Int J Mol Sci. 2022 Mar 23;23(7):3513. doi: 10.3390/ijms23073513.

ABSTRACT

The advent of Cystic fibrosis transmembrane receptor (CFTR) modulators in 2012 was a critical event in the history of cystic fibrosis (CF) treatment. Unlike traditional therapies that target downstream effects of CFTR dysfunction, CFTR modulators aim to correct the underlying defect at the protein level. These genotype-specific therapies are now available for an increasing number of CF patients, transforming the way we view the condition from a life-limiting disease to one that can be effectively managed. Several studies have demonstrated the vast improvement CFTR modulators have on normalization of sweat chloride, CFTR function, clinical endpoints, and frequency of pulmonary exacerbation. However, their impact on other aspects of the disease, such as pathogenic burden and airway infection, remain under explored. Frequent airway infections as a result of increased susceptibility and impaired innate immune response are a serious problem within CF, often leading to accelerated decline in lung function and disease progression. Current evidence suggests that CFTR modulators are unable to eradicate pathogenic organisms in those with already established lung disease. However, this may not be the case for those with relatively low levels of disease progression and conserved microbial diversity, such as young patients. Furthermore, it remains unknown whether the restorative effects exerted by CFTR modulators extend to immune cells, such as phagocytes, which have the potential to modulate the response of people with CF (pwCF) to infection. Throughout this review, we look at the potential impact of CFTR modulators on airway infection in CF and their ability to shape impaired pulmonary defences to pathogens.

PMID:35408875 | DOI:10.3390/ijms23073513

Cells. 2022 Apr 6;11(7):1243. doi: 10.3390/cells11071243.

ABSTRACT

Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding for the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein, expressed on the apical surface of epithelial cells. CFTR absence/dysfunction results in ion imbalance and airway surface dehydration that severely compromise the CF airway microenvironment, increasing infection susceptibility. Recently, novel therapies aimed at correcting the basic CFTR defect have become available, leading to substantial clinical improvement of CF patients. The restoration or increase of CFTR function affects the airway microenvironment, improving local defence mechanisms. CFTR modulator drugs might therefore affect the development of chronic airway infections and/or improve the status of existing infections in CF. Thus far, however, the full extent of these effects of CFTR-modulators, especially in the long-term remains still unknown. This review aims to provide an overview of current evidence on the potential impact of CFTR modulators on airway infections in CF. Their role in affecting CF microbiology, the susceptibility to infections as well as the potential efficacy of their use in preventing/decreasing the development of chronic lung infections and the recurrent acute exacerbations in CF will be critically analysed.

PMID:35406809 | DOI:10.3390/cells11071243

Cancers (Basel). 2022 Apr 1;14(7):1802. doi: 10.3390/cancers14071802.

ABSTRACT

RNF5, an endoplasmic reticulum (ER) E3 ubiquitin ligase, participates to the ER-associated protein degradation guaranteeing the protein homeostasis. Depending on tumor model tested, RNF5 exerts pro- or anti-tumor activity. The aim of this study was to elucidate the controversial role of RNF5 in neuroblastoma and melanoma, two neuroectodermal tumors of infancy and adulthood, respectively. RNF5 gene levels are evaluated in publicly available datasets reporting the gene expression profile of melanoma and neuroblastoma primary tumors at diagnosis. The therapeutic effect of Analog-1, an RNF5 pharmacological activator, was investigated on in vitro and in vivo neuroblastoma and melanoma models. In both neuroblastoma and melanoma patients the high expression of RNF5 correlated with a better prognostic outcome. Treatment of neuroblastoma and melanoma cell lines with Analog-1 reduced cell viability by impairing the glutamine availability and energy metabolism through inhibition of F1Fo ATP-synthase activity. This latter event led to a marked increase in oxidative stress, which, in turn, caused cell death. Similarly, neuroblastoma- and melanoma-bearing mice treated with Analog-1 showed a significant delay of tumor growth in comparison to those treated with vehicle only. These findings validate RNF5 as an innovative drug target and support the development of Analog-1 in early phase clinical trials for neuroblastoma and melanoma patients.

PMID:35406574 | DOI:10.3390/cancers14071802

Nutrients. 2022 Mar 23;14(7):1341. doi: 10.3390/nu14071341.

