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Tumor metastasis accounts for over 90% of tumor-related deaths, prompting the development of fluorescently labeled tumor-specific molecular imaging agents for differentiating tumors from normal tissues. However, early detection of metastasis lesions by tracking tumor markers alone has proven to be challenging. Herein, we reported a glycopeptide-based bispecific fluorescence probe (bsProbe) for earlier detection of bladder cancer and metastasis. By simultaneously recognition (tumor & tumor microenvironment) and in vivo self-assembly, the tumor accumulation of bsProbe (12.3% ID/g) was obviously increased by ∼6 fold compared with that in CXCR4 specific fluorescence probe (sProbe), indicating the obvious advantages of bsProbe over existing tumor metastasis detection probes. Additionally, bsProbe substantially broadens the tumor diagnosis window and enhances the detection signal to noise ratio (SNR: approximately 9.5), permitting early diagnosis of lung micro-metastasis (∼1 mm), precise identifying of tumor boundaries and micro-tumors in orthotopic tumor models. More importantly, bsProbe was demonstrated to distinguish malignant from benign specimen with a specificity of 90.48% and sensitivity of 92.22% in 195 clinical specimens of bladder cancer patients. Taken together, this novel synergetic targeting (CD206 × CXCR4) strategy provides an attractive method for earlier detection of bladder cancer and metastasis, which might be further extended to the imaging-guided surgery of clinical invisible tumors. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that high-mobility group box protein 1(HMGB1) was increased and released to the extracellular and participated in the pathogenesis of steroid-insensitive asthma induced by toluene diisocyanate (TDI). Mitochondrial dysfunction of bronchial epithelia is a critical feature in TDI asthma. However, whether mitochondrial dysfunction regulated HMGB1 release in asthma remains unknown. The aim of this study was to explore whether phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial protein, can regulate HMGB1 release in TDI-induced asthma. The gene expression data series (GSE) 67472 from gene expression omnibus (GEO) database was analyzed to compare the levels of PGAM5 in airway epithelial cells from asthma patients and healthy individuals. Male C57BL/6J mice were sensitized and challenged with TDI and treated with the PGAM5 inhibitor LFHP-1c. In vitro, human bronchial epithelial cells(16HBE) were stimulated by TDI-human serum albumin (HSA) and pretreated with PGAM5 siRNA. In this study, we observed PGAM5 expression was notably increased in airway epithelial cells of asthma patients and TDI-induced asthma mice. In vivo, inhibition of PGAM5 significantly ameliorated airway inflammation, airway hyperresponsiveness (AHR) and mucus hypersecretion, coupled with the decrease of pulmonary HMGB1 expression and release in TDI-exposed mice. In vitro, inhibition of PGAM5 improved mitochondrial dysfunction, decreased the production of reactive oxygen species (ROS) in mitochondrial. Knockdown of PGAM5 reduced the release of cytochrome C (cyt c) and HMGB1 release in TDI-induced asthma. Mechanistically, PGAM5 in bronchial epithelial cells treated by TDI-HSA significantly increased the dephosphorylation of Bax at the S184 residue, promoted the translocation of Bax to mitochondria, and contributed to the activation of mitochondrial-dependent apoptosis in TDI-induced asthma. Based on these findings, we uncovered a novel regulatory mechanism by which high PGAM5 expression promotes airway inflammation by mediating HMGB1 release in TDI-induced asthma, identifying the therapeutic effects of targeting PGAM5 in steroid-insensitive asthma model. [Display omitted] • PGAM5 plays a role in airway inflammation of TDI-induced asthma. • PGAM5 promotes airway inflammation by regulating the release of HMGB1 and mitochondria-dependent apoptosis in lungs from TDI-asthmatic mice. • PGAM5 promotes the mitochondria translocation of Bax, and activates the mitochondria-dependent apoptosis in bronchial epithelial cells exposed to TDI-HSA. [ABSTRACT FROM AUTHOR]

Background: A second primary malignant tumor is one of the most important factors affecting the long-term survival of young women with breast cancer (YWBC). As one of the main treatments for breast cancer YWBC patients, postoperative radiotherapy (PORT) may increase the risk of second primary malignancy (SPM). Methods: Machine learning components, including ridge regression, XGBoost, k-nearest neighbor, light gradient boosting machine, logistic regression, support vector machine, neural network, and random forest, were used to construct a predictive model and identify the risk factors for SPMs with data from the Surveillance, Epidemiology and End Results. Multivariate logistic regression analysis was used to assess the risk of SPM associated with PORT. The cumulative incidence of SPMs was determined by competing risk regression analysis. Results: Among the 44223 YWBC patients included in our study, 3017 developed SPMs. Among all the clinical characteristics, PORT was the most common SPM. YWBC patients receiving PORT had significantly greater risks of second primary solid malignancies (SPSMs, RR = 1.61), including breast cancer (RR = 1.89), lung cancer (RR = 2.12) and thyroid cancer (RR = 1.48), but not second primary hematologic malignancies (RR = 1.32; 0.94–1.88). SPSMs were more common in YWBC individuals who were black, had a lower median household income and had fewer lymph nodes examined. Additionally, we developed a prediction nomogram with an area under the curve of 0.75 to assess the likelihood of developing SPMs. Conclusion: YWBC patients receiving PORT had a greater risk of developing SPSMs (thyroid, lung, and breast cancer), indicating the necessity of long-term surveillance of these patients. Standard adjuvant PORT should not be recommended for breast cancer patients with favorable histology and a low risk of relapse. [ABSTRACT FROM AUTHOR]

We summarize the chest CT manifestations and prognoses of children with Mycoplasma pneumoniae pneumonia combined with necrotizing pneumonia. We retrospectively analyzed the chest CT manifestations and prognoses of 155 cases of necrotizing pneumonia in children due to Mycoplasma pneumoniae infection and compared the differences in clinical features and laboratory indices between the group with unilateral monolobar necrosis of the lungs (Group A) and the group with unilateral multilobar and bilateral necrosis (Group B). The chest CT findings of the children in both groups revealed that the area of lung necrosis was confined to the unilateral monolobe in 124 children. The necrotic condition of the lungs included only hypodense shadows in 80 children (51.61%) and cystic cavities in the necrotic areas in 75 children (48.39%). Bronchoscopic manifestations: Endobronchitis was present in 135 children, ulcerative necrosis of the bronchi in 47, and occlusive bronchitis in four. A total of 101 children were followed up. A small percentage of patients have residual manifestations such as lobar atelectasis and bronchial wall changes. The number of days of fever and cases of respiratory distress were significantly greater in group B than in group A. Chest CT reveals pulmonary necrosis in children due to Mycoplasma pneumoniae infection: the area of pulmonary necrosis is mostly unilateral and unilobar, the lower lungs are predominant, and areas of reduced enhancement can be seen on enhanced CT. CT manifestations after clinical treatment may be approximately normal or leave a striped shadow, lung atelectasis, or pleural thickening. [ABSTRACT FROM AUTHOR]

