Lung Biomarkers Research Articles

Protective effect of essential oil of Foeniculum vulgare Mill. against bleomycin-induced pulmonary fibrosis and oxidative stress in rat

BackgroundWild fennel (Foeniculum vulgare Mill.) is a very common plant used in traditional medicine to treat several diseases. In recent years, scientific research proved its biological properties. However, the protective effect of fennel against bleomycin-induced pulmonary fibrosis (BLM-IPF) is not yet study. PurposeFennel essential oil (FEO) composition was characterized and its protective effect was assessed. MethodsGC–MS was employed to determine the chemical composition of fennel essential oil. The antioxidant activity was evaluated using TAC, DPPH, RAP and ABTS assays. After inducing fibrosis by bleomycin, several biological assays were used to evaluate the protective effect [proteins content, malondialdehyde MD, thiol group, superoxide dismutase (SOD) and catalase (CAT)]. ResultsFEO was rich in estragole (77.55 %), fenchone (9.23 %), and limonene (9.23 %), and phenolic compounds and showed a significant antioxidant potential. The effects on BLM-IPF were revealed by disruption and alteration of oxidative stress biomarkers in lung, liver and kidney. Treatment of rats with FEO improved abnormal fluctuations in protein and thiol levels, decreased oxidative stress in terms of MDA and also restored the response of the antioxidant system, measured in terms of SOD and CAT, in lung, liver and kidney. The biological activity was recorded in a dose response manner. The potential of FEO in limiting the progress of the histopathologic effects of BLM-IPF was confirmed by microscopic histological observations, with a reduction of the fibrosis score and the inflammatory index in the FEO treated lung tissue. ConclusionThese results, proved that FEO could attenuate BLM-induced PF, thus suggesting that the latter could serve as a potential therapeutic approach for PF.

Trimodal Multiplexed Lateral Flow Test Strips Assisted with a Portable Microfluidic Centrifugation Device.

During the COVID-19 pandemic, the use of lateral flow assays (LFAs) expanded significantly, offering testing beyond traditional health care. Their appeal lies in the ease of use, affordability, and quick results. However, LFAs often have lower sensitivity and specificity compared with ELISA and PCR tests. Efforts to improve LFAs have increased detection times and complexity, limiting their use in large-scale point-of-care settings. To address this, we propose a novel approach using probes that generate multiple signals to enhance the sensitivity and selectivity. This concept also allows multiplexed LFAs to detect multiple analytes concurrently. We developed a trimodal probe that integrates fluorescence, color, and magnetism into a single nanohybrid. The strong plasmonic absorption and high fluorescence of Au nanoparticles and polymer dots enable qualitative and semiquantitative diagnosis, while the magnetic signal facilitates accurate quantitative measurements. As proof-of-concept targets, we selected CYFRA 21-1 and CA15-3, biomarkers for lung and breast cancer, respectively. This trimodal LFA demonstrated a remarkable detection limit of 0.26 ng/mL for CYFRA 21-1 and 2.8 U/mL for CA15-3. To the best of our knowledge, this is the first platform of a trimodal LFA with multiplexing ability. The platform's accuracy and reliability were validated using clinical serum samples, showing excellent consistency with electrochemiluminescence immunoassay results. This universal concept can be applied to other targets, paving the way for the next-generation LFAs.

Brain and Lung Biomarker Responses to Hyperoxic Hypobaric Decompression.

INTRODUCTION: Biomarker responses to intensive decompression indicate systemic proinflammatory responses and possible neurological stress. To further investigate responses, 12 additional brain and lung biomarkers were assayed.METHODS: A total of 15 healthy men (20 to 50 yr) undertook consecutive same-day ascents to 25,000 ft (7620 m), following denitrogenation, breathing 100% oxygen. Venous blood was sampled at baseline (T0), after the second ascent (T8), and next morning (T24). Soluble protein markers of brain and lung insult were analyzed by enzyme-linked immunosorbent assay with plasma microparticles quantified using flow cytometry.RESULTS: Levels of monocyte chemoattractant protein-1 and high mobility group box protein 1 were elevated at T8, by 36% and 16%, respectively, before returning to baseline. Levels of soluble receptor for advanced glycation end products fell by 8%, recovering by T24. Brain-derived neurotrophic factor rose by 80% over baseline at T24. Monocyte microparticle levels rose by factors of 3.7 at T8 and 2.7 at T24 due to early and late responses in different subjects. Other biomarkers were unaffected or not detected consistently.DISCUSSION: The elevated biomarkers at T8 suggest a neuroinflammatory response, with later elevation of brain-derived neurotrophic factor at T24 indicating an ongoing neurotrophic response and incomplete recovery. A substantial increase at T8 in the ratio of high mobility group box protein 1 to soluble receptor for advanced glycation end products suggests this axis may mediate the systemic inflammatory response to decompression. The mechanism of neuroinflammation is unclear but elevation of monocyte microparticles and monocyte chemoattractant protein-1 imply a key role for activated monocytes and/or macrophages.Connolly DM, Madden LA, Edwards VC, Lee VM. Brain and lung biomarker responses to hyperoxic hypobaric decompression. Aerosp Med Hum Perform. 2024; 95(9):667-674.

