Prognostic significance of SIRI in patients with late-stage lung adenocarcinoma receiving EGFR-TKI treatment.

OBJECTIVE: In this study, we examined the relationship between the Systemic Inflammatory Response Index (SIRI) and the overall prognosis of patients with late-stage lung adenocarcinoma who harbor epidermal growth factor receptor (EGFR) mutations and are undergoing first-line treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). METHODS: A cohort comprising 52 patients with late-stage lung adenocarcinoma, who received treatment at Jinzhou Central Hospital between January 2018 and December 2022, were carefully selected. Patient data spanning from pre-treatment assessments through follow-up periods were meticulously collected from electronic medical records and subsequently subjected to a comprehensive retrospective analysis. The collected data was subjected to in-depth processing and analyzed using SPSS 27.0 statistical software. To determine the optimal cut-off value of the pre-treatment SIRI, a receiver operating characteristic (ROC) curve was employed. Survival analysis was performed using the Kaplan-Meier method, and both univariate and multivariate prognostic analyses were conducted using Cox regression. RESULTS: The optimal SIRI cut-off value was determined to be 1.659 (with a specificity of 0.964 and sensitivity of 0.652, P = 0.000). Based on this value, patients were categorized into high and low SIRI groups. Chi-squared tests demonstrated that SIRI exhibited statistically significant correlations with patient age and smoking history (P < 0.05). Survival analysis revealed that the group with a lower SIRI had a significantly extended progression-free survival (PFS) (P < 0.001). Cox univariate analysis identified hypertension, pleural metastasis, liver metastasis, and SIRI as factors associated with PFS (P < 0.05). In the subsequent multivariate analysis, liver metastasis and SIRI ≥ 1.659 (P < 0.001) were identified as independent risk factors for patients. CONCLUSION: Pre-treatment SIRI holds predictive significance for the prognosis of patients with late-stage lung adenocarcinoma with EGFR mutations undergoing first-line treatment EGFR-TKI treatment.

Systems Metabolic Engineering for Efficient Violaxanthin Production in Yeast.

Violaxanthin is a plant-derived orange xanthophyll with remarkable antioxidant activity that has wide applications in various industries, such as food, agriculture, and cosmetics. In addition, it is the key precursor of important substances such as abscisic acid and fucoxanthin. Saccharomyces cerevisiae, as a GRAS (generally regarded as safe) chassis, provides a good platform for producing violaxanthin production with a yield of 7.3 mg/g DCW, which is far away from commercialization. Herein, an integrated strategy involving zeaxanthin epoxidase (ZEP) source screening, cytosol redox state engineering, and nicotinamide adenine dinucleotide phosphate (NADPH) regeneration was implemented to enhance violaxanthin production in S. cerevisiae. 58aa-truncated ZEP from Vitis vinifera exhibited optimal efficiency in an efficient zeaxanthin-producing strain. The titer of violaxanthin gradually increased by 17.9-fold (up to 119.2 mg/L, 15.19 mg/g DCW) via cytosol redox state engineering and NADPH supplementation. Furthermore, balancing redox homeostasis considerably improved the zeaxanthin concentration by 139.3% (up to 143.9 mg/L, 22.06 mg/g DCW). Thus, the highest reported titers of violaxanthin and zeaxanthin in S. cerevisiae were eventually achieved. This study not only builds an efficient platform for violaxanthin biosynthesis but also serves as a useful reference for the microbial production of xanthophylls.

Environmental chemical-wide associations with immune biomarkers in US adults: A cross-sectional analysis.

