Adv Exp Med Biol. 2022;1386:117-143. doi: 10.1007/978-3-031-08491-1_5.

ABSTRACT

Pseudomonas is a bacterial genus, with a bona fide environmental habitat that comprises different species, some of them causing diseases in humans and plants, as well as some strains with biotechnological potential. Amongst them, Pseudomonas aeruginosa is currently one of the most important nosocomial pathogens. In addition, this microorganism is a prevalent cause of chronic infections in cystic fibrosis patients and in people suffering from chronic obstructive pulmonary disease. The success of P. aeruginosa in colonising different habitats largely relies on its metabolic versatility and robustness. Besides, this bacterial pathogen harbours in its core genome a large set of virulence determinants that allows it to colonise/infect a variety of hosts, from unicellular organisms to humans. Nevertheless, these are not just the only conditions needed for infecting patients at hospitals. Taking into consideration that infected patients are regularly under antibiotic treatment, the ability to avoid antibiotics' action is also needed. In this sense, P. aeruginosa displays a characteristic low susceptibility to several antibiotics currently used in therapy. This is due to the reduced permeability of its cellular envelopes and the presence in its genome of an arrangement of genes encoding multidrug efflux pumps and antibiotic-inactivating enzymes that contribute to its resilience to antibiotics. Besides intrinsic resistance, P. aeruginosa is able to evolve towards antibiotic resistance through mutations (particularly relevant in the case of chronic infections) and via acquisition of antibiotic resistance genes. It is worth mentioning that acquired resistance is not the only venue that P. aeruginosa has for avoiding the action of antibiotics. Transient resistance can also confer this phenotype. Indeed, the induction of the expression of intrinsic resistance genes by conditions or compounds that P. aeruginosa could face during infection can compromise the effectiveness of antibiotics for treating such infections. In addition, tolerant cells able to survive during the exposure to bactericidal antibiotics without an increase in their antibiotic resistance phenotype are found as well in these patients, and they are the prelude of the evolution towards antibiotic resistance. Finally, P. aeruginosa biofilms, frequently encountered in the lungs of cystic fibrosis patients, in prostheses, or in catheters, present low antibiotic susceptibility and are associated with recalcitrance and disease worsening.

PMID:36258071 | DOI:10.1007/978-3-031-08491-1_5

J Med Chem. 2022 Oct 18. doi: 10.1021/acs.jmedchem.2c01373. Online ahead of print.

ABSTRACT

The Gram-negative pathogen Pseudomonas aeruginosa causes severe infections mainly in immunocompromised or cystic fibrosis patients and is able to resist antimicrobial treatments. The extracellular lectin LecB plays a key role in bacterial adhesion to the host and biofilm formation. For the inhibition of LecB, we designed and synthesized a set of fucosyl amides, sulfonamides, and thiourea derivatives. Then, we analyzed their binding to LecB in competitive and direct binding assays. We identified β-fucosyl amides as unprecedented high-affinity ligands in the two-digit nanomolar range. X-ray crystallography of one α- and one β-anomer of N-fucosyl amides in complex with LecB revealed the interactions responsible for the high affinity of the β-anomer at atomic level. Further, the molecules showed good stability in murine and human blood plasma and hepatic metabolism, providing a basis for future development into antibacterial drugs.

PMID:36256875 | DOI:10.1021/acs.jmedchem.2c01373

PLoS One. 2022 Oct 18;17(10):e0276310. doi: 10.1371/journal.pone.0276310. eCollection 2022.

ABSTRACT

OBJECTIVE: Airway clearance physiotherapy is recommended in cystic fibrosis, but limited evidence exists to suggest how much treatment is enough. As a secondary analysis of a prior study investigating the safety, efficacy, and participants' perceptions of a novel airway clearance technique, specific cough technique (SCT) compared to forced expiration technique (FET), we aimed to evaluate whether the intervention was associated with changes in health-related quality of life (HRQoL).