Prospective validation from a retrospective trial that validated an AI/ML-derived whole-genome biomarker as the most accurate and precise predictor of survival and response to treatment in glioblastoma.

e14028 Background: For 70 years, the best indicator of glioblastoma (GBM) survival has remained age at diagnosis. Factors across the entire genome affect every aspect of the disease. But typical artificial intelligence and machine learning (AI/ML) would require 3B-patient training sets to generate predictive models from the whole 3B-nucleotide genome. As a result, all other attempts to associate a tumor’s DNA copy-number alterations (CNAs) with the patient’s outcome failed. Methods: A genome-wide pattern of DNA CNAs in primary GBM tumors was recently validated in a retrospective clinical trial as the most accurate and precise predictor of survival and response to treatment [doi: 10.1063/1.5142559 ]. Applicable to the general population, this biomarker, the first to encompass the whole genome, and biomarkers in lung, nerve, ovarian, and uterine cancers, were repeatedly identified in open-source datasets from as few as 50–100 patients by using our data-agnostic unsupervised AI/ML, which extends the mathematics of quantum mechanics to overcome the limitations of typical AI/ML [doi: 10.1063/1.5099268 , 10.1073/pnas.0530258100 ]. Results: At 75–95% concordance, our biomarker is more accurate than and independent of age and all other indicators, including the one-gene tests for MGMT, IDH1, and TERT. Platform- and reference genome-agnostic, the biomarker’s >99% precision is greater than the community consensus of <70% reproducibility. It describes disease mechanisms and identifies drug targets and combinations of targets to sensitize tumors to treatment. Now, in follow-up results from the trial we, first, show correct prospective prediction of the outcome of the five of the 79 patients who were alive four years earlier, at the time of first results (log-rank P-value=3.9×10–2). Two patients, who were predicted to have shorter survival, lived less than five years from diagnosis, whereas of the three patients predicted to have longer survival, one lived more than five, and the remaining two are alive >11.5, years from diagnosis. Second, we demonstrate 100%-precise clinical prediction for the 59/79 patients with remaining tumor DNA, by using whole-genome sequencing in a Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) laboratory. Third, we establish that the risk that a tumor’s whole genome confers upon outcome, as is reflected by the biomarker’s univariate Cox hazard ratio of 4.2 and Kaplan-Meier median survival difference of 2.25 years (log-rank P-value=6.0×10–4), is greater than that conferred by the patient’s Karnofsky performance score and access to chemotherapy, and the tumor’s percent resection, and is surpassed only by the patient’s access to radiotherapy. Conclusions: This is a proof of principle that our AI/ML is uniquely suited for personalized medicine.

AI/ML-derived mechanistically interpretable whole-genome biomarkers of patient survival in pre-treatment primary neuroblastoma tumors and whole blood.

10043 Background: Prediction, understanding, and management, of neuroblastoma (NBL) outcomes, from spontaneous regression to relapse and death, remain limited, and rely mostly on the International Neuroblastoma Staging System (INSS) stage, age, and the one-gene test for MYCN amplification. The entire multi-ome affects every aspect of the disease. But typical artificial intelligence and machine learning (AI/ML) cannot discover effective biomarkers from real-life, small-cohort, multi-omic, and noisy data. Methods: We use our AI/ML to identify two whole-genome biomarkers from open-source pre-treatment NBL patient-matched primary tumor and whole blood DNA copy numbers, and primary tumor mRNA expression. Our data-agnostic, unsupervised algorithms extend the mathematics that underlies quantum mechanics to overcome the limitations of typical AI/ML [1,2]. Our platform- and reference genome-agnostic biomarkers in astrocytoma, including glioblastoma, and lung, ovarian, and uterine adenocarcinomas, were mathematically discovered, and computationally and experimentally validated, repeatedly, in federated, imbalanced datasets from as few as 50–100 patients [3]. Results: We discover the biomarkers in “skinny” datasets of minimally preprocessed ≈3M-bin whole-genome sequences from tumors and blood of a set of 101 patients. Blindly, i.e., label-free, we separate both biomarkers from the normal X chromosome-number variation, demonstrating sex-agnostic learning. Combined, the biomarkers are statistically independent of all standard-of-care indicators, with the univariate Cox hazard ratio of 4.0 (log-rank P-value=2.3×10–5) within the 95% confidence intervals of the bivariate ratios. The risk that the tumor’s whole genome confers upon outcome, as is reflected by the bivariate ratios, is greater than that conferred by all standard-of-care indicators, including DNA ploidy, the Children’s Oncology Group (COG) risk, and the mitosis-karyorrhexis index (MKI), except for histopathology. We validate the biomarkers in ≈10K-bin target-capture sequences of a mutually-exclusive set of 419 patients, demonstrating generalizability as well as site-, platform-, and protocol-agnostic transfer learning. At 73–80% concordance, in both the tumor and blood profiles of both the discovery and validation sets, the biomarkers combined are more accurate than MYCN. We show that the biomarkers identify known and previously unrecognized disease mechanisms and druggable gene alterations, including co-amplification of MYCN with genes encoding for extra-embryonic transcripts, as well as the hijacking of embryonic development toward aneuploidy, which can spontaneously regress via embryonic self-correction. Conclusions: Our AI/ML is uniquely suited for personalized medicine. 1. doi: 10.1063/1.5099268 2. doi: 10.1073/pnas.0530258100 3. doi: 10.1063/1.5142559.

