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At least 19 recordsLinked to original sources
PubMed2025

Mitochondrial Lon Peptidase 1 Controls Diaphragm and Lung Development in a Context-Dependent Manner.

Congenital Diaphragmatic Hernia (CDH) is a rare neonatal disorder causing diaphragmatic defects and cardiopulmonary hypoplasia, traditionally attributed to mechanical compression from organ herniation. However, emerging evidence suggests genetic mutations may independently impair lung development, prompting debate over CDH etiology. Here, we investigated the requirement of mitochondrial function guarded by LON peptidase 1 (Lonp1), a CDH risk gene, in either diaphragm or lung development. Lonp1 loss in skeletal muscles of the diaphragm led to its thinning and membranization, recapitulating the pathology of sac-type CDH. On the other hand, lung-specific inactivation caused severe hypoplasia with defective branching morphogenesis, independent of diaphragm anomalies. Molecularly, Lonp1 disruption dysregulated key transcription factors and signaling pathways known to be critical for early lung development. Our findings here revealed that mitochondrial defects contribute to the pathogenesis of CDH in an organ and cell type specific manner, opening new avenues for drug and therapeutic development.

CDH↗
PubMed2024

TGF-β controls alveolar type 1 epithelial cell plasticity and alveolar matrisome gene transcription in mice.

Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease disrupting lung health throughout the life of an individual and that is increasing in incidence. The TGF-β superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that TGFbr2 is critical for alveolar epithelial (AT1) cell fate maintenance and function. Loss of TGFbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analyses reveal the necessity of TGFbr2 expression in AT1 cells for extracellular matrix production. Moreover, TGF-β signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGF-β signaling in maintaining AT1 cell fate and reveal this cell lineage as a major orchestrator of the alveolar matrisome.

Humans↗
PubMed1976

The influence of postnatal nutritional deprivation on the phospholipid content of developing rat lung.

It has been previously reported that fasting may result in decreased lung surfactant production. In order to investigate this relationship and the role of nutrition in lung phospholipid synthesis, 21-day-old rats were exposed for 60 h to one of five dietary regimens: standard rat chow (controls), fasting, pure glucose, pure fat, or pure protein. After the period of fasting there was a 33% decrease in lung protein content, but there was no change in DNA content. Exposure to any of the experimental diets resulted in a decrease in tissue total phospholipid and phosphatidylcholine content per lung, but not per unit lung protein. Similarly lung lavage phospholipid and phosphatidylcholine content was decreased by 25% after fasting when expressed per lung or per unit DNA, but not per unit protein. Pulmonary cholinephosphotransferase (EC 2.7.8.2) activity was decreased in the fasted animals and those fed the protein diet, but not in the glucose or fat-fed animals. The activities of acetyl-CoA carboxylase (EC 6.4.1.2) and microsomal fatty acid elongation were decreased in all the experimental groups except for the glucose-fed group. It is concluded that fasting results in a decrease in lung cell size but not in lung cell number. Total phospholipid and phosphatidylcholine content in lung tissue and lung lavage is decreased per cell but not per unit cell mass.

Acetyl-CoA Carboxylase↗
PubMed1975

The influence of cortisol on the enzymes of fatty acid synthesis in developing mammalian lung and brain.

Administration of cortisol to fetal rabbits resulted in a 42% inhibition of pulmonary de novo fatty acid synthesis from acetyl coenzyme A (CoA) (P = less than 0.025). This was associated with inhibition of acetyl-CoA carboxylase (EC. 6.4.1.2.) activity (P = less than 0.01) and a tendency towards decreased activity of fatty acid synthetase. There was no effect on pulmonary microsomal fatty acid elongation activity. Light and electron microscopic examination of the apex of the right lung of control and cortisol-treated animals revealed changes consistent with accelerated lung maturation in the treated animals. The in vitro activities of acetyl-CoA carboxylase and fatty acid synthetase were similar in rabbit lung and thus acetyl-CoA carboxylase activity does not appear to be rate limiting for de novo fatty acid synthesis in lung. No significant change in the activity of enzymes associated with de novo fatty acid synthesis of microsomal fatty acid elongation was found in fetal brain after cortisol exposure. However, in a parallel study on fatty acid synthesis in fetal liver, cortisol administration resulted in a 30% increase in fatty acid synthetase activity (P less than 0.025). The finding of cortisol-induced inhibition of de novo fatty acid synthesis in fetal rabbit lung may be related to the known inhibitory effect of cortisol on lung growth in the fetus.

