Cystic Fibrosis

Patient perspectives on elexacaftor/tezacaftor/ivacaftor after lung transplant

Thu, 2023-10-05 06:00

J Cyst Fibros. 2023 Oct 3:S1569-1993(23)00921-9. doi: 10.1016/j.jcf.2023.09.017. Online ahead of print.

ABSTRACT

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, including elexacaftor/tezacaftor/ivacaftor (ETI), significantly improve outcomes and quality of life for people with cystic fibrosis (CF). However, little is known about how lung transplant recipients (LTRs) perceive the use of ETI. We conducted a survey to assess perspectives on ETI among LTRs with CF at our lung transplant program. Of 81 CF LTRs, 46 participants (58 %) responded. The majority of respondents (88 %) were aware of ETI. Over 80 % considered treating non-lung symptoms of CF to be very important. Concerns regarding ETI included potential drug interactions with transplant medications (77 %), side effects (53 %), cost of medication (49 %), and lack of clinical trial data for LTRs (43 %). Half reported they would only consider taking ETI if their CF or transplant doctor recommended it. The findings suggest that CF LTRs seek informational support and shared decision-making about ETI from their clinicians.

PMID:37798159 | DOI:10.1016/j.jcf.2023.09.017

Categories: Literature Watch

Standards for the care of people with cystic fibrosis (CF)

Thu, 2023-10-05 06:00

J Cyst Fibros. 2023 Oct 3:S1569-1993(23)00913-X. doi: 10.1016/j.jcf.2023.09.009. Online ahead of print.

NO ABSTRACT

PMID:37798158 | DOI:10.1016/j.jcf.2023.09.009

Categories: Literature Watch

Education-related needs for children with cystic fibrosis: Perspectives of US pediatric care teams

Thu, 2023-10-05 06:00

Pediatr Pulmonol. 2023 Oct 5. doi: 10.1002/ppul.26716. Online ahead of print.

ABSTRACT

OBJECTIVE: Patients with cystic fibrosis (CF) often bring education-related concerns to their medical teams. Concerns around the ability for CF care teams to identify and address these concerns exist. We sought to describe CF care team perceptions of (1) patient and family education-related needs, (2) how these needs are identified, documented and addressed, and (3) education-related resource gaps.

METHODS: A survey was emailed to pediatric care teams in the CF Foundation Care Center Network in April 2022. Individuals or care teams could complete the survey. Responses were aggregated for descriptive analysis.

RESULTS: Sixty-seven programs responded representing 52% of United States pediatric CF centers. Most centers (88%) indicated social workers primarily address school concerns. Care teams often complete school forms (99%), coach families to communicate with schools (96%), communicate with schools directly (90%), and develop educational plans (76%). Formal education risk assessment and support programs are relatively uncommon (19%). Common student-specific needs include carrying medications (75%) and leaving class for gastrointestinal issues (54%). Needs reported are informational materials for families and schools (94%), staff education about school concerns and how to address them (91%), additional staff for education-related issues (65%), and expertise in education plan development (62%).

CONCLUSION: CF care teams often lack comprehensive resources to identify and address education-related concerns. Systematically performing needs assessments, improving training for providers, and evaluating the benefits of education specialists on care teams may better identify and address education-related needs. Supporting educational progression will foster continued independence and well-being in adulthood.

PMID:37796090 | DOI:10.1002/ppul.26716

Categories: Literature Watch

Association of the three-minute step test with the occurrence of pulmonary exacerbations in children with cystic fibrosis: a cross-sectional study

Thu, 2023-10-05 06:00

Minerva Pediatr (Torino). 2023 Oct 5. doi: 10.23736/S2724-5276.23.07306-8. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) patients experience pulmonary exacerbations and the three-minute step test (3-min step test) may be a simple and easy-to-perform functional test to help identify such episodes. The present study aimed to evaluate the association of the 3-min step test with the occurrence of pulmonary exacerbations in children with CF.

