Comprehensive analysis of PPP4C's impact on prognosis, immune microenvironment, and immunotherapy response in lung adenocarcinoma using single-cell sequencing and multi-omics.

Background: Elevated PPP4C expression has been associated with poor prognostic implications for patients suffering from lung adenocarcinoma (LUAD). The extent to which PPP4C affects immune cell infiltration in LUAD, as well as the importance of associated genes in clinical scenarios, still requires thorough investigation. Methods: In our investigation, we leveraged both single-cell and comprehensive RNA sequencing data, sourced from LUAD patients, in our analysis. This study also integrated datasets of immune-related genes from InnateDB into the framework. Our expansive evaluation employed various analytical techniques; these included pinpointing differentially expressed genes, constructing WGCNA, implementing Cox proportional hazards models. We utilized these methods to investigate the gene expression profiles of PPP4C within the context of LUAD and to clarify its potential prognostic value for patients. Subsequent steps involved validating the observed enhancement of PPP4C expression in LUAD samples through a series of experimental approaches. The array comprised immunohistochemistry staining, Western blotting, quantitative PCR, and a collection of cell-based assays aimed at evaluating the influence of PPP4C on the proliferative and migratory activities of LUAD cells. Results: In lung cancer, elevated expression levels of PPP4C were observed, correlating with poorer patient prognoses. Validation of increased PPP4C levels in LUAD specimens was achieved using immunohistochemical techniques. Experimental investigations have substantiated the role of PPP4C in facilitating cellular proliferation and migration in LUAD contexts. Furthermore, an association was identified between the expression of PPP4C and the infiltration of immune cells in these tumors. A prognostic framework, incorporating PPP4C and immune-related genes, was developed and recognized as an autonomous predictor of survival in individuals afflicted with LUAD. This prognostic tool has demonstrated considerable efficacy in forecasting patient survival and their response to immunotherapeutic interventions. Conclusion: The involvement of PPP4C in LUAD is deeply intertwined with the tumor's immune microenvironment. PPP4C's over-expression is associated with negative clinical outcomes, promoting both tumor proliferation and spread. A prognostic framework based on PPP4C levels may effectively predict patient prognoses in LUAD, as well as the efficacy of immunotherapy strategy. This research sheds light on the mechanisms of immune interaction in LUAD and proposes a new strategy for treatment.

Immunogenic cell death inducers for cancer therapy: An emerging focus on natural products.

BACKGROUND: Immunogenic cell death (ICD) is a specific form of regulated cell death induced by a variety of stressors. During ICD, the dying cancer cells release damage-associated molecular patterns (DAMPs), which promote dendritic cell maturation and tumor antigen presentation, subsequently triggering a T-cell-mediated anti-tumor immune response. In recent years, a growing number of studies have demonstrated the potential of natural products to induce ICD and enhance tumor cell immunogenicity. Moreover, there is an increasing interest in identifying new ICD inducers from natural products. PURPOSE: This study aimed to emphasize the potential of natural products and their derivatives as ICD inducers to promote research on using natural products in cancer therapy and provide ideas for future novel immunotherapies based on ICD induction. METHOD: This review included a thorough search of the PubMed, Web of Science, Scopus, and Google Scholar databases to identify natural products with ICD-inducing capabilities. A comprehensive search for clinical trials on natural ICD inducers was also conducted using ClinicalTrials.gov, as well as the approved patents using the Espacenet and CNKI Patent Database. RESULTS: Natural compounds that induce ICD can be categorized into several groups, such as polyphenols, flavonoids, terpenoids, and alkaloids. Natural products can induce the release of DAMPs by triggering endoplasmic reticulum stress, activation of autophagy-related pathways, and reactive oxygen species generation, etc. Ultimately, they activate anti-tumor immune response and improve the efficacy of cancer treatments. CONCLUSION: A growing number of ICD inducers from natural products with promising anti-cancer potential have been identified. The detailed information presented in this review will contribute to the further development of natural ICD inducers and cancer treatment strategies based on ICD-induced responses.

Foxo1 is an iron-responsive transcriptional factor regulating systemic iron homeostasis.

