JAMA Netw Open. 2025 Feb 3;8(2):e2460033. doi: 10.1001/jamanetworkopen.2024.60033.

ABSTRACT

IMPORTANCE: Donation after circulatory death (DCD) heart procurement has increased, but concerns remain about the effect of simultaneous heart and lung procurement, particularly with thoracoabdominal normothermic regional perfusion (TA-NRP), on the use of DCD lungs. Previous analyses exclude critical donor factors and organ nonuse, and rapidly rising DCD use may bias comparisons to historical controls.

OBJECTIVE: To use validated risk-adjusted models to assess whether DCD heart procurement via TA-NRP and direct procurement is associated with lung use.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study involved adult DCD donors between January 1, 2019, and September 30, 2024, listed in the Scientific Registry of Transplant Recipients (SRTR). The SRTR deceased donor yield model was used to develop an observed to expected (O:E) yield ratio of lung use obtained through DCD among 4 cohorts: cardiac DCD donors vs noncardiac DCD donors and cardiac DCD donors undergoing TA-NRP vs direct procurement. Temporal trends in O:E ratios were analyzed with the Cochran-Armitage test.

MAIN OUTCOMES AND MEASURES: The O:E ratios of DCD lung use.

RESULTS: Among 24 431 DCD donors (15 878 [65.0%] male; median [IQR] age, 49.0 [37.0-58.0] years), 22 607 were noncardiac DCD (14 375 [63.6%] male; median [IQR] age, 51.0 [39.0-58.0] years) and 1824 were cardiac DCD (1503 [82.4%] male; median [IQR] age, 32.0 [26.0-38.0] years) donors; noncardiac DCD donors were more likely to be smokers (6873 [30.4%] vs 227 [12.4%]; P < .001). Among cardiac DCD donors, 325 underwent TA-NRP, while 712 underwent direct procurement. TA-NRP donors had shorter median (IQR) lung ischemic times (6.07 [4.38-9.56] hours vs 8.12 [6.16-12.00] hours; P < .001) and distances to recipient hospitals (222 [9-626] nautical miles vs 331 [159-521] nautical miles; P = .050) than direct procurement donors. Lung use was higher among cardiac DCD donations compared with noncardiac DCD donations (16.7% vs 4.4%, P < .001). Within the cardiac DCD cohort, lung use was similar between TA-NRP and direct procurement (19.1% vs 18.7%; P = .88) cohorts. Both noncardiac DCD and cardiac DCD donors had observed lung yields greater than expected (O:E, 1.29 [95% CI, 1.21-1.35] and 1.79 [95% CI, 1.62-1.96]; both P < .001), although cardiac DCD yield was significantly higher than noncardiac DCD yield (P < .001). Both TA-NRP and direct procurement lung yields were greater than expected (O:E, 2.00 [95% CI, 1.60-2.43] and 1.77 [95% CI, 1.52-1.99]; both P < .001) but were not significantly different from each other (P = .83). The O:E ratios did not change significantly over time across all cohorts. Among recipients, the TA-NRP cohort experienced significantly better 90-day mortality (0 of 62 vs 9 of 128 patients [7.0%]; P = .03) and overall survival (4 of 62 patients [6.5%] vs 21 of 128 patients [16.4%]; P = .04) rates compared with the direct procurement cohort.

CONCLUSIONS AND RELEVANCE: In this cohort study of DCD donors, concomitant heart procurement provided better-than-expected rates of lung use as assessed with validated O:E use ratios regardless of procurement technique. The findings also suggest a survival benefit with improved 90-day and overall survival rates for the TA-NRP cohort compared with the direct procurement cohort. Policies should be developed to maximize the benefits of these donations.

PMID:39960670 | PMC:PMC11833517 | DOI:10.1001/jamanetworkopen.2024.60033

Respir Med. 2025 Feb 15:107995. doi: 10.1016/j.rmed.2025.107995. Online ahead of print.

NO ABSTRACT

PMID:39961395 | DOI:10.1016/j.rmed.2025.107995

Elife. 2025 Feb 17;13:RP95952. doi: 10.7554/eLife.95952.

