Thorax. 2023 May 19:thorax-2022-219943. doi: 10.1136/thorax-2022-219943. Online ahead of print.

ABSTRACT

Treatment with elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to improve lung function in people with cystic fibrosis (PWCF). However, its biological effects remain incompletely understood. Here we describe alterations in pulmonary and systemic inflammation in PWCF following initiation of ETI. To address this, we collected spontaneously expectorated sputum and matching plasma from PWCF (n=30) immediately prior to ETI therapy, then again at 3 and 12 months. Within 3 months, PWCF demonstrated reduced activity of neutrophil elastase, proteinase three and cathepsin G, and decreased concentrations of interleukin (IL)-1β and IL-8 in sputum, accompanied by decreased Pseudomonas burden and restoration of secretory leukoprotease inhibitor levels. Once treated with ETI, all airway inflammatory markers studied in PWCF had reduced to levels found in matched non-CF bronchiectasis controls. In PWCF with advanced disease, ETI resulted in decreased plasma concentrations of IL-6, C-reactive protein and soluble TNF receptor one as well as normalisation of levels of the acute phase protein, alpha-1 antitrypsin. These data clarify the immunomodulatory effects of ETI and underscore its role as a disease modifier.

PMID:37208188 | DOI:10.1136/thorax-2022-219943

Plasmid. 2023 May 17:102686. doi: 10.1016/j.plasmid.2023.102686. Online ahead of print.

ABSTRACT

Duchenne Muscular Dystrophy and Cystic Fibrosis are two major monogenetic diseases which could be treated by non-viral gene therapy. For this purpose, plasmid DNA (pDNA) coding for the functional genes requires its equipment with signal molecules favouring its intracellular trafficking and delivery in the nucleus of the target cells. Here, two novel constructions of large pDNAs encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and full-length dystrophin (DYS) genes are reported. The expression of CFTR and DYS genes are driven respectively by the hCEF1 airway epithelial cells and spc5-12 muscle cells specific promoter. Those pDNAs encode also the luciferase reporter gene driven by the CMV promoter to evaluate gene delivery in animals by bioluminescence. In addition, oligopurine • oligopyrimidine sequences are inserted to enable equipment of pDNAs with peptides conjugated with a triple helix forming oligonucleotide (TFO). Furthermore, specific κB sequences are also inserted to promote their NFκB-mediated nuclear import. pDNA constructions are reported; transfection efficiency, tissue specific expression of CFTR and dystrophin in target cells, and triple helix formation are demonstrated. These plasmids are tools of interest to develop non-viral gene therapy of Cystic Fibrosis and Duchenne Muscular Dystrophy.

PMID:37207938 | DOI:10.1016/j.plasmid.2023.102686

Cancer Cell. 2023 May 6:S1535-6108(23)00141-1. doi: 10.1016/j.ccell.2023.04.015. Online ahead of print.

ABSTRACT

Calreticulin (CALR) exposure on the cell surface is known to deliver robust pro-phagocytic signals to myeloid cells. In Nature, Sen Santara et al. demonstrate that surface-exposed CALR also operates as an endogenous activator of natural killer (NK) cells. Collectively, these findings suggest that CALR exposure orchestrates multiple facets of innate immunosurveillance.

PMID:37207656 | DOI:10.1016/j.ccell.2023.04.015

JPGN Rep. 2021 Apr 12;2(2):e060. doi: 10.1097/PG9.0000000000000060. eCollection 2021 May.

NO ABSTRACT

PMID:37207072 | PMC:PMC10191469 | DOI:10.1097/PG9.0000000000000060

Oncoimmunology. 2023 May 15;12(1):2212547. doi: 10.1080/2162402X.2023.2212547. eCollection 2023.

ABSTRACT

In a recent paper in Science, Chen et al. reported the genetic engineering of S. epidermidis expressing tumor cross-reactive antigens that trigger T cell responses and exhibit anticancer effects after topical administration. Here we discuss direct local effects and indirect systemic effects of exposure to engineered S. epidermidis strains.

PMID:37205984 | PMC:PMC10190176 | DOI:10.1080/2162402X.2023.2212547

JPGN Rep. 2021 Jul 12;2(3):e096. doi: 10.1097/PG9.0000000000000096. eCollection 2021 Aug.

ABSTRACT

Exocrine pancreatic insufficiency (EPI) is a common complication of cystic fibrosis (CF). While previously considered to be irreversible, recent reported cases document improved pancreatic function in CF patients with mild mutations after ivacaftor treatment alone. We report a 12-year-old female with homozygous F508del CF and EPI who developed acute pancreatitis after 3 years on lumacaftor/ivacaftor and subsequently had improved pancreatic function. As CF therapies advance, some EPI CF patients with more severe CF transmembrane conductance regulator mutations may see improved pancreatic function and subsequently develop pancreatitis.