The accurate identification of oxygen desaturation (OD) status plays critical role in the clinic diagnosis of chronic obstructive pulmonary disease (COPD), which is a common disease related to the lungs and respiratory tract of the human body. This paper focuses on a specific type of OD status, i.e., exercise-induced oxygen desaturation (EIOD) status in COPD, and try to further improve the performance of EIOD status identification. We propose a new and effective EIOD status identification method by using classifier ensemble strategy. In the proposed method, five different features of each data point from the time series of SpO2 and pulse are extracted and then combined to form the discriminative feature of the corresponding data point; then, multiple base classifiers with different balanced training subsets are trained and then integrated by using AdaBoost Algorithm. The comparative computational results on the 6-min walk test (6MWT) of the recruited participants show that the proposed method achieved the best global performance with AUC (Area Under Curve) value of 0.8532, indicating that the proposed method can be effectively used for the identification of EIOD and could assist the clinic diagnosis of COPD. [ABSTRACT FROM AUTHOR]

The benign and malignant discrimination of pulmonary nodules plays a very important role in diagnosing the extent of lung cancer lesions. There are many methods using Convolutional neural network (CNN) for benign and malignant classification of pulmonary nodules, but traditional CNN models focus more on the local features of pulmonary nodules and lack the extraction of global features of pulmonary nodules. To solve this problem, a Cross fusion attention ViT (Cross-ViT) network that fuses local features extracted by CNN and global features extracted by Transformer is proposed. The network first extracts different features independently through two branches and then performs feature fusion through the Cross fusion attention module. Cross-ViT can effectively capture and process both local and global information of lung nodules, which improves the accuracy of classifying the benign and malignant nature of pulmonary nodules. Experimental validation was performed on the LUNA16 dataset, and the accuracy, precision, recall and F1 score reached 91.04%, 91.42%, 92.45% and 91.92%, respectively, and the accuracy, precision, recall and F1 score with SENet as CNN branch reached 92.43%, 94.27%, 91.68% and 92.96%, respectively. The results show that the accuracy, precision, recall and F1 score of the proposed method are 0.3%, 0.11%, 4.52% and 3.03% higher than those of the average optimal method, respectively, and the performance of Cross-ViT network for benign and malignant classification is better than most classification methods. [ABSTRACT FROM AUTHOR]

PURPOSE: Novel methods generate functional images using image processing techniques combined with four-dimensional computed tomography (4DCT) data (4DCT-ventilation). 4DCT-ventilation was implemented in a phase II, multicenter functional avoidance clinical trial. The work compares functional avoidance patient-reported outcomes (PROs) against historical standards. METHODS: Patients with locally advanced lung cancer undergoing curative-intent chemoradiation were accrued. 4DCT-ventilation imaging was generated and functional avoidance treatment plans created reduced dose to functional lung. PRO instruments included Functional Assessment of Cancer Therapy Lung questionnaire and accompanying subscales (including the Trial Outcome Index [TOI]), EuroQol-5 Dimension (EQ-5D), and EQ-Visual Analog Scale (EQ-VAS). The average change from baseline and percentage of clinically meaningful declines were calculated. We compared results against PROs from RTOG 0617 and PACIFIC trial data using Student t-tests and chi-square tests. RESULTS: Fifty-nine patients completed baseline PRO surveys. The median age was 65 (44-86) years, non–small cell lung cancer comprised 83%, and median dose was 60 Gy in 30 fractions. The percent of patients with clinically meaningful decline in FACT-TOI at 12 months was 47.8% for RTOG 0617% and 26.8% for functional avoidance (P =.03). The functional avoidance cohort demonstrated a significantly (P =.012) higher change in EQ-VAS score at 12 months (9.9 ± 3.3; average ± SE) compared with the PACIFIC cohort (1.6 ± 0.6). CONCLUSION: The current work demonstrates improved PROs from a phase II functional avoidance trial in certain subscales (FACT-TOI and EQ-VAS) compared with PROs from seminal studies (RTOG 0617 and PACIFIC). The presented data support investigation of 4DCT functional avoidance in a phase III setting. [ABSTRACT FROM AUTHOR]

The detailed mechanism of pulmonary arteriovenous malformations after Glenn surgery (G-PAVMs) in cyanotic congenital heart disease (CHD) remains unclear. Microarray in situ hybridization was performed to assess the miRNA (miRNA) profiles of serum from pediatric patients (0–6 years of age) with G-PAVMs and after the Fontan procedure without G-PAVMs. In addition, we investigated the tube formation, migration, and proliferation of human lung microvascular endothelial cells (HMVEC-L) transfected with miR-25-3p mimic, miR-25-3p inhibitor, or PHLPP2 small interfering RNA, and examined HIF-1α/VEGF-A signaling after hypoxic stimulation. Serum miRNAs that showed ≥ 2-fold higher levels in patients with G-PAVMs than in other patients were selected. MiR-25-3p was significantly upregulated in the pulmonary artery sera of the post-Glenn group than in the post-Fontan group. We identified PHLPP2 as a direct target of miR-25-3p. PHLPP2 expression was significantly decreased in HMVEC-L transfected with miR-25-3p mimic compared to the control cells. HIF-1α and VEGF-A expression levels were increased in HMVEC-L transfected with miR-25-3p mimic compared to the control cells in a PHLPP2/Akt/mTOR signaling-dependent manner after hypoxic stimulation. MiR-25-3p promoted HMVEC-L angiogenesis, proliferation, and migration under hypoxic conditions. MiR-25-3p in the pulmonary arteries may contribute to G-PAVM development. [ABSTRACT FROM AUTHOR]

This study aims to establish an animal model of monkeypox virus (MPXV) infection in dormice through intranasal inoculation. Male dormice aged 4–5 months were selected as experimental subjects and administered different titers of MPXV (103.5 PFU, 104.5 PFU, and 105.5 PFU, respectively) via nasal instillation. Within 14 days post-infection, clinical indicators such as survival rate, body weight changes, respiratory status, and mental state were continuously monitored. Additionally, tissue samples from the lungs, liver, spleen, and trachea of dormice from each group were collected on the 5th and 10th days for virus titer detection, and histopathological analysis was performed on lung samples collected on the 5th and 10th days. Dormice infected with MPXV exhibited typical symptoms such as appetite loss, continuous body weight reduction, aggravated respiratory difficulties, accompanied by lethargy, chills, and other clinical manifestations similar to human monkeypox infection. Virological tests further confirmed the distribution of MPXV in multiple vital organs of dormice, including the lungs, liver, spleen, and trachea, with particularly significant pathological damage observed in lung tissue. An MPXV infection model in dormice was successfully established through intranasal inoculation with a titer of 105.5 PFU MPXV, which can be used for studying the infection mechanism and pharmacology of MPXV. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by excessive scarring and fibrosis due to the abnormal accumulation of extracellular matrix components, primarily collagen. This study aims to design and solve an optimal control problem to regulate M2 macrophage activity in IPF, thereby preventing fibrosis formation by controlling the anti-M1 agent. The research models the diffusion of M2 macrophages in inflamed tissue using a novel dynamical system with partial differential equation (PDE) constraints. The control problem is formulated to minimize fibrosis by regulating an anti-M1 agent. The study employs a two-step process of discretization followed by optimization, utilizing the Galerkin spectral method to transform the M2 diffusion PDE into an algebraic system of ordinary differential equations (ODEs). The optimal control problem is then solved using Pontryagin/s minimum principle, canonical Hamiltonian equations, and extended Riccati differential equations. The numerical simulations indicate that without control, M2 macrophage levels increase and stabilize, contributing to fibrosis. In contrast, the optimal control strategy effectively reduces M2 macrophages, preventing fibrosis formation within 120 days. The results highlight the potential of the proposed optimal control approach in modulating tissue repair processes and mitigating the progression of IPF. This study underscores the significance of targeting M2 macrophages and employing mathematical methods to develop innovative therapies for lung fibrosis. [ABSTRACT FROM AUTHOR]