ABSTRACT

While typically considered a pulmonary disease, cystic fibrosis patients develop significant nutritional complications and comorbidities, especially those who are pancreatic insufficient. Clinicians must have a high suspicion for cystic fibrosis among patients with clinical symptoms of pancreatic insufficiency, and pancreatic enzymatic replacement therapy (PERT) must be urgently initiated. PERT presents a myriad of considerations for patients and their supporting dieticians and clinicians, including types of administration, therapy failures, and complications.

PMID:35405954 | DOI:10.3390/nu14071341

Nutrients. 2022 Mar 22;14(7):1330. doi: 10.3390/nu14071330.

ABSTRACT

Most people with cystic fibrosis (pwCF) develop pancreatic insufficiency and are treated with pancreatic enzyme replacement therapy (PERT). We aimed to describe the use of PERT and assess the correlates of PERT dose in adult pwCF. In a cross-sectional study at the Copenhagen CF Centre, the participants reported PERT intake, gastrointestinal (GI) symptoms and the use of concomitant treatments. Demographic and clinical characteristics were extracted from the Danish CF Registry. We used linear regression to assess the correlates of PERT dose per kg bodyweight (U-lipase/kg). We included 120 pwCF with a median age of 32.9 years, 46% women and 72% F508delta homozygote. The PERT dose ranged from 0 to 6160 U-lipase/kg per main meal (mean 1828; SD 1115). The PERT dose was associated with participants' sex (men vs. women: 661; 95% CI: 302; 1020 U-lipase/kg), age (-16; 95% CI: -31; -1 U-lipase/kg per year) and weight (-45; 95% CI: -58; -31 U-lipase/kg per kg). Having less frequent constipation and being lung transplanted were also associated with a higher PERT dose. A third of participants did not take PERT for snacks, and this was associated with the frequency of diarrhoea. These findings indicate that PERT intake may be improved to reduce GI symptoms.

PMID:35405943 | DOI:10.3390/nu14071330

mBio. 2022 Apr 11:e0385321. doi: 10.1128/mbio.03853-21. Online ahead of print.

ABSTRACT

Malassezia species are important fungal skin commensals and are part of the normal microbiota of humans and other animals. However, under certain circumstances these fungi can also display a pathogenic behavior. For example, Malassezia furfur is a common commensal of human skin and yet is often responsible for skin disorders but also systemic infections. Comparative genomics analysis of M. furfur revealed that some isolates have a hybrid origin, similar to several other recently described hybrid fungal pathogens. Because hybrid species exhibit genomic plasticity that can impact phenotypes, we sought to elucidate the genomic evolution and phenotypic characteristics of M. furfur hybrids in comparison to their parental lineages. To this end, we performed a comparative genomics analysis between hybrid strains and their presumptive parental lineages and assessed phenotypic characteristics. Our results provide evidence that at least two distinct hybridization events occurred between the same parental lineages and that the parental strains may have originally been hybrids themselves. Analysis of the mating-type locus reveals that M. furfur has a pseudobipolar mating system and provides evidence that after sexual liaisons of mating compatible cells, hybridization involved cell-cell fusion leading to a diploid/aneuploid state. This study provides new insights into the evolutionary trajectory of M. furfur and contributes with valuable genomic resources for future pathogenicity studies. IMPORTANCE Malassezia furfur is a common commensal member of human/animal microbiota that is also associated with several pathogenic states. Recent studies report involvement of Malassezia species in Crohn's disease, a type of inflammatory bowel disease, pancreatic cancer progression, and exacerbation of cystic fibrosis. A recent genomics analysis of M. furfur revealed the existence of hybrid isolates and identified their putative parental lineages. In this study, we explored the genomic and phenotypic features of these hybrids in comparison to their putative parental lineages. Our results revealed the existence of a pseudobipolar mating system in this species and showed evidence for the occurrence of multiple hybridization events in the evolutionary trajectory of M. furfur. These findings significantly advance our understanding of the evolution of this commensal microbe and are relevant for future studies exploring the role of hybridization in the adaptation to new niches or environments, including the emergence of pathogenicity.

