Commun Integr Biol. 2024 Oct 17;17(1):2415598. doi: 10.1080/19420889.2024.2415598. eCollection 2024.

ABSTRACT

Quorum sensing (QS) is a critical bacterial communication system regulating behaviors like biofilm formation, virulence, and antibiotic resistance. This review highlights QS's role in polymicrobial infections, where bacterial species interactions enhance antibiotic resistance. We examine QS mechanisms, such as acyl-homoserine lactones (AHLs) in Gram-negative bacteria and autoinducing peptides (AIPs) in Gram-positive bacteria, and their impact on biofilm-associated antibiotic resistance. The challenges uniquely associated with polymicrobial infections, such as those found in cystic fibrosis lung infections, chronic wound infections, and medical device infections, are also summarized. Furthermore, we explore various laboratory models, including flow cells and dual-species culture models, used to study QS interactions in polymicrobial environments. The review also discusses promising quorum sensing inhibitors (QSIs), such as furanones and AHL analogs, which have demonstrated efficacy in reducing biofilm formation and virulence in laboratory and clinical studies. By addressing the interplay between QS and antibiotic resistance, this paper aims to advance therapeutic strategies that disrupt bacterial communication and improve antibiotic efficacy, ultimately mitigating the global challenge of antibiotic resistance in polymicrobial infections.

PMID:39430726 | PMC:PMC11487952 | DOI:10.1080/19420889.2024.2415598

JAC Antimicrob Resist. 2024 Oct 17;6(5):dlae160. doi: 10.1093/jacamr/dlae160. eCollection 2024 Oct.

ABSTRACT

BACKGROUND: Chronic bronchopulmonary infection due to MRSA in people with cystic fibrosis (pwCF) has been associated with accelerated decline in lung function, increased hospitalizations and increased mortality.

MATERIAL AND METHODS: We studied microbiological and genomic characteristics of MRSA isolates recovered from pwCF in two Spanish multicentre studies (2013, 2021). Antimicrobial susceptibility was performed. WGS was carried out to determine population structure [MLST, spa-typing, staphylococcal cassette chromosome mec (SCCmec)], resistome and virulome. Clinical charts of MRSA-infected and MRSA-non-infected pwCF were also reviewed.

RESULTS: MRSA infection prevalence decreased between 2013 (29/341, 8.5%) and 2021 (21/326, 6.4%) (P = 0.378). Differences in lung function were observed between infected and non-infected patients (P < 0.005). A higher prevalence of hospital-acquired (HA) clones was found compared with community-acquired (CA) clones (2013: 67% versus 33%; and 2021: 71% versus 29%). Overall, we noted clustering of isolates based on year of sampling, type of acquisition and clonal complex (CC). HA-MRSA population was dominated by CC5, with ST125-MRSA-IVc-t067 the most prevalent lineage (37%). A higher clonal diversity was detected among CA-MRSA. One Panton-Valentine leucocidin (PVL)-positive strain (ST8-MRSA-IV) and three strains of porcine origin (two ST398-MRSA-V-t011, one ST398-MRSA-V-t8567) were found. Additionally, acquired resistance genes (n = 24) were detected, including the cfr gene conferring linezolid resistance. A higher gentamicin resistance was found in 2021 (42%) compared with 2013 (7%) (P = 0.046), associated with the aac(6')-aph(2″) gene.

CONCLUSIONS: Despite a decrease in MRSA prevalence, we showed its potential impact on CF severity and progression. Moreover, we observed great genotypic and phenotypic diversity in MRSA isolates from pwCF as well as an MDR trait.

PMID:39429234 | PMC:PMC11487781 | DOI:10.1093/jacamr/dlae160

Dis Model Mech. 2024 Oct 21:dmm.052074. doi: 10.1242/dmm.052074. Online ahead of print.

