Rev Mal Respir. 2025 Jan 20:S0761-8425(25)00001-4. doi: 10.1016/j.rmr.2025.01.001. Online ahead of print.

ABSTRACT

INTRODUCTION: Following two weeks of application of the triple combination therapy of Elexacaftor (E), Tezacaftor (T), and Ivacaftor (I) known as ETI, substantial pulmonary improvement in patients with cystic fibrosis is well-documented. However, few detailed data are available on the action of this treatment over the course of these first 14 days.

METHODS: In this prospective study (NCT05599230), 20 patients aged≥12 years, all of them eligible for ETI, were recruited at the initiation of treatment. Home spirometry (MIR Spirobank®) was performed during the three days preceding the start of treatment and then daily for 14 days, while a respiratory symptom score (RSS) was calculated and a log maintained concerning the events experienced by each patient.

RESULTS: Mean age (± SD) of the 20 patients was 29.4 (± 11.1) years, mean FEV1 was 84.2% (± 17.7), and the mean BMI z-score was 0.18 (± 0.82). Thirteen of them were already on modulators. When compared to the average scores recorded for the three days preceding the start of treatment, FEV1 improvement became significant from the 6th day (D6). After having significantly worsened on D1 (P<0.05), the RSS improved from D6 onwards. The quality of home FEV1 measurements was high (grade A: 81.2%).

CONCLUSIONS: Under ETI treatment, respiratory benefits were significant from D6. The side effects most commonly perceived by the patients occurred during the first four days of treatment. While daily monitoring of home spirometry could indeed be a valuable tool in follow-up of patients with cystic fibrosis, its administration requires suitable and sustained training.

PMID:39837691 | DOI:10.1016/j.rmr.2025.01.001

J Heart Lung Transplant. 2025 Jan 19:S1053-2498(25)00018-X. doi: 10.1016/j.healun.2025.01.010. Online ahead of print.

ABSTRACT

Bone health after lung transplantation has not been comprehensively reviewed in over two decades. This narrative review summarizes available literature on bone health in the context of lung transplantation, including epidemiology, presentation and post-operative management. Osteoporosis is reported in approximately 30-50% of lung transplant candidates, largely due to disease-related impact on bone and lifestyle, and corticosteroid-related effects during end-stage lung disease (interstitial lung diseases, chronic obstructive pulmonary disease, and historically cystic fibrosis). After lung transplantation, many patients experience steroid-induced bone loss, followed by stabilization or recovery to baseline levels with pharmacological management. Although evidence on fracture incidence is limited, fracture risk appears to increase in the year following transplantation, with common fracture sites including the vertebrae and the ribs. Vertebral and rib fractures restrict chest expansion and affect lung function, underscoring the importance of fracture prevention in lung transplant recipients. There is limited evidence on pharmacological management of osteoporosis after lung transplantation. Existing randomized controlled trials have focused on parenteral bisphosphonates and calcitriol, but have been underpowered to evaluate their effect on fracture outcomes. Resistance training, particularly in conjunction with antiresorptive therapy, has also been shown to improve bone health when initiated two months after transplantation. No studies to date have documented effectiveness of denosumab in lung transplant recipients; more studies on pharmacotherapy are warranted to elucidate optimal medical management. Considering high osteoporosis prevalence and high fracture risk in lung transplant populations, development of formal guidance is warranted to promote improved management after transplantation.

PMID:39837402 | DOI:10.1016/j.healun.2025.01.010

J Leukoc Biol. 2025 Jan 22:qiaf006. doi: 10.1093/jleuko/qiaf006. Online ahead of print.