METHODS: Cross-sectional study of CF patients aged 6 years and older. Pulmonary exacerbations were assessed using both the Fuchs criteria and the Kanga Score. The 3-min step test was performed using a 15 cm-high step and heart rate (HR), oxygen saturation (SpO<inf>2</inf>), and dyspnea were measured before and after the test. Correlations between the test and the scores, as well as comparisons between patients experiencing or not an exacerbation, were performed.

RESULTS: Sixty-two patients (11.1±4.3 years) were included. Both the Fuchs criteria and the Kanga score correlated significantly with age, forced expiratory volume in the first second (FEV<inf>1</inf>), final SpO<inf>2</inf>, and 1-min recovery SpO<inf>2</inf>. A fall greater than 4% in the final SpO<inf>2</inf> was significantly associated with the presence of a pulmonary exacerbation, considering both Fuchs and Kanga criteria. Age, resting HR, and HR after 1-min recovery were significantly higher, while FEV<inf>1</inf>, SpO<inf>2</inf> at rest, final SpO<inf>2</inf>, and SpO<inf>2</inf> after 1-min recovery were significantly lower in patients classified as exacerbated.

CONCLUSIONS: Physiological responses to the 3-min step test are associated with the occurrence of pulmonary exacerbation in children with CF. Desaturation at the end of the test or during 1-min recovery may be the best variable to monitor.

PMID:37796060 | DOI:10.23736/S2724-5276.23.07306-8

Categories: Literature Watch

Membrane-enclosed <em>Pseudomonas</em> quinolone signal attenuates bacterial virulence by interfering with quorum sensing

Thu, 2023-10-05 06:00

Appl Environ Microbiol. 2023 Oct 5:e0118423. doi: 10.1128/aem.01184-23. Online ahead of print.

ABSTRACT

Outer membrane vesicle (OMV)-delivered Pseudomonas quinolone signal (PQS) plays a critical role in cell-cell communication in Pseudomonas aeruginosa. However, the functions and mechanisms of membrane-enclosed PQS in interspecies communication in microbial communities are not clear. Here, we demonstrate that PQS delivered by both OMVs from P. aeruginosa and liposome reduces the competitiveness of Burkholderia cenocepacia, which usually shares the same niche in the lungs of cystic fibrosis patients, by interfering with quorum sensing (QS) in B. cenocepacia through the LysR-type regulator ShvR. Intriguingly, we found that ShvR regulates the production of the QS signals cis-2-dodecenoic acid (BDSF) and N-acyl homoserine lactone (AHL) by directly binding to the promoters of signal synthase-encoding genes. Perception of PQS influences the regulatory activity of ShvR and thus ultimately reduces QS signal production and virulence in B. cenocepacia. Our findings provide insights into the interspecies communication mediated by the membrane-enclosed QS signal among bacterial species residing in the same microbial community. IMPORTANCE Quorum sensing (QS) is a ubiquitous cell-to-cell communication mechanism. Previous studies showed that Burkholderia cenocepacia mainly employs cis-2-dodecenoic acid (BDSF) and N-acyl homoserine lactone (AHL) QS systems to regulate biological functions and virulence. Here, we demonstrate that Pseudomonas quinolone signal (PQS) delivered by outer membrane vesicles from Pseudomonas aeruginosa or liposome attenuates B. cenocepacia virulence by targeting the LysR-type regulator ShvR, which regulates the production of the QS signals BDSF and AHL in B. cenocepacia. Our results not only suggest the important roles of membrane-enclosed PQS in interspecies and interkingdom communications but also provide a new perspective on the use of functional nanocarriers loaded with QS inhibitors for treating pathogen infections.

PMID:37796010 | DOI:10.1128/aem.01184-23

Categories: Literature Watch

<em>In vitro</em> modeling of polyclonal infection dynamics within the human airways by <em>Haemophilus influenzae</em> differential fluorescent labeling

Thu, 2023-10-05 06:00

Microbiol Spectr. 2023 Oct 5:e0099323. doi: 10.1128/spectrum.00993-23. Online ahead of print.

