopathologic and radiologic assessment of lung cancer and other lung diseases.

PMID:34829422 | DOI:10.3390/diagnostics11112075

J Fungi (Basel). 2021 Nov 18;7(11):979. doi: 10.3390/jof7110979.

ABSTRACT

Pneumocystis spp. was discovered in 1909 and was classified as a fungus in 1988. The species that infects humans is called P. jirovecii and important characteristics of its genome have recently been discovered. Important advances have been made to understand P. jirovecii, including aspects of its biology, evolution, lifecycle, and pathogenesis; it is now considered that the main route of transmission is airborne and that the infectious form is the asci (cyst), but it is unclear whether there is transmission by direct contact or droplet spread. On the other hand, P. jirovecii has been detected in respiratory secretions of hosts without causing disease, which has been termed asymptomatic carrier status or colonization (frequency in immunocompetent patients: 0-65%, pregnancy: 15.5%, children: 0-100%, HIV-positive patients: 20-69%, cystic fibrosis: 1-22%, and COPD: 16-55%). This article briefly describes the history of its discovery and the nomenclature of Pneumocystis spp., recently uncovered characteristics of its genome, and what research has been done on the transmission and colonization of P. jirovecii. Based on the literature, the authors of this review propose a hypothetical natural history of P. jirovecii infection in humans.

PMID:34829266 | DOI:10.3390/jof7110979

J Fungi (Basel). 2021 Nov 9;7(11):944. doi: 10.3390/jof7110944.

ABSTRACT

Aspergillus fumigatus is commonly isolated from CF airways. However, the impact on CF lung progression is not completely understood. In this study, using a 16-year retrospective observational cohort study (2000-2015) that included 132 patients, we determined the annual lung function, measured as percent predicted forced expiratory volume in the first second (ppFEV1), decline before and after the first colonization with A. fumigatus. Further, in the same individual, the ratios of lung function when patients were colonized with A. fumigatus and when they were not were calculated. The impact of eradication, with antifungal treatment or spontaneously, was assessed. The annual ppFEV1 was significantly lower after the first colonization with A. fumigatus. Furthermore, within the same individual, colonization with A. fumigatus for two and three years in a row was associated with 4.3% and 7.9% lower ppFEV1, respectively, compared to when not colonized. Finally, patients who eradicated A. fumigatus the following two years after colonization exhibited 9.9% and 14.5% higher ppFEV1 compared to patients who continued to produce cultures with A. fumigatus for two and three years. Our study demonstrated that A. fumigatus colonization was associated with a negative impact on lung function in the long term and eradication, spontaneously or with treatment, was associated with a better pulmonary outcome.

PMID:34829231 | DOI:10.3390/jof7110944

Children (Basel). 2021 Nov 2;8(11):997. doi: 10.3390/children8110997.

ABSTRACT

Nasal polyps (NPs) are benign inflammatory masses causing chronic nasal obstruction, usually associated with underlying chronic rhinosinusitis (CRS), which are rarely reported in childhood. The interest in NPs has recently increased due to new therapeutic options, namely biological agents, such as dupilumab, and an update of the European position paper on this topic was released in 2020, providing a detailed classification for these lesions and also discussing diagnostic and therapeutic approaches also in children. In childhood, NPs usually represent red flags for systemic diseases, such as cystic fibrosis and immunodeficiencies. This review outlines the recent data on NPs in childhood, focusing on predisposing factors for CRS as well as on the potential endotypes in this particular age group, for which further studies are required in order to better clarify their pathogenesis and to identify molecular biomarkers that could help achieve more personalized treatments.

PMID:34828710 | DOI:10.3390/children8110997

Genes (Basel). 2021 Nov 18;12(11):1810. doi: 10.3390/genes12111810.

ABSTRACT

Major advances have recently been made in the development and application of CFTR (cystic fibrosis transmembrane conductance regulator) mutation class-specific modulator therapies, but to date, there are no approved modulators for Class I mutations, i.e., those introducing a premature termination codon (PTC) into the CFTR mRNA. Such mutations induce nonsense-mediated decay (NMD), a cellular quality control mechanism that reduces the quantity of PTC bearing mRNAs, presumably to avoid translation of potentially deleterious truncated CFTR proteins. The NMD-mediated reduction of PTC-CFTR mRNA molecules reduces the efficacy of one of the most promising approaches to treatment of such mutations, namely, PTC readthrough therapy, using molecules that induce the incorporation of near-cognate amino acids at the PTC codon, thereby enabling translation of a full-length protein. In this study, we measure the effect of three different PTC mutations on the abundance, integrity, and stability of respective CFTR mRNAs, using CFTR specific RT-qPCR-based assays. Altogether, our data suggest that optimized rescue of PTC mutations has to take into account (1) the different steady-state levels of the CFTR mRNA associated with each specific PTC mutation; (2) differences in abundance between the 3' and 5' regions of CFTR mRNA, even following PTC readthrough or NMD inhibition; and (3) variable effects on CFTR mRNA stability for each specific PTC mutation.

PMID:34828417 | DOI:10.3390/genes12111810