Historical processes in community assembly, such as species arrival order, influence interactions, causing priority effects. Candida albicans and Pseudomonas aeruginosa often co-occur in biofilm-based infections of the skin, lungs, and medical devices. Their predominantly antagonistic relationship involves complex physical and chemical interactions. However, the presence and implications of priority effects among these microorganisms remain largely unexplored. Here, we investigate the presence and impact of priority effect in dual-species biofilms using clinical isolates. By varying inoculation order, we observe significant changes in biofilm composition, structure, virulence, and antimicrobial susceptibility. The first colonizer has an advantage for surface colonization. Consecutive colonization increases biofilm virulence and negates C. albicans' protective effect on P. aeruginosa PAET1 against meropenem treatment. Finally, we propose N-acetylcysteine as an adjuvant for treating C. albicans and P. aeruginosa interkingdom infections, working independently of priority effects. Polymicrobial biofilms of C. albicans and P. aeruginosa demonstrated that priority effects, influenced by the species' inoculation order, affect biofilm composition, structure, virulence, and antimicrobial susceptibility. [ABSTRACT FROM AUTHOR]

Type VII secretion systems participate in protein export, virulence, conjugation, and metabolic regulation. Five subtypes (ESX-1 to ESX-5) exist, each with specific roles and well-characterized secretion profiles in various mycobacterial species. Mycobacterium abscessus, encodes only ESX-3 and ESX-4. Here, single and double M. abscessus mutants lacking the main ATPases EccC3 and EccC4 were used to define ESX-3 and ESX-4 contributions to substrate secretion and virulence. Our results demonstrate that EsxG/H secretion depends entirely on ESX-3, whereas both ESX-3 and ESX-4 secrete EsxU/T. Furthermore, two newly identified PE/PPE substrates (MAB_0046/MAB_0047) require ESX-3 for secretion. Functional complementation restored secretion and revealed subpolar localization of these systems. Macrophage infections showed that ESX-3 and ESX-4 contribute to bacterial internalization, phagosomal escape, and intracellular survival. In mice, infections with eccC3- and/or eccC4-deletion mutants resulted in complete survival and reduced bacterial loads in the lungs. These findings demonstrate that both ESX systems drive M. abscessus pathogenicity. Investigation of ESX-3 and ESX-4 secretion systems in Mycobacterium abscessus reveals their crucial role in substrate secretion, macrophage infection, and in vivo pathogenicity, highlighting their role in mycobacterial survival and host interactions. [ABSTRACT FROM AUTHOR]

Irreversible damage of the lung epithelium in idiopathic pulmonary fibrosis (IPF) patients causes high mortality worldwide, with no lung repair approaches available currently. Here we show that in murine and monkey models, the KRT5+ P63+ progenitor cells in airway basal layer can enter the alveolar area post fibrotic injury. Aided with an automated culture system, we clone and characterize airway basal progenitor cells from 44 donors with various lung conditions. Transplantation of human progenitor cells into the mouse lung efficiently re-epithelializes the injured alveolar area, forms new respiratory tract and saccule-like structures, which ameliorates fibrotic lesions and improves survival of mice. Mechanistically, the engrafted human progenitor cells do not function by differentiating into mature alveolar cells in mouse lung; instead, they differentiate into saccular cells expressing multiple tight junction proteins such as CLDN4, which help the lung to re-establish epithelial barriers. Furthermore, by cloning P63+ airway basal progenitors from larger mammals and birds, we construct multiple lung-chimerism animals and uncover the evolutionarily conserved roles of these progenitor cells in lung repair. Overall, our data highlight the fate of airway basal progenitor cells in fibrotic lung and provide a potential therapeutic strategy for pulmonary diseases that lack inherent recovery mechanisms. Irreversible damage of the lung epithelium in idiopathic pulmonary fibrosis patients causes high mortality worldwide, with no lung repair approaches available currently. Here, the authors show that cloned human airway basal progenitor cells could repair the fibrotic lung through re-epithelialization of the damaged alveolar area. [ABSTRACT FROM AUTHOR]

Identifying tumor-specific T cell clones that mediate immunotherapy responses remains challenging. Mutation-associated neoantigen (MANA) -specific CD8+ tumor-infiltrating lymphocytes (TIL) have been shown to express high levels of CXCL13 and CD39 (ENTPD1), and low IL-7 receptor (IL7R) levels in many cancer types, but their collective relevance to T cell functionality has not been established. Here we present an integrative tool to identify MANA-specific TIL using weighted expression levels of these three genes in lung cancer and melanoma single-cell RNAseq datasets. Our three-gene "MANAscore" algorithm outperforms other RNAseq-based algorithms in identifying validated neoantigen-specific CD8+ clones, and accurately identifies TILs that recognize other classes of tumor antigens, including cancer testis antigens, endogenous retroviruses and viral oncogenes. Most of these TIL are characterized by a tissue resident memory gene expression program. Putative tumor-reactive cells (pTRC) identified via MANAscore in anti-PD-1-treated lung tumors had higher expression of checkpoint and cytotoxicity-related genes relative to putative non-tumor-reactive cells. pTRC in pathologically responding tumors showed distinguished gene expression patterns and trajectories. Collectively, we show that MANAscore is a robust tool that can greatly enrich candidate tumor-specific T cells and be used to understand the functional programming of tumor-reactive TIL. Although individual genes that distinguish tumor-reactive CD8+ T cells from bystander T cells in tumors have been described, a functionally meaningful integrative signature has not been established. Here authors show that mutation-associated neoantigen-specific CD8+ tumor-infiltrating lymphocytes can be recognized by MANAscore, an algorithm that uses weighted expression levels of CXCL13, ENTPD1 and IL7R in single-cell RNAseq datasets of lung cancer and melanoma patients as input. [ABSTRACT FROM AUTHOR]