ABSTRACT

Despite exciting developments in cancer immunotherapy, its broad application is limited by the paucity of targetable antigens on the tumor cell surface. As an intrinsic cellular pathway, nonsense-mediated decay (NMD) conceals neoantigens through the destruction of the RNA products from genes harboring truncating mutations. We developed and conducted a high-throughput screen, based on the ratiometric analysis of transcripts, to identify critical mediators of NMD in human cells. This screen implicated disruption of kinase SMG1's phosphorylation of UPF1 as a potential disruptor of NMD. This led us to design a novel SMG1 inhibitor, KVS0001, that elevates the expression of transcripts and proteins resulting from human and murine truncating mutations in vitro and murine cells in vivo. Most importantly, KVS0001 concomitantly increased the presentation of immune-targetable human leukocyte antigens (HLA) class I-associated peptides from NMD-downregulated proteins on the surface of human cancer cells. KVS0001 provides new opportunities for studying NMD and the diseases in which NMD plays a role, including cancer and inherited diseases.

PMID:39960487 | DOI:10.7554/eLife.95952

Pediatr Pulmonol. 2025 Feb;60(2):e70000. doi: 10.1002/ppul.70000.

ABSTRACT

BACKGROUND: The COVID-19 pandemic ushered widespread adoption of telehealth (TH) by cystic fibrosis (CF) centers in the USA. TH was initially described as well-accepted by both clinicians and patients. As we move past the unusual circumstances of the pandemic, the sustainability of TH remains untested. This study sought to test the durability of clinician perceptions of TH post-pandemic.

METHODS: This is a cross-sectional, survey study of clinicians at seven US CF centers. We refined a previously disseminated survey initially designed to assess clinician perceptions of TH in 2020. Survey results were analyzed using descriptive statistics and current responses were compared to prior results.

RESULTS: Clinician perceptions surrounding TH remain high but have changed over time with 75% now endorsing satisfaction (90% in 2020, p = 0.02). The most cited barriers were technology limitations (68%) and limited in-person assessments (66%). We found a significant decrease in concern over missing in-person assessments compared to 2020. Benefits of TH included convenience for patients and families (100%) and reduction in missed days of school or work (100%). In total, 83% of current respondents felt TH should remain part of routine CF care. A majority indicated certain patient characteristics increased their preference to conduct at least one TH visit per year.

CONCLUSIONS: Despite restoration of full access to in-person care, clinicians caring for pwCF continue to use TH across the surveyed CF centers post-pandemic. Respondents continue to view TH favorably. Further study is needed to understand for which patient and clinical scenarios TH is most appropriate.

PMID:39960328 | DOI:10.1002/ppul.70000

ACS Omega. 2025 Jan 28;10(5):4336-4352. doi: 10.1021/acsomega.4c06520. eCollection 2025 Feb 11.

ABSTRACT

1,2,4-Oxadiazoles are well recognized for their exceptional physical, chemical, and pharmacokinetic properties, making them promising candidates for various therapeutic applications. These include treatments for cystic fibrosis, Duchenne muscular dystrophy, Alzheimer's disease, and a broad spectrum of other therapeutic interventions such as antituberculosis, anticancer, antibiotic, anti-inflammatory, and anticonvulsant activities. In this study, single crystals of a novel 1,2,4-oxadiazole derivative, methyl-4-(5-(4-(octyloxy)phenyl)-1,2,4-oxadiazol-3-yl)benzoate, were grown by a slow evaporation technique. The structural elucidation was performed using X-ray diffraction analysis, confirming the compound's crystalline structure in the triclinic system. The analysis revealed a linear conformation with bond lengths closely aligned with Cambridge Structural Database (CSD) averages, signifying high precision in the molecular structure. A detailed CSD study identified nine principal configurations of the phenyl octyloxy moiety, underscoring the structural diversity of the compound. Hirshfeld surface analysis highlighted the predominance of C-H···O and C-H···π interactions, with dispersion energy playing a critical role in stabilizing the crystal lattice. Docking studies against key microbial targets, particularly E. coli FabH, demonstrated superior binding energies, suggesting significant antimicrobial potential. The comprehensive suite of structural and computational analyses underscores the potential of the synthesized 1,2,4-oxadiazole derivative, which may be one of the promising candidates for antimicrobial drug development. Future in vitro, in vivo studies will be supportive in optimizing the derivative for enhanced efficacy and further elucidating its pharmacological mechanisms, paving the way for potential clinical applications. This study not only provides insights into the structural and functional properties of a novel 1,2,4-oxadiazole derivative but also highlights its promising role in antimicrobial drug discovery.

