Highly Efficient Fabrication of Biomimetic Nanoscaled Tendrils for High-Performance PM0.3 Air Filters.

Particulate matter pollution has become a serious public health issue, especially with the outbreak of new infectious diseases. However, most existing air filtration materials face challenges such as being too bulky, having high resistance, and a trade-off between filtration efficiency and air permeability. Here, a unique electro-blown spinning technique is used to prepare an air filter made of biomimetic nanoscaled tendril nonwovens (Nano-TN). The introduction of an airflow field significantly increases the whipping frequency and the strain mismatch of composite jets, achieving large-scale and highly efficient preparation of Nano-TN. The resultant Nano-TN has an ultrahigh porosity (97%) and a small pore size (2.9 µm). At the same filtration level, its air resistance is 37% lower than that of traditional straight nanofibrous nonwovens and has a higher dust-holding capacity. Moreover, compared with traditional three-dimensional air filters, the Nano-TN filter is thinner, offering tremendous application prospects in various environmental purification and personal protection fields.

Metformin inhibits human non-small cell lung cancer by regulating AMPK-CEBPB-PDL1 signaling pathway.

Metformin has been found to have inhibitory effects on a variety of tumors. However, its effects on non-small cell lung cancer (NSCLC) remain unclear. We demonstrated that metformin could inhibit the proliferation of A549 and H1299 cells. RNA transcriptome sequencing revealed that PDL1 was significantly downregulated in both cell types following treatment with metformin (P < 0.001). Jaspar analysis and chromatin immunoprecipitation showed that CEBPB could directly bind the promoter region of PDL1. Western blotting showed that protein expression of the isoforms CEBPB-LAP*, CEBPB-LAP, and CEBPB-LIP was significantly upregulated and the LIP/LAP ratio was increased. Gene chip analysis showed that PDL1 was significantly upregulated in A549-CEBPB-LAP cells and significantly downregulated in A549-CEBPB-LIP cells (P < 0.05) compared with CEBPB-NC cells. Dual-luciferase reporter gene assay showed that CEBPB-LAP overexpression could promote transcription of PDL1 and CEBPB-LIP overexpression could inhibit the process. Functional assays showed that the changes in CEBPB isoforms affected the function of NSCLC cells. Western blotting showed that metformin could regulate the function of NSCLC cells via AMPK-CEBPB-PDL1 signaling. Animal experiments showed that tumor growth was significantly inhibited by metformin, and atezolizumab and metformin had a synergistic effect on tumor growth. A total of 1247 patients were retrospectively analyzed, including 166 and 1081 patients in metformin and control groups, respectively. The positive rate of PDL1 was lower than that of the control group (HR = 0.338, 95% CI = 0.235-0.487; P < 0.001). In conclusion, metformin inhibited the proliferation of NSCLC cells and played an anti-tumor role in an AMPK-CEBPB-PDL1 signaling-dependent manner.

Multi-omics characterization and validation of invasiveness-related molecular features across multiple cancer types.

BACKGROUND: Tumor invasiveness reflects many biological changes associated with tumorigenesis, progression, metastasis, and drug resistance. Therefore, we performed a systematic assessment of invasiveness-related molecular features across multiple human cancers. MATERIALS AND METHODS: Multi-omics data, including gene expression, miRNA, DNA methylation, and somatic mutation, in approximately 10,000 patients across 30 cancer types from The Cancer Genome Atlas, Gene Expression Omnibus, PRECOG, and our institution were enrolled in this study. RESULTS: Based on a robust gene signature, we established an invasiveness score and found that the score was significantly associated with worse prognosis in almost all cancers. Then, we identified common invasiveness-associated dysregulated molecular features between high- and low-invasiveness score group across multiple cancers, as well as investigated their mutual interfering relationships thus determining whether the dysregulation of invasiveness-related genes was caused by abnormal promoter methylation or miRNA expression. We also analyzed the correlations between the drug sensitivity data from cancer cell lines and the expression level of 685 invasiveness-related genes differentially expressed in at least ten cancer types. An integrated analysis of the correlations among invasiveness-related genetic features and drug response were conducted in esophageal carcinoma patients to outline the complicated regulatory mechanism of tumor invasiveness status in multiple dimensions. Moreover, functional enrichment suggests the invasiveness score might serve as a predictive biomarker for cancer patients receiving immunotherapy. CONCLUSION: Our pan-cancer study provides a comprehensive atlas of tumor invasiveness and may guide more precise therapeutic strategies for tumor patients.