PMID:37205952 | PMC:PMC10191563 | DOI:10.1097/PG9.0000000000000096

Front Pharmacol. 2023 May 3;14:1207356. doi: 10.3389/fphar.2023.1207356. eCollection 2023.

ABSTRACT

[This corrects the article DOI: 10.3389/fphar.2022.877118.].

PMID:37205908 | PMC:PMC10189544 | DOI:10.3389/fphar.2023.1207356

bioRxiv. 2023 May 7:2023.05.05.539132. doi: 10.1101/2023.05.05.539132. Preprint.

ABSTRACT

Duodenal bicarbonate secretion is critical to epithelial protection, nutrient digestion/absorption and is impaired in cystic fibrosis (CF). We examined if linaclotide, typically used to treat constipation, may also alter duodenal bicarbonate secretion. Bicarbonate secretion was measured in vivo and in vitro using mouse and human duodenum. Ion transporter localization was identified with confocal microscopy and de novo analysis of human duodenal single cell RNA sequencing (sc-RNAseq) was performed. Linaclotide increased bicarbonate secretion in mouse and human duodenum in the absence of CFTR expression or function. Linaclotide-stimulated bicarbonate secretion was eliminated by down-regulated in adenoma (DRA) inhibition, regardless of CFTR activity. Sc-RNAseq identified that 70% of villus cells expressed SLC26A3 , but not CFTR , mRNA. Linaclotide increased apical membrane expression of DRA in non-CF and CF differentiated enteroids. These data provide insights into the action of linaclotide and suggest linaclotide may be a useful therapy for CF individuals with impaired bicarbonate secretion.

PMID:37205513 | PMC:PMC10187319 | DOI:10.1101/2023.05.05.539132

bioRxiv. 2023 May 2:2023.05.02.539145. doi: 10.1101/2023.05.02.539145. Preprint.

ABSTRACT

BACKGROUND: Linezolid is an antibiotic used to treat serious Staphylococcus aureus infections. Resistance to linezolid is considered rare but could emerge with repeated dosing. We recently reported widespread prescription of linezolid for a cohort of patients with cystic fibrosis (CF).

OBJECTIVES: The goals of this study were to determine the incidence of linezolid resistance in CF and identify molecular mechanisms for linezolid resistance.

METHODS: We identified patients with S. aureus resistant to linezolid (MIC > 4) at the University of Iowa CF Center between 2008 and 2018. We obtained isolates from these patients and retested susceptibility to linezolid using broth microdilution. We used whole genome sequencing to perform phylogenetic analysis of linezolid resistant isolates and examine sequences for mutations or accessory genes that confer linezolid resistance.

MAIN RESULTS: Between 2008 and 2018, 111 patients received linezolid and 4 of these patients cultured linezolid resistant S. aureus . We sequenced 11 resistant and 21 susceptible isolates from these 4 subjects. Phylogenetic analysis indicated that linezolid resistance developed in ST5 or ST105 backgrounds. Three individuals had linezolid resistant S. aureus with a G2576T mutation in 23S rRNA. One of these subjects additionally had a mutS - mutL - hypermutating S. aureus that produced 5 resistant isolates with multiple ribosomal subunit mutations. In one subject, the genetic basis for linezolid resistance was unclear.

CONCLUSIONS: Linezolid resistance evolved in 4 of 111 patients in this study. Linezolid resistance occurred by multiple genetic mechanisms. All resistant strains developed in ST5 or ST105 MRSA backgrounds.

KEY POINT: Linezolid resistance arises through multiple genetic mechanisms and could be facilitated by mutator phenotypes. Linezolid resistance was transient, possibly due to growth disadvantage.

PMID:37205485 | PMC:PMC10187253 | DOI:10.1101/2023.05.02.539145

bioRxiv. 2023 May 2:2023.05.02.539134. doi: 10.1101/2023.05.02.539134. Preprint.