ABSTRACT

Airway mucous cell metaplasia is a significant feature of many chronic airway diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma. However, the mechanisms underlying this process remain poorly understood. Here, we employ in vivo mouse genetic models to demonstrate that Hippo and p53 cooperate to modulate the differentiation of club cells into goblet cells. We reveal that ablation of Mst1 and Mst1 (Mst1/2), the core components of Hippo signaling, significantly reduces mucous metaplasia in the lung airways in a lipopolysaccharide (LPS)-induced lung inflammation murine model while promoting club cell proliferation in a Yap-dependent manner. Additionally, we show that deleting Mst1/2 is sufficient to suppress p53 deficiency-mediated goblet cell metaplasia. Finally, single-cell RNA analysis reveals a downregulation of Yap and p53 signaling in goblet cells in the human airways. These findings underscore the important role of Hippo and p53 signaling in regulating airway mucous metaplasia.

PMID:39428818 | DOI:10.1242/dmm.052074

Gut Microbes. 2024 Jan-Dec;16(1):2414975. doi: 10.1080/19490976.2024.2414975. Epub 2024 Oct 20.

ABSTRACT

BACKGROUND: The human gut microbiome develops rapidly during infancy, a key window of development coinciding with the maturation of the adaptive immune system. However, little is known about the microbiome growth dynamics over the first few months of life and whether there are any generalizable patterns across human populations. We performed metagenomic sequencing on stool samples (n = 94) from a cohort of infants (n = 15) at monthly intervals in the first 6 months of life, augmenting our dataset with seven published studies for a total of 4,441 metagenomes from 1,162 infants.

RESULTS: Strain-level de novo analysis was used to identify 592 of the most abundant organisms in the infant gut microbiome. Previously unrecognized consortia were identified which exhibited highly correlated abundances across samples and were composed of diverse species spanning multiple genera. Analysis of a published cohort of infants with cystic fibrosis identified one such novel consortium of diverse Enterobacterales which was positively correlated with weight gain. While all studies showed an increased community stability during the first year of life, microbial dynamics varied widely in the first few months of life, both by study and by individual.

CONCLUSION: By augmenting published metagenomic datasets with data from a newly established cohort, we were able to identify novel groups of organisms that are correlated with measures of robust human development. We hypothesize that the presence of these groups may impact human health in aggregate in ways that individual species may not in isolation.

PMID:39428758 | DOI:10.1080/19490976.2024.2414975

J Cyst Fibros. 2024 Oct 19:S1569-1993(24)01796-X. doi: 10.1016/j.jcf.2024.10.003. Online ahead of print.

ABSTRACT

BACKGROUND: Mucociliary clearance (MCC) impairment can be due to mucus abnormalities or to a ciliary dysfunction, which can be innate, or secondary to infection and/or inflammation. In cystic fibrosis (CF), it is well documented that MCC is impaired due to mucus abnormalities, but little is known concerning ciliary beating. This study aimed to confirm that ciliary dyskinesia is present in CF, and if this might be innate or secondary to the chronic infection and/or inflammation.

METHODS: Ciliated epithelial samples were obtained by nasal brushing from 51 CF patients, and from 30 healthy subjects. Ciliary beating was evaluated using digital high-speed videomicroscopy at 37 °C, allowing to evaluate ciliary beat frequency (CBF) and the percentage of abnormal beat pattern (CBP); this was repeated after air-liquid interface (ALI) cell culture.

RESULTS: Ciliary dyskinesia was higher in CF patients than in healthy subjects, with a lower CBF and a higher percentage of abnormal CBP. Ciliary dyskinesia, already present in childhood, normalized after ALI cell culture. A chronic airway colonization did not worsen ciliary dyskinesia.

CONCLUSIONS: We showed that, in CF, a ciliary dyskinesia, present from childhood, might contribute to the impaired MCC. Our results also found that the abnormal ciliary beating was not associated with a chronic infection, and resolved after ALI cell culture, suggesting that ciliary dyskinesia in CF is not innate, and might be secondary to chronic inflammation.