Identification of differentially expressed genes in lung adenocarcinoma cells using single-cell RNA sequencing not detected using traditional RNA sequencing and microarray.

Lung adenocarcinoma (LUAD) is the leading cause of cancer-related deaths worldwide. Traditional RNA sequencing data fails to detect the exact cellular and molecular changes in tumor cells as they make up only a small proportion of tumor tissue. 10× genomics single-cell RNA sequencing (10× scRNA-seq) and gene expression data of LUAD patients was obtained from the Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, ArrayExpress, TCGA, and GEO databases. Differentially expressed genes (DEGs) were identified in LUAD and alveolar cells (DEGs-scRNA-cancer_cell), tumor- and normal tissue-derived cells (DEGs-scRNA-sample), and normal and LUAD patients (DEGs-Bulk). Flow cytometry and qRT-PCR were performed to validate the significantly differentially expressed ligand-receptor pairs. We selected 159,219 cells and 594 samples in the scRNA-seq data and traditional RNA sequencing, respectively. A total of 1042 DEGs-scRNA-cancer_cell, 788 DEGs-scRNA-sample, and 2510 DEGs-Bulk were identified in this study. We also identified 57 DEGs that were only detected in DEGs-scRNA-cancer_cell (only-DEGs-scRNA-cancer_cell). To explore the relationship between only-DEGs-scRNA-cancer_cell and survival in LUAD, 14 and 22 only-DEGs-scRNA-cancer_cell, which were closely related with survival in TCGA and GEO cohorts were identified. Functional enrichment analyses showed these DEGs-scRNA-cancer_cells were mainly related to cell proliferation and immunoregulation. Our study detected and compared DEGs at different levels and revealed genes that may regulate tumor development. Our results provide a potential new protocol to determine the contribution of DEGs to cancer progression and to help identify potential therapeutic targets.

Identification of immune-related gene signature predicting survival in the tumor microenvironment of lung adenocarcinoma.

The tumor microenvironment (TME) plays an essential role in the occurrence and progression of malignancy. The potential prognostic TME-related biomarkers of lung adenocarcinoma (LUAD) remained unclear, which were investigated in this research. The RNA-sequencing profiles and corresponding clinical parameters were extracted from TCGA and GEO databases, based on which the stromal and immune scores were calculated through the ESTIMATE algorithm. Overlapping differentially expressed genes between stromal and immune score group were analyzed by the LASSO and Random Forrest algorithms and validated in cases from our center. And a prognostic 8-gene signature was constructed using Cox regression. The infiltration of 22 hematopoietic cell phenotypes was assessed by the CIBERSORT algorithms. We found that female, elder patients, and solid predominant subtype had obviously higher stromal and immune scores. And patients with early stage LUAD received a prominently higher immune score. A high stromal or immune score meant a good prognosis. Subsequently, eight TME-related prognostic genes (ATAD5, CYP4F3, CYP4F12, ESPNL, FXYD2, GPX2, NLGN4Y, and SERPINC1) were identified by both LASSO regression and Radom Forest algorithms. High 8-gene signature group exhibited worse overall survival. Furthermore, B cell naïve, plasma cells, T cell follicular helper, and macrophages M1 were prominently more in high signature group. Nevertheless, fewer T cells CD4 memory resting, monocytes, and dendritic cell resting were identified in the high signature group. The composition of the tumor microenvironment significantly affected the prognosis of LUAD patients. We provided a new strategy for the exploration of prognostic TME-related biomarkers and immunotherapy.

Electrospun meta-aramid/polysulfone-amide nanocomposite membranes for the filtration of industrial PM2.5 particles.

Filtering of industrial PM2.5 is a major challenge for global environmental and animal protection. Filtering of materials with excellent thermal stability and other comprehensive performances is required for the removal of fine particles in high-temperature operating industries such as steel, cement, metallurgy, incineration, etc. In this study, a meta-aramid/polysulfone-amide (PMIA/PSA) composite nanofibrous filtration membrane is prepared via solution electrospinning for the development of high-temperature-resistant filtering products. To maximize the merits of each component, PMIA/PSA composite nanofibrous membranes with different mass blending ratios are prepared to determine the optimal balance. It is found that the PMIA/PSA composite nanofibrous membranes show excellent thermal stability and thermal shrinkage performance. They also maintain superb mechanical retention ratios after 200 h treatment at 200 °C. In addition, they exhibit excellent removal efficiency of polystyrene aerosol (PSL) particles of various sizes. It is found that the removal efficiency of PMIA/PSA (3/7) is 96.7% for 0.1 µm, 98.3% for 0.2 µm and 99.6% for 0.3 µm particles and it possesses optimal filtration resistance (79 Pa), while other composite membranes can reach a removal efficiency of over 99.7%. Our experimental results illustrate that the filtration efficiency for PM2.5 of PMIA/PSA (7/3), (5/5) composite nanofibrous membranes is still kept as high as 99.9% even after being treated at 200 °C for 120 h. It indicates that the prepared composite nanofibrous membranes have potential for applications where high-efficiency filtration is desired, such as bag dust filters for use under high temperatures.