ABSTRACT

The healthy human infant gut microbiome undergoes stereotypical changes in taxonomic composition between birth and maturation to an adult-like stable state. During this time, extensive communication between microbiota and the host immune system contributes to health status later in life. Although there are many reported associations between microbiota compositional alterations and disease in adults, less is known about how microbiome development is altered in pediatric diseases. One pediatric disease linked to altered gut microbiota composition is cystic fibrosis (CF), a multi-organ genetic disease involving impaired chloride secretion across epithelia and heightened inflammation both in the gut and at other body sites. Here, we use shotgun metagenomics to profile the strain-level composition and developmental dynamics of the infant fecal microbiota from several CF and non-CF longitudinal cohorts spanning from birth to greater than 36 months of life. We identify a set of keystone species whose prevalence and abundance reproducibly define microbiota development in early life in non-CF infants, but are missing or decreased in relative abundance in infants with CF. The consequences of these CF-specific differences in gut microbiota composition and dynamics are a delayed pattern of microbiota maturation, persistent entrenchment in a transitional developmental phase, and subsequent failure to attain an adult-like stable microbiota. We also detect the increased relative abundance of oral-derived bacteria and higher levels of fungi in CF, features that are associated with decreased gut bacterial density in inflammatory bowel diseases. Our results define key differences in the gut microbiota during ontogeny in CF and suggest the potential for directed therapies to overcome developmental delays in microbiota maturation.

PMID:37205374 | PMC:PMC10187160 | DOI:10.1101/2023.05.02.539134

Pediatr Pulmonol. 2023 May 19. doi: 10.1002/ppul.26491. Online ahead of print.

ABSTRACT

OBJECTIVE: Clinical trial research have provided evidence that omega-3 may have larger potential benefits for treating cystic fibrosis (CF). This study's objective was to assess the impact of three supplementation on pediatric CF patients.

METHODS: Scopus, PubMed/Medline, Web of Science, Cochrane, and Embase databases were searched from commencement until July 20, 2022 using standard keywords to identify all randomized controlled studies (RCTs) examining the effects of omega-3 supplementation on young patients with CF. The eligible studies were subjected to a random-effects model meta-analysis.

RESULTS: A meta-analysis of 12 the eligible studies was performed. Findings of the study showed that omega-3 supplementation significantly increased the levels of docosahexaenoic acid (weighted mean [WMD]: 2.06%, 95% confidence interval [CI]: 1.29, 2.82, p < 0.001) and eicosapentaenoic acid (WMD: 0.32%, 95% CI: 0.15, 0.48, p < 0.001) as well as decreased arachidonic acid (WMD: -0.78%, 95% CI: -1.50, -0.05, p = 0.035) and C-receptive protein (CRP) (WMD: -3.76 mg/L, 95% CI: -7.42, -0.10, p = 0.044) especially when used in higher doses and for a longer period of time compared to the control group. However, no significant effect was observed on other factors including forced expiratory volume 1, forced vital capacity as well as anthropometric parameters. In addition, high heterogeneity was reported for all fatty acids, but heterogeneity was low and nonsignificant for other variables.

CONCLUSION: The finding showed that in pediatric patients with CF, omega-3 supplementation showed benefits only in plasma fatty acid profile and serum CRP.

PMID:37204224 | DOI:10.1002/ppul.26491

Eur Rev Med Pharmacol Sci. 2023 May;27(9):4316-4325. doi: 10.26355/eurrev_202305_32342.

ABSTRACT

Bacterial multidrug resistance has been a serious issue for healthcare systems in recent decades, responsible for many infections and deaths. Due to the increasing incidence of antimicrobial resistance and scarce treatment options, research is focused on finding possible therapeutic adjuvants able to increase the efficacy of antibiotics. The aim of this article is a review of available evidence on the use of N-acetylcysteine (NAC). MEDLINE/PubMed was searched for appropriate keywords. In vitro and in vivo preclinical studies, clinical studies, reviews, and meta-analyses were retrieved and selected based on relevance. A narrative review article was written, reporting published evidence and the expert opinion of the authors. Among possible adjunctive treatments, NAC has attracted the interest of researchers as a candidate for re-purposing. It is a widely used drug with a good tolerability profile, mainly used as a mucolytic agent, with antioxidant, anti-inflammatory properties and antibacterial activity. NAC acts on different mechanisms and stages of infections, resulting in inhibition of biofilm formation, disruption of preformed biofilms, and reduction of bacterial viability. NAC may be administered as an aerosol in many types of infections, including cystic fibrosis, bronchiectasis and infective flare of chronic obstructive pulmonary disease (COPD), and by the intravenous route in severe systemic infections (including septic shock) such as those caused by carbapenemase (KPC)-producing Klebsiella pneumoniae (Kp) and Carbapenem-Resistant Acinetobacter baumannii (CR-Ab). A rationale exists for using NAC as an adjunctive treatment in multidrug-resistant (MDR) infections, based on in vitro, in vivo and clinical evidence, and future research is needed to identify candidate patients and optimal schedules for specific clinical conditions.