Impact of lung biomarker testing on out-of-pocket costs for metastatic non-small cell lung cancer.

11087 Background: Biomarker testing in metastatic non-small lung cancer (NSCLC) is critical for appropriate selection of therapy options. Claims-based datasets offer real-world information on the use and cost of biomarker testing across the United States. Methods: We used de-identified administrative claims data from Optum’s Clinformatics Data Mart Database (CDM) from 2013 to 2021 to assess for trends in biomarker testing. Eligible patients were adults with two or more lung cancer diagnosis codes and with two or more claims of a secondary malignant neoplasm. Patients were excluded if they had another primary cancer or did not have continuous insurance coverage twelve months prior and six months after diagnosis. We assessed claims-based out-of-pocket (OOP) costs associated with testing and treatment. Descriptive statistics were used to assess biomarker testing rates, and multivariable analyses (MVA) were performed to assess factors associated with testing. Results: A total of 4377 patients with metastatic NSCLC were eligible (mean age 60 years (SD: 8.33 years), 49.6% female, 76.7% former smokers). Testing rates within two months of diagnosis increased from 58.15% in 2013 to 69.96% in 2021. On MVA, biomarker testing was associated with younger age, being non-smokers, living in Mountain geographic region, or having point-of-service insurance plans. Biomarker testing was associated with a median OOP cost of $98 (IQR: $43.87-$306.58). Patients who underwent biomarker testing had a median total OOP cost of all services within 6 months of diagnosis of $3560.20 (IQR: $1538.37-$6199.44) compared to $1979.58 (IQR: $725.75-$4003.06) for those who did not undergo biomarker testing. Conclusions: Using claims data, we find that 70% of patients with metastatic NSCLC undergo biomarker testing within two months of diagnosis with metastatic disease. Most patients undergo biomarker testing early in their treatment course (0-60 days), suggesting that testing is appropriately being obtained early on in their treatment course, but this testing is associated with substantially higher overall OOP costs to patients.

SCARLET (Supplemental Citicoline Administration to Reduce Lung injury Efficacy Trial): study protocol for a single-site, double-blinded, placebo-controlled, and randomized Phase 1/2 trial of i.v. citicoline (CDP-choline) in hospitalized SARS CoV-2-infected patients with hypoxemic acute respiratory failure

BackgroundThe SARS CoV-2 pandemic has resulted in more than 1.1 million deaths in the USA alone. Therapeutic options for critically ill patients with COVID-19 are limited. Prior studies showed that post-infection treatment of influenza A virus-infected mice with the liponucleotide CDP-choline, which is an essential precursor for de novo phosphatidylcholine synthesis, improved gas exchange and reduced pulmonary inflammation without altering viral replication. In unpublished studies, we found that treatment of SARS CoV-2-infected K18-hACE2-transgenic mice with CDP-choline prevented development of hypoxemia. We hypothesize that administration of citicoline (the pharmaceutical form of CDP-choline) will be safe in hospitalized SARS CoV-2-infected patients with hypoxemic acute respiratory failure (HARF) and that we will obtain preliminary evidence of clinical benefit to support a larger Phase 3 trial using one or more citicoline doses.MethodsWe will conduct a single-site, double-blinded, placebo-controlled, and randomized Phase 1/2 dose-ranging and safety study of Somazina® citicoline solution for injection in consented adults of any sex, gender, age, or ethnicity hospitalized for SARS CoV-2-associated HARF. The trial is named “SCARLET” (Supplemental Citicoline Administration to Reduce Lung injury Efficacy Trial). We hypothesize that SCARLET will show that i.v. citicoline is safe at one or more of three doses (0.5, 2.5, or 5 mg/kg, every 12 h for 5 days) in hospitalized SARS CoV-2-infected patients with HARF (20 per dose) and provide preliminary evidence that i.v. citicoline improves pulmonary outcomes in this population. The primary efficacy outcome will be the SpO2:FiO2 ratio on study day 3. Exploratory outcomes include Sequential Organ Failure Assessment (SOFA) scores, dead space ventilation index, and lung compliance. Citicoline effects on a panel of COVID-relevant lung and blood biomarkers will also be determined.DiscussionCiticoline has many characteristics that would be advantageous to any candidate COVID-19 therapeutic, including safety, low-cost, favorable chemical characteristics, and potentially pathogen-agnostic efficacy. Successful demonstration that citicoline is beneficial in severely ill patients with SARS CoV-2-induced HARF could transform management of severely ill COVID patients.Trial registrationThe trial was registered at www.clinicaltrials.gov on 5/31/2023 (NCT05881135).Trial statusCurrently enrolling.