Antibacterial Hydrogels for Wound Dressing Applications: Current Status, Progress, Challenges, and Trends.

Bacterial infection treatment for chronic wounds has posed a major medical threat and challenge. Bacteria at the wounded sites can compete with the immune system and subsequently invade live tissues, leading to more severe tissue damage. Therefore, there is an urgent demand for wound dressings with antibacterial and anti-inflammatory properties. Considering the concept of moist healing, hydrogels with a three-dimensional (3D) network structure are widely used as wound dressings due to their excellent hydrophilicity, water retention properties, and biocompatibility. Developing antibacterial hydrogels for the treatment of infected wounds has been receiving extensive attention recently. This article categorizes antibacterial hydrogels according to their materials and antibacterial modes, and introduces the recent findings and progress regarding their status. More importantly, with the development of emerging technologies, new therapies are utilized to prepare antibacterial hydrogels such as nanoenzymes, photothermal therapy (PTT), photodynamic therapy (PDT), metal-organic frameworks (MOFs), and other external stimuli-responsive methods. Therefore, this review also examines their progress, challenges, and future trends as wound dressings. In the following studies, there will still be a focus on antibacterial hydrogels that have a high performance, multi-functions, and intelligence, especially biocompatibility, a high and long-lasting antibacterial property, responsiveness, and on-demand therapeutic ability.

A ZIF-8-encapsulated interpenetrated hydrogel/nanofiber composite patch for chronic wound treatment.

Designing wound dressings necessitates the crucial considerations of maintaining a moist environment and implementing effective bacterial control. Furthermore, developing a three-dimensional framework emulating the extracellular matrix (ECM) confers advantages in fostering cellular migration and proliferation. Inspired by this, hydrogel/nanofiber composites have been demonstrated as promising materials for wound dressings. The composites also overcome the disadvantages of poor mechanical properties and rapid release of traditional pure hydrogels. In this study, we constructed a calcium alginate hydrogel/polylactic acid nanofiber (CAH/PLANF) composite with an interpenetrated network. Additionally, the synthesis of zeolitic imidazolate framework-8 (ZIF-8) incorporated into the composite system endowed the system with enhanced mechanical properties and photodynamic antibacterial attributes. The obtained composite patch (ZIF-8@CAH/PLANF) exhibited excellent swelling, strong mechanical properties, low cytotoxicity, and durable photodynamic antibacterial effect with an antibacterial efficacy of higher than 99.99%. Finally, bacterial infection and wound healing properties were investigated in vivo, and the ZIF-8@CAH/PLANF patch was proven to have the ability to fight infection and accelerate wound healing.

Perioperative outcomes and survival of modified subxiphoid video-assisted thoracoscopic surgery thymectomy for T2-3 thymic malignancies: A retrospective comparison study.