The liver plays a crucial role in maintaining systemic iron homeostasis by secreting hepcidin, which is essential for coordinating iron levels in the body. Imbalances in iron homeostasis are associated with various clinical disorders related to iron deficiency or iron overload. Despite the clinical significance, the mechanisms underlying how hepatocytes sense extracellular iron levels to regulate hepcidin synthesis and iron storage are not fully understood. In this study, we identified Foxo1, a well-known regulator of macronutrient metabolism, that translocates to the nucleus of hepatocytes in response to high-iron feeding, holo-transferrin, and BMP6 treatment. Furthermore, Foxo1 plays a crucial role in mediating hepcidin induction in response to both iron and BMP signals by directly interacting with evolutionally conserved Foxo binding sites within the hepcidin promoter region. These binding sites were found to colocalize with Smad-binding sites. To investigate the physiological relevance of Foxo1 in iron metabolism, we generated mice with hepatocyte-specific deletion of Foxo1. These mice exhibited reduced hepatic hepcidin expression and serum hepcidin levels, accompanied by elevated serum iron and liver non-heme iron concentrations. Moreover, high-iron diet further exacerbated these abnormalities in iron metabolism in mice lacking hepatic Foxo1. Conversely, hepatocyte-specific Foxo1 overexpression increased hepatic hepcidin expression and serum hepcidin levels, thereby ameliorating iron overload in a murine model of hereditary hemochromatosis (Hfe-/- mice). In summary, our study identifies Foxo1 is a critical regulator of hepcidin and systemic iron homeostasis. Targeting Foxo1 may offer therapeutic opportunities for managing conditions associated with aberrant iron metabolism.

Precise Molecular Subtyping Reveals Heterogeneity of Lung Adenocarcinoma Based on DNA Methylation.

BACKGROUND: Due to the high heterogeneity of lung adenocarcinoma (LUAD), which restricts the effectiveness of therapy, precise molecular subgrouping of LUAD is of great significance. Clinical research has demonstrated the significant potential of DNA methylation as a classification indicator for human malignancies. METHODS: WGML framework (which was developed based on weighted gene correlation network analysis (WGCNA), Gene Ontology (GO), and machine learning) was developed to precisely subgroup molecular subtypes of LUAD. This framework included two parts: the WG algorithm and the machine learning part. The WG algorithm part was an original algorithm used to obtain a crucial module, which was characterized by weighted correlation network analysis, functional annotation, and mathematical algorithms. The machine learning part utilized the Boruta algorithm, random forest algorithm, and Gradient Boosting Regression Tree algorithm to select feature genes. Then, based on the results of the WGML framework, subtypes were computed by the hierarchical clustering algorithm. A series of analyses, including dimensionality reduction methods, survival analysis, clinical stage analysis, immune infiltration analysis, tumor environment analysis, immune checkpoints analysis, TIDE analysis, CYT analysis, somatic mutation analysis, and drug sensitivity analysis, were utilized to demonstrate the effectiveness of subgrouping. GEO datasets were used to externally validate the results. Meanwhile, another subgrouping method of LUAD from another study was employed to compare with the WGML framework. RESULT: By importing DNA methylation data into the WGML framework, nine genes were obtained to further subgroup LUAD. Three subtypes, the Carcinogenesis subtype, Immune-infiltration subtype, and Chemoresistance subtype, were identified. The dimensionality reduction method exhibited great distinctness between subtypes. A series of analyses were employed to exhibit the difference among the three subtypes and to demonstrate the accuracy of the definition of subtypes. Besides, the WGML framework was compared with a LUAD subgrouping method from another research, which demonstrated that WGML had better efficiency for subgrouping LUAD. CONCLUSION: This study provides a novel LUAD subgrouping framework named WGML for the accurate subgrouping of lung adenocarcinoma.

[Development and characterization of tobacco suspension cell chassis NBS-1].