PMID:39428275 | DOI:10.1016/j.jcf.2024.10.003

Comput Biol Chem. 2024 Oct 12;113:108249. doi: 10.1016/j.compbiolchem.2024.108249. Online ahead of print.

ABSTRACT

Cystic fibrosis is an autosomal recessive condition caused by mutations in the CFTR gene, which encodes the CFTR protein. Currently, CF is a life-limiting illness that has a limited cure. The present study aimed to identify top leads against CFTR protein with F508del in comparison with Lumacaftor. In this study, a homology model of the NBD domain of CFTR protein was developed using the available NBD domain crystal structure. The protein model was refined through apo dynamics. Energy-optimized pharmacophore mapping was carried out to identify essential features for CFTR, resulting in a model with a hydrogen-bond donor, two hydrogen-bond acceptors, and three aromatic ring sites. A screening of a compound from the NPASS database using these DAARRR six-point-pharmacophore features led to the identification of potential ligands that could act against CFTR protein. Further studies such as ADME/T, molecular dynamics, MM_GBSA, and DFT were performed to identify the top-hit compound from the NPASS database. The compound Anguibactin (NPC41982) has been identified as a top lead that exhibits higher binding affinity and stability than the reference compound Lumacaftor, suggesting their potential to bind to the active site of the CFTR protein. These compounds could serve as starting points for the development of drug-like molecules for treating cystic fibrosis.

PMID:39427605 | DOI:10.1016/j.compbiolchem.2024.108249

BMC Nephrol. 2024 Oct 18;25(1):363. doi: 10.1186/s12882-024-03788-4.

ABSTRACT

BACKGROUND: BK-polyomavirus (BKpyV) nephropathy (BKVN) is associated with end-stage kidney disease in kidney and non-kidney solid organ transplantation, with no curative treatment.

CASE PRESENTATION: A 45-year-old woman with a past medical history of double lung transplantation subsequently developed end-stage kidney disease, of undetermined origin. One month after receiving a kidney transplant, a diagnosis of early BKVN was suspected, and in retrospect was a reasonable cause for the loss of her native kidneys. Minimisation of immunosuppression, achieved through extracorporeal photopheresis, allowed clearance of BKpyV and so prevented nephropathy. Both lung and kidney grafts had a satisfactory and stable function after one year of follow-up, with no rejection.

CONCLUSIONS: Extracorporeal photopheresis may have facilitated minimisation of immunosuppression and BKpyV clearance without lung allograft rejection.

PMID:39425026 | DOI:10.1186/s12882-024-03788-4

J Cyst Fibros. 2024 Oct 17:S1569-1993(24)01793-4. doi: 10.1016/j.jcf.2024.09.025. Online ahead of print.

NO ABSTRACT

PMID:39424519 | DOI:10.1016/j.jcf.2024.09.025

Pneumologie. 2024 Oct;78(10):693-784. doi: 10.1055/a-2194-6914. Epub 2024 Feb 9.

