J Community Genet. 2025 Jun 4. doi: 10.1007/s12687-025-00807-1. Online ahead of print.

ABSTRACT

Recent reports confirm that cystic fibrosis (CF) is a global disease. In Asian populations, both the spectrum of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and the clinical course differ from those observed in Western populations. Although the recognition of CF is increasing in South Asia, comprehensive data from Southeast Asian countries remain sparse. The underdiagnosis of CF in Southeast Asia is attributed to limited awareness among healthcare professionals and restricted access to sweat chloride testing. Until 2021, CF had not been documented in the indigenous population of Vietnam. This study presents the first three confirmed cases of CF in native Vietnamese individuals. Additionally, a literature review of CF cases reported across Southeast Asia was conducted to provide insights into its prevalence and variations in CFTR mutation profiles within the region. A total of 50 cases were identified, distributed across Malaysia (30 cases), Thailand (8), the Philippines (6), Vietnam (5), and Indonesia (1), revealing a mutation spectrum distinct from that observed in Caucasian populations. The most common mutations included p.Phe508del and p.Ile1295PhefsX32, each found in 11.5% of cases. These findings highlight the need for increased clinical awareness, expanded access to sweat chloride testing, and the establishment of CF centers and regional CF registries to better understand and manage CF in Southeast Asia.

PMID:40465100 | DOI:10.1007/s12687-025-00807-1

World J Pediatr. 2025 Jun 3. doi: 10.1007/s12519-025-00916-4. Online ahead of print.

ABSTRACT

BACKGROUND: Pediatric lung transplant (pLTX) is a rare procedure globally; its characteristics and survival outcomes in China remain unknown.

METHODS: This retrospective study analyzed data from pLTX recipients aged ≤ 17 years between January 2019 and December 2023 from the China Lung Transplantation Registry. Pre-, intra-, and post-operative characteristics were described and compared between children aged 2-11 years and 12-17 years and between pLTX conducted in centers with high and low transplant volumes. The Kaplan‒Meier method was used to estimate the postoperative survival rates and 95% confidence intervals (CIs). One-year postoperative survival rates were compared between pediatric and adult lung transplant (LTX) patients via log-rank tests.

RESULTS: Between 2019 and 2023, 63 transplants were performed in 62 pediatric patients, accounting for 1.8% of the total LTX in China. The primary indication for pLTX was bronchiolitis obliterans syndrome (46.0%), followed by cystic fibrosis (12.7%) and idiopathic pulmonary arterial hypertension (11.1%). Infection was the most common complication after pLTX (63.9%), and the incidence of bronchial anastomotic stenosis was slightly higher among recipients aged 2-11 years than among those aged 12-17 years (14.3% vs. 2.9%, P = 0.244). High-volume hospitals had a higher incidence of infections (72.7% vs. 41.2%, P = 0.021) and primary graft failure (20.0% vs. 5.9%, P = 0.260) among pediatric recipients. However, acute rejection was exclusively observed in low-volume hospitals (0.0% vs. 17.6%, P = 0.018). The in-hospital mortality rate was 16.1% (95% CI = 6.7-25.5). The 30-day and one-year survival rates after pLTX were 93.5% (95% CI = 87.6-99.9) and 80.6% (95% CI = 71.4-91.1), respectively, and were significantly higher than those of adult recipients (82.0% and 58.7%, all P < 0.05).

CONCLUSIONS: This research identified the trends, indications, donor and recipient characteristics, and complications of pLTX in China. Despite its small size, pLTX is growing gradually and has favorable outcomes. Future research on the long-term follow-up of pLTX recipients is needed to identify factors associated with the prognosis of pLTX patients.

PMID:40461919 | DOI:10.1007/s12519-025-00916-4

J Cyst Fibros. 2025 Jun 2:S1569-1993(25)01486-9. doi: 10.1016/j.jcf.2025.05.005. Online ahead of print.

ABSTRACT

BACKGROUND: Real-world data demonstrate variability in the response to elexacaftor/tezacaftor/ivacaftor (ETI) treatment among people with CF (pwCF). The aim of this study was to evaluate long-term outcomes in pwCF that had not shown early improvement in the percentage of predicted FEV1 (ppFEV1) following ETI treatment.