ABSTRACT

Standardized clinical procedures for antibiotic administration rely on pathogen identification and antibiotic susceptibility testing, often performed on single-colony bacterial isolates. For respiratory pathogens, this could be questionable, as chronic patients may be persistently colonized by multiple clones or lineages from the same bacterial pathogen species. Indeed, multiple strains of nontypeable Haemophilus influenzae, with different antibiotic susceptibility profiles, can be co-isolated from cystic fibrosis and chronic obstructive pulmonary disease sputum specimens. Despite this clinical evidence, we lack information about the dynamics of H. influenzae polyclonal infections, which limits the optimization of therapeutics. Here, we present the engineering and validation of a plasmid toolkit (pTBH, toolbox for Haemophilus), with standardized modules consisting of six reporter genes for fluorescent or bioluminescent labeling of H. influenzae. This plasmid set was independently introduced in a panel of genomically and phenotypically different H. influenzae strains, and two of them were used as a proof of principle to analyze mixed biofilm growth architecture and antibiotic efficacy, and to visualize the dynamics of alveolar epithelial co-infection. The mixed biofilms showed a bilayer architecture, and antibiotic efficacy correlated with the antibiotic susceptibility of the respective single-species strains. Furthermore, differential kinetics of bacterial intracellular location within subcellular acidic compartments were quantified upon co-infection of cultured airway epithelial cells. Overall, we present a panel of novel plasmid tools and quantitative image analysis methods with the potential to be used in a whole range of bacterial host species, assay types, and/or conditions and generate meaningful information for clinically relevant settings. IMPORTANCE Genomic diversity of nontypeable H. influenzae strains confers phenotypic heterogeneity. Multiple strains of H. influenzae can be simultaneously isolated from clinical specimens, but we lack detailed information about polyclonal infection dynamics by this pathogen. A long-term barrier to our understanding of this host-pathogen interplay is the lack of genetic tools for strain engineering and differential labeling. Here, we present a novel plasmid toolkit named pTBH (toolbox for Haemophilus), with standardized modules for fluorescent or bioluminescent labeling, adapted to H. influenzae requirements but designed to be versatile so it can be utilized in other bacterial species. We present detailed experimental and quantitative image analysis methods, together with proof-of-principle examples, and show the ample possibilities of 3D microscopy, combined with quantitative image analysis, to model H. influenzae polyclonal infection lifestyles and unravel the co-habitation and co-infection dynamics of this respiratory pathogen.

PMID:37795992 | DOI:10.1128/spectrum.00993-23

Categories: Literature Watch

Ocular development after highly effective modulator treatment early in life

Thu, 2023-10-05 06:00

Front Pharmacol. 2023 Sep 19;14:1265138. doi: 10.3389/fphar.2023.1265138. eCollection 2023.

ABSTRACT

Highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapies (HEMT), including elexacaftor-tezacaftor-ivacaftor, correct the underlying molecular defect causing CF. HEMT decreases general symptom burden by improving clinical metrics and quality of life for most people with CF (PwCF) with eligible CFTR variants. This has resulted in more pregnancies in women living with CF. All HEMT are known to be able pass through the placenta and into breast milk in mothers who continue on this therapy while pregnant and breast feeding. Toxicity studies of HEMT in young rats demonstrated infant cataracts, and case reports have reported the presence of congenital cataracts in early life exposure to HEMT. This article reviews the evidence for how HEMT influences the dynamic and interdependent processes of healthy and abnormal lens development in the context of HEMT exposure during pregnancy and breastfeeding, and raises questions that remain unanswered.

PMID:37795027 | PMC:PMC10547496 | DOI:10.3389/fphar.2023.1265138

Categories: Literature Watch

Modified forced expiration technique using expiratory resistance in adults with cystic fibrosis

Wed, 2023-10-04 06:00

Clin Respir J. 2023 Oct 4:e13708. doi: 10.1111/crj.13708. Online ahead of print.

ABSTRACT

BACKGROUND: Participation in airway clearance techniques (ACT) is important to minimise development of irreversible airway obstruction in patients with cystic fibrosis (CF). Positive expiratory pressure (PEP) and expiratory resistance devices (ERD) are often used as they can improve collateral ventilation and aid in the shearing of mucus from airways. This project looked to identify whether utilising an ERD during a forced expiration technique (FET) improves ease of expectoration, sputum amount and coughing frequency in patients with CF.