ABSTRACT

This article is an abridged version of the updated AWMF mould guideline "Medical clinical diagnostics in case of indoor mould exposure - Update 2023", presented in July 2023 by the German Society of Hygiene, Environmental Medicine and Preventive Medicine (Gesellschaft für Hygiene, Umweltmedizin und Präventivmedizin, GHUP), in collaboration with German and Austrian scientific medical societies, and experts. Indoor mould growth is a potential health risk, even if a quantitative and/or causal relationship between the occurrence of individual mould species and health problems has yet to be established. There is no evidence for a causal relationship between moisture/mould damage and human diseases, mainly because of the ubiquitous presence of fungi and hitherto inadequate diagnostic methods. Sufficient evidence for an association between moisture/mould damage and the following health effects has been established for: allergic respiratory diseases, allergic rhinitis, allergic rhino-conjunctivitis, allergic bronchopulmonary aspergillosis (ABPA), other allergic bronchopulmonary mycosis (ABPM), aspergilloma, Aspergillus bronchitis, asthma (manifestation, progression, exacerbation), bronchitis (acute, chronic), community-acquired Aspergillus pneumonia, hypersensitivity pneumonitis (HP; extrinsic allergic alveolitis (EEA)), invasive Aspergillosis, mycoses, organic dust toxic syndrome (ODTS) [workplace exposure], promotion of respiratory infections, pulmonary aspergillosis (subacute, chronic), and rhinosinusitis (acute, chronically invasive, or granulomatous, allergic). In this context the sensitizing potential of moulds is obviously low compared to other environmental allergens. Recent studies show a comparatively low sensitization prevalence of 3-22,5 % in the general population across Europe. Limited or suspected evidence for an association exist with respect to atopic eczema (atopic dermatitis, neurodermatitis; manifestation), chronic obstructive pulmonary disease (COPD), mood disorders, mucous membrane irritation (MMI), odor effects, and sarcoidosis. (iv) Inadequate or insufficient evidence for an association exist for acute idiopathic pulmonary hemorrhage in infants, airborne transmitted mycotoxicosis, arthritis, autoimmune diseases, cancer, chronic fatigue syndrome (CFS), endocrinopathies, gastrointestinal effects, multiple chemical sensitivity (MCS), multiple sclerosis, neuropsychological effects, neurotoxic effects, renal effects, reproductive disorders, rheumatism, sick building syndrome (SBS), sudden infant death syndrome, teratogenicity, thyroid diseases, and urticaria.The risk of infection posed by moulds regularly occurring indoors is low for healthy persons; most species are in risk group 1 and a few in risk group 2 (Aspergillus fumigatus, A. flavus) of the German Biological Agents Act (Biostoffverordnung). Only moulds that are potentially able to form toxins can be triggers of toxic reactions. Whether or not toxin formation occurs in individual cases is determined by environmental and growth conditions, water activity, temperature and above all the growth substrates.In case of indoor moisture/mould damage, everyone can be affected by odor effects and/or mood disorders.However, this is not an acute health hazard. Predisposing factors for odor effects can include genetic and hormonal influences, imprinting, context and adaptation effects. Predisposing factors for mood disorders may include environmental concerns, anxiety, condition, and attribution, as well as various diseases. Risk groups to be protected particularly regarding infection risk are immunocompromised persons according to the classification of the German Commission for Hospital Hygiene and Infection Prevention (Kommission für Krankenhaushygiene und Infektionsprävention, KRINKO) at the Robert Koch-Institute (RKI), persons suffering from severe influenza, persons suffering from severe COVID-19, and persons with cystic fibrosis (mucoviscidosis); with regard to allergic risk, persons with cystic fibrosis (mucoviscidosis) and patients with bronchial asthma must be protected. The rational diagnostics include the medical history, physical examination, and conventional allergy diagnostics including provocation tests if necessary; sometimes cellular test systems are indicated. In the case of mould infections, the reader is referred to the specific guidelines. Regarding mycotoxins, there are currently no useful and validated test procedures for clinical diagnostics. From a preventive medical point of view, it is important that indoor mould infestation in relevant magnitudes cannot be tolerated for precautionary reasons.For evaluation of mould damage in the indoor environment and appropriate remedial procedures, the reader is referred to the mould guideline issued by the German Federal Environment Agency (Umweltbundesamt, UBA).

PMID:39424320 | DOI:10.1055/a-2194-6914

J Heart Lung Transplant. 2024 Oct 16:S1053-2498(24)01892-8. doi: 10.1016/j.healun.2024.10.004. Online ahead of print.

NO ABSTRACT

PMID:39424015 | DOI:10.1016/j.healun.2024.10.004

mSystems. 2024 Oct 18:e0103024. doi: 10.1128/msystems.01030-24. Online ahead of print.