METHODS: A single-center prospective study in pwCF who initiated ETI. Patients were categorized as 'early responders' if showing an improvement of at least 10 % in ppFEV1 within three months of treatment or 'non-early responders' if not. Patients with pretreatment ppFEV1 of above 99 % predicted were excluded. Respiratory and non-respiratory outcomes 18 to 24 months after ETI initiation were evaluated.

RESULTS: A total of 52 pwCF (median age 30 (22-34), 22 (42 %) female) were included, of whom 21 (40 %) were 'non-early responders'. In a multivariable analysis, previous CFTR modulator therapy (p = 0.002), higher pretreatment ppFEV1 (p = 0.002), and higher pretreatment BMI (p = 0.018), were negatively associated with early change in ppFEV1. After 18 to 24 months of ETI therapy, ppFEV1 did not significantly improve in the 'non-early responders' group (p = 0.29). However, rates of ppFEV1 decline (p < 0.001), BMI (p < 0.005), number of pulmonary exacerbations (p < 0.02), days of intravenous antibiotic treatment (p < 0.01), and chest CT scores (p < 0.05), all significantly improved in both patient groups.

CONCLUSIONS: This study provides evidence for the long-term clinical benefits of ETI in pwCF lacking an early ppFEV1 response. The data suggest that a lack of early improvement should not deter clinicians from treatment continuation.

PMID:40461393 | DOI:10.1016/j.jcf.2025.05.005

Enferm Infecc Microbiol Clin (Engl Ed). 2025 Jun-Jul;43(6):309-316. doi: 10.1016/j.eimce.2024.08.008.

ABSTRACT

BACKGROUND: We investigate bronchopulmonary colonization patterns in Spanish people with CF (pwCF), gathering clinical, demographic, and microbiological data to supplement nine years of registry information, comparing 2021 findings with a similar multicenter study conducted in 2013.

METHODS: Sixteen CF units from 14 hospitals across Spain participated, each randomly recruiting around 20 patients. Patients provided sputum samples for culture. The clinical, demographical, microbiological, and treatment data from the previous year were recorded.

RESULTS: Overall, 326 patients (48.5% females) were recruited: 185 adult and 141 pediatrics, with a median age [q3-q1] of 30 [38-24] and 12 [16-6] years, respectively. p.Phe508del mutation was present in 30.6% and 46.4% of patients with homozygosis or heterozygosis, respectively. Median FEV1 (%) was significantly lower in adults (62%, range 75-43%) compared with pediatrics (90%, range 104-81%) (p<0.001). Pancreatic insufficiency was observed in 77.3%, carbohydrate metabolism alteration in 27.3%, and CF-related diabetes in 19.6% of patients. Lower prevalence of Staphylococcus aureus and Pseudomonas aeruginosa colonization were noted compared to 2013, along with a significantly lower correlation in lung function among pwCF colonized by P. aeruginosa (p<0.001). Half of pwCF (51%) exhibited a single pathogen in culture, two in 30%, and three or more in 2.4%. Co-colonization of P. aeruginosa and S. aureus (36.1%) was the most prevalent combination. High resistance rates were observed in P. aeruginosa and methicillin resistant S. aureus isolates.

CONCLUSIONS: We provide a valuable and representative current insight into the observed evolution in the clinical, demographic, and microbiological aspects in recent years among pwCF in Spain.

PMID:40461090 | DOI:10.1016/j.eimce.2024.08.008

Enferm Infecc Microbiol Clin (Engl Ed). 2025 Jun-Jul;43(6):307-308. doi: 10.1016/j.eimce.2025.04.004.

NO ABSTRACT

PMID:40461089 | DOI:10.1016/j.eimce.2025.04.004

Future Oncol. 2025 Jun 3:1-9. doi: 10.1080/14796694.2025.2514417. Online ahead of print.