Plant synthetic biology has significant theoretical advantages in exploration and production of plant natural products. However, its contribution to the field of biosynthesis is currently limited due to the lack of efficient chassis systems and related enabling technologies. Synthetic biologists often avoid tobacco as a chassis system because of its long operation cycle, difficulties in genetic and metabolic modification, complex metabolism and purification background, nicotine toxicity, and challenges in accurately controlling for agricultural production. Nevertheless, the tobacco suspension cell chassis system offers a viable solution to these challenges. The objective of this research was to develop a tobacco suspension cell chassis with high scientific and industrial potential. This chassis should exhibit rapid growth, high biomass, excellent dispersion, high transformation efficiency, and minimal nicotine content. Nicotiana benthamiana, which has high applicability in molecular technology, was used to induce suspension cells. The induced suspension cells, named NBS-1, exhibited rapid growth, excellent dispersion, and high biomass, reaching a maximum biomass of 476.39 g/L (fresh weight), which was significantly higher than that of BY-2. The transformation efficiency of the widely utilized pEAQ-HT transient expression system in NBS-1 reached 81%, which was substantially elevated compared to BY-2. The metabolic characteristics and bias of BY-2 and NBS-1 were analyzed using transcriptome data. It was found that the gene expression of pathways related to biosynthesis of flavonoids and their derivatives in NBS-1 was significantly higher, while the pathways related to alkaloid biosynthesis were significantly lower compared to BY-2. These findings were further validated by the total content of flavonoid and alkaloid. In summary, our research demonstrates NBS-1 possesses minimal nicotine content and provides valuable guidance for selecting appropriate chassis for specific products. In conclusion, this study developed NBS-1, a tobacco suspension cell chassis with excellent growth and transformation, high flavonoid content and minimal nicotine content, which has important guiding significance for the development of tobacco suspension cell chassis.

Efficacy and Safety of 5-Aminolevulinic Acid Photodynamic Therapy for Treating Cervical and Vaginal Intraepithelial Neoplasia.

Persistent HPV infections may cause cervical and vaginal intraepithelial neoplasia (CIN and VaIN). Traditional methods might destroy the structure and function of the cervix. 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is a non-invasive targeted therapy. This study aims to evaluate the efficacy and safety of ALA-PDT for CIN and VaIN and the clearance of HPV. A retrospective study of 303 patients who confirmed CIN or VaIN and received ALA-PDT was conducted. All the patients were followed up at six and twelve months after treatment and then annually thereafter. The effect was evaluated through HPV genotyping, a cytology test, and colposcopy-directed biopsy if necessary. After ALA-PDT, the remission rates for CIN 2, CIN 3, VaIN 2, and VaIN 3 were 90.6%, 88.5%, 87.3%, and 77.8%. For CIN 1, the remission rate at the six-month follow-up was 93.1%. The total HPV clearance rates were 72.5% at the six-month follow-up and 85.7% at the 12-month follow-up. The most common adverse event was vaginal discharge. No severe adverse effect was observed. ALA-PDT is an effective and safe treatment for all grades of CIN and VaIN and is helpful in clearing HPV with minimal side effects. This treatment may not influence fertility and delivery.

Increased miR-3074-5p expression promotes M1 polarization and pyroptosis of macrophages via ERα/NLRP3 pathway and induces adverse pregnancy outcomes in mice.

Decidual macrophages (dMϕs) play critical roles in regulation of immune-microhomeostasis at maternal-fetal interface during pregnancy, but the underlying molecular mechanisms are still unclear. In this study, it was found that litter size and fetal weight were significantly reduced, whereas the rate of embryo resorption was increased in miR-3074-5p knock-in (3074-KI) pregnant mice, compared to that of wild-type (WT) pregnant mice. Plasma levels of pro-inflammatory cytokines in 3074-KI pregnant mice were also significantly elevated compared to WT pregnant mice at GD7.5. The quantity of M1-Mϕs in uterine tissues of 3074-KI pregnant mice was significantly increased compared to WT pregnant mice at GD13.5. Estrogen receptor-α (ERα) was validated to be a target of miR-3074-5p. Either miR-3074-5p overexpression or ERα knockdown promoted transcriptional activity of NF-κB/p65, induced M1-polarization and pyroptosis of THP1-derived Mϕs, accompanied with increased intracellular levels of cleaved Caspase-1, cleaved IL-1ß, NLRP3, cleaved GSDMD and ASC aggregation. Furthermore, ERα could not only bind to NLRP3 or ASC directly, but also inhibit the interaction between NLRP3 and ASC. The endometrial miR-3074-5p expression level at the middle secretory stage of repeated implantation failure (RIF) patients was significantly decreased compared to that of control fertile women. These data indicated that miR-3074-5p could promote M1 polarization and pyroptosis of Mϕs via activation of NLRP3 inflammasome by targeting ERα, and the dysregulation of miR-3074-5p expression in dMϕs might damage the embryo implantation and placentation by interfering with inflammatory microenvironment at the maternal-fetal interface during early pregnancy.