Acetyl Coenzyme A↗
PubMed2025

Cellular imbalance in proximal and distal lung of CFTR-/- sheep in utero and at birth.

BACKGROUND: The Lung is the major focus of therapeutic approaches for the inherited disorder cystic fibrosis (CF) as without treatment lung disease is life-limiting. However, the initiating events that predispose the CF lung to cycles of infection, inflammation and resultant tissue damage are still unclear. Inflammation may occur in the CF lung prior to birth in human and several large animal models suggesting an in utero origin for the disease and encouraging further studies prior to birth. METHODS: Here we used the sheep model of CF (CFTR-/-) and age-matched wild-type (WT) sheep of the same breed to investigate the single cell transcriptomes of proximal and distal lung tissue at 80 days and 120 days of gestation and at term (147 days). Single cell RNA-seq was performed on tissues from 4 to 7 animals of each genotype (WT and CFTR-/-) at each time point. RESULTS: At term, FOXJ1-expressing ciliated cells are overrepresented in both lung regions from CFTR-/- lambs, while secretory epithelial and basal cells are underrepresented in proximal lung, as are T cells and monocytes in distal lung. The imbalance in ciliated and basal cells was confirmed by immunohistochemistry. At 120 days of gestation, lymphoid cells are slightly more abundant in proximal and distal lung from CFTR-/- animals compared to WT, consistent with the transient CF-associated inflammatory response in utero. At 80 days of gestation, T and B cells are underrepresented in both lung regions. CONCLUSIONS: The differences in epithelial cell abundance observed in the CFTR-/- lambs at term may reflect sequelae from the loss of CFTR on lung development and differentiation in utero. These findings provide novel insights into the cellular mechanisms of pathology and may be relevant to the design of new therapeutic approaches for CF lung disease.

Animals↗
PubMed1977

Fetal respiration. A review.

During recent years respiratory movements by the human fetus have been rediscovered. The types of movements have been defined, and their dependence on some physiologic conditions has been described. Pharmacologic agents influence not only the occurrence of the movements but also their rate and depth. A tidal flow of fluid between lung and amnionic sac has been established, which may play an important role in lung development. Demonstration of this route for exchange of water and soluble substances identifies the lung as an organ very likely involved in exchange between fetal compartments. Additionally, the deposition in the lung of the particulate matter contained in amnionic fluid may not be proof of pathologic aspiration as previously thought.

Adrenocorticotropic Hormone↗
PubMed2026

Genetic background influences developmental airway smooth muscle program and susceptibility to airway hyperresponsiveness in mice.

Airway structural remodeling and hyperresponsiveness (AHR), hallmarks of asthma, are influenced by genetic variations and adverse exposures. While intrauterine perturbations in lung development have been linked to adult pulmonary disease, the developmental origins of these abnormalities remain poorly understood. Here, we provide evidence of genetic background playing a key role in this process. Using A/J and C57BL/6J mice known for their distinct susceptibility to AHR, we show that A/J embryos selectively develop an aberrant airway smooth muscle (SM) program and AHR in adulthood when exposed transiently to a vitamin A/retinoic acid (RA)-disrupted intrauterine environment in vivo by maternal BMS493 administration. Single-nucleus multiomics identified a mesenchymal cell population overactivating TGF-β targets in response to BMS493 selectively in A/J lungs. These cells, localized to sites of airway SM initiation and p-SMAD2- and -3, exhibited robust BMS493-mediated upregulation of SMAD2/3 targets, including regulators of SM program Pdgfra and Tnc. Functional analyses in vivo and cultured lungs showed aberrant SM formation in areas of overactive TGF-β of BMS493-exposed lungs. These abnormalities were prevented by inhibiting TGF-β signaling in utero in RA-deficient embryos. These findings underscore how distinct genetic backgrounds respond to intrauterine perturbations that program airway structure and function, with potential lasting consequences in postnatal pulmonary function.

Animals↗
PubMed2026

Generation of an NKX2-1-EGFP reporter iPSC line with inducible Cas9 for lung progenitor cell tracing.