METHODS: We conducted randomised, controlled individual trials with six adults (N-of-1 RCTs). Each trial included eight weeks of treatment, twice a week, using saline inhalation in horizontal positions, one with SCT and one with FET, in random order. Efficacy was measured by sputum wet weight (g) after each session. Perceived usefulness and preference were self-reported at the end of the study. Lung function was assessed at baseline and at the end of study. HRQoL was measured using the Cystic Fibrosis Questionnaire-Revised (CFQ-R) at baseline (week 1) and at completion of the study (week 8). Individual HRQoL scores (0-100) were coded and analysed using CFQ-R Software Program, version 2.0.

RESULTS: Patient-reported outcomes were completed by all subjects. Individual CFQ-R-Respiratory Symptoms Scores (CFQ-R-RSS) showed a positive change, meeting the minimal important difference (MID) ≥ 4 points in five participants and a negative change in one individual. A strong correlation (r = 0.94 (p<0.01) was found between total sputum weight (g) and the positive changes in CFQ-R-RSS, and between changes in lung function and CFQ-R-RSS (r = 0.84 (p = 0.04).

CONCLUSION: The airway clearance intervention was associated with clinically meaningful changes in patient-reported symptoms on the CFQ-R in the majority of the participants. This finding warrants further investigation regarding treatment, duration and frequency. A long-term study may reveal beneficial effects on other clinically meaningful endpoints, such as pulmonary exacerbations, high-resolution computed tomography scores and HRQoL.

TRIAL REGISTRATION: The study was registered in ClinicalTrials.gov, under the number NCT0 1266473.

PMID:36256673 | DOI:10.1371/journal.pone.0276310

Microbiol Spectr. 2022 Oct 18:e0146622. doi: 10.1128/spectrum.01466-22. Online ahead of print.

ABSTRACT

Newborn screening for cystic fibrosis (CF) can identify affected but asymptomatic infants. The selection of omic technique for gut microbiota study is crucial due to both the small amount of feces available and the low microorganism load. Our aims were to compare the agreement between 16S rRNA amplicon sequencing and metaproteomics by a robust statistical analysis, including both presence and abundance of taxa, to describe the sequential establishment of the gut microbiota during the first year of life in a small size sample (8 infants and 28 fecal samples). The taxonomic assignations by the two techniques were similar, whereas certain discrepancies were observed in the abundance detection, mostly the lower predicted relative abundance of Bifidobacterium and the higher predicted relative abundance of certain Firmicutes and Proteobacteria by amplicon sequencing. During the first months of life, the CF gut microbiota is characterized by a significant enrichment of Ruminococcus gnavus, the expression of certain virulent bacterial traits, and the detection of human inflammation-related proteins. Metaproteomics provides information on composition and functionality, as well as data on host-microbiome interactions. Its strength is the identification and quantification of Actinobacteria and certain classes of Firmicutes, but alpha diversity indices are not comparable to those of amplicon sequencing. Both techniques detected an aberrant microbiota in our small cohort of infants with CF during their first year of life, dominated by the enrichment of R. gnavus within a human inflammatory environment. IMPORTANCE In recent years, some techniques have been incorporated for the study of microbial ecosystems, being 16S rRNA gene sequencing being the most widely used. Metaproteomics provides the advantage of identifying the interaction between microorganisms and human cells, but the available databases are less extensive as well as imprecise. Few studies compare the statistical differences between the two techniques to define the composition of an ecosystem. Our work shows that the two methods are comparable in terms of microorganism identification but provide different results in alpha diversity analysis. On the other hand, we have studied newborns with cystic fibrosis, for whom we have described the establishment of an intestinal ecosystem marked by the inflammatory response of the host and the enrichment of Ruminococcus gnavus.

PMID:36255300 | DOI:10.1128/spectrum.01466-22

Front Immunol. 2022 Sep 30;13:944442. doi: 10.3389/fimmu.2022.944442. eCollection 2022.