ABSTRACT

Immune cells express a variety of ion channels and transporters in the plasma membrane and intracellular organelles, responsible of the transference of charged ions across hydrophobic lipid membrane barriers. The correct regulation of ion transport ensures proper immune cell function, activation, proliferation, and cell death. Cystic fibrosis (CF) is a genetic disease in which the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel gene is defective, consequently, the CFTR protein is dysfunctional, and the chloride efflux in CF cells is markedly impaired. Cystic fibrosis is characterized by chronic inflammation in the airways, mainly triggered by neutrophilic infiltration and recurring bacterial infections, causing the decline of lung function and eventually respiratory failure. Novel modulator-based therapies have improved lung function in people with Cystic Fibrosis (pwCF) by increasing expression and function of CFTR in the plasma membrane of lung cells, however, the effects of these drugs in the lung recruited inflammatory cells, specifically neutrophils, remains unknown. Given the complex biology of neutrophils and their short lifespan, we aimed to develop a fluorometric method to evaluate CFTR-mediated chloride transport in human neutrophils by using flow cytometry and the intracellular chloride-binding MQAE dye. Our results show that CFTR-mediated chloride transport in human neutrophils or human neutrophil-like cell lines can be consistently evaluated in vitro by this methodology. Additionally, this assay measured increased chloride efflux in neutrophils collected from pwCF under modulator therapy, as compared to healthy donors, indicating this method can evaluate restoration of CFTR-mediated chloride transport in CF neutrophils.

PMID:39837350 | DOI:10.1093/jleuko/qiaf006

Cell Immunol. 2025 Jan 17;409-410:104926. doi: 10.1016/j.cellimm.2025.104926. Online ahead of print.

ABSTRACT

BACKGROUND: Lungs of people with Cystic Fibrosis (pwCF) are characterized by chronic inflammation and infection with P. aeruginosa. High levels of IL-17 A and F have been observed in sputum of pwCF and the interleukin-17(IL-17) family (A-to-F) has been suggested to play a key role in CF pulmonary disease.

METHODS: We measured mRNA levels of IL-17 receptors (IL-17R) by RT-qPCR in CF bronchial epithelial (CFBE) cultured cells upon infection with P. aeruginosa PAO1 strain or clinical exoproducts (EXO) isolated from pwCF. We measured IL-17 mRNA expression by RT-qPCR and the release of cytokines by ELISA and Bioplex from CF primary nasal epithelial (HNE) cultured cells.

RESULTS: Infection of CFBE cells with PAO1 or EXO isolated from 15 pwCF significantly increased mRNA expression of all IL-17R, except IL-17RD. Infection of HNE cells with EXO isolated from the correspondent donor significantly increased the mRNA levels of all the IL-17 cytokines and receptors, except for IL-17D and IL-17RD, and the release of the cytokines IL-17 A, IL-17B, IL-17C, IL-17E and IL-17F. HNE exposed to IL-17 A and F were induced to release pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), neutrophil chemokines (IL-8, G-CSF) and cytokines known to be involved in chloride and bicarbonate secretion, together with mucin upregulation (IL-4, IL-13).

CONCLUSION: These results highlight a wider expression of IL-17 family member in respiratory epithelial cells, which can play a role as an autocrine inflammatory amplification loop in CF airways. These in-vitro studies using patient-derived cultures underline the relevant role of IL-17 family members in CF pulmonary immune response.

PMID:39837005 | DOI:10.1016/j.cellimm.2025.104926

Ann Am Thorac Soc. 2025 Jan 21. doi: 10.1513/AnnalsATS.202411-1237LE. Online ahead of print.

NO ABSTRACT

PMID:39836962 | DOI:10.1513/AnnalsATS.202411-1237LE

Ann Am Thorac Soc. 2025 Jan 21. doi: 10.1513/AnnalsATS.202410-1070LE. Online ahead of print.

NO ABSTRACT

PMID:39836960 | DOI:10.1513/AnnalsATS.202410-1070LE

Biomedica. 2024 Dec 23;44(Sp. 2):80-93. doi: 10.7705/biomedica.7500.

ABSTRACT

INTRODUCTION: Non-cystic fibrosis bronchiectasis is a complex medical condition with multiple etiologies, characterized by chronic productive cough and radiologic evidence of airway lumen dilation and wall thickening. Associated exacerbations and declining lung function contribute to increasing disability and mortality. There are no data about the prevalence of non-cystic fibrosis bronchiectasis etiologies in the Colombian population.