Environmental chemical exposures influence immune system functions, and humans are exposed to a wide range of chemicals, termed the chemical "exposome". A comprehensive, discovery analysis of the associations of multiple chemical families with immune biomarkers is needed. In this study, we tested the associations between environmental chemical concentrations and immune biomarkers. We analyzed the United States cross-sectional National Health and Nutrition Examination Survey (NHANES, 1999-2018). Chemical biomarker concentrations were measured in blood or urine (196 chemicals, 17 chemical families). Immune biomarkers included counts of lymphocytes, neutrophils, monocytes, basophils, eosinophils, red blood cells, white blood cells, and mean corpuscular volume. We conducted separate survey-weighted, multivariable linear regressions of each log2-transformed chemical and immune measure, adjusted for relevant covariates. We accounted for multiple comparisons using a false discovery rate (FDR). Among 45,528 adult participants, the mean age was 45.7 years, 51.4% were female, and 69.3% were Non-Hispanic White. 71 (36.2%) chemicals were associated with at least one of the eight immune biomarkers. The most chemical associations (FDR<0.05) were observed with mean corpuscular volume (36 chemicals) and red blood cell counts (35 chemicals). For example, a doubling in the concentration of cotinine was associated with 0.16 fL (95% CI: 0.15, 0.17; FDR<0.001) increased mean corpuscular volume, and a doubling in the concentration of blood lead was associated with 61,736 increased red blood cells per µL (95% CI: 54,335, 69,138; FDR<0.001). A wide variety of chemicals, such as metals and smoking-related compounds, were highly associated with immune system biomarkers. This environmental chemical-wide association study identified chemicals from multiple families for further toxicological, immunologic, and epidemiological investigation.

Depressive symptoms are associated with DNA methylation age acceleration in a cross-sectional analysis of adults over age 50 in the United States.

Background: Major depressive disorder affects mental well-being and accelerates DNA methylation age, a marker of biological aging. Subclinical depressive symptoms and DNA methylation aging have not been explored. Objective: To assess the cross-sectional association between depressive symptoms and accelerated DNA methylation aging among United States adults over age 50. Methods: We included 3,793 participants from the 2016 wave of the Health and Retirement Study. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale and operationalized as high versus low/no. Blood DNA methylation GrimAge was regressed on chronologic age to obtain acceleration. Multiple linear regression assessed the relationship between high depressive symptoms and GrimAge acceleration, controlling for demographic factors, health behaviors, and cell type proportions. We investigated sex and race/ethnicity stratified associations. Results: Participants were 42% male, 14% had high depressive symptoms, 44% had accelerated GrimAge, and were mean age 70 years. In our fully adjusted model, those with high depressive symptoms had 0.40 (95%CI: 0.06, 0.73) years accelerated GrimAge, compared to those with low/no depressive symptoms. The association between depressive symptoms and GrimAge acceleration was larger in male participants ( P = 0.04). Conclusion: Higher depressive symptoms were associated with accelerated DNA methylation age among older adults.

The Mediating Role of Systemic Inflammation and Moderating Role of Race/Ethnicity in Racialized Disparities in Incident Dementia: A Decomposition Analysis.

Background: Exposure to systemic racism is linked to increased dementia burden. To assess systemic inflammation as a potential pathway linking exposure to racism and dementia disparities, we investigated the mediating role of C-reactive protein (CRP), a systemic inflammation marker, and the moderating role of race/ethnicity on racialized disparities in incident dementia. Methods: In the US Health and Retirement Study (n=5,143), serum CRP was measured at baseline (2006, 2008 waves). Incident dementia was classified by cognitive tests over a six-year follow-up. Self-reported racialized categories were a proxy for exposure to the racialization process. We decomposed racialized disparities in dementia incidence (non-Hispanic Black and/or Hispanic vs. non-Hispanic White) into 1) the mediated effect of CRP, 2) the moderated portion attributable to the interaction between racialized group membership and CRP, and 3) the controlled direct effect (other pathways through which racism operates). Results: The 6-year cumulative incidence of dementia was 15.5%. Among minoritized participants (i.e., non-Hispanic Black and/or Hispanic), high CRP levels (> 75th percentile or 4.57mcg/mL) was associated with 1.27 (95%CI: 1.01,1.59) times greater risk of incident dementia than low CRP (<4.57mcg/mL). Decomposition analysis comparing minoritized versus non-Hispanic White participants showed that the mediating effect of CRP accounted for 2% (95% CI: 0%, 6%) of the racial disparity, while the interaction effect between minoritized group status and high CRP accounted for 12% (95% CI: 2%, 22%) of the disparity. Findings were robust to potential violations of causal mediation assumptions. Conclusions: Systemic inflammation mediates racialized disparities in incident dementia.