ABSTRACT

The DNAJ/HSP40 family consists of three distinct subfamilies (DNAJA, DNAJB, and DNAJC) and is the largest and most diverse co-chaperone proteins for HSP70. The DNAJA subfamily, comprising four members, assumes a pivotal role in various pathological conditions such as cystic fibrosis, neurodegenerative disorders, and cancer. This review comprehensively investigates the participation and underlying mechanisms of DNAJA proteins in tumor proliferation and metastasis, with a specific focus on their influence on the accumulation of mutant p53 proteins. Furthermore, we conducted an extensive examination of compounds utilizing computer-based techniques that specifically target DNAJA or its associated pathways, thereby offering novel insights for the development of cutting-edge combination therapies in the realm of cancer treatment. Our findings highlight the potential significance of targeting the DNAJA subfamily as a promising approach for anti-tumor therapy. Simultaneously, we also highlighted the limitations of current DNAJA research and proposed future directions for advancement in this field. We anticipate that DNAJA will emerge as a novel therapeutic target for anti-tumor interventions.

PMID:40459049 | DOI:10.1080/14796694.2025.2514417

World Allergy Organ J. 2025 May 5;18(5):101056. doi: 10.1016/j.waojou.2025.101056. eCollection 2025 May.

ABSTRACT

Asthma and obesity are both chronic diseases. Obesity is a common comorbidity and a risk factor of severe asthma, associated with increased asthma exacerbation risk, poorer asthma control and reduced quality of life. However, the responsible mechanisms are poorly understood. The aim of this study was to detect parameters associated with obesity in patients with severe asthma in order to check different pattern of inflammation in obese asthmatics. Baseline data from the Severe Asthma Network in Italy (SANI) registry were analysed in 1922 patients with severe asthma. Demographic, clinical and functional features were compared, according to body mass index (BMI). The prevalence of overweight and obesity among severe asthma patients was 34,8 and 20,3, respectively. Females were more prevalent in the obese cluster (p < 0.001). Asthma onset age in overweight and obese patients was higher than in normal population (p < 0.001). Obese subjects reported less frequently chronic rhinosinusitis with nasal polyposis (CRSwNP) and more frequently impaired sleep quality, cardiovascular disease, and type-2 diabetes (p < 0.001). Severe asthma patients with obesity had lower predicted FVC values (89.0 ± 19.2 vs 93.5 ± 20.2; p 0.002) and higher FEV1/FVC ratio (69.9 ± 11.5 vs 66.9 ± 12.4; p < 0.001) than patients without obesity. Obese asthmatics had lower blood eosinophilic count, and fractional exhaled nitric oxide (FeNO) levels than non-obese asthmatics. Asthma control test (ACT) was significantly poorer in obese patients (17, IQR 12-21) than other subgroups. Regarding treatment, overweight and obese patients were more likely to receive a GINA-Step 5 therapy (p 0.023), with more than 20 of obese asthmatics having frequent exacerbations requiring oral corticosteroid (OCS). Patients with severe asthma and obesity presented different characteristics that support the existence of distinct asthma phenotype in obese patients.

TRIAL REGISTRATION: Trial registry: ClinicalTrials.gov. ID: NCT06625216. Retrospectively registered October 3, 2024.

PMID:40458738 | PMC:PMC12127536 | DOI:10.1016/j.waojou.2025.101056

Clin Pharmacol Ther. 2025 Jun 2. doi: 10.1002/cpt.3733. Online ahead of print.

ABSTRACT

The Joint Heads of Medicines Agencies and European Medicines Agency's (HMA/EMA) big data initiative paves the way for better integration of real-world data, including data from patient registries, into regulatory decisions on medicines. This article focuses on the outcome of a two-day multistakeholder workshop organized by EMA in 2024, which explored ways to optimize the EMA qualification procedure for patient registries, and to establish the value and enable the use of these data across the full spectrum of research questions. Key recommendations include the need to clarify the aim, scope, and added value of the qualification of registries, coupled with a review of the procedural steps to ensure the process is fit-for-purpose to evaluate the use of registries in specific regulatory contexts. Further recommendations focused on strengthening interactions between stakeholders, as well as providing them with enhanced support by increasing awareness of publicly available tools that could leverage the potential of registry data, together with existing guidance. The European Medicines Regulatory Network is now working together with all relevant stakeholders, including the EMA scientific committees and working parties, the Joint HMA/EMA Network Data Steering Group and existing focus groups with external partners, to implement concrete actions that will address these recommendations. Among others, the update of existing guidance, the development of templates and Questions & Answers documents, and the design of appropriate communication and stakeholder engagement plans will aid in achieving the common goal of making optimal use of patient registry data to support public health in the European Union.