OBJECTIVE: To investigate non-cystic fibrosis bronchiectasis etiology and clinical characteristics in adults evaluated in the southwest of Colombia.

MATERIALS AND METHODS: We conducted a cross-sectional, non-interventional study. Subjects diagnosed with non-cystic fibrosis bronchiectasis were referred to by their healthcare providers and then enrolled between October 2018 and April 2021. Medical records and radiological studies were evaluated. Participants underwent laboratory tests, including complete blood count, serum immunoglobulin levels, and, in some cases, additional tests.

RESULTS: We included 161 subjects. The average age was 50 years old, and 59% were females. Bronchiectasis etiology was identified in 84.6% of the cases. Postinfectious (34.6%) and immune disorders (25.3%), represented by autoimmunity (13.6%) and immunodeficiency (11.7%), were the leading causes. Gender differences were noted in autoimmune (females: 18.8% versus males: 6.1%, p = 0.021) and immunodeficiency-related bronchiectasis (males: 21.2% versus females 5.2%, p = 0.002). Immunodeficiencies-associated bronchiectases were more frequent in subjects under 50 years of age, while chronic obstructive pulmonary disease-associated bronchiectases were common in subjects over 50 years of age.

DISCUSSION: The etiologies of non-cystic fibrosis bronchiectasis in Colombia are diverse, exhibiting notable differences from other global regions. Serum immunoglobulin levels and clinical immunologist consultation should be prioritized in diagnosing patients with unclear bronchiectasis etiology, particularly those with recurrent sinopulmonary infections.

PMID:39836848 | DOI:10.7705/biomedica.7500

Biomedica. 2024 Dec 23;44(Sp. 2):131-139. doi: 10.7705/biomedica.7558.

ABSTRACT

Introducción. Los errores innatos de la inmunidad se asocian frecuentemente con bronquiectasias. Actualmente, el diagnóstico de los errores innatos de la inmunidad ha mejorado porque se conoce con certeza la asociación de estas entidades con el daño progresivo de las vías respiratorias. Esto ha permitido el reconocimiento y la intervención adecuada, lo cual reduce el deterioro de la función pulmonar y mejora la calidad de vida. Objetivo. Describir un grupo de pacientes con bronquiectasias no relacionadas con la fibrosis quística y con diagnóstico de errores innatos de la inmunidad, estudiados en un centro de referencia de inmunología en Cali, Colombia. Materiales y métodos. Se desarrolló un estudio observacional, descriptivo y retrospectivo de pacientes menores de 18 años con diagnóstico de errores innatos de la inmunidad y bronquiectasias no relacionadas con fibrosis quística, entre diciembre de 2013 y diciembre de 2023 en la Fundación Valle del Lili, en Cali (Colombia). Resultados. Se incluyeron 17 pacientes con diagnóstico de bronquiectasias no relacionadas con fibrosis quística y errores innatos de la inmunidad, cuya edad media fue de nueve años. El inferior fue el lóbulo pulmonar más frecuentemente afectado y su compromiso fue unilateral en la mayoría de los casos. La inmunodeficiencia con predominio de defectos de los anticuerpos fue la más común, seguida de las inmunodeficiencias combinadas asociadas con síndromes. Trece pacientes presentaron compromiso de la inmunidad humoral y 4 pacientes, alteraciones en la inmunidad humoral y celular. En 12 pacientes se identificaron modificaciones genéticas relacionadas con su fenotipo. Trece pacientes recibieron suplemento de inmunoglobulina intravenosa y 3 fallecieron. Conclusión. La inmunodeficiencia con predominio de defectos de los anticuerpos, seguida de las inmunodeficiencias combinadas asociadas con características sindrómicas, fueron los errores innatos de la inmunidad que con mayor frecuencia se acompañaron de bronquiectasias no relacionadas con la fibrosis quística.

PMID:39836842 | DOI:10.7705/biomedica.7558

J Endocrinol. 2025 Jan 1:JOE-24-0190. doi: 10.1530/JOE-24-0190. Online ahead of print.