Antioxidant Minerals Modified the Association between Iron and Type 2 Diabetes in a Chinese Population.

Inconsistent findings exist regarding the relationship between heme iron intake and type 2 diabetes (T2D) among Western and Eastern populations. Easterners tend to consume a plant-based diet which is abundant in antioxidant minerals. To examine the hypothesis that antioxidant mineral may modify the relationship between iron and T2D, we performed a case-control study by measuring the serum mineral levels in 2198 Chinese subjects. A total of 2113 T2D patients and 2458 controls were invited; 502 T2D patients and 1696 controls were finally analyzed. In the total population, high serum iron showed a positive association with T2D odds (odds ratio [OR] = 1.27 [1.04, 1.55]); high magnesium (OR = 0.18 [0.14, 0.22]), copper (OR = 0.27 [0.21, 0.33]), zinc (OR = 0.37 [0.30, 0.46]), chromium (OR = 0.61 [0.50, 0.74]), or selenium concentrations (OR = 0.39 [0.31, 0.48]) were inversely associated with T2D odds. In contrast, in individuals with higher magnesium (>2673.2 µg/dL), zinc (>136.7 µg/dL), copper (>132.1 µg/dL), chromium (>14.0 µg/dL), or selenium concentrations (>16.8 µg/dL), serum iron displayed no association with T2D (p > 0.05). Serum copper and magnesium were significant modifiers of the association between iron and T2D in individuals with different physiological status (p < 0.05). Our findings support the idea that consuming a diet rich in antioxidant minerals is an effective approach for preventing T2D.

Association of elastic power in mechanical ventilation with the severity of acute respiratory distress syndrome: a retrospective study.

BACKGROUND: Mechanical power (MP) is the total energy released into the entire respiratory system per minute which mainly comprises three components: elastic static power, Elastic dynamic power and resistive power. However, the energy to overcome resistance to the gas flow is not the key factor in causing lung injury, but the elastic power (EP) which generates the baseline stretch of the lung fibers and overcomes respiratory system elastance may be closely related to the ARDS severity. Thus, this study aimed to investigate whether EP is superior to other ventilator variables for predicting the severity of lung injury in ARDS patients. METHODS: We retrieved patient data from the Medical Information Mart for Intensive Care III (MIMIC-III) database. The retrieved data involved adults (≥ 18 years) diagnosed with ARDS and subjected to invasive mechanical ventilation for ≥ 48 h. We employed univariate and multivariate logistic regression analyses to investigate the correlation between EP and development of moderate-severe ARDS. Furthermore, we utilized restricted cubic spline models to assess whether there is a linear association between EP and incidence of moderate-severe ARDS. In addition, we employed a stratified linear regression model and likelihood ratio test in subgroups to identify potential modifications and interactions. RESULTS: Moderate-severe ARDS occurred in 73.4% (296/403) of the patients analyzed. EP and MP were significantly associated with moderate-severe ARDS (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.15-1.28, p < 0.001; and OR 1.15, 95%CI 1.11-1.20, p < 0.001; respectively), but EP showed a higher area-under-curve (95%CI 0.72-0.82, p < 0.001) than plateau pressure, driving pressure, and static lung compliance in predicting ARDS severity. The optimal cutoff value for EP was 14.6 J/min with a sensitivity of 75% and specificity of 66%. Quartile analysis revealed that the relationship between EP and ARDS severity remained robust and reliable in subgroup analysis. CONCLUSION: EP is a good ventilator variable associated with ARDS severity and can be used for grading ARDS severity. Close monitoring of EP is advised in patients undergoing mechanical ventilation. Additional experimental trials are needed to investigate whether adjusting ventilator variables according to EP can yield significant improvements in clinical outcomes.