OBJECTIVE: Our previous study demonstrated that modified subxiphoid video-assisted thoracic surgery thymectomy with an auxiliary sternal retractor is feasible for locally invasive thymic malignancies. This study aimed to compare perioperative and oncological outcomes of modified subxiphoid video-assisted thoracoscopic surgery thymectomy versus median sternotomy thymectomy for locally advanced thymic malignancies. METHODS: In total, 221 patients with T2-3 thymic malignancies who underwent modified subxiphoid video-assisted thoracoscopic surgery thymectomy or median sternotomy thymectomy between 2015 and 2020 were enrolled in our prospectively maintained database. A 1:1 propensity score-matching analysis was performed to balance the bias. Surgical difficulty was evaluated with a modified resection index. Perioperative and oncological results were compared between the modified subxiphoid video-assisted thoracoscopic surgery thymectomy group and the median sternotomy thymectomy group. RESULTS: There were 72 patients in each group in the final analysis. Our results showed that the modified subxiphoid video-assisted thoracoscopic surgery thymectomy group had a shorter operative duration (98 vs 129 minutes, P < .001), less blood loss (40 vs 100 mL, P < .001), shorter drainage duration (3 vs 5 days, P < .001), shorter length of hospital stay (5 vs 6 days, P < .001), and fewer postoperative complications (5.6% vs 23.6%; P = .005). No significant difference was detected in complete resection (98.6% vs 98.6%, P = 1.000) between the 2 groups. Conversion occurred in 5 of 106 patients (4.7%). Survival analyses indicated similar recurrence-free survival (hazard ratio, 0.94; 95% CI, 0.40-2.20; P = .883) and overall survival (hazard ratio, 0.52; 95% CI, 0.05-5.02; P = .590) between the 2 groups. CONCLUSIONS: Modified subxiphoid video-assisted thoracoscopic surgery thymectomy was safe and effective for T2-3 thymic malignancies and could be an alternative for selected patients with locally advanced thymic diseases. Further prospective studies are needed to evaluate the long-term survival of those undergoing modified subxiphoid approach thoracoscopic thymectomy.

Nanofiber-reinforced self-healing polysaccharide-based hydrogel dressings for pH discoloration monitoring and treatment of infected wounds.

The escalating global health concern arises from chronic wounds induced by bacterial infections, posing a significant threat to individuals. Consequently, an imperative exist for the development of hydrogel dressings to facilitate prompt wound monitoring and efficacious wound management. To this end, pH-sensitive bromothymol blue (BTB) and pH-responsive drug tetracycline hydrochloride (TH) were introduced into the polysaccharide-based hydrogel to realize the integration of wound monitoring and controlled treatment. Polysaccharide-based hydrogels were formed via a Schiff base reaction by cross-linking carboxymethyl chitosan (CMCS) on an oxidized sodium alginate (OSA) skeleton. BTB was used as a pH indicator to monitor wound infection through visual color changes visually. TH could be dynamically released through the pH response of the Schiff base bond to provide effective treatment and long-term antibacterial activity for chronically infected wounds. In addition, introducing polylactic acid nanofibers (PLA) enhanced the mechanical properties of hydrogels. The multifunctional hydrogel has excellent mechanical, self-healing, injectable, antibacterial properties and biocompatibility. Furthermore, the multifaceted hydrogel dressing under consideration exhibits noteworthy capabilities in fostering the healing process of chronically infected wounds. Consequently, the research contributes novel perspectives towards the advancement of intelligent and expeditious bacterial infection monitoring and dynamic treatment platforms.

A new pragmatic classification system for thymoma associated myasthenia gravis: a retrospective cohort study.

The management and outcomes of patients with thymoma associated with myasthenia gravis (TAMG) are heterogeneous. Here, we propose a novel classification system based on Masaoka stage and Myasthenia Gravis Foundation of America (MGFA) classification, aiming to guide surgical decisions and perioperative management for these patients. Considering both oncological and neurological factors, this novel TAMG classification provides valuable information on outcome stratification and clinical decision-making for TAMG.

Progress of Hydrogel Dressings with Wound Monitoring and Treatment Functions.

Hydrogels are widely used in wound dressings due to their moisturizing properties and biocompatibility. However, traditional hydrogel dressings cannot monitor wounds and provide accurate treatment. Recent advancements focus on hydrogel dressings with integrated monitoring and treatment functions, using sensors or intelligent materials to detect changes in the wound microenvironment. These dressings enable responsive treatment to promote wound healing. They can carry out responsive dynamic treatment in time to effectively promote wound healing. However, there is still a lack of comprehensive reviews of hydrogel wound dressings that incorporate both wound micro-environment monitoring and treatment functions. Therefore, this review categorizes hydrogel dressings according to wound types and examines their current status, progress, challenges, and future trends. It discusses various wound types, including infected wounds, burns, and diabetic and pressure ulcers, and explores the wound healing process. The review presents hydrogel dressings that monitor wound conditions and provide tailored treatment, such as pH-sensitive, temperature-sensitive, glucose-sensitive, pressure-sensitive, and nano-composite hydrogel dressings. Challenges include developing dressings that meet the standards of excellent biocompatibility, improving monitoring accuracy and sensitivity, and overcoming obstacles to production and commercialization. Furthermore, it provides the current status, progress, challenges, and future trends in this field, aiming to give a clear view of its past, present, and future.