ABSTRACT

Endocrine dysfunction and diabetes can develop secondary to fibrotic diseases within the pancreas including cystic fibrosis (CF). Phenotypic shift within epithelial cells has been recognised in association with pro-fibrotic signalling. We sought evidence of endocrine cell epithelial-to-mesenchymal transition in CF and non-CF pancreas. Post mortem pancreatic sections from 24 people with CF and 10 organ donors without CF or diabetes were stained for insulin/glucagon/vimentin and Sirius Red Fast Green with collagen distribution assessed semi-quantitatively (CF) and quantitatively (non-CF). Analysis of existing single-cell RNA-sequencing data sets (three adult donors without diabetes and nine with chronic pancreatitis) for α-cell vimentin expression was performed. Cells co-expressing glucagon/vimentin were detected in a proportion (32(4,61)% (median(Q1,Q3)) of islets in all CF pancreata except donors dying perinatally. CF histopathology was characterised by peri-islet fibrosis and 60(45,80)% of islets were surrounded by collagen strands. A positive correlation between islet fibrosis and vimentin-expressing α-cells was seen in non-CF donors <31 years (r=0.972, p=0.006). A possible association with donor age was seen in all donors (r=0.343, p=0.047). Single-cell RNA-sequencing analysis of isolated islets from non-diabetic donors and donors with chronic pancreatitis confirmed presence of vimentin-positive and vimentin-negative α-cells. Differentiated α-cell function-associated gene expression was maintained. Differentially upregulated processes in co-expressing cells included pathways associated with extracellular matrix organisation, cell-cell adhesion, migratory capability and self-renewal. We have identified and characterised an intermediate epithelial/mesenchymal state in a sub-population of α-cells present throughout post-natal life which may play a role in their response to extrinsic stressors including fibrosis and ageing.

PMID:39836539 | DOI:10.1530/JOE-24-0190

Am J Physiol Lung Cell Mol Physiol. 2025 Jan 21. doi: 10.1152/ajplung.00328.2024. Online ahead of print.

ABSTRACT

Background: Secondhand smoke exposure (SHSe) is a public health threat for people with cystic fibrosis (CF) and other lung diseases. Primary smoking reduces CFTR channel function, the causative defect in CF. We reported that SHSe worsens respiratory and nutritional outcomes in CF by disrupting immune responses and metabolic signaling. Recently, electronic cigarette (e-cigs) usage by caregivers and peers has increased rapidly, causing new secondhand e-cig vape exposures. Primary vaping is associated with immunologic deficits in healthy people, but it is unknown if e-cigs similarly impacts CF immune function or how it differs from SHSe. Methods: Human CF and non-CF blood monocyte derived macrophages (MDMs) and bronchial epithelial cells (HBECs) were exposed to flavored and unflavored e-cigs. The effect of e-cigs on CFTR expression and function, bacterial killing, cytokine signaling, lipid mediators, and metabolism was measured during treatment with CFTR modulators. Results: E-cigs decreased CFTR expression and function in CF and non-CF MDMs and negated CFTR functional restoration by elexacaftor/tezacaftor/ivacaftor (ETI). E-cigs also negated the restoration of anti-inflammatory PGD2 expression in CF MDMs treated with ETI compared to controls. Flavored but not unflavored e-cigs increased pro-inflammatory cytokine expression in CF MDMs and e-cigs promoted glycolytic metabolism. E-cigs did not impact bacterial killing. Overall, HBECs were less impacted by e-cigs compared to MDMs. Conclusion: E-cigs reduced macrophage CFTR expression and hindered functional CFTR restoration by CFTR modulators, promoting a glycolytic, pro-inflammatory state. E-cigs are an emerging public health threat that may limit the efficacy of CFTR modulators in people with CF.

PMID:39836014 | DOI:10.1152/ajplung.00328.2024

Pediatr Pulmonol. 2025 Jan;60(1):e27487. doi: 10.1002/ppul.27487.