Transport Behavior of Cd2+ in Highly Weathered Acidic Soils and Shaping in Soil Microbial Community Structure.

The mining and smelting site soils in South China present excessive Cd pollution. However, the transport behavior of Cd in the highly weathered acidic soil layer at the lead-zinc smelting site remains unclear. Here, under different conditions of simulated infiltration, the migration behavior of Cd2+ in acid smelting site soils at different depths was examined. The remodeling effect of Cd2+ migration behavior on microbial community structure and the dominant microorganisms in lead-zinc sites soils was analyzed using high-throughput sequencing of 16S rRNA gene amplicons. The results revealed a specific flow rate in the range of 0.3-0.5 mL/min that the convection and dispersion have no obvious effect on Cd2+ migration. The variation of packing porosity could only influence the migration behavior by changing the average pore velocity, but cannot change the adsorption efficiency of soil particles. The Cd has stronger migration capacity under the reactivation of acidic seepage fluid. However, in the alkaline solution, the physical properties of soil, especially pores, intercept the Cd compounds, further affecting their migration capacity. The acid-site soil with high content of SOM, amorphous Fe oxides, crystalline Fe/Mn/Al oxides, goethite, and hematite has stronger ability to adsorb and retain Cd2+. However, higher content of kaolinite in acidic soil will increase the potential migration of Cd2+. Besides, the migration behavior of Cd2+ results in simplified soil microbial communities. Under Cd stress, Cd-tolerant genera (Bacteroides, Sphingomonas, Bradyrhizobium, and Corynebacterium) and bacteria with both acid-Cd tolerance (WCHB 1-84) were distinguished. The Ralstonia showed a high enrichment degree in alkaline Cd2+ infiltration solution (pH 10.0). Compared to the influence of Cd2+ stress, soil pH had a stronger ability to shape the microbial community in the soil during the process of Cd2+ migration.

Using Radiomics to Differentiate Brain Metastases From Lung Cancer Versus Breast Cancer, Including Predicting Epidermal Growth Factor Receptor and human Epidermal Growth Factor Receptor 2 Status.

OBJECTIVE: We evaluated the feasibility of using multiregional radiomics to identify brain metastasis (BM) originating from lung adenocarcinoma (LA) and breast cancer (BC) and assess the epidermal growth factor receptor (EGFR) mutation and human epidermal growth factor receptor 2 (HER2) status. METHODS: Our experiment included 160 patients with BM originating from LA (n = 70), BC (n = 67), and other tumor types (n = 23), between November 2017 and December 2021. All patients underwent contrast-enhanced T1- and T2-weighted magnetic resonance imaging (MRI) scans. A total of 1967 quantitative MRI features were calculated from the tumoral active area and peritumoral edema area and selected using least absolute shrinkage and selection operator regression with 5-fold cross-validation. We constructed radiomic signatures (RSs) based on the most predictive features for preoperative assessment of the metastatic origins, EGFR mutation, and HER2 status. Prediction performance of the constructed RSs was evaluated based on the receiver operating characteristic curve analysis. RESULTS: The developed multiregion RSs generated good area under the receiver operating characteristic curve (AUC) for identifying the LA and BC origin in the training (AUCs, RS-LA vs RS-BC, 0.767 vs 0.898) and validation (AUCs, RS-LA vs RS-BC, 0.778 and 0.843) cohort and for predicting the EGFR and HER2 status in the training (AUCs, RS-EGFR vs RS-HER2, 0.837 vs 0.894) and validation (AUCs, RS-EGFR vs RS-HER2, 0.729 vs 0.784) cohorts. CONCLUSIONS: Our results revealed associations between brain MRI-based radiomics and their metastatic origins, EGFR mutations, and HER2 status. The developed multiregion combined RSs may be considered noninvasive predictive markers for planning early treatment for BM patients.

Elucidating the impact of in vitro cultivation on Nicotiana tabacum metabolism through combined in silico modeling and multiomics analysis.