PMID:39959081 | PMC:PMC11822514 | DOI:10.1021/acsomega.4c06520

Liver Res. 2024 Sep 16;8(3):131-140. doi: 10.1016/j.livres.2024.09.003. eCollection 2024 Sep.

ABSTRACT

Compared with the widely used rodents, pigs are anatomically, physiologically, and genetically more similar to humans, making them high-quality models for the study of liver diseases. Here, we review the latest research progress on pigs as a model of human liver disease, including methods for establishing them and their advantages in studying cystic fibrosis liver disease, acute liver failure, liver regeneration, non-alcoholic fatty liver disease, liver tumors, and xenotransplantation. We also emphasize the importance of genetic engineering techniques, mainly the CRISPR/Cas9 system, which has greatly enhanced the utility of porcine models as a tool for substantially advancing liver disease research. Genetic engineering is expected to propel the pig as one of the irreplaceable animal models for future biomedical research.

PMID:39957748 | PMC:PMC11771255 | DOI:10.1016/j.livres.2024.09.003

J Cyst Fibros. 2025 Feb 16:S1569-1993(25)00054-2. doi: 10.1016/j.jcf.2025.02.005. Online ahead of print.

ABSTRACT

BACKGROUND: Despite the existence of numerous clinical practice guidelines (CPGs) for cystic fibrosis (CF), there is limited understanding of their credibility and consistency. This systematic review aims to comprehensively evaluate the quality of CPGs for CF and its pulmonary complications, focusing on treatment recommendations for pulmonary care.

METHODS: We conducted a comprehensive search across four databases and relevant websites to identify eligible guidelines providing treatment recommendations. The quality of these guidelines was assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool. Pulmonary treatment recommendations were analyzed and synthesized narratively.

RESULTS: A total of 35 guidelines were identified. Most guidelines were of moderate quality according to the AGREE II instrument, with overall scores ranging from 21·05 to 76·13. Only six guidelines were recommended for use. These guidelines provide 359 pulmonary treatment recommendations for seven primary therapies and others. There was inconsistency in the use of airway clearance therapy, anti-inflammatories, antibiotics, inhaled drugs, and cystic fibrosis transmembrane conductance regulator modulator therapy. Four guidelines conditionally advocated for oral corticosteroids, while six opposed routine inhaled corticosteroids. One guideline discouraged lumacaftor-ivacaftor in the general CF population, two recommended only for children under 12 years old, and another strongly advocated for children between 2 and 5 years of age. However, one guideline noted a lack of evidence to recommend it for children under 6.

CONCLUSION: The quality of CPGs for CF and its pulmonary complications has improved over time, reaching a moderate level generally, but there is still room for further improvement. Future efforts should focus on standardizing methodological frameworks and generating robust clinical evidence to enhance the overall quality and applicability of CF guidelines.

PMID:39956717 | DOI:10.1016/j.jcf.2025.02.005

J Cyst Fibros. 2025 Feb 15:S1569-1993(25)00055-4. doi: 10.1016/j.jcf.2025.02.003. Online ahead of print.

ABSTRACT

BACKGROUND: In individuals with cystic fibrosis (CF), respiratory viral infections frequently result in hospitalization and have been linked to secondary bacterial infection and colonization, highlighting viral infections as possible contributors to CF lung disease progression. We hypothesized that expression of antiviral host defense genes is dysregulated in CF airway epithelia.

METHODS: We infected primary CF and Non-CF airway epithelia with respiratory syncytial virus (RSV) and characterized their responses at 12 hr, 24 hr, 48 hr, 72 hr, and 120 hr post infection (hpi) by RNA sequencing (RNAseq).

RESULTS: Our analysis revealed strikingly different gene expression profiles for the CF and Non-CF epithelia over the course of the infection. While both CF and Non-CF cells exhibited an early signature for interferon signaling and antiviral defense pathways, this response was relatively exaggerated and sustained in CF epithelia. We also observed, in both genotypes, a transient downregulation of cilia-associated genes and loss of ciliary activity by 72 hpi. Interestingly, recovery of cilia activity was delayed in the CF epithelia.