ABSTRACT

OBJECTIVE: Although studies have examined changes in C-reactive protein (CRP) during pulmonary exacerbations (PEX) in people with cystic fibrosis (PwCF), few have evaluated CRP profiles across age groups. Here, we characterize age-related CRP responses to PEX treatment.

METHODS: We measured CRP concentrations at the beginning and end of intravenous (IV) antibiotic therapy for PEX in 100 pediatric and 147 adult PwCF at 10 US CF Centers. We examined relationships between CRP and age, lung function, severity of PEX symptoms, and time to next PEX.

RESULTS: CRP measured at initiation of IV antibiotic treatment for PEX was higher in adults than children, median 8 mg/L (IQR 4, 32) versus 5 mg/L (IQR 2, 10), respectively (p < 0.001). There was a significant correlation between the initial CRP and drop in lung from baseline to the beginning of IV antibiotics in adults and children. Adjusted CRP dropped in response to PEX treatment more commonly in adults than in children (70% vs. 48%, respectively). The range of treatment responses was greater in adults, in those with higher symptom scores, and in those with more advanced lung disease. In adults elevated CRP at the end of treatment was also associated with incomplete recovery of lung function. CRP at the start of IV antibiotics was inversely related to time until the next PEX.

CONCLUSION: In children and adults with CF, CRP is increased at the initiation of IV antibiotic therapy for PEX and declines with treatment. The response is more pronounced in highly symptomatic adults with advanced lung disease.

PMID:39835779 | DOI:10.1002/ppul.27487

Pediatr Pulmonol. 2025 Jan;60(1):e27488. doi: 10.1002/ppul.27488.

ABSTRACT

INTRODUCTION: Cellular characteristics of induced sputum (IS) are not investigated in cystic fibrosis (CF) patients.

OBJECTIVES: This pilot study, conducted on 17 expectorating CF adolescents, compared sputa obtained the same day, in a stable period, by autogenic drainage (expectorating sputum, ES) and 4 h later after inhaling hypertonic saline (IS).

RESULTS: No difference was noted concerning weight, volume, and percentage of dead cells between the two collection methods. Sample quality (< 50% of dead cells and < 20% squamous cells) was higher in the case of IS than ES (94.1% vs. 58.8%, p = 0.03), with a doubled cell count (p = 0.01), a higher proportion of alveolar macrophages (p = 0.03), and a lower proportion of squamous cells (p = 0.004). The detection of germs increased by 44% in IS samples, possibly modifying therapeutic management in 17.6% of the patients.

CONCLUSION: IS improves the quality and the microbiological detection of the sample, even among CF patients who spontaneously expectorate.

PMID:39835741 | DOI:10.1002/ppul.27488

Front Immunol. 2025 Jan 6;15:1505752. doi: 10.3389/fimmu.2024.1505752. eCollection 2024.

ABSTRACT

BACKGROUND: Factors leading to severe COVID-19 remain partially known. New biomarkers predicting COVID-19 severity that are also causally involved in disease pathogenesis could improve patient management and contribute to the development of innovative therapies. Autophagy, a cytosolic structure degradation pathway is involved in the maintenance of cellular homeostasis, degradation of intracellular pathogens and generation of energy for immune responses. Acyl-CoA binding protein (ACBP) is a key regulator of autophagy in the context of diabetes, obesity and anorexia. The objective of our work was to assess whether circulating ACBP levels are associated with COVID-19 severity, using proteomics data from the plasma of 903 COVID-19 patients.

METHODS: Somalogic proteomic analysis was used to detect 5000 proteins in plasma samples collected between March 2020 and August 2021 from hospitalized participants in the province of Quebec, Canada. Plasma samples from 903 COVID-19 patients collected during their admission during acute phase of COVID-19 and 295 hospitalized controls were assessed leading to 1198 interpretable proteomic profiles. Levels of anti-SARS-CoV-2 IgG were measured by ELISA and a cell-binding assay.