The systematical characterization and understanding of the metabolic behaviors are the basis of the efficient plant metabolic engineering and synthetic biology. Genome-scale metabolic networks (GSMNs) are indispensable tools for the comprehensive characterization of overall metabolic profile. Here we first constructed a GSMN of tobacco, which is one of the most widely used plant chassis, and then combined the tobacco GSMN and multiomics analysis to systematically elucidate the impact of in-vitro cultivation on the tobacco metabolic network. In-vitro cultivation is a widely used technique for plant cultivation, not only in the field of basic research but also for the rapid propagation of valuable horticultural and pharmaceutical plants. However, the systemic effects of in-vitro cultivation on overall plant metabolism could easily be overlooked and are still poorly understood. We found that in-vitro tobacco showed slower growth, less biomass and suppressed photosynthesis than soil-grown tobacco. Many changes of metabolites and metabolic pathways between in-vitro and soil-grown tobacco plants were identified, which notably revealed a significant increase of the amino acids content under in-vitro condition. The in silico investigation showed that in-vitro tobacco downregulated photosynthesis and primary carbon metabolism, while significantly upregulated the GS/GOGAT cycle, as well as producing more energy and less NADH/NADPH to acclimate in-vitro growth demands. Altogether, the combination of experimental and in silico analyses offers an unprecedented view of tobacco metabolism, with valuable insights into the impact of in-vitro cultivation, enabling more efficient utilization of in-vitro techniques for plant propagation and metabolic engineering.

Advancements in autologous stem cell transplantation for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease marked by comparatively focal dopaminergic neuron degeneration in the substantia nigra of the midbrain and dopamine loss in the striatum, which causes motor and non-motor symptoms. Currently, pharmacological therapy and deep brain stimulation(DBS) are the primary treatment modalities for PD in clinical practice. While these approaches offer temporary symptom control, they do not address the underlying neurodegenerative process, and complications often arise. Stem cell replacement therapy is anticipated to prevent further progression of the disease due to its regenerative capacity, and considering the cost of immunosuppression and the potential immune dysfunctions, autologous stem cell transplantation holds promise as a significant method against allogeneic one to treat Parkinson's disease. In this review, the safety concerns surrounding tumorigenicity and complications associated with transplantation are discussed, along with methods utilized to evaluate the efficacy of such procedures. Subsequently, we summarize the preclinical and clinical studies involving autologous stem cell transplantation for PD, and finally talk about the benefits of autologous stem cell transplantation against allogeneic transplants.

Identification of immunotherapy biomarkers for improving the clinical outcome of homologous recombination deficiency patients with lung adenocarcinoma.

Homologous recombination deficiency (HRD) is a common molecular signature of genomic instability and has been shown to be a biomarker for targeted therapies. However, there is a lack of studies on the role of HRD changes in lung adenocarcinoma (LUAD) transcriptomics. HRD scores were determined using single nucleotide polymorphism (SNP) array data from LUAD patients from The Cancer Genome Atlas (TCGA) database. Transcriptional data from patients with different scores were analyzed to identify biomarkers associated with HRD. Candidate biomarkers were validated using Gene Expression Omnibus (GEO)-sourced datasets and an immunotherapy cohort. According to the bulk transcriptome and clinical characteristics of 912 LUAD patients and Single-cell RNA-seq of 9 LUAD patients from TCGA and GEO databases, we observed increased MS4A6A expression in HRD tumors; high MS4A6A expression predicted improved survival outcomes. Furthermore, a comprehensive analysis of the tumor immune microenvironment (TIME) revealed a positive correlation between MS4A6A expression and neoantigen loading and immune cell infiltration. Additionally, the immunotherapy cohort confirmed the possibility of using MS4A6A as a biomarker. Collectively, we suggest that MS4A6A is associated with HRD and provide a new perspective toward identifying promising biomarkers for immunotherapy.