ABSTRACT

E.PathDash facilitates re-analysis of gene expression data from pathogens clinically relevant to chronic respiratory diseases, including a total of 48 studies, 548 samples, and 404 unique treatment comparisons. The application enables users to assess broad biological stress responses at the KEGG pathway or gene ontology level and also provides data for individual genes. E.PathDash reduces the time required to gain access to data from multiple hours per data set to seconds. Users can download high-quality images such as volcano plots and boxplots, differential gene expression results, and raw count data, making it fully interoperable with other tools. Importantly, users can rapidly toggle between experimental comparisons and different studies of the same phenomenon, enabling them to judge the extent to which observed responses are reproducible. As a proof of principle, we invited two cystic fibrosis scientists to use the application to explore scientific questions relevant to their specific research areas. Reassuringly, pathway activation analysis recapitulated results reported in original publications, but it also yielded new insights into pathogen responses to changes in their environments, validating the utility of the application. All software and data are freely accessible, and the application is available at scangeo.dartmouth.edu/EPathDash.

IMPORTANCE: Chronic respiratory illnesses impose a high disease burden on our communities and people with respiratory diseases are susceptible to robust bacterial infections from pathogens, including Pseudomonas aeruginosa and Staphylococcus aureus, that contribute to morbidity and mortality. Public gene expression datasets generated from these and other pathogens are abundantly available and an important resource for synthesizing existing pathogenic research, leading to interventions that improve patient outcomes. However, it can take many hours or weeks to render publicly available datasets usable; significant time and skills are needed to clean, standardize, and apply reproducible and robust bioinformatic pipelines to the data. Through collaboration with two microbiologists, we have shown that E.PathDash addresses this problem, enabling them to elucidate pathogen responses to a variety of over 400 experimental conditions and generate mechanistic hypotheses for cell-level behavior in response to disease-relevant exposures, all in a fraction of the time.

PMID:39422483 | DOI:10.1128/msystems.01030-24

Pediatr Dent. 2024 Sep 15;46(5):318-323.

ABSTRACT

Purpose: To assess oral hygiene, gingivitis, and the association between them for adolescents with cystic fibrosis (CF) compared to nonCF controls. Methods: This was a cross-sectional study of adolescents with CF aged 12 to 17 years (n=27), compared to two non-CF control groups: Medicaid-enrolled adolescents with special health care needs (ASHCN; n=60) and healthy Medicaid-enrolled adolescents (n=185). Dental plaque was a proxy for oral hygiene, and gingival bleeding was a proxy for gingivitis. This study employed confounder-adjusted binomial logistic regression to compare outcomes between adolescents with CF and controls. Results: After adjusting for confounders, adolescents with CF had significantly poorer oral hygiene than controls (CF versus ASHCN odds ratio [OR] = 2.9, 95 percent confidence interval [95% CI] = 2.0 to 4.4, P<0.001; CF versus healthy OR = 1.7, 95% CI=1.3 to 2.2, P<0.001), but there was no significant difference in gingivitis (CF versus ASHCN OR=1.3, 95% CI=0.87 to 1.9, P=0.21; CF versus healthy OR = 0.80, 95% CI=0.60 to 0.99, P=0.04). Poor oral hygiene was significantly associated with gingivitis for all adolescents (CF OR=1.2, 95% CI=1.1 to 1.4, P<0.001; ASHCN OR = 1.8, 95% CI=1.6 to 2.0, P<0.001; healthy OR = 1.2, 95% CI=1.1 to 1.3, P<0.001). Conclusions: Adolescents with CF had poorer oral hygiene than non-CF controls but similar levels of gingivitis. Future efforts should identify factors that protect adolescents with CF from gingivitis.

PMID:39420492

Paediatr Respir Rev. 2024 Sep 12:S1526-0542(24)00075-7. doi: 10.1016/j.prrv.2024.09.001. Online ahead of print.