A novel syndrome of silent rhinovirus-associated bronchoalveolitis in children with recurrent wheeze

BackgroundRhinovirus (RV) infections trigger wheeze episodes in children. Thus, understanding of the lung inflammatory response to RV in children with wheeze is important. ObjectiveTo examine the associations of RV on lung lavage (BAL) granulocyte patterns and biomarkers of inflammation with age in children with treatment-refractory, recurrent wheeze (n=616). MethodsChildren underwent BAL to examine viral nucleic acid sequences, bacterial cultures, granulocyte counts, and phlebotomy for both general and type-2 inflammatory markers. ResultsDespite the absence of cold symptoms, RV was the most common pathogen detected (30%), and when present, was accompanied by BAL granulocytosis in 75% of children. Compared to children with no BAL pathogens (n=341), those with RV alone (n=127) had greater (p < 0.05) isolated neutrophilia (43% versus 16%), mixed eosinophils and neutrophils (26% versus 11%), and less pauci-granulocytic (27% versus 61%) BAL. Children with RV alone furthermore had biomarkers of active infection with higher total blood neutrophils and serum c-reactive protein (CRP), but no differences in blood eosinophils or total IgE. With advancing age, the log odds of BAL RV alone were lower, 0.82 [0.76-0.88, p < 0.001], but higher, 1.58 [1.01-2.51, p = 0.04], with high-dose daily corticosteroid treatment. ConclusionsChildren with severe recurrent wheeze often (22%) have a silent syndrome of lung RV infection with granulocytic bronchoalveolitis and elevated systemic markers of inflammation. The syndrome is less prevalent by school age, and not informed by markers of type-2 inflammation. We speculate that dysregulated mucosal innate antiviral immunity is a responsible mechanism.

Programmed Death Ligand-1 and Tumor Mutation Burden Testing of Patients With Lung Cancer for Selection of Immune Checkpoint Inhibitor Therapies: Guideline From the College of American Pathologists, Association for Molecular Pathology, International Association for the Study of Lung Cancer, Pulmonary Pathology Society, and LUNGevity Foundation.

Rapid advancements in the understanding and manipulation of tumor-immune interactions have led to the approval of immune therapies for patients with non-small cell lung cancer. Certain immune checkpoint inhibitor therapies require the use of companion diagnostics, but methodologic variability has led to uncertainty around test selection and implementation in practice. To develop evidence-based guideline recommendations for the testing of immunotherapy/immunomodulatory biomarkers, including programmed death ligand-1 (PD-L1) and tumor mutation burden (TMB), in patients with lung cancer. The College of American Pathologists convened a panel of experts in non-small cell lung cancer and biomarker testing to develop evidence-based recommendations in accordance with the standards for trustworthy clinical practice guidelines established by the National Academy of Medicine. A systematic literature review was conducted to address 8 key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, recommendations were created from the available evidence, certainty of that evidence, and key judgments as defined in the GRADE Evidence to Decision framework. Six recommendation statements were developed. This guideline summarizes the current understanding and hurdles associated with the use of PD-L1 expression and TMB testing for immune checkpoint inhibitor therapy selection in patients with advanced non-small cell lung cancer and presents evidence-based recommendations for PD-L1 and TMB testing in the clinical setting.

Abstract 5873: ERα coordinates with squalene synthase to confer statin resistance in lung cancer

Abstract Statins are widely used to treat hypercholesterolemia by inhibiting hydroxymethylglutaryl coenzyme A reductase (HMGCR). Accumulating evidence suggests that statins also have protective effects against cancer recurrence. However, the role of statins in preventing lung cancer and biomarkers for predicting statin treatment response remains lacking. This study analyzes molecular features that dictate statin sensitivity in lung cancer by correlating large-scale statin sensitivity data and basal gene expression in a collection of 125 lung cancer patients. We identified a gene signature associated with lovastatin sensitivity and showed that gene expression in mesenchymal molecular features, the cholesterol biosynthesis pathway, and estrogen receptor alpha (ERα) signaling were key determinants of lovastatin sensitivity in lung cancer cells. To this end, we further discovered that overexpression of a committed step enzyme in cholesterol biosynthesis farnesyl-diphosphate farnesyltransferase 1 (FDFT1), also known as squalene synthase (SQS), is capable of activating ERα and is associated with increased statin tolerance. In clinical specimens, overexpression of SQS positively correlated with nuclear expression of ERα in lung cancer patients, and the combination of SQS and ERα is a powerful prognostic predictor for lung cancer. Activation of the SQS-ERα signaling axis and epithelial-to-mesenchymal transition (EMT) status represents two important features in determining statin sensitivity in lung cancer. Keywords: Statin, cholesterol biosynthesis, squalene synthase, estrogen receptor α, Epithelial-mesenchymal transition Citation Format: Yi-Fang Yang. ERα coordinates with squalene synthase to confer statin resistance in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5873.