Immunogenic cell death-based prognostic model for predicting the response to immunotherapy and common therapy in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a malignant tumor in the respiratory system. The efficacy of current treatment modalities varies greatly, and individualization is evident. Therefore, finding biomarkers for predicting treatment prognosis and providing reference and guidance for formulating treatment options is urgent. Cancer immunotherapy has made distinct progress in the past decades and has a significant effect on LUAD. Immunogenic Cell Death (ICD) can reshape the tumor's immune microenvironment, contributing to immunotherapy. Thus, exploring ICD biomarkers to construct a prognostic model might help individualized treatments. We used a lung adenocarcinoma (LUAD) dataset to identify ICD-related differentially expressed genes (DEGs). Then, these DEGs were clustered and divided into subgroups. We also performed variance analysis in different dimensions. Further, we established and validated a prognostic model by LASSO Cox regression analysis. The risk score in this model was used to evaluate prognostic differences by survival analysis. The treatment prognosis of various therapies were also predicted. LUAD samples were divided into two subgroups. The ICD-high subgroup was related to an immune-hot phenotype more sensitive to immunotherapy. The prognostic model was constructed based on six ICD-related DEGs. We found that high-risk score patients responded better to immunotherapy. The ICD prognostic model was validated as a standalone factor to evaluate the ICD subtype of individual LUAD patients, which might contribute to more effective therapies.

An anoikis-based gene signature for predicting prognosis in malignant pleural mesothelioma and revealing immune infiltration.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is an aggressive, treatment-resistant tumor. Anoikis is a particular type of programmed apoptosis brought on by the separation of cell-cell or extracellular matrix (ECM). Anoikis has been recognized as a crucial element in the development of tumors. However, few studies have comprehensively examined the role of anoikis-related genes (ARGs) in malignant mesothelioma. METHODS: ARGs were gathered from the GeneCard database and the Harmonizome portals. We obtained differentially expressed genes (DEGs) using the GEO database. Univariate Cox regression analysis, and the least absolute shrinkage and selection operator (LASSO) algorithm were utilized to select ARGs associated with the prognosis of MPM. We then developed a risk model, and time-dependent receiver operating characteristic (ROC) analysis and calibration curves were employed to confirm the ability of the model. The patients were divided into various subgroups using consensus clustering analysis. Based on the median risk score, patients were divided into low- and high-risk groups. Functional analysis and immune cell infiltration analysis were conducted to estimate molecular mechanisms and the immune infiltration landscape of patients. Finally, drug sensitivity analysis and tumor microenvironment landscape were further explored. RESULTS: A novel risk model was constructed based on the six ARGs. The patients were successfully divided into two subgroups by consensus clustering analysis, with a striking difference in the prognosis and landscape of immune infiltration. The Kaplan-Meier survival analysis indicated that the OS rate of the low-risk group was significantly higher than the high-risk group. Functional analysis, immune cell infiltration analysis, and drug sensitivity analysis showed that high- and low-risk groups had different immune statuses and drug sensitivity. CONCLUSIONS: In summary, we developed a novel risk model to predict MPM prognosis based on six selected ARGs, which could broaden comprehension of personalized and precise therapy approaches for MPM.

Development and validation of a nomogram for predicting overall survival of resected N2 non-small cell lung cancer patients undergoing neoadjuvant radiotherapy.

INTRODUCTION: Currently, the prognosis of resected N2 non-small cell lung cancer patients undergoing neoadjuvant radiotherapy is poor. The goal of this research was to develop and validate a novel nomogram for exactly predicting the overall survival (OS) of resected N2 NSCLC patients undergoing neoadjuvant radiotherapy. METHODS: The data applied in our research were downloaded from the Surveillance, Epidemiology, and End Results (SEER) database. We divided selected data into a training cohort and a validation cohort using R software, with a ratio of 7:3. Univariate Cox regression and multivariate Cox regression were utilized to select significant variables to build the nomogram. To validate our nomogram, calibration curves, receiver operating characteristic curves (ROC), decision curve analysis (DCA), and Kaplan-Meier survival curves were employed. The nomogram model was also compared with the tumor-node-metastasis (TNM) staging system by utilizing net reclassification index (NRI) and integrated discrimination improvement (IDI). RESULTS: Eight variables-age, sex, operative type, LN removed number, chemotherapy, AJCC stage, M stage, histology-were statistically significant in the multivariate Cox regression analysis and were selected to develop our nomogram. Based on ROC curves, calibration curves, and DCA analysis, our novel nomogram demonstrated good predictive accuracy and clinical utility. Using Kaplan-Meier (KM) survival curves and log-rank tests, the risk stratification system was able to stratify patients based on their estimated mortality risk. The nomogram performed better than the TNM staging system based on the NRI and IDI indexes. CONCLUSIONS: We developed and validated a nomogram to predict prognosis of resected N2 NSCLC patients undergoing neoadjuvant radiotherapy. Using this nomogram, clinicians may find this nomogram useful in predicting OS of targeted patients and making more appropriate treatment decisions.