ABSTRACT

INTRODUCTION: Pseudohypoaldosteronism type 1b (PHA1B) is a rare autosomal recessive disease caused by dysfunction of amiloride-sensitive epithelial sodium channels (ENaC), that might present with a wide variety of pulmonary symptoms.

METHODS: We provide a systematic review of published cases with PHA1B and respiratory symptoms, adding a relevant case from our clinic.

RESULTS: Thirty-seven publications presenting 61 cases were identified apart from our case. Parental consanguinity was reported in 24/62 patients. In 39 patients the onset of pulmonary manifestations was early in infancy. Lower respiratory tract infections caused by Pseudomonas aeruginosa and Staphylococcus aureus were reported in 3 cases each, while 2 patients developed bronchiectasis. Pathological sweat test results were recorded in all 34 patients with available data. In 36/47 patients the underlying pathogenic variant was identified in SCNN1A gene.

CONCLUSION: High clinical suspicion is required when treating patients with PHA1B for the potential need for early treatment of respiratory symptoms to avert any permanent pulmonary damage.

PMID:39419738 | DOI:10.1016/j.prrv.2024.09.001

J Cyst Fibros. 2024 Oct 16:S1569-1993(24)01790-9. doi: 10.1016/j.jcf.2024.09.022. Online ahead of print.

ABSTRACT

BACKGROUND: The constellation of hypertension, truncal obesity, impaired fasting glucose, low high-density lipoprotein, and hypertriglyceridemia is known as metabolic syndrome (MetSyn) and is associated with cardiovascular and other diseases. Elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) is associated with weight gain but effects on cardiovascular risk are unknown. This study sought to investigate ETI exposure and risk for development of MetSyn in pwCF.

METHODS: A prospective cohort study including pwCF ≥ 18 years old exposed to ETI was performed. All data for calculating MetSyn was collected from the electronic medical record at initiation and 1 year ± 3 months after starting ETI. A total of 152 pwCF exposed to ETI and 34 pwCF never exposed to CF transmembrane conductance regulator modulators were included in the analysis. Changes to hypertension classification was also examined over this period.

RESULTS: After 1 year of ETI there was an increase in MetSyn from 13 to 30 pwCF, p < 0.0001. No new cases of MetSyn were seen in the group not exposed to ETI. After 1 year of ETI, more people met criteria for class 1 (BP 130-139/90-99 mm Hg) or class 2 hypertension (BP ≥140/≥90 mm Hg) regardless of prior modulator exposure, p < 0.0001.

CONCLUSIONS: Exposure to ETI for 1 year resulted in an increased number of cases of MetSyn. There was an increased incidence of hypertension associated with ETI exposure. Additional studies are needed to further examine this trend and to determine if these changes will translate to cardiovascular complications over time.

PMID:39419654 | DOI:10.1016/j.jcf.2024.09.022

ACS Chem Biol. 2024 Oct 17. doi: 10.1021/acschembio.4c00571. Online ahead of print.

ABSTRACT

Mutations in creatine transporter SLC6A8 cause creatine transporter deficiency (CTD), which is responsible for 2% of all cases of X-linked intellectual disability. CTD has no current treatments and has a high unmet medical need. Inspired by the transformational therapeutic impact of small molecule "correctors" for the treatment of cystic fibrosis, which bind to mutated versions of the CFTR ion channel to promote its trafficking to the cell surface, we sought to identify small molecules that could stabilize SLC6A8 as a potential treatment for CTD. We leveraged a novel chemoproteomic technology for ligand discovery, reactive affinity probe interaction discovery, to identify small-molecule fragments with photoaffinity handles that bind to SLC6A8 in a cellular environment. We synthesized a library of irreversible covalent analogs of these molecules to characterize in functional assays, which revealed molecules that could promote the trafficking of mutant SLC6A8 variants to the cell surface. Further medicinal chemistry was able to identify reversible drug-like small molecules that both promoted trafficking of the transporter and also rescued creatine uptake. When profiled across the 27 most prevalent 27 SLC6A8 missense variants, we found that 10-20% of patient mutations were amenable to correction by our molecules. These results were verified in an endogenous setting using the CRISPR knock-in of selected missense alleles. We established in vivo proof-of-mechanism for correctors in a novel CTD mouse model with the P544L patient-defined variant knocked in to the SLC6A8 locus, where treatment with our orally bioavailable and brain penetrant tool corrector increased brain creatine levels in heterozygous female mice, validating correctors as a potential therapeutic approach for CTD.