METHOD: Patients with CF admitted for a respiratory exacerbation completed two sessions of 10 cycles of their usual ACT with half of the FET components performed with an ERD, half with FET alone.

RESULTS: EOE, sputum wet weight, cough frequency and patient preference were similar between groups. Improved EOE without the ERD was found in participants who usually use PEP for their ACT regime.

CONCLUSION: Combining the FET with a PEP mask did not improve EOE and other outcomes in this small study. Investigating the efficacy of this technique within a larger population is warranted.

PMID:37793978 | DOI:10.1111/crj.13708

Categories: Literature Watch

The pharmacokinetics and pharmacodynamics of continuous infusion vancomycin in adult people with cystic fibrosis

Wed, 2023-10-04 06:00

Pediatr Pulmonol. 2023 Oct 4. doi: 10.1002/ppul.26714. Online ahead of print.

ABSTRACT

BACKGROUND: The American Thoracic Society Guidelines recommend vancomycin as first line option for treatment of methicillin-resistant Staphylococcus aureus. Two studies have described the pharmacokinetics (PK) of intermittent intravenous (IV) vancomycin in adult people with cystic fibrosis (PwCF). Currently, there have not been any studies describing the PK of continuous infusion vancomycin in PwCF. Our study aimed to describe the PK of continuous infusion vancomycin in adult PwCF.

METHODS: Included patients were adult PwCF, who were admitted to University of Utah Hospital between May 11, 2014 and August 31, 2020, and received continuous infusion vancomycin for the treatment of an pulmonary exacerbations. The primary outcome was to describe vancomycin clearance rate (CLvanco ) and total daily dose (TDD). Secondary outcomes included rates of acute kidney injury (AKI), liver injury, and infusion-related reactions.

RESULTS: Twenty patients were included in this study. The mean CLvanco was 5.08 L/h on Day 3 and 4.58 L/h on Day 7 (p = .04), and the TDD increased from 2444 mg on Day 3 to 2556 on Day 7, although not statistically significant (p = 0.26). Zero patients experienced an AKI, two patients experienced liver injury, and no patients experienced infusion-related reactions.

CONCLUSIONS: This study demonstrates that continuous infusion vancomycin PK, namely CLvanco , is similar to previously reported CLvanco for intermittent dosed IV vancomycin in adult PwCF. This study suggests that continuous infusion vancomycin is likely safe to use in adult PwCF.

PMID:37792309 | DOI:10.1002/ppul.26714

Categories: Literature Watch

Reply to "A failure of Fourier transform infrared spectroscopy to type <em>Burkholderia</em> isolates from chronically infected patients with cystic fibrosis"

Wed, 2023-10-04 06:00

Microbiol Spectr. 2023 Oct 4:e0228823. doi: 10.1128/spectrum.02288-23. Online ahead of print.

NO ABSTRACT

PMID:37791803 | DOI:10.1128/spectrum.02288-23

Categories: Literature Watch

A failure of Fourier transform infrared spectroscopy to type <em>Burkholderia</em> isolates from chronically infected patients with cystic fibrosis

Wed, 2023-10-04 06:00

Microbiol Spectr. 2023 Oct 4:e0221423. doi: 10.1128/spectrum.02214-23. Online ahead of print.

NO ABSTRACT

PMID:37791769 | DOI:10.1128/spectrum.02214-23

Categories: Literature Watch

Extracellular DNA enhances biofilm integrity and mechanical properties of mucoid <em>Pseudomonas aeruginosa</em>