Objective. Electrical impedance tomography (EIT) is a non-invasive technique used for lung imaging. A significant challenge in EIT is reconstructing images of deeper thoracic regions due to the low sensitivity of boundary voltages to internal conductivity variations. The current injection pattern is decisive as it influences the current path, boundary voltages, and their sensitivity to tissue changes. Approach. This study introduces a novel current injection pattern with radially placed electrodes excited in a rotating radial pattern. The effectiveness of the proposed pattern was investigated using a 3D computational model that mimics the human thorax, replicating its geometry and tissue electrical properties. To examine the detection of lung anomalies, models representing both healthy and unhealthy states, including cancer-like anomalies in three different positions, were developed. The new pattern was compared to common patterns—adjacent, skip 1, and opposite—using finite element analysis. The comparison focused on the current density within lung nodules and the sensitivity to changes in anomaly positions. Main results. Results showed that the new pattern achieved the maximum current density within anomalies compared to surrounding tissues, with peak values near the closest electrode pairs to the anomalies. Specifically, current density magnitudes reached 72.73 ⋅ 10 − 9 A ⋅ m , 145.24 ⋅ 10 − 9 A ⋅ m , and 26.43 ⋅ 10 − 9 A ⋅ m for the three different positions, respectively. Furthermore, the novel pattern's sensitivity to anomaly position changes surpassed the common patterns. Significance. These results demonstrate the efficiency of the proposed injection pattern in detecting lung anomalies compared to the common injection patterns. [ABSTRACT FROM AUTHOR]

Zusammenfassung: Lungenfunktionstests (LuFu) sind für die Diagnose und Behandlung einer Vielzahl von Atemwegserkrankungen von entscheidender Bedeutung. Sie liefern wichtige Informationen über die Gesundheit der Lunge und helfen bei der Diagnose, der Beurteilung des Schweregrads der Erkrankung und der Entwicklung von Behandlungsstrategien für die Patienten. Diese Übersichtsarbeit befasst sich mit der Komplexität und den Nuancen, die mit der Interpretation von LuFu-Daten verbunden sind, insbesondere im Hinblick auf die jüngsten Aktualisierungen der European Respiratory Society (ERS) und der American Thoracic Society (ATS). Diese Aktualisierungen haben die Interpretationsstrategien verfeinert, weg von der definitiven diagnostischen Verwendung der Spirometrie hin zu einem eher probabilistischen Ansatz, der die individuelle Variabilität durch die Verwendung von Z-Scores und unteren Grenzwerten (lower limits of normal, LLN) besser berücksichtigt. Diese Übersichtsarbeit befasst sich mit dem philosophischen Wandel in der Interpretation der Spirometrie und hebt den Übergang von einer direkten klinischen Diagnose zu einer nuancierteren Beurteilung hervor, die sich auf die Bestimmung der Wahrscheinlichkeit einer Erkrankung konzentriert. Die Abhängigkeit von festen Verhältnissen wird kritisch betrachtet und die Notwendigkeit von Referenzwerten, die demographische Variablen wie Alter, Geschlecht, Körpergröße und ethnische Zugehörigkeit in Übereinstimmung mit den neuesten Gleichungen der Global Lung Function Initiative (GLI) berücksichtigen, wird betont. Trotz dieser Fortschritte bleibt es eine Herausforderung, die Konsistenz der verschiedenen prädiktiven Modelle und Referenzgleichungen zu gewährleisten, was die Genauigkeit und Einheitlichkeit der Interpretationen beeinträchtigen kann. In dieser Arbeit wird ein rationalisierter, 3-stufiger Rahmen für die Interpretation von Lungenfunktionstests vorgeschlagen, der darauf abzielt, den Prozess zu vereinheitlichen und zu vereinfachen, um die Klarheit und Zuverlässigkeit in allen medizinischen Fachbereichen zu verbessern. Dieser Ansatz unterstützt nicht nur eine genaue Patientenbeurteilung, sondern reduziert auch das Potenzial für Fehldiagnosen und gewährleistet ein effektiveres Patientenmanagement. Durch die Zusammenfassung aktueller Leitlinien und die Integration solider physiologischer Prinzipien fördert diese Übersichtsarbeit einen standardisierten, aber dennoch flexiblen Ansatz zur Interpretation von Lungenfunktionstests, der sowohl wissenschaftlich fundiert als auch praktisch umsetzbar ist. [ABSTRACT FROM AUTHOR]

Sox17-Erg direct reprogramming is a potent tool for the in vitro and in vivo generation of arterial-like induced-endothelial cells from fibroblasts. In this study, we illustrate the pioneering roles of both Sox17 and Erg in the endothelial cell reprogramming process and demonstrate that emergent gene expression only occurs when both factors are co-expressed. Bioinformatic analyses and molecular validation reveal both Bach2 and Etv4 as integral mediators of Sox17-Erg reprogramming with different roles in lung and heart fibroblast reprogramming. The generated organ-specific induced endothelial cells express molecular signatures similar to vasculature found in the starting cell's organ of origin and the starting chromatin architecture plays a role in the acquisition of this organ-specific identity. Overall, the Sox17-Erg reprogramming mechanism provides foundational knowledge for the future recapitulation of vascular heterogeneity through direct reprogramming. [Display omitted] • Co-expression of both Sox17 and Erg is required to efficiently activate endothelial identity in reprogramming fibroblasts • Bach2 and Etv4 work downstream of Sox17-Erg in iEC reprogramming • Heart and lung fibroblasts generate iECs with organ-specific markers when compared to organ-specific native endothelial cells [ABSTRACT FROM AUTHOR]

Introduction: Primary pulmonary salivary gland-type carcinomas are rare malignancies arising from minor salivary gland tissue in the lower respiratory tract. Given their rarity, constituting <1% of all primary lung malignancies, their epidemiological features and outcomes remain poorly documented. This study analyzed data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database to identify primary pulmonary salivary gland carcinomas, including the most prevalent tumor types. Methods: All patients diagnosed with mucoepidermoid carcinoma, adenoid cystic carcinoma, and epithelial-myoepithelial carcinoma, with the lung designated as the primary site between 1975 and 2019, were subject to analysis. Overall and disease-specific survival were calculated using Kaplan-Meier curves and Cox proportional hazards models. Results: The study identified 323 mucoepidermoid carcinoma, 284 adenoid cystic carcinoma, and 6 epithelial-myoepithelial carcinoma diagnosed as pulmonary salivary gland-type carcinoma. An analysis of age distribution revealed a unimodal pattern for both mucoepidermoid carcinoma and adenoid cystic carcinoma, with most patients diagnosed after age 40. Most patients were Caucasians (77% for mucoepidermoid carcinoma and 83% for adenoid cystic carcinoma). Both disease-specific and overall survival were worse for patients diagnosed at the age of 60 years or above. Race or sex did not significantly impact patient survival. High-grade mucoepidermoid carcinoma demonstrated a significantly worse prognosis than low or intermediate-grade mucoepidermoid carcinoma. Conclusion: A comprehensive review of clinical and epidemiological features of pulmonary salivary gland-type carcinomas reveals that the age of diagnosis and tumor grade are the most significant factors in determining patient survival. [ABSTRACT FROM AUTHOR]