PMID:39418577 | DOI:10.1021/acschembio.4c00571

J Physiol. 2024 Oct 17. doi: 10.1113/JP287289. Online ahead of print.

ABSTRACT

Heavy alcohol intake is one of the most common causes of acute pancreatitis (AP). We have previously shown that ethanol (EtOH) decreases the expression and activity of the cystic fibrosis transmembrane conductance regulator (CFTR), which plays a key role in alcohol-induced AP development. The prescription drug, Orkambi (a combination of ivacaftor and lumacaftor) can correct impaired CFTR function and expression in cystic fibrosis (CF) patients. Thus, the present study aimed to investigate whether Orkambi can mitigate alcohol-induced AP. Intact guinea-pig pancreatic ducts were pre-treated with different concentrations of ethanol (EtOH; 30, 50 and 100 mm) for 12 h alone or in combination with ivacaftor (VX770) and/or lumacaftor (VX-809), and CFTR expression and activity were evaluated by immunostaining and by the patch clamp technique, respectively. Alcoholic AP was induced in Orkambi-treated guinea-pigs, and standard laboratory and histological parameters were measured. Ivacaftor and lumacaftor alone or in combination dose-dependently restored the apical expression and activity of CFTR after EtOH treatment in vitro. Oral administration of Orkambi reduced the severity of alcohol-induced AP and restored impaired CFTR activity and expression. Orkambi is able to restore the CFTR defect caused by EtOH and decreases the severity of alcohol-induced pancreatitis. This is the first in vivo pre-clinical evidence of Orkambi efficacy in the treatment of alcohol-induced AP. KEY POINTS: Acute pancreatitis is one of the leading causes of hospital admission among gastrointestinal diseases in which the lack of a specific drug therapy plays a crucial role. The cystic fibrosis transmembrane conductance regulator (CFTR) plays an essential role in pancreatic ductal HCO3 - secretion; inappropriate CFTR function, as seen in heavy alcohol consumption, increases the risk of pancreatitis development. CFTR modulators are able to prevent the inhibitory effect of ethanol and reduce pancreatic ductal injury and the severity of alcohol-induced pancreatitis. CFTR modulators present a novel option in the pharmacotherapy of alcohol-induced pancreatitis by enhancing pancreatic functions or preventing recurrence.

PMID:39418107 | DOI:10.1113/JP287289

JAMA Netw Open. 2024 Oct 1;7(10):e2441127. doi: 10.1001/jamanetworkopen.2024.41127.

NO ABSTRACT

PMID:39418025 | DOI:10.1001/jamanetworkopen.2024.41127

Am J Respir Cell Mol Biol. 2024 Oct 17. doi: 10.1165/rcmb.2023-0209OC. Online ahead of print.