CONCLUSIONS: These findings further our understanding of innate immune dysfunction in the CF airway epithelium and suggest that virus-induced cilia injury may further compromise host defenses in CF airways.

PMID:39956716 | DOI:10.1016/j.jcf.2025.02.003

J Cyst Fibros. 2025 Feb 15:S1569-1993(25)00052-9. doi: 10.1016/j.jcf.2025.02.001. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) has been associated with impaired cardiovascular and endothelial function. CF transmembrane conductance regulator (CFTR) modulator therapy, most recently Elexacaftor/Tezacaftor/Ivacaftor (ETI), has led to improved CFTR function and life expectancy. However, the rising prevalence of obesity in adults is concerning. This study assessed the micro- and macrovascular endothelial function, cardiovascular disease (CVD) risk factors, and physical activity (PA) profiles in people with CF (pwCF) on ETI compared to healthy matched controls.

METHODS: In 15 pwCF and 15 age- and sex-matched controls, microvascular endothelial function (via transdermal delivery of insulin [INS] and acetylcholine [ACh] on the forearm), macrovascular endothelial function (via flow-mediated dilation [FMD] of the brachial artery), central haemodynamic parameters, including heart rate (HR), stroke volume index (SVi) and cardiac output index (Q̇I) (via thoracic impedance cardiography), body mass index (BMI), blood pressure (BP), and accelerometer-assessed PA were measured.

RESULTS: There were no differences in INS or FMD-mediated vasodilation between the groups (P > 0.05). However, a reduced vasodilatory response was evident in pwCF following ACh-mediated vasodilation (P = 0.01) and FMD normalised for shear rate (P = 0.03). No differences in resting HR, SVi, Q̇I, BP, BMI or PA were found (P > 0.05).

CONCLUSION: This study demonstrated reduced micro- and macrovascular function in pwCF. This dysfunction may have potential health implications, particularly regarding long-term cardiovascular risk and further longitudinal assessments are warranted.

PMID:39956715 | DOI:10.1016/j.jcf.2025.02.001

J Cyst Fibros. 2025 Feb 15:S1569-1993(25)00060-8. doi: 10.1016/j.jcf.2025.02.007. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Cystic fibrosis hepatobiliary involvement is a heterogeneous and systemic entity. The primary objective was to determine the prevalence of steatosis, by magnetic resonance-proton density fat fraction (MR-PDFF), and liver fibrosis, by magnetic resonance elastography (MRE), in a cohort of adults with cystic fibrosis. The secondary objective was to determine the diagnostic yield of widely available non-invasive liver markers for steatosis and fibrosis, and vibration controlled transitional elastography (VCTE) releasing Control Attenuation Parameter (CAP) (dB/m) and stiffness (kPa), with the aim of proposing a diagnostic algorithm.

METHODS: We conducted a cross-sectional study including 101 adult patients with cystic fibrosis seen in a multidisciplinary unit. The study encompassed a clinical evaluation, morpho-functional assessment, VCTE, non-invasive liver markers and MR-PDFF and MRE. Diagnostic accuracy was assessed using ROC curves and 2 × 2 tables.

RESULTS: MR-PDFF detected hepatic steatosis in 18 of 101 (17.8 %) patients, while MRE detected significant liver fibrosis in 15 of 101 (14.9 %). The VCTE cut-off with the best diagnostic yield, determined by the Youden index, was 222 dB/m for the presence of steatosis (AUC 0.864 (95 % CI 0.768-0.961; p < 0.001) and the VCTE cut-off was 6.65 kPa for liver fibrosis (AUC 0.951(95 % CI 0.81-1; p = 0.053). A screening algorithm for hepatic steatosis was developed using the fatty liver index (FLI) and CAP, with a negative predictive value of 83.3 %. For liver fibrosis, it was outperformed by the Hepamet Fibrosis Score (HFS) and VCTE, with a negative predictive value of 100 %.

CONCLUSIONS: The prevalence of hepatic steatosis and liver fibrosis was 17.8 % and 14.9 %, respectively. VCTE alone or in combination with FLI for steatosis or HFS for fibrosis demonstrated high diagnostic accuracy. This approach effectively allows for the exclusion of steatosis and fibrosis, thereby reducing the need for MR-PDFF and MRE studies.