ABSTRACT

BACKGROUND: Tacrolimus (FK506) is the cornerstone of immunosuppression after liver transplantation (LT), however, clinically, switching from FK506 to cyclosporine (SFTC) is common in LT patients with tacrolimus intolerance. The aim of this study was to investigate the genetic risk of patients with tacrolimus intolerance.

METHODS: A total of 114 LT patients were enrolled in this retrospective study. SNPs were genotyped using Infinium Human Exome-12 v1.2 BeadChip, and genome-wide gene expression levels were profiled using Agilent G4112F array.

RESULTS: SFTC was a potential risk factor of dyslipidemia (OR=4.774[1.122-20.311], p = 0.034) and insulin resistance (IR) (OR=6.25[1.451-26.916], p = 0.014), but did not affect the survival of LT patients. Differential expression analysis showed donor CYP3A5, CYP2C9, CFTR, and GSTP1, four important pharmacogenetic genes were significantly up-regulated in the tacrolimus intolerance group. Twelve SNPs of these four genes were screened to investigate the effects on tacrolimus intolerance. Regression analysis showed donor rs4646450 (OR=3.23 [1.22-8.60] per each A allele, p = 0.01), donor rs6977165 (OR=6.44 [1.09-37.87] per each C allele, p = 0.02), and donor rs776746 (OR=3.31 [1.25-8.81] per each A allele, p = 0.01) were independent risk factors of tacrolimus intolerance.

CONCLUSIONS: These results suggested that SFTC was a potential risk factor for dyslipidemia and IR after LT. Besides, rs4646450, rs6977165, and rs776746 of CYP3A5 might be the underlying genetic risks of tacrolimus intolerance. This might help transplant surgeons make earlier clinical decisions about the use of immunosuppression.

PMID:36248867 | PMC:PMC9562471 | DOI:10.3389/fimmu.2022.944442

J Cyst Fibros. 2022 Oct 14:S1569-1993(22)01383-2. doi: 10.1016/j.jcf.2022.10.001. Online ahead of print.

ABSTRACT

BACKGROUND: Studies have demonstrated a higher risk of developing colorectal cancer (CRC) in individuals with Cystic Fibrosis (CF), and also a potentially increased risk in carriers of cystic fibrosis transmembrane conductance regulator (CFTR) mutations. Life expectancy for those with CF is rising, increasing the number at risk of developing CRC.

METHODS: The incidence of CRC amongst individuals with CF was calculated using data from CORECT-R and linked UK CF Registry and Secondary User Services (SUS) data. Crude, age-specific and age-standardised rates were compared to those without CF. The presence of CFTR mutations in individuals with CRC was assessed using 100,000 Genomes Project data.

FINDINGS: The crude incidence rate of CRC in the CF population was 0.29 per 1,000 person-years (28 cases). The CF population were significantly younger than those without (median age at CRC diagnosis 52 years versus 73 years; p<0·01). When age-adjusted, there was a 5-fold increased CRC incidence amongst individuals with CF compared to those without (SIR 5.0 95%CI 3.2-6.9). When compared to other population studies the overall prevalence of CFTR mutations in the CRC population was significantly higher than expected (p<0·01).

INTERPRETATION: CF is linked to an increased risk of CRC. The incidence of CFTR mutations in the CRC population is higher than would be expected, suggesting an association between CFTR function and CRC risk. Further research is needed to develop effective screening strategies for these populations.

FUNDING: Cancer Research UK (grants C23434/A23706 & C10674/A27140).

PMID:36253274 | DOI:10.1016/j.jcf.2022.10.001

Dig Liver Dis. 2022 Oct 14:S1590-8658(22)00694-6. doi: 10.1016/j.dld.2022.09.005. Online ahead of print.