Effects of occupational exposure to metal fume PM2.5 on lung function and biomarkers among shipyard workers: a 3-year prospective cohort study

ObjectiveThis study investigates the associations of α1-antitrypsin, inter-α-trypsin inhibitor heavy chain (ITIH4), and 8-isoprostane with lung function in shipyard workers exposed to occupational metal fume fine particulate matter (PM2.5), which is known to be associated with adverse respiratory outcomes.MethodsA 3-year follow-up study was conducted on 180 shipyard workers with 262 measurements. Personal exposure to welding fume PM2.5 was collected for an 8-h working day. Pre-exposure, post-exposure, and delta (∆) levels of α1-antitrypsin, ITIH4, and 8-isoprostane were determined in urine using enzyme-linked immunosorbent assays. Post-exposure urinary metals were sampled at the beginning of the next working day and analyzed by inductively coupled plasma-mass spectrometry. Lung function measurements were also conducted the next working day for post-exposure.ResultsAn IQR increase in PM2.5 was associated with decreases of 2.157% in FEV1, 2.806% in PEF, 4.328% in FEF25%, 5.047% in FEF50%, and 7.205% in FEF75%. An IQR increase in PM2.5 led to increases of 42.155 µg/g in ∆α1-antitrypsin and 16.273 µg/g in ∆ITIH4. Notably, IQR increases in various urinary metals were associated with increases in specific biomarkers, such as post-urinary α1-antitrypsin and ITIH4. Moreover, increases in ∆ α1-antitrypsin and ∆ITIH4 were associated with decreases in FEV1/FVC by 0.008% and 0.020%, respectively, and an increase in ∆8-isoprostane resulted in a 1.538% decline in FVC.ConclusionOur study suggests that urinary α1-antitrypsin and ITIH4 could indicate early lung function decline in shipyard workers exposed to metal fume PM2.5, underscoring the need for better safety and health monitoring to reduce respiratory risks.Graphical abstract

Multi-targeted therapeutic potential of stigmasterol from the Euphorbia ammak plant in treating lung and breast cancer

Cancer is the most prevalent disease globally, which presents a significant challenge to the healthcare industry, with breast and lung cancer being predominant malignancies. This study used RNA-seq data from the TCGA database to identify potential biomarkers for lung and breast cancer. Tumor Necrosis Factor (TNFAIP8) and Sulfite Oxidase (SUOX) showed significant expression variation and were selected for further study using structure-based drug discovery (SBDD). Compounds derived from the Euphorbia ammak plant were selected for in-silico study with both TNFAIP8 and SUOX. Stigmasterol had the greatest binding scores (normalized scores of −8.53 kcal/mol and −9.69 kcal/mol) with both proteins, indicating strong stability in their binding pockets throughout the molecular dynamics’ simulation. Although Stigmasterol first changed its initial conformation (RMSD = 0.5 nm with the starting conformation) in SUOX, it eventually reached a stable conformation (RMSD of 1.5 nm). The compound on TNFAIP8 showed a persistent shape (RMSD of 0.35 nm), indicating strong protein stability. The binding free energy of the complex was calculated using the MM/GBSA technique; TNFAIP8 had a ΔGTOTAL of −24.98 kcal/mol, with TYR160 being the most significant residue, contributing −2.52 kcal/mol. On the other hand, the SUOX complex had a binding free energy of −16.87 kcal/mol, with LEU151 being the primary contributor (-1.17 kcal/mol). Analysis of the complexes' free energy landscape unveiled several states with minimum free energy, indicating robust interactions between the protein and ligand. In its conclusion, this work emphasises the favourable ability of Stigmasterol to bind with prospective targets for lung and breast cancer, indicating the need for more experimental study.

The Journey to Improve the College of American Pathologists Cancer Biomarker Reporting Protocols.

Biomarker reporting has increasingly become a key component of pathology reporting, providing diagnostic, prognostic, and actionable therapeutic data for patient care. To expand and improve the College of American Pathologists (CAP) biomarker protocols. We surveyed CAP members to better understand the limitations they experienced when reporting cancer biomarker results. A Biomarker Workgroup reviewed the survey results and developed a strategy to improve and standardize biomarker reporting. Drafts of new and revised biomarker protocols were reviewed in both print and electronic template formats during interactive webinars presented to the CAP House of Delegates. Feedback was collected, and appropriate revisions were made to finalize the protocols. The first phase of the CAP Biomarker Workgroup saw the development of (1) a new stand-alone general Immunohistochemistry Biomarker Protocol that includes reporting for ER (estrogen receptor), PR (progesterone receptor), Ki-67, HER2 (human epidermal growth factor receptor 2), PD-L1 (programmed death ligand-1), and mismatch repair; (2) a new Head and Neck Biomarker Protocol that updates the prior 2017 paper-only version into an electronic template, adding new diagnostic and theranostic markers; (3) a major revision to the Lung Biomarker Protocol to streamline it and add in pan-cancer markers; and (4) a revision to the Colon and Rectum Biomarker Protocol to add HER2 reporting. We have taken a multipronged approach to improving biomarker reporting in the CAP cancer protocols. We continue to review current biomarker reporting protocols to reduce and eliminate unnecessary methodologic details and update with new markers as needed. The biomarker templates will serve as standardized modular units that can be inserted into cancer-reporting protocols.