PMID:39956714 | DOI:10.1016/j.jcf.2025.02.007

Lancet Respir Med. 2025 Feb 12:S2213-2600(25)00017-7. doi: 10.1016/S2213-2600(25)00017-7. Online ahead of print.

NO ABSTRACT

PMID:39954705 | DOI:10.1016/S2213-2600(25)00017-7

BMC Gastroenterol. 2025 Feb 14;25(1):80. doi: 10.1186/s12876-025-03682-9.

ABSTRACT

BACKGROUND: Intestinal failure (IF) is a broad term encompassing various conditions that hinder the body's ability to absorb nutrients for growth and maintenance. These conditions can significantly affect child's well-being, leading to physical limitations, psychological distress, and social isolation. We aimed to evaluate the available data on health-related quality of life (HRQoL) in pediatric patients with IF and without neurodevelopmental delay.

METHODS: For this systematic review and meta-analysis, we searched CINAHL, EMBASE, PsycINFO, PubMed, and Web of Science. All observational studies of pediatric patients (< 18 years) with IF which measured HRQOL and with evidence of absence of neurodevelopmental delay were included, without language or date restrictions, up to June 2024. We did separate random-effects meta-analyses for overall HRQOL and subgroup domains. Evidence from observational studies was synthesised as differences between standardised mean differences (SMDs) for all subgroup domains. Heterogeneity was assessed using the I² statistic and the Cochran Q test. The quality of the evidence was assessed with the Newcastle-Ottawa scale. This study is registered on PROSPERO, number CRD42024561812.

RESULTS: Of 491 records identified, 14 were eligible and data were available for 12 studies, all of which had a fair/good quality. The included studies involved a pooled sample of 510 participants (mean age = 7.0 ± 3.6 years). The analysis disclosed that compared to healthy children, pediatric patients with IF had lower overall quality of life in both child- and parent-report (Standardized Mean Difference [SMD]= -0.62; 95% CI [-0.80, -0.43]; p < 0.001, and SMD= -0.70; 95% CI [-1.11, -0.28]; p < 0.001, respectively), except for emotional and social domains (SMD[child] = -0.23; 95% CI [ -0.38, -0.08]; p = 0.001 Vs SMD[parent]= -0.23; 95% CI [ -0.60, 0.14]; p = 0.21, and SMD[child] = -0.40; 95% CI [ -0.70, -0.10]; p = 0.007 Vs SMD[parent]= -0.24; 95% CI [ -0.62, 0.14]; p = 0.21, respectively), where parents overestimate emotional and social HRQOL of their children.

CONCLUSIONS: This study highlights the significant impact of IF on well-being of pediatric patients. Targeted interventions addressing both physical and psychosocial needs are crucial to improve HRQOL in this population.

PMID:39953378 | DOI:10.1186/s12876-025-03682-9

Adv Med Sci. 2025 Feb 12:S1896-1126(25)00009-4. doi: 10.1016/j.advms.2025.01.009. Online ahead of print.

NO ABSTRACT

PMID:39952431 | DOI:10.1016/j.advms.2025.01.009

PLoS One. 2025 Feb 14;20(2):e0316721. doi: 10.1371/journal.pone.0316721. eCollection 2025.

ABSTRACT

BACKGROUND: Non-cystic fibrosis bronchiectasis (NCFBE) is a disease that exhibits dilatation of airways, airflow obstruction, persistent cough, excessive sputum production, and refractory respiratory infections. NCFBE exhibits clinical and pathological manifestations similar to key features of cystic fibrosis (CF) lung disease. In CF, pathogenesis results from dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), and diagnosis is made by demonstrating elevated sweat chloride concentrations (typically ≥60 mEq/L), two CFTR mutations known to be causal, multi-organ tissue injury, or combination(s) of these findings.

OBJECTIVE: Based on a considerable body of evidence, we believe many patients with NCFBE have disease likely to benefit from drugs such as elexacaftor/tezacaftor/ivacaftor (ETI) that activate CFTR-dependent ion transport. ETI is currently prescribed solely for treatment of CF and has not been adequately tested or proposed for patients with NCFBE, many of whom exhibit decreased CFTR function. Accordingly, we are conducting a clinical trial of ETI in subjects carrying a diagnosis of NCFBE.