The Mediating Role of Systemic Inflammation and Moderating Role of Race/Ethnicity in Racialized Disparities in Incident Dementia: A Decomposition Analysis.

Background: Exposure to systemic racism is linked to increased dementia burden. To assess systemic inflammation as a potential pathway linking exposure to racism and dementia disparities, we investigated the mediating role of C-reactive protein (CRP), a systemic inflammation marker, and the moderating role of race/ethnicity on racialized disparities in incident dementia. Methods: In the US Health and Retirement Study (n=5,143), serum CRP was measured at baseline (2006, 2008 waves). Incident dementia was classified by cognitive tests over a six-year follow-up. Self-reported racialized categories were a proxy for exposure to the racialization process. We decomposed racialized disparities in dementia incidence (non-Hispanic Black and/or Hispanic vs. non-Hispanic White) into 1) the mediated effect of CRP, 2) the moderated portion attributable to the interaction between racialized group membership and CRP, and 3) the controlled direct effect (other pathways through which racism operates). Results: The 6-year cumulative incidence of dementia was 15.5%. Among minoritized participants (i.e., non-Hispanic Black and/or Hispanic), high CRP levels (> 75th percentile or 4.57µg/mL) was associated with 1.27 (95%CI: 1.01,1.59) times greater risk of incident dementia than low CRP (≤4.57µg/mL). Decomposition analysis comparing minoritized versus non-Hispanic White participants showed that the mediating effect of CRP accounted for 2% (95% CI: 0%, 6%) of the racial disparity, while the interaction effect between minoritized group status and high CRP accounted for 12% (95% CI: 2%, 22%) of the disparity. Findings were robust to potential violations of causal mediation assumptions. Conclusions: Systemic inflammation mediates racialized disparities in incident dementia.

Systematic Engineering to Enhance 8-Hydroxygeraniol Production in Yeast.

8-Hydroxygeraniol, an important component of insect sex pheromones and defensive secretions, can be used as a potential biological insect repellent in agriculture. Microbial production provides sustainable and green means to efficiently gain 8-hydroxygeraniol. The conversion of geraniol to 8-hydroxygeraniol by P450 geraniol-8-hydroxylase (G8H) was regarded as the bottleneck for 8-hydroxygeraniol production. Herein, an integrated strategy consisting of the fitness between G8H and cytochrome P450 reductase (CPR), endoplasmic reticulum (ER) engineering, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) supply is implemented to enhance the production of 8-hydroxygeraniol in Saccharomyces cerevisiae. The titer of 8-hydroxygeraniol was gradually increased by 2.1-fold (up to 158.1 mg/L). Moreover, dehydrogenase ADH6 and reductase ARI1 responsible for the reduction of 8-hydroxygeraniol toward shunt products were also deleted, elevating 8-hydroxygeraniol production to 238.9 mg/L at the shake flask level. Consequently, more than 1.0 g/L 8-hydroxygeraniol in S. cerevisiae was achieved in 5.0 L fed-batch fermentation by a carbon restriction strategy, which was the highest-reported titer in microbes so far. Our work not only provides a sustainable way for de novo biosynthesis of 8-hydroxygeraniol but also sets a good reference in P450 engineering in microbes.

Development of Organogels for Live Yarrowia lipolytica Encapsulation.

Encapsulation of cells/microorganisms attracts great attention in many applications, but current studies mainly focus on hydrophilic encapsulation materials. Herein, we develop a new class of hydrophobic and lipophilic organogels for highly efficient encapsulation of Yarrowia lipolytica, an oleaginous yeast, by a mild and nonsolvent photopolymerization method. The organogels allow free diffusion of hydrophobic molecules that oleaginous yeasts require to survive and function. Moreover, they are mechanically robust and possess favorable biocompatibility, thus providing a free-standing platform and an ideal survival environment for oleaginous Y. lipolytica encapsulation. By tuning monomer structures and cross-linking densities, the optimized organogel, Gel12-1.5%, achieves the highest viability of ∼96%. Furthermore, organogels can inhibit the cryoinjuries to oleaginous yeasts in cryopreservation, exhibiting the potential for long-term storage. It is also found that with varying alkyl lengths, the organogels show different temperature-dependent phase transition properties, which enable the rapid selection of targeted yeasts for steganography. Findings in this work provide guidance for designing biocompatible, hydrophobic, and lipophilic encapsulation materials.