Gene expression changes of isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 affect carcinogenesis and survival probability

Isocitrate dehydrogenase (IDH) is an essential metabolic enzyme in the regulation of cellular metabolism. IDH gene encodes three protein isoforms, IDH1, IDH2, and IDH3, and the expression level of isoforms is altered in human cancer types. Examining the gene expression level of IDH is a therapeutic advantage that could help find a new target to use in cancer metabolism. The present study aimed to explore the gene expression level of IDH1 and IDH2 isoforms in the ten common human cancers using bioinformatic tools. In addition, the effect of gene expression changes on IDH1 and IDH2 on carcinogenesis and survival probability was examined in publicly available data deposited in the TCGA database. The results showed that the expression of IDH isoforms showed tissue-specific differences. IDH1 expression increased in esophageal and lung squamous cell carcinoma and lung and stomach adenocarcinoma tumors. Bladder urothelial, breast urothelial, and lung squamous cell carcinoma, colon, and lung adenocarcinoma displayed a significant upregulation of IDH2 expression. There was a direct relationship between the expression of IDH isoforms and the progression of various cancer types. High IDH1 expression led to decreased survival probability in esophageal carcinoma, lung, and stomach adenocarcinoma. Elevated IDH2 expression level led to decreased survival probability in bladder urothelial, breast urothelial, and lung squamous cell carcinoma and colon adenocarcinoma. In conclusion, all data showed that IDH1 could be a biomarker for esophageal carcinoma, lung and stomach adenocarcinoma, and IDH2 for bladder urothelial, breast urothelial, and lung squamous cell carcinoma, and colon adenocarcinoma.

PM2.5-bound metals and blood metals are associated with pulmonary function and Th17/Treg imbalance: A panel study of asthmatic adults

Growing research has demonstrated that exposure to fine particulate matter (PM2.5) was associated with decreased pulmonary function and obvious inflammatory response. However, few pieces of research focus on the effects of PM2.5-bound metals on people with asthma. Here, we assessed whether PM2.5 and PM2.5-bound metals exposure could worsen pulmonary function in asthmatic patients and further elucidate the possible mechanisms. Thirty-four asthmatic patients were recruited to follow up for one year with eight visits in 2019–2020 in Taiyuan City, China. The index of pulmonary function was detected and blood and nasal epithelial lining fluid (ELF) samples were acquired for biomarkers measurement at each follow-up. Linear mixed-effect (LME) models were used to evaluate the relations between PM2.5, PM2.5-bound metals, and blood metals with lung function and biomarkers of Th17/Treg balance. The individual PM2.5 exposure concentration varied from 37 μg/m3 to 194 μg/m3 (mean: 59.63 μg/m3) in the present study. An interquartile range (IQR) increment of PM2.5 total mass was associated with a faster decline in maximal mid-expiratory flow (MMEF) and higher interleukin-23 (IL-23). PM2.5-bound metals [e.g. copper (Cu), nickel (Ni), manganese (Mn), titanium (Ti), and zinc (Zn)] were significantly associated with IL-23 (Cu: 5.1126%, 95% CI: 9.3708, 0.8544; Mn: 14.7212%, 95% CI: 27.926, 1.5164; Ni: 1.0269%, 95% CI: 2.0273, 0.0264; Ti: 16.7536%, 95% CI: 31.6203, 1.8869; Zn: 24.5806%, 95% CI: 46.609, 2.5522). Meanwhile, blood lead (Pb) and Cu were associated with significant declines of 0.382–3.895% in MMEF and maximum ventilatory volume (MVV). Blood Pb was associated with descending transforming growth factor β (TGF-β). In conclusion, exposure to PM2.5-bound metals and blood metals is a risk factor for decreased pulmonary function, especially in small airways. These alterations might be partially attributed to the imbalance of Th17/Treg.

Attenuation of pulmonary damage in aged lipopolysaccharide-induced inflammation mice through continuous 2 % hydrogen gas inhalation: A potential therapeutic strategy for geriatric inflammation and survival