METHODS: Participants will exhibit one disease-causing CFTR mutation and/or sweat chloride measurements of 30-59 mEq/L. Cutaneous punch biopsy or blood samples will be obtained for iPS cell differentiation into airway epithelial monolayers-which will then be tested for response to ETI. Each patient will be given CFTR modulator treatment for approximately four weeks, with monitoring of clinical endpoints that include FEV1 (forced expiratory volume in one second), sweat chloride, quality of life questionnaire, and weight. The study will evaluate response of patients with NCFBE to ETI, and test usefulness of iPSC-derived airway epithelial monolayers as a novel in vitro technology for predicting clinical benefit.

TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov (Identifier: NCT05743946. Date: 02/23/2023).

PMID:39951444 | DOI:10.1371/journal.pone.0316721

JAMA Netw Open. 2025 Feb 3;8(2):e2459557. doi: 10.1001/jamanetworkopen.2024.59557.

ABSTRACT

IMPORTANCE: Textbooks attribute 80% of meconium-related small bowel obstructions to cystic fibrosis and 15% of colonic obstructions to Hirschsprung disease. It is unknown whether these estimates are accurate, particularly among preterm infants, whose immature bowel predisposes them to meconium-related obstruction (MRO).

OBJECTIVE: To estimate the incidence of MRO by type and to assess its association with clinical outcomes.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study of live-born infants included in the National Inpatient Sample from January 1, 2016, to December 31, 2020, used survey weighting methods to estimate the national incidence of MRO by etiology. Data were analyzed from November 27, 2023, to November 12, 2024.

EXPOSURE: MRO.

MAIN OUTCOMES AND MEASURES: The primary outcome was diagnosis with MRO. Secondary outcomes included mortality, need for abdominal surgery, hospitalization duration, and cost. Multivariable regression models were developed to evaluate characteristics associated with MRO and to assess the association of MRO of prematurity with clinical outcomes after adjusting for demographic and clinical covariates.

RESULTS: Of 3 550 796 infants, 51.2% were male and 46.7% were privately insured. Overall, 9.1% (n = 322 499) were born preterm. Of 1844 (0.1%) infants treated for MRO, 41 (2.2%) had cystic fibrosis, 60 (3.3%) had Hirschsprung disease, and 1743 (94.5%) had neither predisposing condition. Preterm infants were at highest risk for MRO, with 4.7 MRO cases per 100 000 births associated with cystic fibrosis, 4.7 MRO cases per 100 000 births associated with Hirschsprung disease, and 187.3 MRO cases per 100 000 births associated with neither predisposing condition. Among infants with neither cystic fibrosis nor Hirschsprung disease, those with gestational ages from 28 weeks to 31 weeks 6 days were most likely to develop MRO compared with term infants (adjusted odds ratio, 6.08 [95% CI, 4.27-8.67]). Among preterm infants, having an MRO was associated with a 4.2 percentage point increase in the probability of abdominal surgery (95% CI, 3.1-5.4 percentage points), a 7.3-day increase in length of stay (95% CI, 5.8-8.8 days), and a $23 215 increase in hospitalization costs (95% CI, $17 739-$28 690) compared with infants who did not have an obstruction, with no change in mortality rate (0.1 percentage point change [95% CI, -0.6 to 0.8 percentage points]).

CONCLUSIONS AND RELEVANCE: In this cohort study of over 3.5 million infants, MRO was most likely to occur among preterm infants without cystic fibrosis or Hirschsprung disease. These infants more frequently required surgery and had longer and more costly hospitalizations, indicating a need for dedicated prevention and treatment pathways for this understudied disease.

PMID:39951267 | DOI:10.1001/jamanetworkopen.2024.59557

J Bacteriol. 2025 Feb 14:e0053124. doi: 10.1128/jb.00531-24. Online ahead of print.