RESULTS: The median age of the participants was 59 years, 46% were female, 65% had comorbidities. Plasma ACBP levels correlated with COVID-19 severity, in association with inflammation and anti-SARS-CoV-2 antibody levels, independently of sex or the presence of comorbidities. Samples collected during the second COVID-19 wave in Quebec had higher levels of plasma ACBP than during the first wave. Plasma ACBP levels were negatively correlated with biomarkers of T and NK cell responses interferon-γ, tumor necrosis factor-α and interleukin-21, independently of age, sex, and severity.

CONCLUSIONS: Circulating ACBP levels can be considered a biomarker of COVID-19 severity linked to inflammation. The contribution of extracellular ACBP to immunometabolic responses during viral infection should be further studied.

PMID:39835130 | PMC:PMC11743960 | DOI:10.3389/fimmu.2024.1505752

Cureus. 2024 Dec 19;16(12):e76002. doi: 10.7759/cureus.76002. eCollection 2024 Dec.

ABSTRACT

Aquagenic syringeal acrokeradermatoma (ASA) is a dermatological condition characterized by the transient appearance of edematous, white, translucent papules on the palms, typically triggered by water exposure. While ASA is most commonly associated with cystic fibrosis (CF) and predominantly affects young females, there has been a significant increase in ASA cases since the most recent update in 2015. The COVID-19 pandemic increased the number of patients diagnosed with ASA following exposure to the viral infection. The growing body of literature suggests a multifactorial etiology for ASA, with potential links to CF, medication use, and possibly COVID-19-related behavioral changes. Due to the recent increase in cases of ASA, an updated review seeks to quantify the existing literature that has been published on the prevalence of this condition. This review sought to find those newly diagnosed cases between the years 2014 and 2024. Through a literature review, we were able to find 57 cases of ASA since the last significant update to the total number of cases found in the literature. This review includes the prevalence of CF, a known etiology of ASA, as well as demographic information and known status of exposure to COVID-19.

PMID:39835050 | PMC:PMC11743320 | DOI:10.7759/cureus.76002

Respir Med Case Rep. 2024 Dec 27;53:102159. doi: 10.1016/j.rmcr.2024.102159. eCollection 2025.

ABSTRACT

INTRODUCTION: Acute fibrinous and organizing pneumonia (AFOP) is a severe form of acute lung injury which can occur after lung transplantation. Treatment is empiric, based on immunosuppressive regimens and the mortality rate is very high.

CASE PRESENTATION: We report the case of a young lung transplant (LT) recipient who developed AFOP following a respiratory viral infection while on suboptimal maintenance immunosuppression due to adherence issues. Diagnosis was confirmed by cryobiopsies showing intra-alveolar fibrin balls. Despite high dose systemic corticosteroids, the patient developed severe respiratory failure requiring mechanical ventilation. IV infliximab and tocilizumab were administered. The patient was extubated 11 days later and discharged to home 42 days after intubation with 1L/min O2. She developed severe pleuritic pain needing opioid treatment and died 4 months later.

CONCLUSION: While high-dose systemic corticosteroids remain the first line of treatment, the use of anti TNF-α has shown promising results in case reports. Furthermore, we propose prompt realization of a cytokine panel analysis in both blood and bronchoalveolar lavage to better guide the adjuvant administration of a targeted anti-inflammatory therapy.

PMID:39834689 | PMC:PMC11743898 | DOI:10.1016/j.rmcr.2024.102159

Cureus. 2025 Jan 19;17(1):e77681. doi: 10.7759/cureus.77681. eCollection 2025 Jan.