PMID:40457718 | DOI:10.1002/cpt.3733

BMC Pulm Med. 2025 Jun 2;25(1):276. doi: 10.1186/s12890-025-03745-3.

ABSTRACT

BACKGROUND: Severe respiratory failure in patients with cystic fibrosis (CF) requiring invasive mechanical ventilation is associated with poor clinical outcomes. The purpose of this study was to evaluate the role of extracorporeal membrane oxygenation (ECMO) in this clinical setting.

METHODS: In this descriptive retrospective monocentric cohort study, we collected data by using electronic medical records from all patients with CF who received ECMO therapy during the period 2012-2021.

SETTING: A monocentric setting at the non-surgical intensive care unit of the University Hospital of Frankfurt, Germany (tertiary care level center and nationally certified CF center).

RESULTS: During the study period 72 cases of CF patients with intensive care treatment were detected. Of these, 46 cases required mechanical ventilation. Nine patients received ECMO therapy for severe respiratory failure due to pulmonary exacerbation. Eight of the nine patients died in the hospital. This corresponds to an in-hospital mortality rate of 88.9%. None of the patients underwent lung transplantation. The most common CF mutation was the p.Phe508del homo- or heterozygous genotype. Pseudomonas aeruginosa colonization was significantly associated with the in-hospital mortality.

CONCLUSIONS: ECMO support in CF patients and severe hypoxemic failure is associated with high mortality and its use must take into account the increased risk and poor patient outcome in this clinical setting.

CLINICAL TRIAL NUMBER: This was a retrospective, unregistered analysis. A clinical trial number is not applicable.

PMID:40457261 | DOI:10.1186/s12890-025-03745-3

Nat Biotechnol. 2025 Jun 2. doi: 10.1038/s41587-025-02675-z. Online ahead of print.

ABSTRACT

Alpha-1 antitrypsin (A1AT) deficiency (AATD) is caused by a mutation in the SERPINA1 gene (PiZ allele), where misfolded A1AT liver accumulation leads to liver damage, and A1AT deficiency in the lungs results in emphysema due to unregulated neutrophil elastase activity. Base editing offers a potential cure for A1AT; however, effective treatment is hindered by the absence of dual-target delivery systems that can target key tissues. We developed Dual Selective ORgan-Targeting lipid nanoparticles (SORT LNPs) to deliver base editors to the liver and lungs. Dual SORT LNPs correct the PiZ mutation, achieving 40% correction editing in liver cells and 10% in lung AT2 cells. The liver maintains stable editing for 32 weeks, reducing Z-A1AT levels by over 80% and restoring a normal liver phenotype. In parallel, 89% neutrophil elastase inhibition is achieved in lung bronchoalveolar lavage fluid. Taken together, Dual SORT LNP therapy offers a promising approach for long-lasting genome correction for multi-organ diseases such as AATD.

PMID:40457105 | DOI:10.1038/s41587-025-02675-z

Reprod Biol Endocrinol. 2025 Jun 2;23(1):85. doi: 10.1186/s12958-025-01417-9.

ABSTRACT

BACKGROUND: Nearly all males with cystic fibrosis (MwCF) are infertile and, thus, require the use of assisted reproductive technology (ART) to have biologic children. This study aims to describe the fertility and family-building knowledge, experiences, and care utilization of this population and to compare these findings to the general United States (US) population.

METHODS: We conducted an anonymous cross-sectional study of self-reported survey data compared to data from the 2017-2019 US National Survey for Family Growth (NSFG). We recruited MwCF age 15 years and older at seven US cystic fibrosis (CF) centers.