Wed, 2023-10-04 06:00

J Bacteriol. 2023 Oct 4:e0023823. doi: 10.1128/jb.00238-23. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is one of the most common biofilm-forming pathogens responsible for lung infections of individuals with cystic fibrosis (CF). P. aeruginosa becomes tolerant to antimicrobials in the biofilm state and is difficult to treat. Production of extracellular polymeric substances (EPS), such as alginate and extracellular DNA (eDNA), can allow adherence to abiotic and biotic surfaces, antimicrobial evasion, and resilience to environmental pressures. Alginate-producing mucoid variants of P. aeruginosa are frequently isolated from CF airway samples and are associated with worsening patient outcomes. While eDNA is a major structural component of nonmucoid P. aeruginosa biofilms, the potential role of eDNA in mucoid biofilms is unclear. Here, we investigate how eDNA contributes to clinical mucoid biofilm physiology and integrity. We predicted that eDNA plays a structural and mechanical role in mucoid biofilms. To test this, we quantified biofilm eDNA in mucoid biofilms and used microscopy and rheology to visualize eDNA and detect changes in biofilm structure and mechanics upon DNaseI treatment. We showed that biofilm eDNA abundance is diverse across clinical mucoid strains and observed a temporal increase in foci of eDNA within intact mucoid biofilms. Increased cell dispersal and reduced biomass were also observed following DNaseI treatment of mucoid biofilms. Degradation of eDNA also impacted the mechanical integrity of mucoid biofilms by increasing the stiffness and decreasing the cohesion of the biofilm. These findings advance our understanding of clinical mucoid P. aeruginosa biofilms and facilitate the development of new approaches to target biofilms by exploiting the functions of EPS components. IMPORTANCE Understanding the role of eDNA in mucoid Pseudomonas aeruginosa biofilms will lead to therapeutic strategies that combat the biophysical and structural function of EPS for the eradication of bacteria in mucoid biofilms during chronic infections. This knowledge can be used to further identify unknown matrix component interactions within pathogenic biofilm-forming clinical isolates.

PMID:37791754 | DOI:10.1128/jb.00238-23

Categories: Literature Watch

Predicting return of lung function after a pulmonary exacerbation using the cystic fibrosis respiratory symptom diary-chronic respiratory infection symptom scale

Wed, 2023-10-04 06:00

Res Sq. 2023 Sep 13:rs.3.rs-3232522. doi: 10.21203/rs.3.rs-3232522/v1. Preprint.

ABSTRACT

Background Pulmonary exacerbations (PExs) in people with cystic fibrosis (PwCF) are associated with increased healthcare costs, decreased quality of life and the risk for permanent decline in lung function. Symptom burden, the continuous physiological and emotional symptoms on an individual related to their disease, may be a useful tool for monitoring PwCF during a PEx, and identifying individuals at high risk for permanent decline in lung function. The purpose of this study was to investigate if the degree of symptom burden severity, measured by the Cystic Fibrosis Respiratory Symptom Diary (CFRSD)- Chronic Respiratory Infection Symptom Scale (CRISS), at the onset of a PEx can predict failure to return to baseline lung function by the end of treatment. Methods A secondary analysis of a longitudinal, observational study (N = 56) was conducted. Data was collected at four time points: year-prior-to-enrollment annual appointment, termed "baseline", day 1 of PEx diagnosis, termed "Visit 1", day 10-21 of PEx diagnosis, termed "Visit 2" and two-weeks post-hospitalization, termed "Visit 3". A linear regression model was performed to analyze the research question. Results A regression model predicted that recovery of lung function decreased by 0.2 points for every increase in CRISS points, indicating that participants with a CRISS score greater than 48.3 were at 14% greater risk of not recovering to baseline lung function by Visit 2, than people with lower scores. Conclusion Monitoring CRISS scores in PwCF is an efficient, reliable, non-invasive way to determine a person's status at the beginning of a PEx. The results presented in this paper support the usefulness of studying symptoms in the context of PEx in PwCF.

PMID:37790510 | PMC:PMC10543508 | DOI:10.21203/rs.3.rs-3232522/v1

Categories: Literature Watch

The modern landscape of fertility, pregnancy, and parenthood in people with cystic fibrosis

Wed, 2023-10-04 06:00

Curr Opin Pulm Med. 2023 Nov 1;29(6):595-602. doi: 10.1097/MCP.0000000000001009. Epub 2023 Sep 1.

ABSTRACT

PURPOSE OF REVIEW: With improved long-term survival and the expanding availability of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies that treat the underlying genetic defect in cystic fibrosis, more people are interested in parenthood. Cystic fibrosis care centers and people with cystic fibrosis need more information to guide decisions related to parenting.