ABSTRACT

Bronchiectasis is a well-recognized chronic respiratory disease characterized by a productive cough and multi-microbial activation syndrome (MMAS) of various respiratory infections due to what can be the permanent dilatation of the bronchi. Bronchiectasis represents an ongoing challenge to conventional antibiotic treatment as the damaged bronchial environment remains conducive to ongoing opportunistic infections and microbial mutations, leading to multi-drug resistance. Standard treatment guidelines are designed to promptly identify and address the primary infection. Despite the strong focus on identification of the primary infection in each new episode, by combining clinical history, and high-resolution computed tomography (HRCT), a high proportion of patients remain classified as "idiopathic". Important underlying infections, such as Aspergillus and other mold infections, Pseudomonas aeruginosa, Mycobacterium, Mycoplasma, and various viruses, are frequently not identified for prolonged periods of time, and selected broad-spectrum antibiotics are often ineffective. The introduction of Induced Native Phage Therapy in 2021 and Induced Native Phage cocktails in 2024 provides a new treatment alternative that induces naturally occurring phages to eliminate specifically targeted acute and chronic mixed infections even in cases of multi-drug resistant infections as seen in chronic bronchiectasis. This article will present the successful long-term results in a case study demonstrating the speed, gentleness, and effectiveness of induced native phage cocktails in a 45-year-old male with life-long asthma resulting in multi-microbial activation syndrome in severe non-cystic fibrosis bronchiectasis for the last 20 years.

PMID:39834667 | PMC:PMC11744022 | DOI:10.7759/cureus.77681

Cell Death Differ. 2025 Jan 20. doi: 10.1038/s41418-024-01430-2. Online ahead of print.

ABSTRACT

Accumulating evidence suggests that genetic and epigenetic biomarkers hold potential for enhancing the early detection and monitoring of breast cancer (BC). Epigenetic alterations of the Homeobox A2 (HOXA2) gene have recently garnered significant attention in the clinical management of various malignancies. However, the precise role of HOXA2 in breast tumorigenesis has remained elusive. To address this point, we conducted high-throughput RNA sequencing and DNA methylation array studies on laser-microdissected human BC samples, paired with normal tissue samples. Additionally, we performed comprehensive in silico analyses using large public datasets: TCGA and METABRIC. The diagnostic performance of HOXA2 was calculated by means of receiver operator characteristic curves. Its prognostic significance was assessed through immunohistochemical studies and Kaplan-Meier Plotter database interrogation. Moreover, we explored the function of HOXA2 and its role in breast carcinogenesis through in silico, in vitro, and in vivo investigations. Our work revealed significant hypermethylation and downregulation of HOXA2 in human BC tissues. Low HOXA2 expression correlated with increased BC aggressiveness and unfavorable patient survival outcomes. Suppression of HOXA2 expression significantly heightened cell proliferation, migration, and invasion in BC cells, and promoted tumor growth in mice. Conversely, transgenic HOXA2 overexpression suppressed these cellular processes and promoted apoptosis of cancer cells. Interestingly, a strategy of pharmacological demethylation successfully restored HOXA2 expression in malignant cells, reducing their neoplastic characteristics. Bioinformatics analyses, corroborated by in vitro experimentations, unveiled a novel implication of HOXA2 in the lipid metabolism of BC. Specifically, depletion of HOXA2 leaded to a concomitantly decreased expression of PPARγ and its target CIDEC, a master regulator of lipid droplet (LD) accumulation, thereby resulting in reduced LD abundance in BC cells. In summary, our study identifies HOXA2 as a novel prognosis-relevant tumor suppressor in the mammary gland.

PMID:39833374 | DOI:10.1038/s41418-024-01430-2

BMJ Open Respir Res. 2025 Jan 19;12(1):e002960. doi: 10.1136/bmjresp-2024-002960.

ABSTRACT

BACKGROUND: The most common cause of death in those with cystic fibrosis (CF) is respiratory failure due to bronchiectasis resulting from repeated cycles of respiratory infection and inflammation. Protease-activated receptor 1 (PAR1) is a cell surface receptor activated by serine proteases including neutrophil elastase, which is recognised as a potent modulator of inflammation. While PAR1 is known to play an important role in regulating inflammation, nothing is known about any potential role of this receptor in CF pathogenesis.

METHODS: PAR1 (PAR1-/- ) and intestinal-corrected CFTR (Cftr-/- ) deficient mice were crossed to generate double knock-out (DKO) mutants lacking both PAR1 and CFTR, as well as matching sibling single mutant and wildtype (WT) littermate controls. Mice were weighed weekly to 15 weeks of age; then, the lungs and intestines were examined.