RESULTS: A total of 532 MwCF (mean age 35.3 ± 11.6 years) completed the survey. 83% knew that almost all MwCF are infertile and 84% were aware that MwCF can have biological children. 71% correctly identified the most common cause of male CF infertility. One third of MwCF stated they had never been told by anyone they were infertile due to their CF (mean age of discussion 19.3 ± 8.8 years). 31% reported being a parent. Among parents, 66% were a parent to a biological child born of a partner's pregnancy, 20% via step-parenthood, 15% adoption, 4.3% surrogacy, and 0.6% foster parenthood. Compared to 44% of NSFG males, 18% of MwCF age 15-49 years reported being a parent to a biological child born of their partner's pregnancy (p < 0.001). Among all MwCF, 82% with a biological child reported that they required medical assistance. Among those age 15-49 years, 87% of MwCF with a biological child required medical assistance compared to 9.4% of NSFG males (p < 0.001). Nearly three-quarters (73%) of MwCF who were biological parents underwent sperm retrieval via a variety of extraction techniques. 91% of those utilizing ART underwent in vitro fertilization and 9% intrauterine insemination of their partner.

CONCLUSIONS: MwCF face significant disease-related fertility and family-building implications with suboptimal counseling. Most MwCF who are parents pursue biological parenthood via a variety of ART services, but one-third chose alternative paths to parenthood. Further research is needed to best understand and support the family-building of MwCF.

CLINICAL TRIAL NUMBER: Not applicable.

PMID:40457440 | DOI:10.1186/s12958-025-01417-9

Respir Med. 2025 May 31:108187. doi: 10.1016/j.rmed.2025.108187. Online ahead of print.

ABSTRACT

BACKGROUND: Haemoptysis is common in adults with cystic fibrosis (CF). Tranexamic acid (TA), an antifibrinolytic agent, blocks the binding of plasminogen and plasmin to fibrin to inhibit clot breakdown. Despite its theoretical benefits, there is limited data on the use of inhaled TA for management of haemoptysis in CF.

METHODS: A 3-year retrospective audit of inhaled TA in CF patients with haemoptysis was conducted. Baseline demographics, hospitalisation status, haemoptysis volume, adverse events, adjuvant therapies and time to resolution of haemoptysis were extracted. We report on the safety, efficacy of nebulised TA, and outline our hospital-specific protocol for its use.

RESULTS: Twenty-six adults [female, 12; age (yrs), 27.2 ± 3.1 95% CI] with haemoptysis were trialled on nebulised TA, in addition to standard therapy. Nebulised TA was generally well tolerated; six patients reported chest tightness during dosing, which resolved in all cases with bronchodilators or a reduction in TA dose. In 65.4% of cases, haemoptysis resolved within 48 hours with TA use. A home haemoptysis management plan, with guidance for outpatient TA use was provided to 19 adults.

CONCLUSIONS: Nebulised TA is a well-tolerated, non-invasive and inexpensive pharmacological option for in- and outpatient management of haemoptysis in CF. Our data support the use of TA to minimise further bleeding in CF outpatients, while waiting for further intervention from their CF service. However, first-dose trials should be supervised to assess for safety and side effects, and a personalised home haemoptysis management plan should be provided prior to use.

PMID:40456472 | DOI:10.1016/j.rmed.2025.108187

Immunotherapy. 2025 Jun 2:1-6. doi: 10.1080/1750743X.2025.2510892. Online ahead of print.

ABSTRACT

Chronic spontaneous urticaria (CSU) is a complex inflammatory skin condition that significantly impacts patients' quality of life. Conventional treatments, such as antihistamines, often fail to provide adequate symptom control. The next step involves administering omalizumab, a monoclonal antibody targeting IgE, however, a subset of patients may not respond to this treatment underscoring the necessity for alternative treatment options. Remibrutinib, an oral, selective inhibitor of Bruton's tyrosine kinase (BTK), has emerged as a promising therapy in CSU. BTK is vital for the activation of mast cells and basophils. The inhibitory action of remibrutinib on BTK may help alleviate CSU symptoms by addressing mast cell-mediated inflammation. Clinical trials, including Phase II and III studies, have shown promising efficacy and a favorable safety profile for remibrutinib in treating CSU. Patients experienced rapid symptom relief, with notable improvements in the Urticaria Activity Score (UAS7) concerning both itch intensity and the severity of hives. The safety profile was also commendable, with no significant treatment-related adverse events requiring therapy cessation or posing immediate health risks to patients. These results indicate that remibrutinib may become a preferred oral treatment for patients with moderate to severe CSU who do not adequately respond to standard therapies.