ABSTRACT

Phenotypic diversity in bacteria often results from adaptation to changing environmental conditions, exemplified by variable colony morphotypes. In Burkholderia pseudomallei, discrete genomic alterations and modulation of gene expression facilitate adaptation. Adapted variants of species within the Burkholderia cepacia complex (Bcc) often lose the pC3 virulence megaplasmid, impacting their colony morphology and their production of virulence factors. In this study, we characterize variants arising in Burkholderia ambifaria clinical isolates using proteomics and phenotypic tests and show that some of them have retained the pC3, indicating a distinct phase variation mechanism at play in this Bcc species. Interestingly, variants of B. ambifaria strains CEP0996 (pC3-null) and HSJ1 (pC3-positive) still share similarities in phenotypes controlled by the Cep quorum-sensing (QS) system. We further investigated the role of QS in B. ambifaria HSJ1 phase variation and confirmed that the Cep QS system is important for the emergence of variants. Given that DNA methylation is a key epigenetic factor regulating virulence factors in Burkholderia cenocepacia, we hypothesized that adenosine DNA methylation also governs phase variation in B. ambifaria HSJ1. By deleting the genes encoding putative adenosine DNA methyltransferases, we discovered that an orphan type II DNA methyltransferase inhibits the emergence of phase variants. This study is the first to demonstrate that quorum sensing and adenosine DNA methylation are two antagonistic systems independently controlling phase variation in B. ambifaria.IMPORTANCESome Burkholderia species are pathogenic to plants, animals, or humans. In immunocompromised individuals, and people suffering from cystic fibrosis, infection from the Burkholderia cepacia complex (Bcc) can lead to "cepacia syndrome." In northern Australia and southeast Asia, melioidosis caused by Burkholderia pseudomallei is prevalent among native population, particularly among people with diabetes, chronic lung or kidney disease or alcoholism. Burkholderia's phenotypic plasticity, including colony morphotype variation (CMV), enables rapid adaptation to diverse environments, enhancing its survival and pathogenicity. This study reveals phase variation as a new CMV mechanism within the Bcc group and is the first to report that quorum sensing and DNA methylation are involved in phase variation. Understanding the underlying mechanisms of CMV could lead to the development of targeted therapies against these highly antibiotic-tolerant bacteria.

PMID:39950805 | DOI:10.1128/jb.00531-24

Front Tuberc. 2024;2:1473341. doi: 10.3389/ftubr.2024.1473341. Epub 2024 Oct 30.

ABSTRACT

INTRODUCTION: Chronic pulmonary infection with Mycobacterium abscessus (M. abscessus) is a significant cause of morbidity and mortality in people with cystic fibrosis (CF). Developing an animal model of M. abscessus pulmonary infection, especially under CF conditions, is essential to understanding clinical pulmonary M. abscessus infection. βENaC transgenic mice are known to develop spontaneous CF-like disease characterized by airway mucus obstruction and inflammation. The aim of this study was to evaluate the suitability of βENaC mice as a preclinical model and characterize their respiratory function during M. abscessus lung infection.

METHODS: Mice received an intrapulmonary aerosol of M. abscessus using a high-pressure syringe device (Penn-Century) for subsequent characterization of disease progression and respiratory function. Whole body unrestrained plethysmography (WBP) data was collected to monitor lung function and endpoints determined organ bacterial burden and associated pathology.

RESULTS: Endpoint CFU data in the lung and spleen showed that there was no significant difference in bacterial clearance between βENaC and WT mice. WBP data showed an impairment in overall respiratory function during and after M. abscessus infection in both strains of mice. Interestingly, even in wildtype control mice, lung dysfunction persisted after bacterial clearance.

DISCUSSION: Even with CF-like features, the βENaC transgenic mice cleared M. abscessus at a similar rate than WT mice, however, the associated respiratory monitoring revealed that there are long-term implications of M. abscessus lung exposure. The clear decline in respiratory function, even after M. abscessus clearance, suggests that WBP coupled animal modeling provides important insight that is relevant to disease burden and treatment efficacy. The M. abscessus clearance in the βENaC mice may help improve the fields understanding of CF-modulated immune deficiencies in M. abscessus pulmonary infection.

PMID:39950136 | PMC:PMC11822858 | DOI:10.3389/ftubr.2024.1473341

Med Pharm Rep. 2025 Jan;98(1):29-35. doi: 10.15386/mpr-2806. Epub 2025 Jan 31.

ABSTRACT

BACKGROUND: Patients with cystic fibrosis (CF) frequently require modulatory therapies such as Lumacaftor/Ivacaftor (LI) and Elexacaftor/Tezacaftor/Ivacaftor (ETI) to manage their condition. Given the potential hepatic complications associated with CF, it is critical to understand the impact of these therapies on liver function and fibrosis indices. This study aimed to evaluate the changes in liver function markers and fibrosis indices in CF patients undergoing LI and ETI therapies, with a specific focus on the influence of underlying hepatic disease.