RECENT FINDINGS: Here we present currently available data on fertility, pregnancy, and parenthood in the modern era of cystic fibrosis care. Fertility may be improving in female individuals with cystic fibrosis with the use of CFTR modulator therapies, and there is an associated increase in annual pregnancies. Infertility in male individuals with cystic fibrosis remains approximately 97-98% and is unchanged with CFTR modulators in those already born with cystic fibrosis. As more female individuals with cystic fibrosis experience pregnancy, questions remain about the impact of pregnancy on their health and that of their child. Fortunately, there are multiple routes to becoming a parent; however, more work is needed to understand the impact of pregnancy and parenthood in the context of CF as some previous data suggests potential challenges to the health of parents with cystic fibrosis.

SUMMARY: We encourage cystic fibrosis care teams to have knowledge and resources available to support the reproductive goals of all individuals with cystic fibrosis.

PMID:37789771 | DOI:10.1097/MCP.0000000000001009

Categories: Literature Watch

Validity of claims-based diagnoses for infectious diseases common among immunocompromised patients in Japan

Tue, 2023-10-03 06:00

BMC Infect Dis. 2023 Oct 3;23(1):653. doi: 10.1186/s12879-023-08466-8.

ABSTRACT

BACKGROUND: To validate Japanese claims-based disease-identifying algorithms for herpes zoster (HZ), Mycobacterium tuberculosis (MTB), nontuberculous mycobacteria infections (NTM), and Pneumocystis jirovecii pneumonia (PJP).

METHODS: VALIDATE-J, a multicenter, cross-sectional, retrospective study, reviewed the administrative claims data and medical records from two Japanese hospitals. Claims-based algorithms were developed by experts to identify HZ, MTB, NTM, and PJP cases among patients treated 2012-2016. Diagnosis was confirmed with three gold standard definitions; positive predictive values (PPVs) were calculated for prevalent (regardless of baseline disease-free period) and incident (preceded by a 12-month disease-free period for the target conditions) cases.

RESULTS: Of patients identified using claims-based algorithms, a random sample of 377 cases was included: HZ (n = 95 [55 incident cases]); MTB (n = 100 [58]); NTM (n = 82 [50]); and PJP (n = 100 [84]). PPVs ranged from 67.4-70.5% (HZ), 67.0-90.0% (MTB), 18.3-63.4% (NTM), and 20.0-45.0% (PJP) for prevalent cases, and 69.1-70.9% (HZ), 58.6-87.9% (MTB), 10.0-56.0% (NTM), and 22.6-51.2% (PJP) for incident cases, across definitions. Adding treatment to the algorithms increased PPVs for HZ, with a small increase observed for prevalent cases of NTM.

CONCLUSIONS: VALIDATE-J demonstrated moderate to high PPVs for disease-identifying algorithms for HZ and MTB using Japanese claims data.

PMID:37789253 | PMC:PMC10548573 | DOI:10.1186/s12879-023-08466-8

Categories: Literature Watch

Use of CFTR modulators in special populations, part 1: Pregnancy and lactation

Tue, 2023-10-03 06:00

Pediatr Pulmonol. 2023 Oct 3. doi: 10.1002/ppul.26706. Online ahead of print.

ABSTRACT

Safety and efficacy data regarding cystic fibrosis transmembrane conductance regulator (CFTR) modulator use in the setting of pregnancy or breastfeeding remains lacking due to exclusion from key trials and lack of multicenter prospective and retrospective studies in the post-CFTR modulator era. A scoping review of English articles from the period of January 1, 2012, to July 31, 2023, was conducted utilizing PubMed and EmBase databases with the following terms: "special population (pregnancy, lactation, breastfeeding)" AND "ivacaftor OR lumacaftor OR tezacaftor OR elexacaftor"; "cystic fibrosis transmembrane conductance regulator" AND "off label drug use." Search results were reviewed by title and abstract for duplications and relevance. Relative to pregnancy or breastfeeding, a total of 18 publications were included for review. Majority of case reports and surveys concluded maternal and infant health were preserved throughout gestation. Likewise, breastfeeding infant case reports show possible changes in liver function and lens opacities, though risk may be increased with both in-utero and breastfeeding exposure. Ivacaftor (IVA) and lumacaftor (LUM) concentrations in fetal cord blood and maternal blood were found to be equivalent. Yet, low concentrations of IVA and LUM were detectable in breastmilk and infant plasma. Current safety data surrounding CFTR modulator use in the setting of pregnancy and lactation is relatively reassuring; however, long-term safety remains unclear, necessitating ongoing observation, and reporting by care teams. As such, treatment decisions should be individualized and coproduced.

