Loss of Growth Differentiation Factor 15 Exacerbates Lung Injury in Neonatal Mice

Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor-β (TGF-β) superfamily, and its expression increases under various stress conditions, including inflammation, hyperoxia, and senescence. GDF15 expression is increased in neonatal murine bronchopulmonary dysplasia (BPD) models, and GDF15 loss exacerbates oxidative stress and decreases cellular viability in vitro. Our overall hypothesis is that the loss of GDF15 will exacerbate hyperoxic lung injury in the neonatal lung in vivo. We exposed neonata

Loss of Cytochrome P450 (CYP)1B1 Mitigates Hyperoxia Response in Adult Mouse Lung by Reprogramming Metabolism and Translation

Oxygen supplementation is life saving for premature infants and for COVID-19 patients but can induce long-term pulmonary injury by triggering inflammation, with xenobiotic-metabolizing CYP enzymes playing a critical role. Murine studies showed that CYP1B1 enhances, while CYP1A1 and CYP1A2 protect from, hyperoxic lung injury. In this study we tested the hypothesis that Cyp1b1-null mice would revert hyperoxia-induced transcriptomic changes observed in WT mice at the transcript and pathway level. Wild type (WT) C57BL/6J and Cyp1b1-null mice aged 8-10 weeks were maintained in room air (21%

Effect of stress level on the frost resistance and uniaxial compressive properties of desert sand concrete

Rapid freeze-thaw (F-T) tests were conducted to study the frost resistance of desert sand concrete (DSC) at different stress levels (SL), desert sand replacement rate (DSRR) and the number of F-T cycles. The impact of the SL, DSRR, and number of F-T cycles on the mass loss rate, ultrasonic wave velocity, and stress-strain curve of DSC was investigated through uniaxial compression tests. Scanning electron microscope (SEM) was used to examine the microstructure of DSC. The constitutive relationship was established considering the influence of the SL and number of F-T cycles. The results indicated that the frost resistance and uniaxial compressive mechanical properties of DSC could be effectively enhanced when desert sand was added at 40%. The peak strain initially decreased and then increased as the DSRR increased. In contrast, the peak stress first increased and reached a maximum value as the DSRR increasing to 40%, followed by a gradual decrease. The F-T cycles gradually deteriorated the macroscopic properties of DSC. The proposed constitutive model of DSC was established by combining the two classical models as the ascending and descending sections, respectively. The model prediction results matched well with the experimental results, which can provide a theoretical basis for the engineering application of DSC under F-T cycles and loading environments

Role of Cytochrome P450 (CYP)1A in Hyperoxic Lung Injury: Analysis of the Transcriptome and Proteome

AbstractHyperoxia contributes to lung injury in experimental animals and diseases such as acute respiratory distress syndrome in humans. Cytochrome P450 (CYP)1A enzymes are protective against hyperoxic lung injury (HLI). The molecular pathways and differences in gene expression that modulate these protective effects remain largely unknown. Our objective was to characterize genotype specific differences in the transcriptome and proteome of acute hyperoxic lung injury using the omics platforms: microarray and Reverse Phase Proteomic Array. Wild type (WT), Cyp1a1−/− and Cyp1a2−/− (8–10 wk, C57BL/6J background) mice were exposed to hyperoxia (FiO2 &gt; 0.95) for 48 hours. Comparison of transcriptome changes in hyperoxia-exposed animals (WT versus knock-out) identified 171 genes unique to Cyp1a1−/− and 119 unique to Cyp1a2−/− mice. Gene Set Enrichment Analysis revealed pathways including apoptosis, DNA repair and early estrogen response that were differentially regulated between WT, Cyp1a1−/− and Cyp1a2−/− mice. Candidate genes from these pathways were validated at the mRNA and protein level. Quantification of oxidative DNA adducts with 32P-postlabeling also revealed genotype specific differences. These findings provide novel insights into mechanisms behind the differences in susceptibility of Cyp1a1−/− and Cyp1a2−/− mice to HLI and suggest novel pathways that need to be investigated as possible therapeutic targets for acute lung injury.</jats:p

Predictive value of label-free surface-enhanced Raman spectroscopy for locally advanced gastric cancer following neoadjuvant chemoimmunotherapy