Analysis of factors affecting the prognosis of COVID-19 patients and viral shedding duration.

The clinical characteristics of patients with COVID-19 were analysed to determine the factors influencing the prognosis and virus shedding time to facilitate early detection of disease progression. Logistic regression analysis was used to explore the relationships among prognosis, clinical characteristics and laboratory indexes. The predictive value of this model was assessed with receiver operating characteristic curve analysis, calibration and internal validation. The viral shedding duration was calculated using the Kaplan-Meier method, and the prognostic factors were analysed by univariate log-rank analysis and the Cox proportional hazards model. A retrospective study was carried out with patients with COVID-19 in Tianjin, China. A total of 185 patients were included, 27 (14.59%) of whom were severely ill at the time of discharge and three (1.6%) of whom died. Our findings demonstrate that patients with an advanced age, diabetes, a low PaO2/FiO2 value and delayed treatment should be carefully monitored for disease progression to reduce the incidence of severe disease. Hypoproteinaemia and the fever duration warrant special attention. Timely interventions in symptomatic patients and a time from symptom onset to treatment <4 days can shorten the duration of viral shedding.

Identification of a Mutation in the Novel Compound Heterozygous CFTR in a Chinese Family with Cystic Fibrosis.

Cystic fibrosis (CF) is one of the most common autosomal recessive disorders among Caucasians of Northern European descent but is uncommon in the Chinese population. Objectives. To elucidate the mutation in the novel compound heterozygous CFTR causing CF in Chinese family. Materials and Methods. Clinical samples were obtained from a Chinese family, the brother and sister with recurrent airway infections, hypoxemia and obstructive ventilatory impairment, sinusitis, clubbed fingers, salty sweat, and nasal polyposis. We performed whole-exome sequencing on the family and validated all potential variants by Sanger sequencing. Results. Next-generation sequencing showed a novel compound heterozygous CFTR mutation (c.400 A > G p.Arg134Gly and c.3484 C > T p.Arg1162 ∗ ) which resulted in CF in the family. Conclusions. As this mutation is consistent with the observed clinical manifestations of CF and no other mutations were detected after scanning the gene sequence, we suggest that their CF phenotypes are caused by the compound heterozygous mutation, c.400 A > G p.Arg134Gly and c.3484 C > T p.Arg1162 ∗ . As c.400 A > G is not currently listed in the Cystic Fibrosis Mutation Database, this information, regarding the CF-causing mutations in two Chinese patients, is of interest.

LncRNA analysis of lung tissues after hUC-MSCs and FTY720 treatment of lipopolysaccharide-induced acute lung injury in mouse models.

Acute lung injury (ALI), a persistent lung inflammatory response syndrome, may evolve into acute respiratory distress syndrome (ARDS). Characterized by rapid onset, critical features, and a complex etiology, ALI remains a challenging critical respiratory disease. Recently, mesenchymal stem cells (MSCs) have provided a new solution for the treatment of ALI. We built a lipopolysaccharide (LPS)-induced ALI model in mice. After treatment with human umbilical cord mesenchymal stem cells (hUC-MSCs), FTY720, or a combination of hUC-MSCs and FTY207, the lung inflammatory response was apparently attenuated. To understand the mechanism underlying MSCs treatment of ALI at the genetic level, significant differentially expressed long non-coding RNAs (lncRNAs) between the treatment and model groups were analyzed using microarray technology. Moreover, genetic gene prediction, gene ontology (GO) analysis, pathway analysis, and transcription factor (TF) prediction were carried out. The results showed that a total of 66 lncRNAs were differentially expressed in all three treatment groups, including 8 up-regulated and 58 down-regulated lncRNAs. LncRNA A_30_P01029806 and A_30_P01029194, which were down-regulated, were involved in the signaling pathways closely related to ALI. Through further TF analysis, we identified several significant TFs which lay a foundation for revealing the mechanism underlying lncRNAs treatment of ALI. LncRNA A_30_P01029806 and A_30_P01029194 may serve as candidate biomarkers in the diagnosis and treatment of ALI.