ABSTRACT

BACKGROUND: Evidence on the effectiveness of proton pump inhibitors (PPI) as adjuvant therapy to improve maldigestion in people with cystic fibrosis (pwCF) is limited and there is increasing concern on possible side effects.

METHODS: We conducted a matched cohort study based on paediatric and adult pwCF who received PPI for ≥3 months. Treated patients were matched to a group of patients who never received PPI using a nearest neighbour propensity score matching based on sex, year of birth, CFTR genotype and pancreatic insufficiency.

RESULTS: The study included 160 pwCF: 80 treated and 80 untreated patients. Over a median follow-up of 2 years, no significant differences in changes in BMI z-score were detected between groups (adjusted mean difference: 0.06, 95% CI: -0.17-0.30). At baseline 25% (n = 20) of the treated patients and 22.5% (n = 18) of the untreated patients had a positive culture for P. aeruginosa (Pa). At follow-up percentages of Pa positive cultures increased to 47.5% (n = 38) in the treated group and to 26.3% (n = 21) in the untreated group (adjusted mean difference: 23.1%, 95% CI: 10.8-35.3).

CONCLUSIONS: Prolonged PPI therapy should be used cautiously in pwCF since it may increase the risk of respiratory infection by Pa. In addition, such treatment does not seem to improve nutritional status.

PMID:36253246 | DOI:10.1016/j.dld.2022.09.005

Am J Respir Cell Mol Biol. 2022 Oct 17. doi: 10.1165/rcmb.2022-0196OC. Online ahead of print.

ABSTRACT

Hypoxia contributes to the exaggerated yet ineffective airway inflammation that fails to oppose infections in cystic fibrosis (CF). However, the potential for impairment of essential immune functions by the hypoxia-inducible factor (HIF)-1α inhibition demands for a better comprehension of downstream hypoxia-dependent pathways that are amenable for manipulation. We assessed here whether hypoxia may interfere with the activity of the aryl hydrocarbon receptor (AhR), a versatile environmental sensor highly expressed in the lungs where it plays a homeostatic role. We resorted to murine models of Aspergillus fumigatus infection in vivo and to human cells in vitro to define the functional role of AhR in CF, evaluate the impact of hypoxia on AhR expression and activity, and assess whether AhR agonism may antagonize hypoxia-driven inflammation. We demonstrated that there is an important interferential crosstalk between the AhR and HIF-1α signaling pathways in murine and human CF, in that HIF-1α induction squelched the normal AhR response through an impaired formation of the AhR: ARNT/HIF-1β heterodimer. However, functional studies and analysis of the AhR genetic variability in patients with CF proved that AhR agonism could prevent the hypoxia-driven inflammation, restore immune homeostasis and improve lung function. This study emphasizes the contribution of environmental factors, such as infections, in CF disease progression and suggests the exploitation of the hypoxia:xenobiotic receptor cross-talk for anti-inflammatory therapy in CF.

PMID:36252182 | DOI:10.1165/rcmb.2022-0196OC

Pediatr Pulmonol. 2022 Oct 17. doi: 10.1002/ppul.26180. Online ahead of print.

ABSTRACT

RATIONALE: The lung clearance index (LCI) is increasingly being used in the clinical surveillance of patients with cystic fibrosis (CF). However, there are limited data on long-term variability and clinically relevant changes in LCI during routine clinical surveillance.

OBJECTIVES: To evaluate long-term variability of LCI and propose a threshold for a physiologically relevant change.

METHODS: Children with CF aged 4-18 years performed LCI measurements every three months as part of routine clinical surveillance during 2011-2020 in two centers. The variability of LCI during periods of clinical stability was assessed using mixed-effects models and was used to identify thresholds for clinically relevant changes.

RESULTS: Repeated LCI measurements of acceptable quality (N= 858) were available in 100 patients with CF, for 74 patients 399 visits at clinical stability were available. Variability of repeated LCI measurements over time expressed as coefficient of variation (CV%) was 7.4%. The upper limit of normal (ULN) for relative changes in LCI between visits was 19%.