ABSTRACT

Cystic Fibrosis (CF) is the most common inherited disorder and is characterized by an inflammatory phenotype. Here, we found that in bronchial epithelium reconstituted form lung tissue biopsies from patients with CF, the RNA-binding protein tristetraprolin (TTP), a key regulator of inflammation, is dysregulated in cells that strongly express cytokines and interleukins. TTP activity is regulated by extensive post-translational modifications, particularly phosphorylation. We found that in addition to mRNA downregulation, phosphorylated TTP (which cannot bind to mRNA) accumulated in CF cultures, suggesting that the imbalance in TTP phosphorylation status could contribute to the inflammatory phenotype in CF. We confirmed TTP destabilizing role on IL8 mRNA through its 3'UTR sequence in CF cells. We next demonstrated that TTP phosphorylation is mainly regulated by MK2 through activation of ERK, which also was hyperphosphorylated. TTP is considered a mRNA decay factor with some exception, and we present a new positive role of TTP in CF cultures. We determined that TTP binds to specific ARE motifs on the 3'UTR of mRNA sequences and also, for the first time, to the 3'UTR of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) where TTP binding stabilizes the mRNA level. This study identified new partners that can be targeted in CF and proposes a new way to control CFTR gene expression.

PMID:39417720 | DOI:10.1165/rcmb.2023-0209OC

Pediatr Pulmonol. 2024 Oct 17. doi: 10.1002/ppul.27337. Online ahead of print.

ABSTRACT

The severity of lung disease as well as other disease manifestations have dramatically improved in those patients with cystic fibrosis (CF) that both have mutations responsive to small molecule- based therapies with CF transmembrane regulator (CFTR) modulators and do have access to these drugs. Unfortunately, these medications are not available to many patients with CF across the globe with access largely limited to high income countries. For those eligible to CFTR modulators new questions have arisen regarding the ongoing need for other medications addressing CF lung disease as well current care models with tight monitoring. This article aims to summarize how CF care may change in the future making a plea to expand the availability of highly effective medications to every child with CF that could benefit from treatment.

PMID:39417643 | DOI:10.1002/ppul.27337

Postgrad Med J. 2024 Oct 17:qgae144. doi: 10.1093/postmj/qgae144. Online ahead of print.

ABSTRACT

BACKGROUND: To determine the conditions that prevented transplant in patients referred to our center due to end-stage lung disease.

STUDY DESIGN: Descriptive study.

PLACE AND DURATION OF THE STUDY: Department of lung transplant clinic, Koşuyolu High Specialization Education and Research Hospital, Istanbul, Turkey, from December 2017 to January 2022.

METHODS: Patients with end-stage lung disease referred to our clinic were retrospectively evaluated with regard to reasons for exclusion, diagnosis, and demographic data. The Karnofsky Performance Status scoring scale was used to measure the functional status of the patients.

RESULTS: A total of 311 patients were evaluated during the study period. The mean age was 44.2 (range 4-73) years. There were 207 (66.6%) male patients. The most common indications were idiopathic interstitial pneumonia in 104 (33.4%) patients, chronic obstructive pulmonary disease in 53 (17%) patients, bronchiectasis in 49 (15.7%) patients, and cystic fibrosis in 28 (9%) patients. Of the patients, 106 (34%) were not appropriate candidates for a lung transplant. The most common reasons for refusal were preventable situations such as activity limitation and poor performance in 53 (50%) patients, weight in 49 (46.2%) patients, and smoking in 10 (9.4%) patients.

CONCLUSION: Impaired performance status was the most common cause of lung transplant exclusion. Weight and smoking were preventable causes of exclusion. Implementing pulmonary rehabilitation in very few patients was the most important handicap. It is believed that providing optimal treatment with a multidisciplinary approach and timely referral to transplant centers will significantly reduce the reasons for exclusion. Key message What is already known on this topic? Referring lung transplant candidates to clinics at the earliest stage is essential for assessing their condition and exploring treatment options. What this study adds? Factors like smoking, obesity, and muscle loss can hinder the transplantation process; thus, timely interventions are crucial. The primary reason for excluding candidates from lung transplantation is the decline in performance status. How this study might affect research, practice or policy? Programs focused on smoking cessation, weight management, and muscle strengthening can play a vital role in enhancing patients' health before transplantation. It is imperative to expand and enhance the accessibility of pulmonary rehabilitation programs.

PMID:39417288 | DOI:10.1093/postmj/qgae144