PMID:35404119 | DOI:10.1128/mbio.03853-21

Indian J Pediatr. 2022 Apr 11. doi: 10.1007/s12098-022-04203-2. Online ahead of print.

NO ABSTRACT

PMID:35403937 | DOI:10.1007/s12098-022-04203-2

Am J Transplant. 2022 Apr 11. doi: 10.1111/ajt.17058. Online ahead of print.

ABSTRACT

Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis (CF), and restoring metabolic control in these patients may improve their management after lung transplantation. In this this multicenter, prospective, phase 1-2 trial, we evaluate the feasibility and metabolic efficacy of combined pancreatic islet-lung transplantation from a single donor in patients with CFRD, terminal respiratory failure and poorly controlled diabetes. Islets were infused via the portal vein under local anesthesia, one week after lung transplantation. At one year, the primary outcome was transplant success as evaluated by a composite score including four parameters (weight, fasting glycaemia, HbA1c, insulin requirements). 10 participants (age: 24 years [17-31], diabetes duration: 8 years [4-12]) received a combined islet-lung transplant with 2892 IEQ/kg [2293 - 6185]. Transplant success was achieved in 7/10 participants at one year post-transplant. Fasting plasma C-peptide increased from 0.91μg/L [0.56-1.29] to 1.15μg/L [0.77-2.2], HbA1c decreased from 7.8% [6.5-8.3] (62 mmol/mol [48-67]) to 6.7% [5.5-8.0] (50 mmol/mol [37-64]), with 38% decrease in daily insulin doses. No complications related to the islet injection procedure were reported. In this pilot study, combined pancreatic islet-lung transplantation restored satisfactory metabolic control and pulmonary function in patients with CF, without increasing the morbidity of lung transplantation.

PMID:35403818 | DOI:10.1111/ajt.17058

Bioengineered. 2022 Apr;13(4):9131-9144. doi: 10.1080/21655979.2021.2008737.

ABSTRACT

The LaSota strain of Newcastle disease virus (NDV) is a commonly used vaccine to control Newcastle disease. However, improper immunization is a common reason for vaccine failure. Hence, it is imperative to thoroughly explore innate immunity-related molecular regulatory responses to the LaSota vaccine. In this text, 140 long non-coding RNAs (lncRNAs), 8 microRNAs (miRNAs), and 1514 mRNAs were identified to be differentially expressed by RNA sequencing analysis in the thymic tissues of Chinese Partridge Shank chickens after LaSota vaccine inoculation. Moreover, 70 dysregulated genes related to innate immunity were identified based on GO, Reactome pathway, and InnateDB annotations and differential expression analysis. Additionally, dysregulated lncRNAs and innate immunity-related mRNAs that could interact with dysregulated miRNAs were identified based on bioinformatics prediction analysis via the miRanda software and differential expression analysis. Among these transcripts, expression patterns of five lncRNAs, seven miRNAs, and six mRNAs were further examined by RT-qPCR assay. Both RNA-seq and RT-qPCR outcomes showed that 10 transcripts (MSTRG.22689.1, ENSGALT00000065826, ENSGALT00000059336, ENSGALT00000060887, gga-miR-6575-5p, gga-miR-6631-5p, gga-miR-1727, paraoxonase 2 (PON2), mitogen-activated protein kinase 10, and cystic fibrosis transmembrane conductance regulator (CFTR) were highly expressed, and 4 transcripts (MSTRG.188121.10, gga-miR-6655-5p, gga-miR-6548-3p, and matrix metallopeptidase 9 (MMP9) were low expressed after NDV infection. Additionally, two potential competing endogenous RNA networks (ENSGALT00000060887/gga-miR-6575-5p/PON2 or MSTRG.188121.10/gga-miR-6631-5p/MMP9) and some co-expression axes (ENSGALT00000065826/gga-miR-6631-5p, MSTRG.188121.10/gga-miR-6575-5p, MSTRG.188121.10/CFTR, ENSGALT00000060887/MMP9) were identified based on RT-qPCR and co-expression analyses. In conclusion, we identified multiple dysregulated lncRNAs, miRNAs, and mRNAs after LaSota infection and some potential regulatory networks for these dysregulated transcripts.