CONCLUSION: We report the variability of LCI in children and adolescents with CF during routine clinical surveillance. According to our data, a change in LCI beyond 19% may be considered physiologically relevant. These findings will help guide clinical decisions according to LCI changes. This article is protected by copyright. All rights reserved.

PMID:36251441 | DOI:10.1002/ppul.26180

Health Commun. 2022 Oct 17:1-11. doi: 10.1080/10410236.2022.2134705. Online ahead of print.

ABSTRACT

The COVID-19 pandemic's effects on people's lives and society induced a need for rapid individual and collective sensemaking, including communication forums enabling stakeholders in the health ecosystem to share information, solve problems, and learn. This study specifically focused on the needs of the patients and family caregivers living with cystic fibrosis (CF) or primary ciliary dyskinesia (PCD), conditions that lead to chronic infections and inflammation in the airways. We explored how CF and PCD patients, family caregivers, and clinicians collectively received, processed, and used information about COVID-19 to facilitate self-care and health care decisions at the beginning of the pandemic. We applied macrocognitive theory to analyze qualitatively the questions and answers exchanged in a series of six webinars facilitated by a CF learning network at the beginning of the pandemic (March - April 2020). We identified three macrocognitive functions: sensemaking, decision-making, and replanning. We further generated nine themes: (a) understanding the nature of COVID-19, (b) exploring self-care needs and possibilities, (c) understanding health care possibilities, (d) making decisions about prevention and testing, (e) managing COVID-19 within families, (f) adjusting planned care, (g) replanning chronic care management, (h) defining COVID-19 health care strategies, and (i) refining health care policies. The exchange of questions and answers played a central role in facilitating important cognitive processes, which enabled a rapid anticipation of needs and adaptation of services to support patients, family caregivers, and clinicians during the COVID-19 pandemic.

PMID:36250348 | DOI:10.1080/10410236.2022.2134705

Clin Nurs Res. 2022 Oct 17:10547738221129711. doi: 10.1177/10547738221129711. Online ahead of print.

ABSTRACT

Hospitalized patients and their families may be reluctant to express safety concerns. We aimed to describe safety and quality concerns experienced by hospitalized patients and families and factors and outcomes surrounding decisions about voicing concerns, including those related to the COVID-19 pandemic. We conducted semi-structured interviews with 19 discharged inpatients or family members in a qualitative descriptive design. Some participants reported concern about staff competency or knowledge, communication and coordination, potential treatment errors, or care environment. Factors influencing feeling safe included healthcare team member characteristics, communication and coordination, and safe care expectations. Reasoning for voicing concerns often included personal characteristics. Reasons for not voicing concerns included feeling no action was needed or the concern was low priority. Outcomes for voicing a concern were categorized as resolved, disregarded, and unknown. These findings support the vital importance of open safety communication and trustworthy response to patients and family members who voice concerns.

PMID:36250248 | DOI:10.1177/10547738221129711

Front Cell Infect Microbiol. 2022 Sep 29;12:1033739. doi: 10.3389/fcimb.2022.1033739. eCollection 2022.