New insights into muscularis macrophages in the gut: from their origin to therapeutic targeting.

Muscularis macrophages, as the most abundant immune cells in the intestinal muscularis externa, exhibit tissue protective phenotype in the steady state. Owing to tremendous advances in technology, we now know the fact that muscularis macrophages are a heterogeneous population of cells which could be divided into different functional subsets depending on their anatomic niches. There is emerging evidence showing that these subsets, through molecular interactions with their neighbours, take part in a wide range of physiological and pathophysiological processes in the gut. In this review, we summarize recent progress (particularly over the past 4 years) on distribution, morphology, origin and functions of muscularis macrophages and, where possible, the characteristics of specific subsets in response to the microenvironment they occupy, with particular emphasis on their role in muscular inflammation. Furthermore, we also integrate their role in inflammation-related gastrointestinal disorders, such as post-operative ileus and diabetic gastroparesis, in order to propose future therapeutic strategies.

A Novel Prognostic Signature Revealed the Interaction of Immune Cells in Tumor Microenvironment Based on Single-Cell RNA Sequencing for Lung Adenocarcinoma.

Background: The tumor immune microenvironment (TIME) played an important role in immunotherapy prognosis and treatment response. Immune cells constitute a large part of the tumor microenvironment and regulate tumor progression. Our research is dedicated to studying the infiltrating immune cell in lung adenocarcinoma (LUAD) and seeking potential targets. Methods: The scRNA-seq data were collected from our FDZSH and two public datasets. The code for cell-type mapping algorithms was downloaded from the CIBERSORTx portal. The bioinformatics data of LUAD patients could be approached from The Cancer Genome Atlas (TCGA) portal. Weighted gene coexpression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) analyses were performed to construct a risk model. TIMER2 and TIDE helped with the immune infiltration estimation, while PROGENy helped the cancer-related pathways' enrichment analysis. GSE31210 dataset and IMVigor ICB therapy cohort validated our findings as the external validation datasets. Results: We clustered the scRNA-seq dataset (integrating our FDZSH datasets and other public datasets) into 23 subpopulations. After curated cell annotation, we implemented Cibersort and WGCNA analysis to anchor the brown module and natural killer cell cluster1 due to the most relationship with tumor trait. The overlap of the brown module gene, natural killer cell signature, and DEGs of tumor and adjacent normal samples was screened by LASSO Cox regression. The obtained 5-gene risk model showed an excellent prognostic performance in the validation dataset. Furthermore, there was a correlation between risk score and tumor-infiltrating immune cells and tumor genomics abnormity. Patients with higher risk scores had a significantly lower immunotherapy response rate. Conclusion: Our observations implied that immune cells played a pivotal role in TIME and established a 5-gene signature (including IDH2, ADRB2, SFTPC, CCDC69, and CCND2) on the basement of nature killer markers targeted by WGCNA analysis. The significance of clinical outcome and immunotherapy response prediction was validated robustly.

Identification and analysis of a prognostic ferroptosis and iron-metabolism signature for esophageal squamous cell carcinoma.

Background: The role of ferroptosis in esophageal squamous cell carcinoma (ESCC) is still unclear. Methods: The association of iron metabolism and ferroptosis-related genes with the prognosis, copy number variation (CNV), TMB, and immune cell infiltration of ESCC was explored using data from the GEO and TCGA database and validated by immunofluorescence in 112 ESCC patients from our center. The potential anti-cancer drugs and compounds from the GDSC and the Connectivity Map database were also screened. Results: A total of 117 iron metabolism and ferroptosis-related genes were identified. We found the expressions of PRNP, SLC3A2, SLC39A8, and SLC39A14 negatively related to the prognosis of ESCC patients, while ATP6V0A1 and LCN2 were opposite, which was validated in 112 ESCC samples from our center. And a prognostic signature was constructed based on their expressions and Cox regression coefficient (ß). The low-score group exhibited a significantly worse OS. Besides, analysis of 179 ESCC samples from GSE53625 revealed that patients of poorly differentiation, more than 60 years, T4 stage, advanced N stage, advanced stage, and adjuvant therapy also exhibited a significantly shorter OS, based on which a nomogram to predict the OS was established. Moreover, the low-score group exhibited significantly higher CNV and TMB and more frequent mutations of TP53, MUC16, and NOTCH1. Higher proportion of Macrophages M2, and lower proportion of T cells follicular helper were observed in the low-score group. We discovered that AZD7762, Sunitinib, Cytarabine, Docetaxel, Vinblastine, and Elesclomol exhibited lower IC50 in the low-score group. And 20 potential compounds were identified from the CMap database. Conclusions: Six iron metabolism and ferroptosis-related genes were associated with the prognosis, CNV, TMB, and immune cell infiltration of ESCC. Some potential anti-cancer drugs and compounds may be helpful for OS.

miR-6077 promotes cisplatin/pemetrexed resistance in lung adenocarcinoma via CDKN1A/cell cycle arrest and KEAP1/ferroptosis pathways.