IntroductionWith the global population aging, there is an increased prevalence of sepsis among the elderly, a demographic particularly susceptible to inflammation. This study aimed to evaluate the therapeutic potential of hydrogen gas, known for its anti-inflammatory and antioxidant properties, in attenuating inflammation specifically in the lungs and liver, and age-associated molecular markers in aged mice. MethodsMale mice aged 21 to 23 months, representative of the human elderly population, were subjected to inflammation via intraperitoneal injection of lipopolysaccharide (LPS). The mice were allocated into eight groups to examine the effects of varying durations and concentrations of hydrogen gas inhalation: control, saline without hydrogen, saline with 24-hour 2 % hydrogen, LPS without hydrogen, LPS with 24-hour 2 % hydrogen, LPS with 6-hour 2 % hydrogen, LPS with 1-hour 2 % hydrogen, and LPS with 24-hour 1 % hydrogen. Parameters assessed included survival rate, activity level, inflammatory biomarkers, and organ injury. ResultsExtended administration of hydrogen gas specifically at a 2 % concentration for 24 h led to a favorable prognosis in the aged mice by reducing mRNA expression of inflammatory biomarkers in lung and liver tissue, mitigating lung injury, and diminishing the expression of the senescence-associated protein p21. Moreover, hydrogen gas inhalation selectively ameliorated senescence-related markers in lung tissue, including C-X-C motif chemokine 2, metalloproteinase-3, and arginase-1. Notably, hydrogen gas did not alleviate LPS-induced liver injury under the conditions tested. ConclusionThe study highlights that continuous inhalation of hydrogen gas at a 2 % concentration for 24 h can be a potent intervention in the geriatric population for improving survival and physical activity by mitigating pulmonary inflammation and modulating senescence-related markers in aged mice with LPS-induced inflammation. This finding paves the way for future research into hydrogen gas as a therapeutic strategy to alleviate severe inflammation that can lead to organ damage in the elderly.

Biomarkers of lung alveolarization and microvascular maturation in response to intermittent hypoxia and/or early antioxidant/fish oil supplementation in neonatal rats.

Extremely preterm infants experience frequent intermittent hypoxia (IH) episodes during oxygen therapy which causes significant damage to the lungs and curtails important signaling pathways that regulate normal lung alveolarization and microvascular maturation. We tested the hypothesis that early supplementation with fish oil and/or antioxidants in rats exposed to neonatal IH improves expression of lung biomarkers of alveolarization and microvascular maturation, and reduces IH-induced lung injury. From birth (P0) to P14, rat pups were exposed to room air (RA) or neonatal IH during which they received daily oral supplementation with either: (1) olive oil (OO) (control); (2) Coenzyme Q10 (CoQ10) in OO; (3) fish oil; (4) glutathione nanoparticles (nGSH); or (5) fish oil +CoQ10. At P14 pups were placed in RAuntil P21 with no further treatment. RA controls were similarly treated. Lung growth and alveolarization, histopathology, apoptosis, oxidative stress and biomarkers of alveolarization and microvascular maturation were determined. Neonatal IH was associated with reduced lung weights and severe histopathological outcomes. These effects were curtailed with fish oil and nGSH. nGSH was also protective against apoptosis, while CoQ10 prevented IH-induced ROS production. Of all treatments, nGSH and CoQ10 + fish oil-induced vascular endothelial growth factor165 and CD31 (Platelet endothelial cell adhesion molecule-1), which are associated with angiogenesis. CoQ10 + fish oil improved alveolarization in RA and IH despite evidence of hemorrhage. The benefits of nGSH and CoQ10 + fish oil suggest an antioxidant effect which may be required to curtail IH-induced lung injury. Further clinical assessment of the effectiveness of nGSH is warranted.

Early Natural Menopause Is Associated With Poor Lung Health and Increased Mortality Among Female Smokers

ABSTRACT Menopause results from the decline of estrogen levels and is driven by ovarian aging. Some tissues, including the lung, may contribute to local estrogen synthesis in the postmenopausal state. Cigarette smoking is the most established factor for early menopause, and previous studies have shown that the menopause transition accelerated age-related decline of lung function following a restrictive disease pattern. In addition, studies have supported a potential synergistic effect of cigarette smoking and menopause on lung function. Delineating the effect of menopause timing and estrogen exposure on subsequent disease development may have important benefits for health maintenance and disease prevention in older women. This study aimed to assess the associations between early menopause and lung biomarkers, lung cancer risk, and cause-specific mortality. Data were obtained from the Pittsburg Lung Screening Study, a community-based research cohort of current and former smokers screened with low-dose computed tomography (CT) at baseline and 1 year later. Menstrual and reproductive history and data on respiratory symptoms were collected through questionnaires. Radiographic emphysema score was calculated from the baseline CT scan. Early menopause was defined as age at menopause of &lt;45 years. The study cohort included female Pittsburg Lung Screening Study participants who reported natural (n = 1038) or surgical (n = 628) menopause at study entry. A total of 1064 participants (63.9%) were current smokers with an average pack-years of 46.1 ± 19.8 at baseline. Early menopause was associated with several pathologies including self-reported wheezing (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.18–2.30; P &lt; 0.01), chronic bronchitis (OR, 1.73; 95% CI, 1.19–2.53; P &lt; 0.01), cardiovascular diseases (OR, 1.87; 95% CI, 1.13–3.11; P = 0.02), radiographic emphysema (OR, 1.70; 95% CI, 1.25–2.31; P &lt; 0.001), and incident airway obstruction (OR, 2.02; 95% CI, 1.03–3.96; P = 0.04) in women with natural menopause, but not surgical menopause except for physician-diagnosed cardiovascular diseases (OR, 4.03; 95% CI, 1.78–9.14; P &lt; 0.001). Trend tests for each of these outcomes in women with natural menopause identified monotonically increasing risk associated with younger age at menopause. Early menopause was associated with lower measurements of the lung function measurements forced expiratory volume in 1 second (FEV1; −104.8 ± 36.7 mL/s; P &lt; 0.01), forced vital capacity (FVC; −78.6 ± 38.2 mL; P = 0.04), and FEV1-to-FVC ratio (−2.1% ± 0.8%; P = 0.01) at baseline in women with natural menopause but not surgical menopause. The use of hormone therapy at any point was associated with higher baseline FEV1 levels and higher FEV1-to-FVC ratio at baseline among women with natural menopause. Early natural menopause was associated with a 40% increased risk of all-cause death with respiratory diseases (hazard ratio [HR], 2.32; 95% CI, 1.52–3.52; P &lt; 0.001), and early menopause was associated with twice the risk of lung cancer-specific mortality (HR, 1.94; 95% CI, 1.05–3.58; P = 0.03). This association was exacerbated by continuous cigarette smoking, with HRs of 4.65 (95% CI, 2.55–8.49; P &lt; 0.001) and 4.61 (95% CI, 2.63–8.07; P &lt; 0.001) for lung cancer and cancer mortality, respectively, among continuous smokers with early menopause compared with women with noncontinuous smoking and nonearly menopause. The results of this study demonstrate that among a postmenopausal cohort of middle-aged and older smokers, natural early menopause is associated with worse lung health and accelerated lung aging.