NO ABSTRACT

PMID:36250058 | PMC:PMC9558226 | DOI:10.3389/fcimb.2022.1033739

Balkan J Med Genet. 2022 Jun 5;24(2):25-31. doi: 10.2478/bjmg-2021-0023. eCollection 2021 Nov.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive disease. The genetic transition occurs with CF transmembrane conductance regulator (CFTR) gene mutation. We aimed to determine the frequency of CF mutations and also new mutations in the CFTR gene in neonates with respiratory distress. Newborn babies hospitalized due to respiratory distress were included in the patient group. The control group consisted of infants who had no respiratory distress. The CFTR genes of both groups were analyzed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. A total of 40 patients (20 in the patient group and 20 in the control group) were evaluated. The CFTR gene analysis was normal in 16 neonates in the patient group, whereas in others: A46D (c.137C>A) (n = 1), D1312G (c.3935A>G) (n = 1), R117H (c.350G>A) (n = 1), S1426P (c.4276T>C) (n = 1) heterozygotes were detected; CFTR gene analysis was normal at 14 neonates in the control group, whereas in others: E1228G (c.3683A>G) (n = 1), E217G (c.650A>G) (n = 1), E632TfsX9 (c1894_1895delAG) (n = 1), I807M (c.2421 A>G) (n = 2), S573F (c.1718C>T) (n = 1) heterozygotes were detected. There was no significant difference in the patient and control groups' CFTR gene analysis (p = 0.340). This study demonstrates the importance of CFTR gene analysis in asymptomatic newborn infants for follow-up and early diagnosis of CFTR-related disorders. In this study, a c.1894_1895delAG (E632TfsX9) heterozygous mutation detected in the CFTR gene in an asymptomatic newborn infant, was first encountered in the literature.

PMID:36249513 | PMC:PMC9524182 | DOI:10.2478/bjmg-2021-0023

Front Immunol. 2022 Sep 29;13:1012310. doi: 10.3389/fimmu.2022.1012310. eCollection 2022.

ABSTRACT

The progressive lung destruction in cystic fibrosis (CF) is tightly associated with chronic bacterial infection and neutrophil-dominated airway inflammation. CF pulmonary disease is complicated by episodes of acute exacerbations, contributing to irreversible lung damage. We hypothesized that circulating subsets of neutrophils from clinically stable adults with CF present some phenotypic specificities that could amplify their activation during an infectious episode. The aim of the present study was to examine the different neutrophil subsets in whole blood and in the low density neutrophils (LDN) that co-purify with peripheral blood mononuclear cells (PBMC) in clinically stable adults with CF and in CF adults during pulmonary exacerbations compared to healthy donors. Blood samples were obtained from 22 adults with CF (16 in stable state and 6 during pulmonary exacerbations) and from 20 healthy donors. Flow cytometry analysis of 13 different markers related to lineage (CD45, CD15), maturity (CD16, CD10, and CD33), activation (CD62L, CD11b, CD66b, and CD114), metabolism (GLUT-1, LOX1) and immunosuppression (PD1, PD-L1) was carried out within whole blood and within the LDN fraction. Unsupervised analysis of flow cytometry data was performed using visual t-distributed stochastic neighbor embedding (vi-tSNE). A significant increase in the CD11b expression in neutrophils from CF patients during exacerbations was observed compared to neutrophils from stable CF patients or to healthy donors, indicative of a circulating activation state due to an infectious status. The percentage of LDN was not increased in stable CF patients but increased during exacerbations. Analysis of neutrophil subsets using the double CD16/CD62L labeling revealed a significant increase in the CD16high/CD62Llow subset in all CF patients compared to healthy donors. In contrast, an increase in the CD16low/CD62Lhigh subset was observed only in CF patients during exacerbations. Unsupervised analysis identified a PD-L1high/CD114high population that was present in stable CF patients and as well as in CF patients during exacerbations.

PMID:36248793 | PMC:PMC9560797 | DOI:10.3389/fimmu.2022.1012310

Beilstein J Org Chem. 2022 Sep 30;18:1379-1384. doi: 10.3762/bjoc.18.142. eCollection 2022.

ABSTRACT

Sufferers of cystic fibrosis are at significant risk of contracting chronic bacterial lung infections. The dominant pathogen in these cases is mucoid Pseudomonas aeruginosa. Such infections are characterised by overproduction of the exopolysaccharide alginate. We present herein the design and chemoenzymatic synthesis of sugar nucleotide tools to probe a critical enzyme within alginate biosynthesis, GDP-mannose dehydrogenase (GMD). We first synthesise C6-modified glycosyl 1-phosphates, incorporating 6-amino, 6-chloro and 6-sulfhydryl groups, followed by their evaluation as substrates for enzymatic pyrophosphorylative coupling. The development of this methodology enables access to GDP 6-chloro-6-deoxy-ᴅ-mannose and its evaluation against GMD.