PMID:40455080 | DOI:10.1080/1750743X.2025.2510892

Am J Respir Crit Care Med. 2025 Jun 2. Online ahead of print.

ABSTRACT

RATIONALE: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children 6 through 11 years of age with cystic fibrosis (CF) and at least one F508del allele in a 24-week phase 3 study. Children completing this study could enroll into a 192-week extension study.

OBJECTIVES: Evaluate long-term safety and efficacy of ELX/TEZ/IVA in children ≥6 years.

METHODS: In this 2-part (Part A [96-weeks] and Part B [96-weeks]) phase 3 extension study, children <12 years weighing <30 kg received ELX 100 mg once daily (qd)/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) and children weighing ≥ 30 kg or aged ≥12 years received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h.

MEASUREMENTS AND MAIN RESULTS: Sixty-four children (F/MF [n=36] and F/F [n=28]) received ≥ 1 dose of ELX/TEZ/IVA. Mean exposure was 156.2 weeks and 60.9% of children (n=39) completed treatment in both parts of this 192-week study. The primary endpoint was safety. All children had adverse events (AEs), which for most were mild (31.3%) or moderate (64.1%) and generally consistent with common manifestations of CF. Two children (3.1%) had non-serious AEs that lead to treatment discontinuation (increased alanine aminotransferase [n=1] and aggression [n=1]). Secondary endpoints focused on efficacy. From parent study baseline, improvements were seen in ppFEV1 (9.6 percentage points; 95% CI: 5.4, 13.7), sweat chloride concentration (-57.9 mmol/L; 95% CI: -63.3, -52.5), CFQ-R respiratory domain score (10.0 points; 95% CI: 6.9, 13.0), LCI2.5 (-2.33; 95% CI: -2.87, -1.79), and BMI z-score (0.39; 95% CI: 0.19, 0.59) at Week 192. Rate of pulmonary exacerbations per year was 0.05. The annualized rate of change in ppFEV1 and LCI2.5 was -0.09 percentage points (95% CI: -1.01, 0.84) and -0.07 units (95%CI: -0.12, -0.01), respectively.

CONCLUSIONS: In this 4-year extension study in children ≥6 years, the longest clinical trial experience with a CFTR modulator in this pediatric population, ELX/TEZ/IVA remained generally safe and well-tolerated with no new safety findings. Clinically meaningful improvements in lung function, CFTR function, and nutritional status reported in the parent study were maintained. These results confirm the long-term safety and efficacy of ELX/TEZ/IVA in children ≥6 years. Clinical trial registration available at www.

CLINICALTRIALS: gov, ID: NCT04183790.

PMID:40454869

Health Expect. 2025 Jun;28(3):e70312. doi: 10.1111/hex.70312.

ABSTRACT

BACKGROUND: Engaging patients and family members in healthcare quality improvement (QI) is essential to meet the needs of those who receive care. The objective of this study was to describe the experience of patient/family partners (PFPs) in a national QI collaborative and to develop recommendations for best practices for patient engagement.

METHODS: We conducted focus groups with PFPs in a national QI collaborative focused on improving transitions of care between cystic fibrosis (CF) and lung transplant programmes. Audio recordings were transcribed verbatim, coded inductively and analysed through thematic analysis. Member checking with PFPs, clinicians and team coaches was used to refine the findings and develop recommendations.

RESULTS: Five PFPs participated in two focus groups, which revealed that PFPs (1) were motivated to participate as members of the QI team because they felt deeply connected to their CF care teams and wanted to help other patients, (2) felt engaged in the QI collaborative and appreciated the sense of community, support from the team coach and the opportunity to take ownership of projects, and (3) suggested improvements related to timing of meetings, compensation, being mindful when discussing sensitive information and setting clear expectations. Member checking revealed the need for equitable recruitment processes and tailoring the role to the individual participants. The findings were used to develop and change processes in the collaborative.

CONCLUSIONS: The structure of the national QI collaborative supported patient/family partnership through structured meetings and a focus on building relationships of mutual respect. The findings demonstrated the need for a more equitable recruitment process, better expectation setting and customisation of the role to the individual skills, needs and preferences of the participants.

PATIENT OR PUBLIC CONTRIBUTION: Patients and family members of people living with CF participated in this study through focus groups and member checking. One CF patient (B.D.) is a co-author of this paper and contributed to data analysis, sensemaking, writing and editing.