PMID:35403571 | DOI:10.1080/21655979.2021.2008737

Front Med (Lausanne). 2022 Mar 23;9:841887. doi: 10.3389/fmed.2022.841887. eCollection 2022.

ABSTRACT

INTRODUCTION: Making bench to bedside advances in cystic fibrosis (CF) care requires the sustained engagement and trust of people living with CF. However, there is a scarcity of studies exploring their concerns and priorities regarding research and its end products. The aim of this qualitative study was to generate empirical evidence regarding patient and caregiver perspectives on cystic fibrosis research and personalized medicine to foster developments in translational research in Canada.

METHODS: A total of 15 focus groups were conducted, engaging 22 adults with CF and 18 caregivers (e.g., parents, siblings and partners) living in Canada. Inductive thematic analysis relied on an iterative process involving themes derived from both participant meaning-making and existing scientific literature. Participant perspectives were considered along intrapersonal, intracommunity, interpersonal, and structural lines.

RESULTS: Overall, participants described a relationship to CF research inextricable from the lived experience of CF as a lifelong progressive and terminal disease and from the goal of advancing medical science. They were enthusiastic and excited about the emergence of CFTR modulators, although they had some knowledge gaps regarding the associated research. They largely spoke to positive experiences with researcher communication but had feedback regarding informed consent processes and the return of study results. Participants also voiced concerns about structural access barriers to research and to its end products. Extensive histories of research participation, a relatively small and intercommunicative CF community, and structural overlap between research and care settings contributed to their perspectives and priorities.

CONCLUSION: Study findings are valuable for researchers and policy-makers in CF and rare or progressive diseases more broadly. Continuing to solicit and listen to the voices of patients and caregivers is crucial for research ethics and the translation of new therapies in the area of personalized medicine.

PMID:35402437 | PMC:PMC8984098 | DOI:10.3389/fmed.2022.841887

Front Cell Infect Microbiol. 2022 Mar 25;12:861866. doi: 10.3389/fcimb.2022.861866. eCollection 2022.

ABSTRACT

BACKGROUND: The modified International Society for Human and Animal Mycology (ISHAM) allergic bronchopulmonary aspergillosis (ABPA) working group (AWG) criteria lists up to five components for diagnosing ABPA in asthmatics. Whether eliminating specific components of the existing criteria would have the same diagnostic utility as the original remains unknown.

OBJECTIVE: To evaluate the performance of several simplified criteria for diagnosing ABPA.

METHODS: We compared the performance of seven new criteria (after excluding or modifying one or more of the components of the ISHAM-AWG criteria) with the modified ISHAM-AWG criteria in asthmatic subjects using latent class analysis (LCA). We also tested the performance of the newer criteria using accuracy measures against a multidisciplinary team (MDT) diagnosis of ABPA. We considered the diagnostic accuracy of the newer criteria to be acceptable if the correct classification and false-negative rates were >95% and <5%, respectively, on an MDT evaluation.

RESULTS: We analyzed data from 543 asthmatic subjects (58.8% women; mean age, 36.8 years). Using LCA, the sensitivity of the A.fumigatus-specific IgE-based criteria ranged from 92-99%, while the specificity varied between 92% and 100%. The MDT diagnosed ABPA in 106 (19.5%) subjects. Using MDT as the reference standard, the correct classification and false-negative rates were >95% for three of the seven and <5% for four of the seven newer criteria.

CONCLUSIONS: We found several of the newly developed criteria to perform, like the modified ISHAM-AWG criteria, for diagnosing ABPA complicating asthma. A prospective study in current clinical algorithms is required for validating our observations.

PMID:35402294 | PMC:PMC8990730 | DOI:10.3389/fcimb.2022.861866

Transl Cancer Res. 2022 Mar;11(3):436-443. doi: 10.21037/tcr-21-2296.

ABSTRACT

BACKGROUND: The role of cystic fibrosis transmembrane conductance regulator (CFTR) in hematopoiesis and adult leukemia has been demonstrated using a zebrafish model and leukemia cell lines in our previous works. Here, we continue to explore the association between CFTR and human childhood B-cell acute lymphoblastic leukemia (B-ALL).