PMID:37787417 | DOI:10.1002/ppul.26706

Categories: Literature Watch

STING-Dependent Sensing of Self-DNA Driving Pyroptosis Contributes to Radiation-Induced Lung Injury

Tue, 2023-10-03 06:00

Int J Radiat Oncol Biol Phys. 2023 Oct 1;117(2S):S10. doi: 10.1016/j.ijrobp.2023.06.221.

ABSTRACT

PURPOSE/OBJECTIVE(S): Radiation therapy (RT) is indispensable for managing thoracic carcinomas. However, its application is limited by radiation-induced lung injury (RILI), one of the most common and fatal complications of thoracic RT. Nonetheless, the exact molecular mechanisms of RILI remain poorly understood.

MATERIALS/METHODS: To elucidate the underlying mechanisms, various knockout (KO) mouse strains were subjected to 16 Gy whole-thoracic RT. RILI was assessed by qRT-PCR, ELISA, histology, western blot, immunohistochemistry, and CT examination. To perform further mechanistic studies on the signaling cascade during the RILI process, pulldown, CHIP, and rescue assays were conducted.

RESULTS: We found that the cGAS-STING pathway was significantly upregulated after irradiation exposure in both the mouse models and clinical lung tissues. Knocking down either cGAS or STING led to attenuated inflammation and fibrosis in mouse lung tissues. NLRP3 is hardwired to the upstream DNA-sensing cGAS-STING pathway to trigger of the inflammasome and amplification of the inflammatory response. STING deficiency suppressed the expressions of the NLRP3 inflammasome and pyroptosis-pertinent components containing IL-1β, IL-18, and cleaved caspase-1. Mechanistically, interferon regulatory factor 3, the essential transcription factor downstream of cGAS-STING, promoted the pyroptosis by transcriptionally activating NLRP3. Moreover, we found that RT triggered the release of self-dsDNA in the bronchoalveolar space, which is essential for the activation of cGAS-STING and the downstream NLRP3-mediated pyroptosis. Of note, Pulmozyme, an old drug for the management of cystic fibrosis, was revealed to have the potential to mitigate RILI by degrading extracellular dsDNA and then inhibiting the cGAS-STING-NLRP3 signaling pathway.

CONCLUSION: These results delineated the crucial function of cGAS-STING as a key mediator of RILI, and described a mechanism of pyroptosis linking cGAS-STING activation with the amplification of initial RILI. These findings indicate that the dsDNA-cGAS-STING-NLRP3 axis might be potentially amenable to therapeutic targeting for RILI.

PMID:37784263 | DOI:10.1016/j.ijrobp.2023.06.221

Categories: Literature Watch

Longitudinal bacterial prevalence in cystic fibrosis airways: Fact and artifact

Mon, 2023-10-02 06:00

J Cyst Fibros. 2023 Oct 1:S1569-1993(23)00914-1. doi: 10.1016/j.jcf.2023.09.011. Online ahead of print.

ABSTRACT

BACKGROUND: Opportunistic bacterial infection is a hallmark of cystic fibrosis (CF) lung disease and early mortality. Poorly characterized prevalence changes have accompanied two decades of health improvements, with CFTR modulators likely to further affect infection epidemiology.

METHODS: Bacterial prevalence change trends across birth cohorts were assessed with linear regression using 2001-2019 US CF Foundation Patient Registry data. Informative missingness was assessed, as was age-to-age infection status.