PMID:40454855 | DOI:10.1111/hex.70312

J Am Chem Soc. 2025 Jun 2. doi: 10.1021/jacs.5c04167. Online ahead of print.

ABSTRACT

The Burkholderia cepacia complex (BCC) is a group of Gram-negative bacteria known for their pathogenicity to patients suffering from cystic fibrosis (CF). The BCC-belonging strain B. pyrrocinia BC11 (formerly B. cepacia BC11) produces AFC-BC11, a compound with strong activity against phytopathogenic fungi. In this contribution, we report on the unprecedented N-acyl-tetrapeptide structure and antifungal potency of this natural product. We further provide insights into central steps of its biosynthesis mediated by a nonclassical nonribosomal peptide synthesis machinery lacking condensation domains. With the involvement of a sole acyl/peptidyl carrier protein AfcK, an acyltransferase AfcL and coenzyme A, the growing acyl-peptide chain is shuffled between different thioester carriers during the intricate biosynthetic assembly. The knowledge of the AFC-BC11 structure may contribute to the development of antifungals against phytopathogens and, with the afc gene cluster being conserved in various Burkholderia strains, possibly to an understanding of the human pathogenesis of the BCC.

PMID:40454803 | DOI:10.1021/jacs.5c04167

Am J Physiol Lung Cell Mol Physiol. 2025 Jun 2. doi: 10.1152/ajplung.00009.2025. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a chronic disease caused by dysfunctional or absent cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is expressed in immune cells and regulates innate immunity, both directly and indirectly. The epithelial sodium channel (ENaC) contributes to dysfunction in CF airway epithelial cells. However, the impact of non-CFTR ion channel dysfunction on CF immune responses is not understood. Improved understanding of how immune function is regulated by ion channels may allow antibiotic- and mutation-agnostic treatment approaches to chronic infection and inflammation. Therefore, we hypothesized that ENaC is aberrantly expressed in CF macrophages and directly contributes to impaired phagocytic and inflammatory functions. ENaC expression was characterized in immune cells isolated from CF and non-CF blood donors. Monocyte-derived macrophage (MDM) function and bacterial killing was tested with ENaC modulation. Baseline ENaC expression in human CF MDMs, lymphocytes, and granulocytes was increased at both the transcript and protein level relative to non-CF and persisted after infection. CFTR inhibition in non-CF MDMs resulted in ENaC overexpression. CFTR modulator treatment reduced but did not eliminate ENaC overexpression in CF MDMs. Interestingly, ENaC inhibition increased CFTR expression. Amiloride-treated CF MDMs also showed normalized ROS production, improved autophagy, and decreased pro-inflammatory cytokine production. Sodium channel expression in CF MDMs normalized after Amiloride treatment with minimal effect on other ion channels. In summary, ENaC modulation in immune cells is a novel potential therapeutic target for CF infection control, either in combination with CFTR modulators, or as a sole agent for people not eligible for CFTR modulators.

PMID:40454714 | DOI:10.1152/ajplung.00009.2025

J Surg Case Rep. 2025 May 30;2025(5):rjaf315. doi: 10.1093/jscr/rjaf315. eCollection 2025 May.

ABSTRACT

Diverticula of the appendix have been the subject of study since the early 1900s. Appendiceal diverticulitis has varying presentations that can be acute or chronic and has features that differentiate it from classical acute appendicitis. We present the case of a 61-year-old female who was incidentally found to have appendiceal diverticulitis. Appendiceal diverticula are divided into two types, congenital and acquired. This patient developed an acquired appendiceal diverticula. The exact etiology and pathogenesis of acquired appendiceal diverticulosis is unknown. Risk factors associated with acquired appendiceal diverticulosis include male gender, older adults (>30 years old), Hirschsprung's disease, and cystic fibrosis. They were not found to be associated with colonic diverticulosis. Of these known risk factors, our patient only met the criteria of being an older adult. With the post-operative diagnosis of appendiceal diverticulitis, the patient does not require any further intervention beyond the appendectomy which was already completed.