PMID:37203858 | DOI:10.26355/eurrev_202305_32342

Cardiol Young. 2023 May 19:1-6. doi: 10.1017/S1047951123001178. Online ahead of print.

ABSTRACT

As the life expectancy improves in cystic fibrosis, cardiac dysfunction is becoming an important risk factor for morbidity and mortality. Here, the association of cardiac dysfunction with proinflammatory markers and neurohormones between cystic fibrosis patients and healthy children was investigated. Echocardiographic measurements of right and left ventricular morphology and functions together with levels of proinflammatory markers and neurohormones (renin, angiotensin-II, and aldosterone) were obtained and analysed in a study group of 21 cystic fibrosis children aged 5-18 years and compared with age- and gender-matched healthy children. It was shown that patients had significantly higher interleukin-6, C-reactive protein, renin and aldosterone levels (p < 0.05), dilated right ventricles, decreased left ventricle sizes, as well as both right and left ventricular dysfunction. These echocardiographic changes correlated with hypoxia, interleukin-1 α, interleukin-6, C-reactive protein, and aldosterone (p < 0.05) levels. The current study revealed that hypoxia, proinflammatory markers, and neurohormones are major determinants of subclinical changes in ventricular morphology and function. While the right ventricle anatomy was affected by cardiac remodeling, the left ventricle changes were induced by right ventricle dilation and hypoxia. A significant but subclinical systolic and diastolic right ventricle dysfunction in our patients was associated with hypoxia and inflammatory markers. Systolic left ventricle function was affected by hypoxia and neurohormones. Echocardiography is a reliable and non-invasive method that is used safely in cystic fibrosis children for screening and detection of cardiac anatomical and functional changes. Extensive studies are needed to determine the time and frequency of screening and treatment suggestions for such changes.

PMID:37203789 | DOI:10.1017/S1047951123001178

Stud Health Technol Inform. 2023 May 18;302:480-481. doi: 10.3233/SHTI230180.

ABSTRACT

We have designed a prototype N-of-1 analytics makerspace, which is a collaborative work environment that provides a space for different stakeholders in healthcare to learn new skills and work together on projects that can improve individual patient care and the effectiveness of healthcare systems. Our prototype was designed to study the use of antibiotics in self-management for children with cystic fibrosis in Sweden but is intended to be disease agnostic and potentially include other complex medical conditions in the future.

PMID:37203724 | DOI:10.3233/SHTI230180

Int Forum Allergy Rhinol. 2023 May 19. doi: 10.1002/alr.23180. Online ahead of print.

NO ABSTRACT

PMID:37203268 | DOI:10.1002/alr.23180

Clin Nutr ESPEN. 2023 Jun;55:400-406. doi: 10.1016/j.clnesp.2023.04.008. Epub 2023 Apr 15.

ABSTRACT

BACKGROUND & AIMS: Cystic fibrosis (CF) is a multisystem disease that can compromise several human body organs. The autosomal recessive genetic disorder is caused by different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, responsible for chloride ion transport across apical membranes of epithelial cells in tissues and bicarbonate secretion. In this study, we provide a systematic review of the profile of the intestinal microbiota of cystic fibrosis individuals.

METHODS: The review was conducted according to Preferred Items of Reports for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. PubMed/MEDLINE and Scopus databases were searched for relevant articles until Jully 2022.

RESULTS: Eighteen studies (1304 participants) met the inclusion criteria. The quality and bias was assessed using the Methodological index for non-randomized studies (MINORS) tool, with the majority of the studies indicating medium to high quality. Results showed significant changes in the composition of the intestinal microbiota of the individuals with CF compared with healthy controls, with increased of Enterococcus, Veillonella, and Streptococcus, and decreased of Bifidobacterium, Roseburia, and Alistipes genus. The intestinal bacterial community of CF patients was marked by a reduction in its richness and diversity.

CONCLUSION: The systematic review suggests a change in the intestinal microbiota of CF individuals, characterized by a reduction in microbial diversity and abundance of some bacterial markers.

PMID:37202074 | DOI:10.1016/j.clnesp.2023.04.008

J Cyst Fibros. 2023 May 16:S1569-1993(23)00132-7. doi: 10.1016/j.jcf.2023.05.002. Online ahead of print.

NO ABSTRACT

PMID:37202324 | DOI:10.1016/j.jcf.2023.05.002

PLoS Pathog. 2023 May 18;19(5):e1011318. doi: 10.1371/journal.ppat.1011318. eCollection 2023 May.