NK2 homeobox 1 (NKX2-1), a master regulator robustly expressed in lung, thyroid, and forebrain, is indispensable for specifying lung epithelial fate and serves as a definitive marker of lung progenitors. Here, we generated a human induced Pluripotent Stem Cell (iPSC) line harboring a doxycycline (dox)-inducible Cas9 and an NKX2-1-EGFP-puro reporter via CRISPR/Cas9-mediated homology-directed repair. This dual-function line combines inducible genome editing with real-time tracing of early lung progenitors, enabling their prospective isolation and screening for stage-specific maturation regulators. Therefore, this engineered iCas9-NKX2-1 EGFP line is a key resource for dissecting human lung development, modeling pulmonary disease, and advancing regenerative therapies.

Humans↗
PubMed1977

Quantitative characteristics of the Feyrter (APUD) cells of the neonatal rabbit lung in normoxia and chronic hypoxia.

Our studies show that the apparent number of Feyrter cells in the lung declines during the neonatal period in normoxic rabbits, and that in hypoxic animals a uniformly and significantly lower number of cells occurs as compared with the normoxic rabbits. There is some indication of degranulation of cells in the hypoxic groups. It is suggested that environmental and/or physiological factors associated with the start of extrauterine life, or lung development, may affect the apparent number and probable level of activity of these cells. These changes seem to be enhanced by hypoxia. Mast cells are scarce, and Feyrter cells are relatively more numerous along the airways. These cell types could possibly represent storage sites for 5-hydroxytryptamine, as suggested also by other investigators. Intraepithelial nerve fibres in bronchi and bronchioles were found but they were not limited to innervations of Feyrter cells or related cell bodies.

APUD Cells↗
PubMed1976

Trypsin inhibitors in bovine lung and pancreas during development.

1. The activity of trypsin inhibitors in lung and pancreas increased with age of the animals. 2. In foetal lung the activity of the basic Kunitz-type inhibitor was 1% that, and in calf lung 5-30% that, found in adult animals. 3. In foetal pancreas the basic Kunitz-type inhibitor was not detected, and in calf pancreas its activity was much lower than in adult animals. The activity of the acidic Kazal-type inhibitor in foetal pancreas was significantly lower than in calf or adult animal.

Age Factors↗
PubMed2026

Characterizing Time Toxicity in Lung Cancer Clinical Trials: Development and Application of a Novel Time Burden Metric.

PURPOSE: Participation in clinical trials imposes additional time commitments beyond routine care; however, trial-associated time toxicity (TT) remains underinvestigated and poorly characterized. The purpose of this study was to develop a scalable, procedure-based metric to quantify total time required for trial participation using the protocol schedule of events. We applied this framework to lung cancer clinical trials to estimate trial-associated burden and explore changes in TT over time. MATERIALS AND METHODS: Protocols for clinical trials associated with United States (US) Food and Drug Administration (FDA) approvals of oral lung cancer therapies were obtained from public sources. Using each protocol's schedule of events, study-mandated procedures were assigned time toxicity units (TTUs) based on standardized time estimates. TTUs for each procedure were multiplied by their frequency and summed for screening through cycle 5 to determine a trial's total time toxicity (TTT). Days with health care contact (DHC) were summed over the same period to determine total DHC (TDHC). Median (m) TTT and TDHC were compared between studies published in 2005-2014 and 2015-2024 to assess temporal trends. Two-sample Mann-Whitney U tests were used for nonparametric comparisons. RESULTS: Thirty-two phase-specific protocols from trials published between 2005 and 2024 were included. Among studies published in 2005-2014 (n = 7), the median TTT (mTTT) was 63.8 (41.8-109.3) versus 82 (50.3-139.5) in 2015-2024 (n = 25) (P = .042). Corresponding median TDHC values were 14 (10-21) versus 15 (11-44), respectively (P = .16). CONCLUSION: More contemporary studies demonstrated higher TTT, with significantly greater mTTT observed in studies published in 2015-2024 versus 2005-2014. TDHC demonstrated less sensitivity in capturing differences in time burden. These findings demonstrate the feasibility and practical applicability of the proposed TT framework for characterizing protocol-associated time burden. Prospective validation and broader implementation may help inform patients and encourage streamlined protocol development.

Journal Article↗
PubMed2025

Functional Mapping of Epigenomic Regulators Uncovers Coordinated Tumor Suppression by the HBO1 and MLL1 Complexes.