Background: In daily work, there are still many pathologists who have difficulty handling the diagnosis of atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic adenocarcinoma, and the boundaries are not clear enough. Sometimes, the diagnosis is difficult, and there is sometimes poor reproducibility between different pathologists. Accurate diagnosis and differential diagnosis require a certain amount of experience. Methods: During the COVID-19 pandemic, we collected a large number (n = 381) of specimens of early lung adenocarcinoma, most of which (n = 356) were solitary lesions and 25 were multifocal lesions. There were 78 nodules in multifocal lesions, total 434 nodules. We summarized very careful microscopic observation and comparative analysis on all frozen and paraffin sections collected from many early lung adenocarcinoma specimens, continuously summarizing our experience. Results: Based on the World Health Organization's 2021 classification and diagnostic criteria for lung adenocarcinoma, new perspectives have been proposed on how to distinguish between atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic adenocarcinoma. In particular, new perspectives have been proposed on how to identify invasive aspects, and there are also some new perspectives on early lung mucinous lesions. Conclusion: Atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic adenocarcinoma all have corresponding morphological diagnostic criteria, but the morphological boundaries are sometimes not easy to determine and require some experience accumulation. The intraoperative frozen pathological diagnosis of early adenocarcinoma of the lung needs to be closely combined with imaging examination, and has very rich morphological experience. [ABSTRACT FROM AUTHOR]

• Usnic acid protected against methotrexate-induced lung toxicity in rats. • It suppressed oxidative stress and inflammation caused by methotrexate exposure. • Usnic acid alleviated endoplasmic reticulum stress and apoptosis in the lungs. • It improved histopathological findings and the levels of antioxidant enzymes. • Usnic acid normalized the levels of Nrf2 and HO-1 in the lungs. Pulmonary toxicity represents a significant adverse effect of methotrexate (MTX), characterised by increased oxidative stress (OS) and inflammation. This study focused on revealing the therapeutic role of usnic acid (UA) against MTX-induced lung injury through biochemical and histological approaches by involving the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. A single dose of MTX was administered to rats to induce pulmonary toxicity, and the therapeutic effect of UA was investigated with two different doses (5 and 10 mg/kg). The administration of UA treatments resulted in a significant reduction in the levels of MTX-induced OS, inflammation, endoplasmic reticulum stress and apoptosis in the lungs of rats. The administration of UA treatments was found to ameliorate the morphological damage induced by MTX in the lungs of rats. Furthermore, the administration of a particularly high dose of UA resulted in a significant increase in the levels of Nrf2 and HO-1 proteins in rats compared to those treated with MTX. These findings provide new insight and the first experimental evidence that UA may serve as an effective therapeutic agent in alleviating MTX-induced acute pulmonary toxicity by regulating the Nrf2/HO-1 pathway. [ABSTRACT FROM AUTHOR]

Objective. Lung tumors can be obscured in x-rays, preventing accurate and robust localization. To improve lung conspicuity for image-guided procedures, we isolate the lungs in the anterior-posterior (AP) x-rays using a lung extraction network (LeX-net) that virtually removes overlapping thoracic structures, including ribs, diaphragm, liver, heart, and trachea. Approach. 73 965 thoracic 3DCTs and 106 thoracic 4DCTs were included. The 3D lung volume was extracted using an open-source lung volume segmentation model. AP digitally reconstructed radiographs (DRRs) of the full anatomy CT and extracted lungs were computed as the input and reference to train a network (LeX-net) to generate lung-extracted DRRs (LeX-net DRRs) from full anatomy DRRs, which adopted a Swin-UNet model with conditional GAN. Subsequently, the trained LeX-net on 3DCT was applied to 4DCT-derived DRRs. Lung tumor tracking was then performed on DRRs using a template-matching method on a holdoff 4DCT test set of 79 patients whose gross tumor volumes were smaller than 20 cm3. Main results. LeX-net successfully isolated the lungs in DRRs, achieving an SSIM of 0.9581 ± 0.0151 and a PSNR of 30.78 ± 2.50 on the testing set of 3DCT-derived DRRs. Its performance declined slightly when applied to the 4DCT but maintained useable lung-only 2D views. On the challenging test set including cases of organ overlap, high tumor mobility, and small tumor size, the individual tumor tracking error for LeX-net DRRs was 0.97 ± 0.86 mm, significantly lower than that of 3.13 ± 5.82 mm using the full anatomy DRRs. LeX-net improved success rates of using 5 mm, 3 mm, and 1 mm tracking windows from 88.1%, 80.0%, and 58.7% to 98.1%, 94.2%, and 73.8%, respectively. Significance. LeX-net removes overlapping anatomies and enhances visualization of the lungs in x-rays. The model trained using 3DCTs is generalizable to 4DCT-derived DRRs, achieving significantly improved tumor tracking outcome. [ABSTRACT FROM AUTHOR]

Available evidence illustrates that microbiome is a promising target for the study of growth, diagnosis and therapy of various types of cancer. Lung cancer is a leading cause of cancer death worldwide. The relationship of microbiota and their products with diverse pathologic conditions has been getting large attention. The novel research suggests that the microbiome plays an important role in the growth and progression of lung cancer. The lung microbiome plays a crucial role in maintaining mucosal immunity and synchronizing the stability between tolerance and inflammation. Alteration in microbiome is identified as a critical player in the progression of lung cancer and negatively impacts the patient. Studies suggest that healthy microbiome is essential for effective therapy. Various clinical trials and research are focusing on enhancing the treatment efficacy by altering the microbiome. The regulation of microbiota will provide innovative and promising treatment strategies for the maintenance of host homeostasis and the prevention of lung cancer in lung cancer patients. In the current review article, we presented the latest progress about the involvement of microbiome in the growth and diagnosis of lung cancer. Furthermore, we also assessed the therapeutic status of the microbiome for the management and treatment of lung cancer. [ABSTRACT FROM AUTHOR]

Macrophages are key players in maintaining the balance of tissues and dealing with inflammation, carrying out vital functions specific to different tissues while safeguarding the body against infections. The intricate interplay between oxidative stress and macrophage polarization and how this contributes to pneumonia is not fully understood. Herein, a predominant accumulation of baicalein in lung macrophages of pathogen-infected mice was observed by an alkynyl-modified probe. Baicalein effectively reduces oxidative stress in vivo and in vitro by modulating the KEAP1-NRF2/ARE signaling pathway. Further investigation indicated that baicalein has inhibitory effects on M1 macrophage polarization and phagocytic capacity, reducing inflammatory cytokine expression. As a protein-protein interaction (PPI) inhibitor, baicalein disrupts the KEAP1-NRF2 interaction by competitively binding to the DGR/Kelch domain of KEAP1. This process helps NRF2 move to the nucleus, which activates the antioxidant transcriptional program, suppresses the production of reactive oxygen species (ROS), and mitigates oxidative stress damage. These findings suggest a different approach to developing treatments for oxidative stress that focuses on inhibiting the interaction between KEAP1-NRF2. [Display omitted] • Baicalein accumulates in macrophages within lung tissue and suppresses M1 macrophage polarization. • Baicalein targets the DGR/Kelch domain of KEAP1, disrupting the interaction between KEAP1 and ETGE motif of NRF2. • Baicalein alleviates oxidative stress injury in vivo and in vitro by regulating the KEAP1-NRF2/ARE pathway. [ABSTRACT FROM AUTHOR]