PMID:36247981 | PMC:PMC9531554 | DOI:10.3762/bjoc.18.142

Transl Pediatr. 2022 Sep;11(9):1521-1533. doi: 10.21037/tp-22-381.

ABSTRACT

BACKGROUND: Linked deoxyribonucleic acid (DNA) hypermethylation investigations of promoter methylation levels of candidate genes may help to increase the progressiveness and mortality rates of juvenile myelomonocytic leukemia (JMML), which is a unique myelodysplastic/myeloproliferative neoplasm caused by excessive monocyte and granulocyte proliferation in infancy/early childhood. However, the roles of hypermethylation in this malignant disease are uncertain.

METHODS: Bone marrow samples from a JMML patient and peripheral blood samples from a healthy monozygotic twin and an unrelated healthy donor were collected with the informed consent of the participant's parents. Whole-genome bisulfite sequencing (WGBS) was then performed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to analyze specific differentially methylated region (DMG) related genes. The target genes were screened with Cytoscape and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), which are gene/protein interaction databases. A data mining platform was used to examine the expression level data of the healthy control and JMML patient tissues in Gene Expression Omnibus data sets, and a survival analysis was performed for all the JMML patients.

RESULTS: The STRING analysis revealed that the red node [i.e., the cystic fibrosis transmembrane conductance regulator (CFTR)] was the gene of interest. The gene-expression microarray data set analysis suggested that the CFTR expression levels did not differ significantly between the JMML patients and healthy controls (P=0.81). A statistically significant difference was observed in the CFTR promoter methylation level but not in the CFTR gene body methylation level. The overall survival analysis demonstrated that a high level of CFTR expression was associated with a worse survival rate in patients with JMML (P=0.039).

CONCLUSIONS: CFTR promoter hypermethylation may be a novel biomarker for the diagnosis, monitoring of disease progression, and prognosis of JMML.

PMID:36247890 | PMC:PMC9561505 | DOI:10.21037/tp-22-381

Front Chem. 2022 Sep 28;10:1006618. doi: 10.3389/fchem.2022.1006618. eCollection 2022.

ABSTRACT

Serine proteases play varied and manifold roles in important biological, physiological, and pathological processes. These include viral, bacterial, and parasitic infection, allergic sensitization, tumor invasion, and metastasis. The use of activity-based profiling has been foundational in pinpointing the precise roles of serine proteases across this myriad of processes. A broad range of serine protease-targeted activity-based probe (ABP) chemotypes have been developed and we have recently introduced biotinylated and "clickable" peptides containing P1 N-alkyl glycine arginine N-hydroxy succinimidyl (NHS) carbamates as ABPs for detection/profiling of trypsin-like serine proteases. This present study provides synthetic details for the preparation of additional examples of this ABP chemotype, which function as potent irreversible inhibitors of their respective target serine protease. We describe their use for the activity-based profiling of a broad range of serine proteases including trypsin, the trypsin-like protease plasmin, chymotrypsin, cathepsin G, and neutrophil elastase (NE), including the profiling of the latter protease in clinical samples obtained from patients with cystic fibrosis.

PMID:36247662 | PMC:PMC9555310 | DOI:10.3389/fchem.2022.1006618

Front Pediatr. 2022 Sep 28;10:983367. doi: 10.3389/fped.2022.983367. eCollection 2022.

ABSTRACT

OBJECTIVE: We inspected efficacious interventions to improve the transition readiness of adolescent and young adult patients with childhood-onset chronic illnesses using the Transition Readiness Assessment Questionnaire (TRAQ).