METHODS: In this retrospective analysis, liver function markers and fibrosis indices were assessed in CF patients receiving ETI (n=24), LI (n=4), or LI transitioned to ETI (LI/ETI, n=8). Key liver function markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, platelet count, and fibrosis indices (APRI and FIB-4), were measured at baseline and at various time points up to 12 months.

RESULTS: In patients receiving LI therapy, ALT and AST levels demonstrated a slight but non-significant decrease over six months, accompanied by significant fluctuations in total bilirubin levels. Among those receiving ETI therapy, ALT and AST levels initially increased but stabilized over time, while total bilirubin levels significantly increased from baseline to 12 months. No significant differences were observed in liver function markers between patients with and without hepatic disease under ETI therapy. Trends in fibrosis indices (APRI and FIB-4) were modest and largely non-significant across both therapies.

CONCLUSIONS: ETI therapy appears to be safe for CF patients, including those with pre-existing hepatic disease, with no significant deterioration in liver function over a 12-month period. However, the observed fluctuations in bilirubin levels underscore the necessity for ongoing monitoring. Further research is warranted to investigate the long-term hepatic effects of LI and ETI therapies.

PMID:39949910 | PMC:PMC11817584 | DOI:10.15386/mpr-2806

Cureus. 2025 Jan 13;17(1):e77407. doi: 10.7759/cureus.77407. eCollection 2025 Jan.

ABSTRACT

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a complex and often underdiagnosed disorder characterized by impaired water homeostasis, leading to hyponatremia and associated complications. This comprehensive review explores the intersection of SIADH with chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), pulmonary tuberculosis, cystic fibrosis, and interstitial lung disease. The review looks at current evidence on pathophysiology, diagnostic challenges, and treatment approaches, highlighting the need for specialized management strategies to improve patient outcomes. Through an analysis of clinical and observational studies, this review highlights the significant impact of SIADH on morbidity and mortality among patients with respiratory diseases. It illustrates the necessity for further research to refine diagnostic and therapeutic modalities.

PMID:39949461 | PMC:PMC11822327 | DOI:10.7759/cureus.77407

Cancers (Basel). 2025 Jan 24;17(3):394. doi: 10.3390/cancers17030394.

ABSTRACT

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, characterized by aggressive and heterogeneous tumors originating from B-cells. Especially in patients with relapsed or refractory (R/R) disease, DLBCL remains a challenging cancer to treat. Metabolic reprogramming is a hallmark of malignant cells. Our research focuses on developing strategies to enhance clinical outcomes for R/R DLBCL patients by targeting metabolic vulnerabilities. Methods: We investigated the effects of combining metformin and L-asparaginase, two FDA-approved antimetabolic drugs, on DLBCL cell metabolism and survival. Nuclear magnetic resonance (NMR) spectroscopy was employed to assess metabolic disturbances induced by the drug combination. The impact on lipid metabolism, glycolysis, glutaminolysis, the tricarboxylic acid (TCA) cycle, and antioxidant responses was examined. Induction of apoptosis was evaluated by FACS analysis. Results: The combination of metformin and L-asparaginase strongly sensitized DLBCL cells to apoptosis, independently of their oxidative phosphorylation (OxPhos) or BCR/glycolytic status. NMR spectroscopy revealed that this combination induces broader metabolic disturbances than either drug alone. It disrupts lipid metabolism by altering levels of phospholipids, cholesterol, and fatty acids. Additionally, it counteracts the pro-glycolytic effect of metformin, decreases glycolysis, and reduces glutaminolysis. It also affects the TCA cycle and antioxidant responses, critical for cellular energy production and redox balance. Furthermore, this combination interferes with two key cancer survival pathways, mTORC1 and MAPK signaling. Importantly, proof of principle for its beneficial effect was demonstrated in DLBCL patients. Conclusions: Combining metformin and L-asparaginase affects DLBCL cell survival by targeting multiple metabolic pathways and may represent a novel therapeutic approach for R/R DLBCL patients.

PMID:39941763 | PMC:PMC11816127 | DOI:10.3390/cancers17030394