The article discusses the concept of "heterogeneous response" in patients with breast cancer undergoing treatment, highlighting the importance of recognizing this phenomenon in assessing treatment outcomes. Heterogeneous response refers to the situation where some tumor lesions respond well to treatment while others do not, impacting the overall prognosis of the patient. The article suggests that patients with heterogeneous response may benefit from personalized treatment approaches targeting specific lesions, and further research is needed to understand the clinical implications of this response pattern. The use of [18 F]FDG PET/CT imaging is emphasized as a valuable tool in monitoring treatment response and identifying heterogeneous response in patients with metastatic breast cancer. [Extracted from the article]

• A single-chain variable fragment (1B7)-Fc fusion antibody effectively disrupts the interaction between MMP-7 and SDC-2. • 1B7-Fc fusion antibody exhibits significant anticancer effects against colon cancer cells and in mouse models. • 1B7-Fc has a promising therapeutic potential in the field of treatment for colon cancer. Disrupting the interaction between matrix metalloproteinase-7 (MMP-7) and syndecan-2 (SDC-2) can yield anticancer effects in colon cancer cells. Here, a single-chain variable fragment (scFv) targeting the pro-domain of MMP-7 was generated as a potential candidate anticancer agent. Among the generated scFvs, those designated 1B7 and 1C3 showed the strongest abilities to inhibit the ability of MMP-7 pro-domain to directly interact with SDC-2 in vitro and decrease the cancer activities of human HT29 colon adenocarcinoma cells. Consistently, 1B7 and 1C3 inhibited the cell-surface localization of pro-MMP-7, reduced the gelatinolytic activity of MMP-7, and suppressed the cancer activities of metastatic HCT116 human colon carcinoma cells. Notably, 1B7 inhibited the primary tumor growth and lung metastasis of CT26 mouse colon cancer cells in a mouse model. Compared to 1B7, the 1B7-Fc fusion antibody showed better anti-tumorigenic activity against HCT116 cells in culture and a syngeneic mouse model. Together, these data suggest that 1B7-Fc exerts anticancer effects by interfering with the interaction of MMP-7 and SDC-2 and could be a promising therapeutic antibody for colon cancer. [ABSTRACT FROM AUTHOR]

• Lung parenchyma is composed of numerous microvessels and epithelial cells in an architecture organized in a network maintained by basement membranes. • The composition of lung basement membranes regulates metastases growth and development. • Basement membranes and ECM regulate all the steps of the metastatic cascade: from the acquisition of invasiveness of the primary tumor cells to the metastatic growth of distant metastases. • Targeting basement membranes is a very interesting approach to target metastatic growth and metastatic vascularization. The lung is a highly vascularized tissue that often harbors metastases from various extrathoracic malignancies. Lung parenchyma consists of a complex network of alveolar epithelial cells and microvessels, structured within an architecture defined by basement membranes. Consequently, understanding the role of the extracellular matrix (ECM) in the growth of lung metastases is essential to uncover the biology of this pathology and developing targeted therapies. These basement membranes play a critical role in the progression of lung metastases, influencing multiple stages of the metastatic cascade, from the acquisition of an aggressive phenotype to intravasation, extravasation and colonization of secondary sites. This review examines the biological composition of basement membranes, focusing on their core components—collagens, fibronectin, and laminin—and their specific roles in cancer progression. Additionally, we discuss the function of integrins as primary mediators of cell adhesion and signaling between tumor cells, basement membranes and the extracellular matrix, as well as their implications for metastatic growth in the lung. We also explore vascular co-option (VCO) as a form of tumor growth resistance linked to basement membranes and tumor vasculature. Finally, the review covers current clinical therapies targeting tumor adhesion, extracellular matrix remodeling, and vascular development, aiming to improve the precision and effectiveness of treatments against lung metastases. [ABSTRACT FROM AUTHOR]

Mycobacterium bovis and Mycobacterium tuberculosis are the most relevant among pathogenic mycobacteria, both belonging to the M. tuberculosis complex (MTC). Samples of blood, liver, spleen, kidneys, lungs and caseous tubercles were collected from a free‐ranging juvenile black capuchin monkey (Sapajus nigritus) showing non‐specific signs of illness. Macroscopic findings included emaciation, a caseous lesion in a tooth and gingiva, disseminated nodules in both lungs and left kidney parenchyma and caseous nodules on the pleura and mesentery. The lesions suggested MTC infection, a diagnosis subsequently supported in the lung by bacilloscopy, immunochromatography and PCR. A multiplex PCR further validated the presence of M. bovis genes. Cases of tuberculosis in platyrrhine primates have only been reported in animals maintained in captivity. We describe for the first time the pathological and molecular findings of M. bovis infection in a free‐ranging platyrrhine monkey within an area of intense human–wildlife interaction, which has important implications from a One Health perspective. [ABSTRACT FROM AUTHOR]

Objective: To investigate the safety of COVID-19 inactivated vaccine in immature mice. Methods: We selected 3-week-old immature BALB/c mice, continuously observed until 7 weeks old after continuous immunization with fully inactivated vaccine (initial strengthening), and sacrificed BALB/c mice at 7 weeks old, and used H&E, Masson, mast cells and Ki-67 staining to analyze the changes of heart, liver, spleen, kidney, lung and brain. In addition, RNA was extracted from important organs such as the heart, liver, spleen, kidney, lung, and brain, and to evaluate whether there was any effect after vaccination through bulk-RNA sequencing. Results: After H&E, Masson, mast cells and Ki-67 staining analyses, there are no significant differences between tissues and organs in the vaccine group and the PBS group, and RNA-Seq did not show that the vaccine had any effect on immature mice. Conclusion: COVID-19 inactivated vaccine is safe in immature mice. [ABSTRACT FROM AUTHOR]

Adverse drug reactions (ADRs) in elderly patients are frequently attributed to age-related altered pharmacokinetics and the complexities of polypharmacy to manage multiple chronic conditions, making elderly patients more susceptible to ADRs. The following is a case report of an 80-year-old female patient with systemic symptoms of chest pain, low blood sugar, mouth ulcers, and concentrates on peripheral edema due to nitrate vasodilator isosorbide mononitrate (ISMN). She had hypertension, diabetes, ischemic heart disease, and chronic obstructive pulmonary disease (COPD).On the third day of therapy, she exhibited peripheral edema, prompting the initiation of furosemide and the cessation of ISMN; the patient's condition markedly improved. ISMN primarily reduces preload by inducing venodilation, which leads to blood pooling and hence peripheral edema. The simultaneous administration of other contributing drugs like antifungal agent fluconazole which can potentiate the ADR by elevating plasma levels of ISMN, leading to an enhanced vasodilatory impact. The evaluation conducted using the modified Schumock and Thornton scale classified the adverse medication response as likely, of moderate intensity, and avoidable. This example emphasizes the need of vigilant monitoring of adverse drug responses in the elderly patients, with importance of dosage modifications as well as highlights cautious prescribing of contributing drugs to prevent ADRs. [ABSTRACT FROM AUTHOR]