Preoperative computed tomography-based tumoral radiomic features prediction for overall survival in resectable non-small cell lung cancer.

Objectives: The purpose of this study was to evaluate whether preoperative radiomics features could meliorate risk stratification for the overall survival (OS) of non-small cell lung cancer (NSCLC) patients. Methods: After rigorous screening, the 208 NSCLC patients without any pre-operative adjuvant therapy were eventually enrolled. We segmented the 3D volume of interest (VOI) based on malignant lesion of computed tomography (CT) imaging and extracted 1542 radiomics features. Interclass correlation coefficients (ICC) and LASSO Cox regression analysis were utilized to perform feature selection and radiomics model building. In the model evaluation phase, we carried out stratified analysis, receiver operating characteristic (ROC) curve, concordance index (C-index), and decision curve analysis (DCA). In addition, integrating the clinicopathological trait and radiomics score, we developed a nomogram to predict the OS at 1 year, 2 years, and 3 years, respectively. Results: Six radiomics features, including gradient_glcm_InverseVariance, logarithm_firstorder_Median, logarithm_firstorder_RobustMeanAbsoluteDeviation, square_gldm_LargeDependenceEmphasis, wavelet_HLL_firstorder_Kurtosis, and wavelet_LLL_firstorder_Maximum, were selected to construct the radiomics signature, whose areas under the curve (AUCs) for 3-year prediction reached 0.857 in the training set (n=146) and 0.871 in the testing set (n=62). The results of multivariate analysis revealed that the radiomics score, radiological sign, and N stage were independent prognostic factors in NSCLC. Moreover, compared with clinical factors and the separate radiomics model, the established nomogram exhibited a better performance in predicting 3-year OS. Conclusions: Our radiomics model may provide a promising non-invasive approach for preoperative risk stratification and personalized postoperative surveillance for resectable NSCLC patients.

Calpain inhibitor MDL28170 alleviates cerebral ischemia­reperfusion injury by suppressing inflammation and autophagy in a rat model of cardiac arrest.

Cerebral ischemia-reperfusion injury (CIRI) is associated with a poor neurological prognosis in patients who have experienced cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). The aim of the current study was to investigate the potential role of a calpain inhibitor in CIRI using a rat model of CA. CA was induced in adult male Sprague-Dawley rats, and MDL28170 (a calpain inhibitor) was administered to the rats within 30 min after the return of spontaneous circulation. Differences between groups were evaluated by measuring survival rate, CPR duration and neurological deficit score. Hematoxylin-eosin staining and Nissl staining were performed to assess cerebral injury, and microstructure and autophagy were assessed by transmission electron microscopy. The levels of calpain-1, calpain-2, calpastatin, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, P62, beclin-1 and LC3 in the brain tissues were determined using western blotting and double immunofluorescence staining. There was no significant difference in CPR duration or survival rate among the groups. At 24 h after CPR, the CA group demonstrated damaged tissue morphology; decreased neurological deficit scores, and P62 expression; and upregulated calpain-2, IL-1ßp17, TNF-α, beclin-1 and LC3 levels in the cortex. However, MDL28170 improved neuronal function and suppressed inflammation and autophagy by inhibiting calpain-2 level, but there were no differences in the calpain-1 and calpastatin levels. These results suggest that calpain-2, inflammation and autophagy are involved in CA-induced CIRI. MDL28170 inhibited calpain-2 expression, inflammation and autophagy, which suggests its potential efficacy in treating post-CA nerve damage.