PMID:40453748 | PMC:PMC12122285 | DOI:10.1093/jscr/rjaf315

Front Immunol. 2025 May 16;16:1583460. doi: 10.3389/fimmu.2025.1583460. eCollection 2025.

ABSTRACT

INTRODUCTION: Extracorporeal photopheresis (ECP) is a viable treatment that slows the progression of chronic lung allograft dysfunction. Despite its immunoregulatory potential, data on extracorporeal photopheresis as an induction therapy remain rather limited.

METHODS: We conducted a pilot randomized controlled study on ECP as induction therapy in cystic fibrosis patients undergoing primary lung transplantation. Primary endpoints included safety, assessed based on the incidence of adverse events, treatment-related toxicity, and procedure-related complication rates; and feasibility, evaluated through the completion rate of scheduled ECP sessions, patient tolerability, and treatment discontinuation rates. Secondary endpoint consisted of an exploratory assessment of efficacy, using a composite measure that included three key components: freedom from biopsy-proven acute rejection within the first 12 months, absence of chronic lung allograft dysfunction at 36 months, and optimal graft function, defined as a predicted forced expiratory volume in the first second ≥ 90% at 36 months. Finally, exploratory endpoints included cell phenotypic and functional analyses, secreted immune protein profiling, and gene expression analysis for mechanistic insights. Patients were randomly assigned to receive either standard immunosuppressive therapy alone or standard therapy plus six sessions of extracorporeal photopheresis, with a follow-up period of 36 months.

RESULTS: Among 36 cystic fibrosis patients who underwent lung transplantation between 2018 and 2021 and met the eligibility criteria, 21 were randomized (9 to the study group and 12 to the control group). No patients in the treatment group experienced adverse events. The enrollment rate was 61%, and the treatment discontinuation rate was 22%. The clinical composite endpoint was achieved by 28.6% of patients in the treatment group and 16.7% in the control group. Exploratory endpoint analyses revealed significant decreases in pro-inflammatory cytokines, degranulating CD8+ T lymphocytes, and NK cells in the treatment group. Moreover, significant increases in Treg lymphocytes, IL-10-producing NK cells, and anti-inflammatory cytokines appeared to be associated with improved pulmonary function in the treatment group.

CONCLUSIONS: Induction therapy with extracorporeal photopheresis is safe and feasible in lung transplantation for cystic fibrosis. Some clinical benefits appear to persist for the first 36 months of follow-up. Interestingly, a correlation between immunological modulation induced by extracorporeal photopheresis and pulmonary function was observed.

CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT03500575?cond=NCT03500575&rank=1, identifier NCT03500575.

PMID:40453071 | PMC:PMC12122324 | DOI:10.3389/fimmu.2025.1583460

Expert Rev Clin Immunol. 2025 Jun 1. doi: 10.1080/1744666X.2025.2514604. Online ahead of print.

ABSTRACT

INTRODUCTION: Chronic airway inflammatory diseases mainly comprise chronic rhinosinusitis (CRS), allergic rhinitis (AR), asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD). Epithelial cells fulfill a protective role as a barrier; however, when stimulated, these cells also release a variety of cytokines that attract and activate immune cells, including macrophages, neutrophils, and T-lymphocytes. Excessive activation and aggregation of immune cells disrupts the balance of the cellular microenvironment, and leads to impaired immune defense of the airway mucosa, which can further exacerbate an inflammatory response.

AREAS COVERED: In this article, we discuss the key cytokines and immune pathways involved in epithelial-immune cell interactions, and we detail discoveries in the emerging field of single-cell sequencing and summarize monoclonal antibody-targeted therapies. A comprehensive search was conducted using the search terms 'epithelial cell,' 'immune,' 'interaction,' 'cytokines,' 'asthma,' 'chronic sinusitis,' 'allergic rhinitis,' 'monoclonal antibodies,' and 'single-cell sequencing' by querying Google Scholar and PubMed.

EXPERT OPINION: The intricate pathophysiology of airway inflammation remains to be fully elucidated. Emerging technologies, such as single-cell sequencing, have led to a more comprehensive characterization of the immune mechanisms underlying the pathophysiology of airway inflammatory diseases, which points the way to further precision medicine in the future.

PMID:40452271 | DOI:10.1080/1744666X.2025.2514604