METHODS: We continued to collect the peripheral blood and bone marrows of human childhood patients diagnosed with primary B-ALL as well as non-leukemia controls and isolated lymphocytes for analysis using western blotting and quantitative real-time polymerase chain reaction (qPCR) assay. Then, we used immunofluorescence, co-immunoprecipitation, western blotting, luciferase, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assays to identify the interaction of CFTR with Wnt signaling in B-ALL. Finally, we established B-ALL xenograft model in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice using SUP-B15 cells, and examined whether the CFTR inhibitor CFTR-inh172 could active against SUP-B15-Dependent B-ALL in vivo.

RESULTS: Highly expressed CFTR protein and mRNA are associated with primary childhood B-ALL patients. Aberrantly upregulated CFTR and Wnt signaling, our previously reported CFTR-Dvl2-β-catenin pathway, is found in human childhood B-ALL patients. Interference with CFTR in B-ALL cell lines induces the downregulation of DVL2/β-catenin and Wnt downstream target accompanied by a reduction of cell proliferation. Furthermore, B-ALL cell lines SUP-B15 cell-transplanted NOD/SCID mice treated with CFTR inhibitor CFTRinh-172 had significantly longer survival and slower leukemia progression compared with mice treated with vehicle dimethyl sulfoxide (DMSO).

CONCLUSIONS: These findings demonstrate that highly expressed CFTR is associated with human childhood B-ALL and the potential of CFTR inhibitor CFTR-inh172 for the treatment of human B-ALL.

PMID:35402186 | PMC:PMC8990221 | DOI:10.21037/tcr-21-2296

Radiol Case Rep. 2022 Apr 4;17(6):1836-1842. doi: 10.1016/j.radcr.2022.03.024. eCollection 2022 Jun.

ABSTRACT

Pulmonary artery pseudoaneurysm (PAP) is a rare cause of life-threatening hemoptysis and tends to develop in the setting of infection, neoplasm, or trauma. Successful endovascular coil embolization has demonstrated effectiveness in treating PAPs and is now the treatment of choice for these patients. Vascular supply to PAPs is highly variable and often requires embolization of both the systemic and pulmonary feeding vessels. This is a case report of a successful transcatheter coil embolization of a complex PAP with a thyrocervical trunk-pulmonary arterial fistula in a patient with massive hemoptysis in the setting of advanced cystic fibrosis.

PMID:35401900 | PMC:PMC8990057 | DOI:10.1016/j.radcr.2022.03.024

J Cyst Fibros. 2022 Apr 7:S1569-1993(22)00088-1. doi: 10.1016/j.jcf.2022.03.011. Online ahead of print.

ABSTRACT

BACKGROUND: Therapy with Elexacaftor/Tezacaftor/Ivacaftor (ETI) was recently approved for adult cystic fibrosis (CF) patients with at least one F508del mutation. However, its effects on structural and functional lung abnormalities and chronic rhinosinusitis have not been studied by imaging.

METHODS: 19 adults with CF (mean age 31±9y, range 19-55y) underwent standardized chest magnetic resonance imaging (MRI), and nine also same-session sinonasal MRI, before (MRI1) and after (MRI2) at least one month (mean duration 5 ± 3mon) on ETI. 24 control CF patients (30±7y, range 20-44y) without ETI underwent longitudinal chest MRI, and eleven also sinonasal MRI, twice (mean interval 40±15mon). MRI was assessed using the validated chest MRI score and chronic rhinosinusitis (CRS)-MRI score. Forced expiratory volume in 1 s percent predicted (FEV1%) was measured in all patients.

RESULTS: In controls, the chest MRI global score and CRS-MRI sum score were stable from MRI1 to MRI2. In patients under ETI, the chest MRI global score improved (-11.4 ± 4.6, P<0.001), mainly due to reduction of bronchiectasis/wall thickening and mucus plugging subscores (-3.3 ± 2.2 and -5.2 ± 1.5, P<0.001, respectively). The improvement in chest MRI score correlated well with improved FEV1% (r=-0.703, P<0.001). The CRS-MRI sum score also improved in patients under ETI (-6.9 ± 3.0, P<0.001), mainly due to a reduction of mucopyoceles in the maxillary and ethmoid sinus (-50% and -39%, P<0.05, respectively).