UNLABELLED: Epigenomic dysregulation is widespread in cancer. However, the specific epigenomic regulators and the processes they control to drive cancer phenotypes are poorly understood. We used a novel high-throughput in vivo method to perform iterative functional screens of >250 epigenomic regulators within autochthonous oncogenic Kras-driven lung tumors. We identified many previously unappreciated epigenomic tumor suppressor and tumor dependency genes. We show that a specific HBO1 complex and MLL1 complex are robust tumor suppressors in lung adenocarcinoma. Histone modifications generated by the HBO1 complex are frequently reduced in human lung adenocarcinomas and are associated with worse clinical features. HBO1 and MLL1 complexes co-occupy shared genomic regions, affect chromatin accessibility, and control the expression of canonical tumor suppressor genes and lineage fidelity. The HBO1 complex is epistatic with the MLL1 complex and other tumor suppressor genes in lung adenocarcinoma development. Collectively, these results provide a phenotypic roadmap of epigenomic regulators in lung tumorigenesis in vivo. SIGNIFICANCE: Using a novel functional genomics method in vivo, we investigated epigenomic regulators in lung tumorigenesis. We discovered multiple novel genes that affect tumor growth. We show that the HBO1 and MLL1 complexes interact to suppress lung adenocarcinoma. Our findings provide broad insights into the epigenomic regulatory landscape of lung cancer.

Humans↗
PubMed1978

Pleuropulmonary lung infection by anaerobic bacteria.

Two patients with severe pleuropulmonary infection caused by non-sporing anaerobic bacteria are described. One had an empyema with foul-smelling pus and developed bacteraemia, and the other developed a lung abscess. Both were successfully treated with antibiotics and drainage, chest surgery being avoided. The successful diagnosis and treatment of these patients involved close liaison between clinical and laboratory staff.

Adult↗
PubMed2026

Type I Interferon Signature is Associated With Lung Disease, Drug-Associated Immune Reactions, and Genetic Variation in Interferon-Linked Pathways in Still Disease.

OBJECTIVE: To evaluate the relationship across type I interferon (IFN-I)-stimulated gene (ISG) expression, Still disease, and the development of lung disease (LD) and drug-associated immune reactions (DAIR) to interleukin-1 (IL-1) and/or IL-6 inhibitors. METHODS: Whole blood ISG expression was quantified by NanoString array. ISG-28 scores were calculated in consecutive patients with Still or Still-like disease. Exome sequencing with family-based variant prioritization identified candidate genes harboring rare candidate causative variants. Lists of candidate genes were subjected to functional enrichment analysis. RESULTS: Among 57 patients (32 children, 25 adults), 16 had elevated ISG-28 scores. This group exhibited higher prevalence of LD (0.44 vs 0.1, P = 0.007) and DAIR (0.63 vs 0.17, P = 0.003) and lower IL-6 inhibitor use (0 vs 0.25, P = 0.048) compared to others. No significant differences were found in the rates of macrophage activation syndrome, active disease, elevated IL-18, or current IL-1 inhibition. The combination of HLA-DRB1*15 with high ISG-28 scores is associated with LD and DAIR with high specificity, whereas absence of both biomarkers had high negative predictive value. Candidate genes from high ISG-28 individuals were enriched in IFN-related pathways, including autophagy, IFN-I production, toll-like receptor signaling, macrophage activation, cytoskeletal organization, and responses to stress. CONCLUSION: High IFN-I expression correlates with LD and DAIR in Still disease, linked to rare genetic variation in immune pathways. Combining high ISG-28 with HLA-DRB1*15 significantly improves post hoc stratification of patients for these complications. If prospectively validated, these findings may guide molecular risk assessment and targeted therapies, including IFN-I directed treatments in Still disease with IFN-I signature.

Humans↗
PubMed2025

Precision projections of the delay of resistance mutations in non-small cell lung cancer via suppression of APOBEC.

Genomic instability driven by stress-response-dependent mutagenesis is a key factor in cancer progression. Tyrosine kinase inhibitor therapy, a common treatment for non-small cell lung cancer, induces mutations that can facilitate the evolution of drug resistance and therapeutic failure. Here we quantified the contribution of APOBEC to mutational signatures in non-small cell lung cancer patients undergoing TKI therapy. By analyzing tumor sequence data to infer gene-specific and patient-specific trinucleotide mutation rates, we projected the potential delay of resistance obtained by suppression of APOBEC mutation. Our data-driven analysis indicates that inhibition of APOBEC activity would substantially extend therapeutic efficacy, with the degree of benefit varying based on patient-specific APOBEC mutagenesis levels. Personalized therapeutic strategies that target APOBEC offer promise for the enhancement of TKI treatment efficacy by delaying the evolution of drug resistance in lung cancer. Development of clinically safe inhibitors for use in combination with tyrosine kinase inhibitors could significantly limit tumor genetic variation and improve outcomes for non-small cell lung cancer patients.