Silica nanoparticles exert detrimental effects on the respiratory system, regardless of the exposure route. The adverse outcome pathway framework has been recently developed in toxicological research to characterize the pathways that lead to harmful outcomes. Here, we review the adverse effects of amorphous silica nanoparticles on respiratory health with focus on underlying mechanisms and influencing factors, using the adverse outcome pathway framework for the first time. We found that the increase in reactive oxygen species levels induces oxidative stress and leads to mitochondrial dysfunction. Molecular changes further lead to cellular alterations such as epithelial injury, macrophage, and fibroblast activation. Respiratory cellular damage further induces inflammation and fibrosis in the lungs and airways. [ABSTRACT FROM AUTHOR]

Cigarette smoke decreases DNA methylation level of GADD45B promoter in bronchial epithelial cell, thereby promotes GADD45B expression. Subsequently, GADD45B upregulation can directly promote release of inflammatory cytokines through phosphorylation of p38, and can also promote cell senescence by interacting with FOS, which furtherly aggravates inflammation via phosphorylating p38. [Display omitted] • GADD45B expression was increased in the bronchial epithelium of COPD patients and reversely associated with lung function. • In vivo and in vitro experiments furtherly demonstrated that GADD45B facilitated inflammatory response and cellular senescence in bronchial epithelial cells. • Mechanically, GADD45B-facilitated inflammation was directly mediated by p38 phosphorylation, while GADD45B interacted with FOS to promote cellular senescence. • Cigarette smoke-induced GADD45B upregulation in COPD was partially mediated by DNA hypomethylation. • GADD45B will serve as a promising intervention target for COPD. Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease typically characterized by chronic airway inflammation, with emerging evidence highlighting the driving role of cellular senescence-related lung aging. Accelerated lung aging and inflammation mutually reinforce each other, creating a detrimental cycle that contributes to disease progression. Growth arrest and DNA damage-inducible (GADD45) family has been reported to involve in multiple biological processes, including inflammation and senescence. However, the role of GADD45 family in COPD remains elusive. To investigate the role and mechanism of GADD45 family in COPD pathogenesis. Expressions of GADD45 family were evaluated by bioinformatic analysis combined with detections in clinical specimens. The effects of GADD45B on inflammation and senescence were investigated via constructing cell model with siRNA transfection or overexpression lentivirus infection and animal model with Gadd45b knockout. Targeted bisulfite sequencing was performed to probe the influence of DNA methylation in GADD45B expression in COPD. GADD45B expression was significantly increased in COPD patients and strongly associated with lung function, whereas other family members presented no changes. GADD45B upregulation was confirmed in mice exposed by cigarette smoke (CS) and HBE cells treated by CS extract as well. Moreover, experiments involving bidirectional modulation of GADD45B expression in HBE cells further substantiated its positive regulatory role in inflammatory response and cellular senescence. Mechanically, GADD45B-facilitated inflammation was directly mediated by p38 phosphorylation, while GADD45B interacted with FOS to promote cellular senescence in a p38 phosphorylation-independent manner. Furthermore, Gadd45b deficiency remarkably alleviated inflammation and senescence of lungs in CS-exposed mice, as well as improved emphysema and lung function. Eventually, in vivo and vitro experiments demonstrated that GADD45B overexpression was partially mediated by CS-induced DNA hypomethylation. Our findings have shed light on the impact of GADD45B in the pathogenesis of COPD, thereby offering a promising target for intervention in clinical settings. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease characterised by irreversible lung structure and function. Phillygenin (PHI) is a lignan extracted from Forsythiae fructus with the activities of anti‐inflammatory and antioxidant. This study aimed to explore the protective effect of PHI on IPF. The mouse model of IPF was established by bleomycin (BLM), and then treated with PHI. After 15 days of administration, the lung index was calculated. H&E staining, Masson staining and immunohistochemical methods were used to detect the effect of PHI on pulmonary fibrosis. MDA and SOD were tested to evaluate the effect of PHI on lung tissue oxidative stress. Western blot was used to detect the effect of PHI on the expressions of α‐SMA, p‐smad2, TGF‐ β1, Nrf2, HO‐1 and NQO‐1. Network pharmacology was used to identify the key signalling pathways for PHI to improve IPF, and Western blot was used to validate the result. The results showed that PHI prevented mice from BLM‐induced IPF, manifested by reducing lung index, improving lung tissue pathological damage, inhibiting collagen deposition and expression of fibrosis markers including α‐SMA, collagen1, p‐smad2 and TGF‐β1. PHI inhibited oxidative stress by upregulating the expressions of Nrf2, HO‐1 and NQO‐1. Network pharmacology revealed that PI3K‐Akt–mTOR signalling pathway was the underlying target of PHI for IPF. Molecular docking indicated strong binding of PHI with PIK3CA, AKT1 and RELA. Western blot validated that PHI downregulated the PI3K‐Akt–mTOR signalling pathway and stimulated autophagy. This study indicated that PHI prevented BLM‐induced pulmonary fibrosis by inhibiting PI3K‐Akt–mTOR signalling pathway. [ABSTRACT FROM AUTHOR]

Inert gas washout methods have been shown to detect pathological changes in the small airways that occur in the early stages of obstructive lung diseases such as asthma and COPD. Numerical lung models support the analysis of characteristic washout curves, but are limited in their ability to simulate the complexity of lung anatomy over an appropriate time period. Therefore, the interpretation of patient-specific washout data remains a challenge. A new numerical lung model is presented in which electrical components describe the anatomical and physiological characteristics of the lung as well as gas-specific properties. To verify that the model is able to reproduce characteristic washout curves, the phase 3 slopes (S3) of helium washouts are simulated using simple asymmetric lung anatomies consisting of two parallel connected lung units with volume ratios of 1.25 0.75 , 1.50 0.50 , and 1.75 0.25 and a total volume flow of 250 ml/s which are evaluated for asymmetries in both the convection- and diffusion-dominated zone of the lung. The results show that the model is able to reproduce the S3 for helium and thus the processes underlying the washout methods, so that electrical components can be used to model these methods. This approach could form the basis of a hardware-based real-time simulator. [ABSTRACT FROM AUTHOR]

Small molecule drugs often exhibit short half-lives, requiring frequent administrations to maintain therapeutic concentrations over an extended period. To address this issue, the fragment crystallizable (Fc) region of IgG, known to prolong the half-life of antibodies via its interaction with the Fc neonatal receptor, was harnessed as a carrier protein to extend the half-life of a small molecule drug, florfenicol. Florfenicol, was chemically coupled to a recombinant Fc protein expressed using the eukaryotic expression system in HEK293 cells. The Fc-florfenicol conjugate exhibited a substantially prolonged half-life of from 3.8 to 9.1 h compared to unconjugated florfenicol and demonstrated excellent therapeutic properties in treating pneumonia in a mouse model. Our results, combined with the literature analysis on Fc-small molecule conjugates, show that Fc can substantially enhance the drug's half-life and suggest the potential for its use as a carrier in novel delivery systems. [Display omitted] • The eukaryotic IgG-Fc protein was prepared in HEK293 cells with high purity of 96 %. • Florfenicol was successfully coupled to Fc protein using the mixed anhydride method. • Fc-conjugation was significantly improved florfenicol's pharmacokinetic parameters. • Fc-conjugation effectively reduced inflammatory factors in mouse pneumonia models. • Fc-conjugation greatly improved lung tissue morphology in mouse pneumonia models. [ABSTRACT FROM AUTHOR]