BackgroundAlthough neoadjuvant chemoimmunotherapy (NACI) is increasingly applied in clinical settings, its therapeutic efficacy and prognostic significance remain unclear. This study sought to establish a surface-enhanced Raman spectroscopy (SERS)-based approach for assessing treatment efficacy and predicting prognosis in patients with locally advanced gastric cancer (LAGC) undergoing NACI. In addition, the utility of SERS for molecular and pathological profiling was investigated.MethodsThis retrospective study enrolled 31 patients with LAGC treated with anti-PD-1 inhibitors plus chemotherapy before gastrectomy (May 2018–December 2022). A Raman score (RS) was established from SERS spectral features to predict overall survival (OS). The area under the time-dependent receiver operating characteristic curve (AUC), Cox proportional hazards regression, and concordance index (C-index) were used to evaluate model performance. A nomogram combining RS and ypTNM stage was constructed. Kaplan-Meier analysis assessed the risk stratification capacity. Key spectral bands were analyzed for biomarker identification, and machine learning (ML) models were used for histopathological and molecular classification.ResultsA total of 3,670 spectra from 31 patients were analyzed. The RS, based on Raman spectral features, achieved AUCs of 0.854 (1-year OS) and 0.920 (3-year OS). Lower RS correlated with longer OS (p&lt;0.05). RS served as an independent prognostic factor in multivariable analysis. The nomogram incorporating RS and ypTNM improved prediction for 3-year OS (AUC = 0.955) while maintaining 1-year accuracy. Kaplan–Meier analysis confirmed effective risk stratification (P = 0.01). Nine significant Raman bands were linked to nucleotides, collagen, and proteins. ML models achieved &gt;0.85 accuracy in classifying microsatellite instability (MSI), combined positive score (CPS) of programmed cell death ligand-1 (PD-L1), and tumor regression grade (TRG) based on SERS data.ConclusionsThis study demonstrates that label-free SERS can effectively predict prognosis in NACI-treated LAGC patients and shows promise in molecular and pathological profiling, supporting its potential for clinical application

Abstract 3471: Reciprocal roles of cytochromes P4501A1 and 1A2 in polycyclic aromatic hydrocarbon (PAH)-mediated tumorigenesis in mice: Implications for lung cancer in humans

Abstract Humans are constantly exposed to environmental carcinogenic polycyclic aromatic hydrocarbons (PAHs) through cigarette smoke, diesel exhausts, charcoal-broiled meats, etc. Cytochrome P4501A (CYP1A) enzymes play important roles in the activation of PAHs such as 3-methylcholanthrene (MC) to carcinogenic DNA-binding metabolites. The resulting DNA adducts may lead to mutations of tumor suppressor genes such as p53, thereby leading to tumorigenesis. In this study, we tested the hypothesis that CYP1A1 and 1A2 have reciprocal roles in PAH-mediated tumorigenesis. Eight week-old female wild type (WT) (A/J) mice or mice lacking the gene for CYP1A1 or CYP1A2 on the A/J background were treated with a single dose of MC (40 µmol/kg), benzo[a]pyrene (BP), or vehicle (corn oil), and liver and lung tumors were studied after 28 weeks. While 100% of WT or Cyp1a2-null mice exposed to MC showed lung tumors after 28 weeks, about 80% of the Cyp1a1-null mice showed lung tumors. However, there were striking differences in the Cyp1a1-null and Cyp1a2-null in regard to lung tumor multiplicities and sizes of tumors. The WT mice treated with MC had about 15 lung tumors/animal. On the other hand, the Cyp1a2-null mice displayed about 40 lung tumors/animal, while the Cyp1a1-null mice showed about 2-3 tumors/mouse. Also, the tumor sizes were much larger in the Cyp1a2-null mice, compared to the much smaller sizes in the Cyp1a1-null mice. Although BP was less potent in inducing lung tumors in the WT mice compared to MC, it was similar to MC In that tumors were suppressed in the Cyp1a1-null mice and augmented in the Cyp1a2-null mice. Immunohistochemical studies showed that CYP1A1 was overexpressed in the tumorous portions of the lung in the Cyp1a2-null or WT mice, compared to non-tumorous regions, These results suggest that CYP1A1 contributes to the formation of tumorigenesis by PAHs, while CYP1A2 plays an important role in the protection against carcinogenesis mediated by PAHs, presumably through it role in PAH detoxification. In conclusion, our results strongly suggest that CYP1A1 and 1A2 could be novel candidates for cancer prevention and therapy though either inhibition of CYP1A1 or induction of CYP1A2. Thus, CYP1a1-null and Cyp1a2-null mice could be developed as novel animal models for future cancer prevention and/or therapeutic intervention in humans exposed to environmental PAHs. (Supported by NIH grant ES009132.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3471.</jats:p

FISHERVIOCE: A DISCRIMINANT SUBSPACE FRAMEWORK FOR SPEAKER RECOGNITION

We propose a new framework for speaker recognition, referred as Fishervoice. It includes the design of a feature representation known as the structured score vector (SSV), which relates acoustic structures with “key ” frames in an input utterance in capturing relevant speaker characteristics. The framework also applies nonparametric Fisher’s discriminant analysis to map the SSVs into a compressed discriminant subspace, where matching is performed between a test sample and reference speaker samples to achieve speaker recognition. The objective is to reduce intra-speaker variability and emphasize discriminative class boundary information to facilitate speaker recognition. Experiments based on the XM2VTSDB corpus shows that the Fishervoice framework gave superior performance, compared with other commonly used approaches, e.g. GMM-UBM and Eigenvoice. Index Terms — speaker recognition, GMM, subspace model, discriminant analysis, Fishervoic