Levels of Clara cell secretory protein and surfactant protein A in municipal solid waste management workers in Ibadan, Southwest Nigeria

Toxic pneumonitis and related respiratory symptoms are common among waste management workers (WMWs). Products of different cellular responses following exposure to toxic components of wastes can lead to the production of a variety of biomolecules. There is a growing recognition of the importance of biomarkers in risk assessment and a strong advocacy for their determination and use as indicators of health and safety. This study assessed the prevalence of respiratory symptoms and the relevance of pulmonary surfactant protein A (SP-A) and Clara cell 16 protein (CC16) as indicators of occupational inhalation exposure to toxic substances and irritants in WMW. A total of 172 subjects consisting of 112 WMWs and 60 Non-WMWs were recruited by purposive sampling. Data on socio-economic and work-related symptoms were collected using structured questionnaire. CC16 and SP-A were determined by ELISA in serum samples. Clinical history reveals a slightly higher prevalence of respiratory symptoms in WMWs relative to control subjects. Increased permeability of the lung-blood barrier, characterized by significant elevation of serum SP-A and serum CC16, was associated with respiratory symptoms in WMWs. Steady increases in SP-A and CC16, respectively, in relation to occupational duration were observed in WMWs relative to control. Receiver operating characteristic curve and multivariate analyses revealed SP-A and CC16 as important lung biomarkers for assessing sub-clinical effects of occupational exposure. Our data suggest SP-A and CC16 may be relevant indicators for assessing occupational inhalation exposure to toxic substances and irritants among WMWs.

PULMONARY VASCULAR ENDOTHELIAL GLYCOCALYX DEGRADATION CONTRIBUTES TO ACUTE LUNG INJURY IN EXPERIENCING HEATSTROKE.

Objectives: This study investigated the role and potential involvement of pulmonary vascular glycocalyx degradation in acute lung injury in rats with severe heatstroke (HS). Methods: Rats in an established HS model were exposed to a heated environment for 60 min in an incubator (temperature, 40°C ± 2°C; humidity, 65% ± 5%). Following pretreatment with heparanase III (HPSE III) or heparin, pathological lung injury, arterial blood gas, alveolar barrier disruption, and hemodynamic changes were evaluated. The vascular endothelial structures of the lungs were examined using electron microscopy. The concentration of Evans blue dye in the lungs and arterial blood gas were assessed. An enzyme-linked immunosorbent assay was used to quantify the plasma concentration of heparan sulfate proteoglycan. The expression of glypican-1 and syndecan-1 in pulmonary vessels was measured using immunofluorescence. Western blots were used to detect the expression of TNF-α, IL-6, and vascular endothelial biomarkers in the rat lungs. Pulmonary apoptosis was assessed using a TUNEL (terminal dUTP nick end labeling) assay, and the concentrations of malondialdehyde were measured. Results: Glycocalyx shedding aggravated lung injuries. Severe histopathological damage was observed, and indexes of lung function deviated from abnormal ranges. In addition, pulmonary vascular endothelial cells were disrupted. Compared with the HS group, the plasma concentration of heparan sulfate proteoglycan significantly increased in the HPSE group ( P < 0.05). The expression of glypican-1 and syndecan-1 decreased, and the extravasation of Evans blue dye increased ( P < 0.01). Endothelial biomarker expression increased in the lung tissue, whereas occludin expression decreased. Moreover, TNF-α and IL-6 were overexpressed following heat stress. Furthermore, apoptosis of pulmonary tissues and the concentration of malondialdehyde in rat lungs increased in the HS and HPSE groups. Conclusions : Heatstroke induced pulmonary glycocalyx degradation, which increased vascular permeability and aggravated vascular endothelial dysfunction, contributing to apoptosis, inflammation, and oxidation in the pulmonary tissues.