CONCLUSIONS: MRI detects improvements of chest MRI and CRS-MRI scores in adult CF patients who first received ETI, demonstrating reversibility of structural lung and paranasal sinus abnormalities in patients with established disease.

PMID:35400600 | DOI:10.1016/j.jcf.2022.03.011

Front Physiol. 2022 Mar 23;13:834716. doi: 10.3389/fphys.2022.834716. eCollection 2022.

ABSTRACT

The use of airway clearance strategies as supplementary treatment in respiratory disease has been best investigated in patients with cystic fibrosis (CF) and non-cystic fibrosis bronchiectasis (NCFBE), conditions which are traditionally characterized by excessive mucus stasis and mucociliary dysfunction. A variety of airway clearance therapies both pharmacological and non-pharmacological have been shown to ameliorate disease progression in this population and have hence been assimilated into routine respiratory care. This self-propagating cycle of mucus retention and airway damage leading to chronic inflammation and infections can also be applied to patients with respiratory failure requiring mechanical ventilation. Furthermore, excessive trachea-bronchial secretions have been associated with extubation failure presenting an opportunity for intervention. Evidence for the use of adjunctive mucoactive agents and other therapies to facilitate secretion clearance in these patients are not well defined, and this subgroup still remains largely underrepresented in clinical trials. In this review, we discuss the role of mucus clearance techniques with a proven benefit in patients with CF and NCFBE, and their potential role in patients requiring mechanical ventilation while highlighting the need for standardization and adoption of mucus clearance strategies in these patient populations.

PMID:35399263 | PMC:PMC8984116 | DOI:10.3389/fphys.2022.834716

Int J Pediatr Otorhinolaryngol. 2022 Mar 29;156:111125. doi: 10.1016/j.ijporl.2022.111125. Online ahead of print.

ABSTRACT

OBJECTIVES: Pediatric chronic rhinosinusitis (PCRS) is a unique clinical entity and the underlying source of inflammation is unknown. Certain subgroups, such as children with nasal polyps and cystic fibrosis (CF) sinusitis are often recalcitrant to standard medical PCRS treatments that target bacterial inflammation. Fungal infection and allergy to fungal proteins drive inflammation in other airway diseases, resulting in chronic inflammation of both the upper and lower airways. However, there is limited understanding of the role of fungi in the pathophysiology of PCRS. The objective of this study is to define the frequency of fungal infection in pediatric CRS patients, hypothesizing that certain subgroups may have more frequent positive fungal sinus cultures than other subgroups of pediatric sinusitis.

METHODS: Retrospective study of patients undergoing sinus surgery at a tertiary care pediatric hospital to determine the period prevalence of positive fungal cultures in subgroups of patients.

RESULTS: 400 children from 2012 to 2019 were included. 265 patients had surgical culture results available. Of the 52 patients with CF 11 (21%) had positive fungal sinus cultures. Similarly, 28% of the 25 patients with non-CF nasal polyps had positive cultures. Only 8.2% of 110 CRS without polyps patients had positive cultures, significantly fewer than other subgroups (X2 (1, N = 240) = 17.22, p < 0.01).

CONCLUSION: Children with CF and children with nasal polyps had more frequent positive fungal cultures than children without nasal polyps having sinus surgery. This confirms that pediatric CF and pediatric CRS with polyps represent unique populations to study the impact of fungal infection in CRS. Further research is required to determine if these fungi represent colonization or contribute to the inflammatory environment of the airways.

PMID:35398790 | DOI:10.1016/j.ijporl.2022.111125

NPJ Genom Med. 2022 Apr 8;7(1):28. doi: 10.1038/s41525-022-00299-9.

ABSTRACT

Over 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF. We investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD). Rs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p = 0.008); and for gating (p = 0.033) and p.Phe508del/ p.Phe508del (p = 0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p = 0.0022). Beyond CF, rs7512462 is associated with peak expiratory flow in a meta-analysis of the UK Biobank and Spirometa Consortium (p = 2.74 × 10-44) and provides p = 0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry. These findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.

PMID:35396391 | DOI:10.1038/s41525-022-00299-9

J Cyst Fibros. 2022 Apr 5:S1569-1993(22)00087-X. doi: 10.1016/j.jcf.2022.03.010. Online ahead of print.