Type 2 Diabetes (T2D) is a chronic disease with increasing incidence and prevalence and serious chronic complications, especially from cardiovascular system. However, other organs can be affected too. Several studies have associated T2D, especially when poorly controlled, with multiple pulmonary diseases. T2D is a common comorbidity among patients with asthma, Chronic Obstructive Pulmonary Disease (COPD), and Obstructive Sleep Apnea Syndrome (OSAS), and it is related to higher respiratory infection incidence, prevalence and severity. Glucagon-like peptide-1 receptor agonists (GLP-1RA) and Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) are novel antihyperglycaemic agents with established cardiovascular benefits. There are also limited studies indicating their potential benefit in respiratory function. The aim of this article is to review data on the impact of GLP-1RA and SGLT-2i on respiratory function and describe the possible clinical benefits. Key findings indicate that GLP-1RA significantly improve lung function in patients with COPD, evidenced by improvements in spirometry measurements. Additionally, both GLP-1RA and SGLT-2i are associated with a decreased risk of severe and moderate exacerbations in COPD patients and have shown potential in reducing the incidence of respiratory disorders, including asthma and pneumonia. The mechanisms underlying these benefits are not yet fully understood and include multiple effects, such as anti-inflammatory action and oxidative stress reduction. [ABSTRACT FROM AUTHOR]

The article explores the long-term effects of low-dose radiation from atomic bombs on lifespan and cancer mortality, focusing on the experiences of survivors in Hiroshima and Nagasaki. While some studies suggest longer lifespans and lower cancer death rates among survivors, most research indicates increased cancer incidence, cardiovascular diseases, and reduced life expectancy. The ongoing presence of survivors offers a unique opportunity for continued research on the physical and psychological impacts of radiation exposure, informing disaster preparedness and response strategies. The conflicting reports highlight the need for further longitudinal studies to understand the complex effects of radiation exposure on health outcomes. [Extracted from the article]

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CXCL14 (C-X-C motif chemokine ligand 14) is expressed in the airway epithelial cells of patients with asthma. However, the mechanisms of CXCL14 secretion and its effects on asthma pathogenesis remain unclear. Here, we investigated the role of CXCL14 in allergic airway inflammation and its effects on eosinophil infiltration. Our findings showed that Alternaria alternata, a major environmental allergen, stimulated CXCL14 secretion from airway epithelial cells via reactive oxygen species generated in mitochondrial oxidative phosphorylation complexes, especially in oxidative phosphorylation complex II. In vivo, in a mouse model of allergic airway inflammation, intranasal administration of anti-CXCL14 antibody suppressed eosinophil and dendritic cell infiltration into the airways and goblet cell hyperplasia. In vitro, in human eosinophil-like cells, CXCL14 promoted cell migration through CXCR4 binding. Eosinophil CXCR4 expression was upregulated by Alternaria stimulation via reactive oxygen species production. These findings suggest that the cross-talk between Alternaria-stimulated airway epithelial CXCL14 secretion and eosinophil CXCR4 upregulation plays an important role in eosinophil infiltration into the lungs during allergic airway inflammation. In summary, this study demonstrates that CXCL14 could be a therapeutic target for allergic airway inflammation. [ABSTRACT FROM AUTHOR]

Severe lung injury requiring mechanical ventilation may lead to secondary fibrosis. Senescence, a cell response characterized by cell cycle arrest and a shift toward a proinflammatory/profibrotic phenotype, is one of the involved mechanisms. In this study, we explore the contribution of mechanical stretch as a trigger of senescence of the respiratory epithelium and its link with fibrosis. Human lung epithelial cells and fibroblasts were exposed in vitro to mechanical stretch, and senescence was assessed. In addition, fibroblasts were exposed to culture media preconditioned by senescent epithelial cells, and their activation was studied. Transcriptomic profiles from stretched, senescent epithelial cells and activated fibroblasts were combined to identify potential activated pathways. Finally, the senolytic effects of digoxin were tested in these models. Mechanical stretch induced senescence in lung epithelial cells, but not in fibroblasts. This stretch-induced senescence has specific features compared with senescence induced by doxorubicin. Fibroblasts were activated after exposure to supernatants conditioned by epithelial senescent cells. Transcriptomic analyses revealed Notch signaling as potentially responsible for the epithelial–mesenchymal cross-talk, because blockade of this pathway inhibits fibroblast activation. Treatment with digoxin reduced the percentage of senescent cells after stretch and ameliorated the fibroblast response to preconditioned media. These results suggest that lung fibrosis in response to mechanical stretch may be caused by the paracrine effects of senescent cells. This pathogenetic mechanism can be pharmacologically manipulated to improve lung repair. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a life-threatening syndrome associated with hyperproliferation of pulmonary artery smooth muscle cells (PASMCs), which exhibit features similar to those of cancer cells. Currently, there is no curative treatment for PH. LKB1 is known as a tumor suppressor gene with an antiproliferative effect on cancer cells. However, its role and mechanism in the development of PH remain unclear. Gain- and loss-of-function strategies were used to elucidate the mechanisms of LKB1 in regulating the occurrence and progression of PH. Sugen 5416/hypoxia (SuHx) PH model was utilized for in vivo study. We observed a decreased expression of LKB1 not only in the lung vessels of the SuHx mouse model but also in human PASMCs (HPASMCs) exposed to hypoxia. Smooth muscle–specific LKB1 knockout significantly aggravated SuHx-induced PH in mice. RNA-sequencing analysis revealed a substantial increase in bone morphogenetic protein 4 (BMP4) in the aortas of LKB1SMKO mice compared with controls, identifying BMP4 as a novel target of LKB1. LKB1 knockdown in HPASMCs cultured under hypoxic conditions increased BMP4 protein level and HPASMC proliferation and migration. The coimmunoprecipitation analysis revealed that LKB1 directly modulates BMP4 protein degradation through phosphorylation. Therapeutically, suppressing BMP4 expression in smooth muscle cells alleviates PH in LKB1SMKO mice. Our findings demonstrate that LKB1 attenuates PH by enhancing the lysosomal degradation of BMP4, thus suppressing the proliferation and migration of HPASMCs. Modulating the LKB1-BMP4 axis in smooth muscle cells could be a promising therapeutic strategy of PH. [ABSTRACT FROM AUTHOR]

The article from the Annals of the American Thoracic Society discusses the impact of chronic obstructive pulmonary disease (COPD) on pulmonary hypertension, affecting nearly 40% of COPD patients. The text highlights the need for improved phenotyping and diagnosis of COPD-PH, emphasizing the role of chest computed tomography (CT) in identifying pulmonary vascular disease. The article also reviews ongoing clinical trials investigating the efficacy of therapies for COPD-PH, such as phosphodiesterase 5-inhibitors, and the potential benefits of CT imaging in enhancing treatment response assessment. [Extracted from the article]