RESULTS: Bacterial prevalence constantly changed from 2001 to 2019, with changes differing across birth cohorts. Informative censoring affected prevalence change for some organisms. Age-to-age infection status changes were greater than net changes in bacterial prevalence and varied by age.

CONCLUSIONS: CF infection epidemiology changed over two decades and will continue to do so. Understanding how modulators affect infection epidemiology will require creative designs for longitudinal prevalence change studies emphasizing prevalence changes independent of effects on lung biology.

PMID:37783605 | DOI:10.1016/j.jcf.2023.09.011

Categories: Literature Watch

Estimating the true stability of the prehydrolytic outward-facing state in an ABC protein

Mon, 2023-10-02 06:00

Elife. 2023 Oct 2;12:e90736. doi: 10.7554/eLife.90736. Online ahead of print.

ABSTRACT

CFTR, the anion channel mutated in cystic fibrosis patients, is a model ABC protein whose ATP-driven conformational cycle is observable at single-molecule level in patch-clamp recordings. Bursts of CFTR pore openings are coupled to tight dimerization of its two nucleotide binding domains (NBDs) and in wild-type (WT) channels are mostly terminated by ATP hydrolysis. The slow rate of non-hydrolytic closure - which determines how tightly bursts and ATP hydrolysis are coupled - is unknown, as burst durations of catalytic site mutants span a range of ~200-fold. Here we show that Walker A mutation K1250A, Walker B mutation D1370N, and catalytic glutamate mutations E1371S and E1371Q all completely disrupt ATP hydrolysis. True non-hydrolytic closing rate of WT CFTR approximates that of K1250A and E1371S. That rate is slowed ~15-fold in E1371Q by a non-native inter-NBD H-bond, and accelerated ~15-fold in D1370N. These findings uncover unique features of the NBD interface in human CFTR.

PMID:37782012 | DOI:10.7554/eLife.90736

Categories: Literature Watch

The great divide: rhamnolipids mediate separation between <em>P. aeruginosa</em> and <em>S. aureus</em>

Mon, 2023-10-02 06:00

Front Cell Infect Microbiol. 2023 Sep 15;13:1245874. doi: 10.3389/fcimb.2023.1245874. eCollection 2023.

ABSTRACT

The interactions between bacterial species during infection can have significant impacts on pathogenesis. Pseudomonas aeruginosa and Staphylococcus aureus are opportunistic bacterial pathogens that can co-infect hosts and cause serious illness. The factors that dictate whether one species outcompetes the other or whether the two species coexist are not fully understood. We investigated the role of surfactants in the interactions between these two species on a surface that enables P. aeruginosa to swarm. We found that P. aeruginosa swarms are repelled by colonies of clinical S. aureus isolates, creating physical separation between the two strains. This effect was abolished in mutants of S. aureus that were defective in the production of phenol-soluble modulins (PSMs), which form amyloid fibrils around wild-type S. aureus colonies. We investigated the mechanism that establishes physical separation between the two species using Imaging of Reflected Illuminated Structures (IRIS), which is a non-invasive imaging method that tracks the flow of surfactants produced by P. aeruginosa. We found that PSMs produced by S. aureus deflected the surfactant flow, which in turn, altered the direction of P. aeruginosa swarms. These findings show that rhamnolipids mediate physical separation between P. aeruginosa and S. aureus, which could facilitate coexistence between these species. Additionally, we found that a number of molecules repelled P. aeruginosa swarms, consistent with a surfactant deflection mechanism. These include Bacillus subtilis surfactant, the fatty acids oleic acid and linoleic acid, and the synthetic lubricant polydimethylsiloxane. Lung surfactant repelled P. aeruginosa swarms and inhibited swarm expansion altogether at higher concentration. Our results suggest that surfactant interactions could have major impacts on bacteria-bacteria and bacteria-host relationships. In addition, our findings uncover a mechanism responsible for P. aeruginosa swarm development that does not rely solely on sensing but instead is based on the flow of surfactant.

PMID:37780859 | PMC:PMC10540625 | DOI:10.3389/fcimb.2023.1245874

Categories: Literature Watch

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