Humans↗
PubMed2026

Endoscopic ultrasound-guided biopsy of left and right adrenal metastases enabling pathological diagnosis and genomic profiling after nondiagnostic conventional biopsies: two case reports.

Obtaining adequate tissue for histologic diagnoses and genomic testing can be challenging in metastatic lung cancer, particularly when conventional biopsy approaches are nondiagnostic. The study reports an effective salvage strategy using endoscopic ultrasound (EUS)-guided adrenal tissue acquisition in two cases. A 66-year-old woman (case 1) developed recurrent lung adenocarcinoma with progressive metastases to the left adrenal, liver, and lungs following multiple lines of systemic therapy. A percutaneous biopsy of a suspected liver metastasis proved nondiagnostic. Subsequently, transgastric EUS-guided biopsy was performed, which confirmed metastatic adenocarcinoma originating in the lung. Oncomine-based genomic testing detected a human epidermal growth factor receptor 2 exon 20 insertion. Trastuzumab deruxtecan was subsequently introduced, resulting in disease stabilization for 6 months. A 75-year-old man (case 2) developed bilateral pulmonary nodules and a right adrenal mass detected on positron emission tomography. Bronchoscopy failed to yield diagnostic tissue. Following careful review of cross-sectional anatomy, EUS-guided biopsy of the right adrenal gland was safely performed via the duodenal bulb, confirming metastatic squamous cell carcinoma and yielding adequate tissue for genomic testing. EUS-guided adrenal biopsy, including transduodenal sampling of the right adrenal gland, may provide tissue for histopathologic and precision oncology testing, facilitating definitive diagnoses.

Adrenal metastasis↗
PubMed2026

Efficacy and safety of microwave ablation for the treatment of pulmonary osteosarcoma oligometastases.

PURPOSE: Evaluate efficacy and safety of microwave ablation (MWA) for pulmonary osteosarcoma oligometastases. METHODS: Twenty-two patients (median age, 16 years [range, 9-41 years]; 15 male) with pulmonary osteosarcoma oligometastases who underwent MWA from January 2018 to December 2023 were included, with 27 MWA sessions for 36 lung metastases. Technical success and complications were evaluated in all 22 patients, while efficacy and survival were evaluated in 19 patients with 24 MWA sessions in treatment of 32 tumors. Technical success was assessed for each tumor. Local tumor control, progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. Complications were classified using Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Technical success was achieved in all 36 tumors (100.0%). Local tumor progression occurred in five of 32 tumors (15.6%). The estimated local tumor control rates at 12, 24 and 36 months were 96.9%, 86.1% and 81.5%, respectively. No significant difference in local control was found between tumors ≤ 10 mm and > 10 mm (p = .470). Twelve of 19 patients (63.2%) developed new lung metastases outside the ablation area, including one with concurrent newly developed bone metastases and one with recurrence of primary osteosarcoma. The median PFS was 21.5 months. The estimated OS rates at 12, 24 and 60 months were 100.0%, 94.4% and 94.4%, respectively. Major complications occurred in five of 27 sessions (18.5%). CONCLUSIONS: MWA preliminarily demonstrates a high technical success rate, notable local tumor control, promising overall survival and acceptable safety for pulmonary osteosarcoma oligometastases.

Adolescent↗
PubMed2017

Smoking and Lung Cancer: A Geo-Regional Perspective.

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) represents the most frequently diagnosed subtype of this morbid malignancy. NSCLC is causally linked to tobacco consumption with more than 500 million smokers worldwide at high risk for this fatal malignancy. We are currently lagging in our knowledge of the early molecular (e.g., genomic) effects of smoking in NSCLC pathogenesis that would constitute ideal markers for early detection. This limitation is further amplified when considering the variable etiologic factors in NSCLC pathogenesis among different regions around the globe. In this review, we present our current knowledge of genomic alterations arising during early stages of smoking-induced lung cancer initiation and progression, including discussing the premalignant airway field of injury induced by smoking. The review also underscores the wider spectra and higher age-adjusted rates of tobacco (e.g., water-pipe smoke) consumption, along with elevated environmental carcinogenic exposures and relatively poorer socioeconomic status, in low-middle income countries (LMICs), with Lebanon as an exemplar. This "cocktail" of carcinogenic exposures warrants the pressing need to understand the complex etiology of lung malignancies developing in LMICs such as Lebanon.

early detection↗