RESULTS: Cftr-deficient mice gained body weight at a significantly slower rate than WT controls and presented with no lung inflammation, but had increased weights of their ilea and proximal colons. DKO mice (lacking both CFTR and PAR1) gained body weight at a similar rate to Cftr-/- mice but only gained weight in their proximal colons. Weight gain in the ilea of Cftr-/- but not DKO mice was associated with increased ileal levels in the pro-inflammatory cytokine interleukin (IL)-6.

CONCLUSIONS: This study provides the first evidence of PAR1 contributing to the pathological effects of Cftr deficiency in the intestine and suggests a possible effect of PAR1 on the regulation of IL-6 in CF pathogenesis.

PMID:39832889 | DOI:10.1136/bmjresp-2024-002960

Gene. 2025 Jan 18:149257. doi: 10.1016/j.gene.2025.149257. Online ahead of print.

ABSTRACT

CRISPR-Cas9 technology has revolutionized genetic engineering, offering precise and efficient genome editing capabilities. This review explores the application of CRISPR-Cas9 for cystic fibrosis (CF), particularly targeting mutations in the CFTR gene. CF is a multiorgan disease primarily affecting the lungs, gastrointestinal system (e.g., CF-related diabetes (CFRD), CF-associated liver disease (CFLD)), bones (CF-bone disease), and the reproductive system. CF, a genetic disorder characterized by defective ion transport leading to thick mucus accumulation, is often caused by mutations like ΔF508 in the CFTR gene. This review employs a systematic methodology, incorporating an extensive literature search across multiple academic databases, including PubMed, Web of Science, and ScienceDirect, to identify 40 high-quality studies focused on CRISPR-Cas9 applications for CFTR gene editing. The data collection process involved predefined inclusion criteria targeting experimental approaches, gene-editing outcomes, delivery methods, and verification techniques. Data analysis synthesized findings on editing efficiency, off-target effects, and delivery system optimization to present a comprehensive overview of the field. The review highlights the historical development of CRISPR-Cas9, its mechanism, and its transformative role in genetic engineering and medicine. A detailed examination of CRISPR-Cas9's application in CFTR gene correction emphasizes the potential for therapeutic interventions while addressing challenges such as off-target effects, delivery efficiency, and ethical considerations. Future directions include optimizing delivery systems, integrating advanced editing tools like prime and base editing, and expanding personalized medicine approaches to improve treatment outcomes. By systematically analyzing the current landscape, this review provides a foundation for advancing CRISPR-Cas9 technologies for cystic fibrosis treatment and related disorders.

PMID:39832688 | DOI:10.1016/j.gene.2025.149257

Medicine (Baltimore). 2025 Jan 17;104(3):e41272. doi: 10.1097/MD.0000000000041272.

ABSTRACT

Cystic fibrosis (CF), a historically fatal childhood disease, now became a manageable adulthood disease. The transition of the disease to adulthood and the patients to adult physicians raised a new question: What is the extent of adult physicians' contributions to CF literature? We examined the data of all CF publications from Web of Sciences between 1945 and 2023. We determined the adult CF articles by searching for the term "adult" in titles. We analyzed the data in terms of publication years, study types, countries, and languages. A total of 30,944 articles examined. From 1945 to 2023, both the number of published articles (88-10,460), and the number of publishing journals (31-1770) on CF have increased. The number of articles on adult CF has also increased, from only 3 in the first 3 decades up to 716 between 2010 and 2019. While pediatrics was initially the leading journal with the highest number of articles published on CF, general medicine journals, and finally the Journal of Cystic Fibrosis became the leading publisher. The USA were the most productive country on behalf of publication on CF. The increasing number of annual publications clearly shows the growing interest in CF. The increase in the number of articles on adult CF along with the increase in publishing journals provide evidence that the disease is now acknowledged as a disease concerning adults.

PMID:39833061 | DOI:10.1097/MD.0000000000041272