ABSTRACT

Strong emphasis has been placed historically on increasing weight and improving nutritional status in cystic fibrosis patients. Due to correlation between nutritional indices (e.g. BMI) and lung function, CF Nutrition Guidelines have recommended BMI percentile goals at the 50th percentile or higher. Trends in increasing BMI across CF programs suggest significantly increasing proportions of overweight and obese status in recent years. We identify that between 2000 and 2019 there has been a relative decrease in underweight status by ∼40%, simultaneously with a > 300% increase in overweight status, and >400% increase in obesity. Patient specific factors associated with higher prevalence of obesity included age ≥46, living in a zip code where the median income was < $20,000, having at least one allele with a class IV or V mutation, a ppFEV1 >90 prescribed ivacaftor, and not prescribed pancreatic enzymes. Program specific factors were not identified.

PMID:35396178 | DOI:10.1016/j.jcf.2022.03.010

Sci Rep. 2022 Apr 7;12(1):5838. doi: 10.1038/s41598-022-09618-7.

ABSTRACT

Oxylipins are signaling molecules originated by fatty acids that modulate vascular and bronchial tone, bronchial secretion, cytokine production and immune cell activity. The unbalanced production of pro-inflammatory and pro-resolving (i.e., anti-inflammatory) oxylipins has a relevant role in the pathogenesis of pulmonary inflammation like in cystic fibrosis (CF). We analyzed by LC-MRM/MS 65 oxylipins and 4 fatty acids in resting saliva from 69 patients with CF and 50 healthy subjects (controls). The salivary levels of 48/65 oxylipins were significantly different between CF patients and controls. Among these, EpETE, DHET, 6ketoPGE1 and HDHA were significantly higher in saliva from CF patients than in controls. All these molecules display anti-inflammatory effects, i.e., releasing of bronchial and vascular tone, modulation of cytokine release. While 20-hydroxyPGF2A, PGB2, EpDPE, 9 K-12-ELA, bicyclo-PGE2, oleic acid, LTC4, linoleic acid, 15oxoEDE, 20 hydroxyPGE2 and DHK-PGD2/PGE2 (mostly associated to pro-inflammatory effects) resulted significantly lower in CF patients than in controls. Our data suggest that the salivary oxylipins profile in CF patients is addressed toward a global anti-inflammatory effect. Although these findings need be confirmed on larger populations in prospective studies, they will contribute to better understand the pathogenesis of CF chronic inflammation and to drive targeted therapies based on the modulation of oxylipins synthesis and degradation.

PMID:35393448 | DOI:10.1038/s41598-022-09618-7

BMC Pulm Med. 2022 Apr 7;22(1):131. doi: 10.1186/s12890-022-01919-x.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) are often associated with airway fluid acidification. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene leads to impaired bicarbonate secretion contributing to CF airway pathology. Chronic cigarette smoke (CS) -the major cause of COPD- is reported to induce acquired CFTR dysfunction underlying airway acidification and inflammation. We hypothesize that bicarbonate-containing aerosols could be beneficial for patients with CFTR dysfunctions. Thus, we investigated the safety of hypertonic sodium bicarbonate (NaHCO3) inhalation in CS-exposed guinea pigs.

METHODS: Animals were divided into groups inhaling hypertonic NaCl (8.4%) or hypertonic NaHCO3 (8.4%) aerosol for 8 weeks. Subgroups from each treatment groups were further exposed to CS. Respiratory functions were measured at 0 and after 2, 4, 6 and 8 weeks. After 8 weeks blood tests and pulmonary histopathological assessment were performed.

RESULTS: Neither smoking nor NaHCO3-inhalation affected body weight, arterial and urine pH, or histopathology significantly. NaHCO3-inhalation did not worsen respiratory parameters. Moreover, it normalized the CS-induced transient alterations in frequency, peak inspiratory flow, inspiratory and expiratory times.

CONCLUSION: Long-term NaHCO3-inhalation is safe in chronic CS-exposed guinea pigs. Our data suggest that bicarbonate-containing aerosols might be carefully applied to CF patients.

PMID:35392868 | DOI:10.1186/s12890-022-01919-x