ABSTRACT

Mycobacterium abscessus is a nontuberculosis mycobacterium (NTM) that has shown an exponential rise in its ability to cause disease. Due to its ubiquitous presence in the environment, M. abscessus is widely implicated in secondary exacerbations of many nosocomial infections and genetic respiratory disorders, such as cystic fibrosis (CF). Contrary to other rapidly growing NTMs, the cell envelope of M. abscessus harbors several prominent features and undergoes modifications that are responsible for its pathogenesis. Compositional changes of the mycobacterial outer membrane (MOM) significantly decrease the presence of glycopeptidolipids (GPLs) and enable the transition from a colonizing, smooth morphotype into a virulent, rough morphotype. The GPLs are transported to the MOM by the Mycobacterial membrane proteins Large (MmpL), which further act as drug efflux pumps and confer antibiotic resistance. Lastly, M. abscessus possesses 2 type VII secretion systems (T7SS): ESX-3 and ESX-4, both of which have recently been implicated in host-pathogen interactions and virulence. This review summarizes the current knowledge of M. abscessus pathogenesis and highlights the clinically relevant association between the structure and functions of its cell envelope.

PMID:37200238 | DOI:10.1371/journal.ppat.1011318

Microbiol Spectr. 2023 May 18:e0405722. doi: 10.1128/spectrum.04057-22. Online ahead of print.

ABSTRACT

16S-based sequencing provides broader information on the respiratory microbial community than conventional culturing. However, it (often) lacks species- and strain-level information. To overcome this issue, we used 16S rRNA-based sequencing results from 246 nasopharyngeal samples obtained from 20 infants with cystic fibrosis (CF) and 43 healthy infants, which were all 0 to 6 months old, and compared them to both standard (blind) diagnostic culturing and a 16S-sequencing-informed "targeted" reculturing approach. Using routine culturing, we almost uniquely detected Moraxella catarrhalis, Staphylococcus aureus, and Haemophilus influenzae (42%, 38%, and 33% of samples, respectively). Using the targeted reculturing approach, we were able to reculture 47% of the top-5 operational taxonomical units (OTUs) in the sequencing profiles. In total, we identified 60 species from 30 genera with a median of 3 species per sample (range, 1 to 8). We also identified up to 10 species per identified genus. The success of reculturing the top-5 genera present from the sequencing profile depended on the genus. In the case of Corynebacterium being in the top 5, we recultured them in 79% of samples, whereas for Staphylococcus, this value was only 25%. The success of reculturing was also correlated with the relative abundance of those genera in the corresponding sequencing profile. In conclusion, revisiting samples using 16S-based sequencing profiles to guide a targeted culturing approach led to the detection of more potential pathogens per sample than conventional culturing and may therefore be useful in the identification and, consequently, treatment of bacteria considered relevant for the deterioration or exacerbation of disease in patients like those with CF. IMPORTANCE Early and effective treatment of pulmonary infections in cystic fibrosis is vital to prevent chronic lung damage. Although microbial diagnostics and treatment decisions are still based on conventional culture methods, research is gradually focusing more on microbiome and metagenomic-based approaches. This study compared the results of both methods and proposed a way to combine the best of both worlds. Many species can relatively easily be recultured based on the 16S-based sequencing profile, and it provides more in-depth information about the microbial composition of a sample than that obtained through routine (blind) diagnostic culturing. Still, well-known pathogens can be missed by both routine diagnostic culture methods as well as by targeted reculture methods, sometimes even when they are highly abundant, which may be a consequence of either sample storage conditions or antibiotic treatment at the time of sampling.

PMID:37199622 | DOI:10.1128/spectrum.04057-22

Adv Drug Deliv Rev. 2023 May 15:114866. doi: 10.1016/j.addr.2023.114866. Online ahead of print.

ABSTRACT

Epithelial cells from mucociliary portions of the airways can be readily grown and expanded in vitro. When grown on a porous membrane at an air-liquid interface (ALI) the cells form a confluent, electrically resistive barrier separating the apical and basolateral compartments. ALI cultures replicate key morphological, molecular and functional features of the in vivo epithelium, including mucus secretion and mucociliary transport. Apical secretions contain secreted gel-forming mucins, shed cell-associated tethered mucins, and hundreds of additional molecules involved in host defense and homeostasis. The respiratory epithelial cell ALI model is a time-proven workhorse that has been employed in various studies elucidating the structure and function of the mucociliary apparatus and disease pathogenesis. It serves as a critical milestone test for small molecule and genetic therapies targeting airway diseases. To fully exploit the potential of this important tool, numerous technical variables must be thoughtfully considered and carefully executed.

PMID:37196698 | DOI:10.1016/j.addr.2023.114866