METHODS: Our narrative review was conducted on randomized control studies assessed with TRAQ for outcome measurement before and after the interventions. We included all patients with chronic diseases. We searched eight electronic database(s): Allied and Complementary Medicine Database (AMED) Allied and Complementary Medicine, BioSciences Information Service of Biological Abstracts (BIOSIS) Previews, Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Library, Embase, Ichu-shi, Medline, and Web of Science. The text words for the search of data sources were as follows: "("transition readiness assessment questionnaire" OR TRAQ) AND 2011/01:2022/06[DP] AND (clinical AND trial OR clinical trials OR clinical trial OR random* OR random allocation)." More studies were identified from the references in our reported study. This data set was independently cross-checked by two reviewers.

RESULTS: We identified 261 reports and collected three articles. The target diseases were type-1 diabetes, congenital heart disease, cystic fibrosis, and inflammatory bowel disease. All the studies excluded patients with intellectual disabilities. The age of the participants was distributed between 12 and 20 years. Nurse-provided web-based intervention of transition readiness was constructed using digital resources in two studies. The intervention ranged from 6 to 18 months. All the interventions were efficacious in improving transition readiness assessed with TRAQ scores, except for the self-advocacy score.

CONCLUSIONS: We obtained three randomized control studies with TRAQ for outcome measurement. In two studies, web-based and nurse-led organized interventions were shown to improve transition readiness.

PMID:36245732 | PMC:PMC9554476 | DOI:10.3389/fped.2022.983367

EMBO J. 2022 Oct 17:e111869. doi: 10.15252/embj.2022111869. Online ahead of print.

ABSTRACT

Mucus is made of enormous mucin glycoproteins that polymerize by disulfide crosslinking in the Golgi apparatus. QSOX1 is a catalyst of disulfide bond formation localized to the Golgi. Both QSOX1 and mucins are highly expressed in goblet cells of mucosal tissues, leading to the hypothesis that QSOX1 catalyzes disulfide-mediated mucin polymerization. We found that knockout mice lacking QSOX1 had impaired mucus barrier function due to production of defective mucus. However, an investigation on the molecular level revealed normal disulfide-mediated polymerization of mucins and related glycoproteins. Instead, we detected a drastic decrease in sialic acid in the gut mucus glycome of the QSOX1 knockout mice, leading to the discovery that QSOX1 forms regulatory disulfides in Golgi glycosyltransferases. Sialylation defects in the colon are known to cause colitis in humans. Here we show that QSOX1 redox control of sialylation is essential for maintaining mucosal function.

PMID:36245281 | DOI:10.15252/embj.2022111869

Best Pract Res Clin Obstet Gynaecol. 2022 Sep 13:S1521-6934(22)00126-2. doi: 10.1016/j.bpobgyn.2022.09.001. Online ahead of print.

ABSTRACT

This chapter aims to provide expert guidance to obstetricians, general practitioners, allied health staff and women with lung disease about the interactions between pregnancy and different lung diseases. This chapter will cover other airway diseases such as bronchiectasis and cystic fibrosis (CF) together with sarcoidosis and interstitial lung disease (ILD), noting that another chapter covers asthma. The physiological changes which occur in pregnancy, such as the changes in airway physiology, resting ventilation and sleep, are summarised in another chapter. This chapter extends the evidence-based approach and clinical expertise of the recent European Respiratory Society/Thoracic Society of Australia and New Zealand (ERS/TSANZ) taskforce. The papers selected were based on the population (pregnant women with lung disease other than asthma) and the effects of these diseases on risks of pregnancy-associated complications and miscarriages, breastfeeding, nutritional considerations, lung function, long-term maternal outcomes and management considerations during pregnancy. As there are very few randomised control trials in the area, the majority of the literature consists of observational studies (prospective or retrospective), cross-sectional surveys and case series. Other guidelines have also recently been published, which may be helpful to the reader.

PMID:36244873 | DOI:10.1016/j.bpobgyn.2022.09.001