Identification and characterization of a plastidial ω-3 fatty acid desaturase EgFAD8 from oil palm (Elaeis guineensis Jacq.) and its promoter response to light and low temperature.

In higher plants, ω-3 fatty acid desaturases are the key enzymes in the biosynthesis of alpha-linolenic acid (18:3), which plays key roles in plant metabolism as a structural component of both storage and membrane lipids. Here, the first ω-3 fatty acid desaturase gene was identified and characterized from oil palm. The bioinformatic analysis indicated it encodes a temperature-sensitive chloroplast ω-3 fatty acid desaturase, designated as EgFAD8. The expression analysis revealed that EgFAD8 is highly expressed in the oil palm leaves, when compared with the expression in the mesocarp. The heterologous expression of EgFAD8 in yeast resulted in the production of a novel fatty acid 18:3 (about 0.27%), when fed with 18:2 in the induction culture. Furthermore, to detect whether EgFAD8 could be induced by the environment stress, we detected the expression efficiency of the EgFAD8 promoter in transgenic Arabidopsis treated with low temperature and darkness, respectively. The results indicated that the promoter of EgFAD8 gene could be significantly induced by low temperature and slightly induced by darkness. These results reveal the function of EgFAD8 and the feature of its promoter from oil palm fruits, which will be useful for understanding the fuction and regulation of plastidial ω-3 fatty acid desaturases in higher plants.

C3-Luc Cells Are an Excellent Model for Evaluation of Cellular Immunity following HPV16L1 Vaccination.

C3 and TC-1 are the two model cell lines most commonly used in studies of vaccines and drugs against human papillomavirus (HPV) infection. Because C3 cells contain both the HPV16 E and L genes, but TC-1 cells contain only the HPV16 E genes, C3 cells are usually used as the model cell line in studies targeting the HPV16 L protein. However, expression of the L1 protein is difficult to detect in C3 cells using common methods. In our study, Short tandem repeat analysis (STR) was used to demonstrate that C3 cells are indeed derived from mice, PCR results show that HPV16 L1, E6 and E7 genes were detected in C3 genomic DNA, and RT-PCR results demonstrated that L1 transcription had occurred in C3 cells. However, the expression of C3 protein was not found in the results of western blot and immunohistochemistry (IHC). Growth and proliferation of C3 were inhibited by mice spleen lymphocytes that had been immunized with a vaccine against HPV16L1. The luciferase gene was integrated into C3 cells, and it was confirmed that addition of the exogenous gene had no effect on C3 cells by comparing cell growth and tumor formation with untransformed cells. Cells stably expressing luciferase (C3-luc) were screened and subcutaneously injected into the mice. Tumors became established and were observed using a Spectrum Pre-clinical in Vivo Imaging System. Tumor size of mice in the different groups at various time points was calculated by counting photons. The sensitivity of the animals to the vaccine was quantified by statistical comparison. Ten or 30 days following injection of the C3-luc cells, tumor size differed significantly between the PBS and vaccine groups, indicating that C3 cells were susceptible to vaccination even after tumors were formed in vivo.

One-prime multi-boost strategy immunization with recombinant DNA, adenovirus, and MVA vector vaccines expressing HPV16 L1 induces potent, sustained, and specific immune response in mice.

Human papillomavirus (HPV) is associated with various human diseases, including cancer, and developing vaccines is a cost-efficient strategy to prevent HPV-related disease. The major capsid protein L1, which an increasing number of studies have confirmed is typically expressed early in infection, is a promising antigen for such a vaccine, although the E6 and E7 proteins have been characterized more extensively. Thus, the L1 gene from HPV16 was inserted into a recombinant vector, AdHu5, and MVA viral vectors, and administered by prime-boost immunization. Virus-like particles were used as control antigens. Our results indicate that prime-boost immunization with heterologous vaccines induced robust and sustained cellular and humoral response specific to HPV16 L1. In particular, sera obtained from mice immunized with DNA + DNA + Ad + MVA had excellent antitumor activity in vivo. However, the data also confirm that virus-like particles can only elicit low levels cellular immunity and not be long-lasting, and are therefore unsuitable for treatment of existing HPV infections.