Lung adenocarcinoma (LUAD) is one of the most common malignancies worldwide. Combination chemotherapy with cisplatin (CDDP) plus pemetrexed (PEM) remains the predominant therapeutic regimen; however, chemoresistance greatly limits its curative potential. Here, through CRISPR-Cas9 screening, we identified miR-6077 as a key driver of CDDP/PEM resistance in LUAD. Functional experiments verified that ectopic overexpression of miR-6077 desensitized LUAD cells to CDDP/PEM in both cell lines and patient-derived xenograft models. Through RNA sequencing in cells and single-cell sequencing of samples from patients with CDDP/PEM treatments, we observed CDDP/PEM-induced upregulation of CDKN1A and KEAP1, which in turn activated cell-cycle arrest and ferroptosis, respectively, thus leading to cell death. Through miRNA pull-down, we identified and validated that miR-6077 targets CDKN1A and KEAP1. Furthermore, we demonstrated that miR-6077 protects LUAD cells from cell death induced by CDDP/PEM via CDKN1A-CDK1-mediated cell-cycle arrest and KEAP1-NRF2-SLC7A11/NQO1-mediated ferroptosis, thus resulting in chemoresistance in multiple LUAD cells both in vitro and in vivo. Moreover, we found that GMDS-AS1 and LINC01128 sensitized LUAD cells to CDDP/PEM by sponging miR-6077. Collectively, these results imply the critical role of miR-6077 in LUAD's sensitivity to CDDP/PEM, thus providing a novel therapeutic strategy for overcoming chemoresistance in clinical practice.

Identification and validation of the mitochondrial function related hub genes by unsupervised machine learning and multi-omics analyses in lung adenocarcinoma.

Background: The mitochondrion and its associated genes were heavily implicated in developing and therapy tumors as the primary cellular organelle in charge of metabolic reprogramming and ferroptosis. Our work focuses on discovering new potential targets while analyzing the multi-omics data of mitochondria-related genes in lung adenocarcinoma (LUAD). Methods: The Cancer Genome Atlas (TCGA) database provided multi-omics data for LUAD patients. Based on the expression profile of the genes associated with mitochondria, the patients were grouped by the unsupervised clustering method. R was used to explore the differential expressed protein-code gene, miRNA, and lncRNA, as well as their enriched functions and ceRNA networks. Additionally, the discrepancy between immune infiltration and genetic variation was comprehensively characterized. Our clinical samples and in vitro experiments investigated the hub gene determined by LASSO and batch analysis. Results: Two clusters are distinguished using unsupervised consensus clustering based on mitochondrial heterogeneity. The integrated analysis emphasized that patients in cluster B had a worse prognosis, higher mutation frequencies, and less immune cell infiltration. The hub genes DARS2 and COX5B are identified by further analysis using LASSO penalization. In vitro experiments indicated that DARS2 and COX5B knockdown inhibited tumor cell proliferation. The specimen of our hospital cohort conducted the immunohistochemistry analysis and validated that DARS2 and COX5B's expression was significantly higher in the tumor than in adjacent normal tissue and correlated to LUAD patients' prognosis. Conclusion: Our observations implied that LUAD patients' tumors had distinct mitochondrial function heterogeneity with different clinical and molecular characteristics. DARS2 and COX5B might be critical genes involved in mitochondrial alterations and potential therapeutic targets.

Identification and Validation of a Proliferation-Associated Score Model Predicting Survival in Lung Adenocarcinomas.

AIM: This study is aimed at building a risk model based on the genes that significantly altered the proliferation of lung adenocarcinoma cells and exploring the underlying mechanisms. METHODS: The data of 60 lung adenocarcinoma cell lines in the Cancer Dependency Map (Depmap) were used to identify the genes whose knockout led to dramatical acceleration or deacceleration of cell proliferation. Then, univariate Cox regression was performed using the survival data of 497 patients with lung adenocarcinoma in The Cancer Genome Atlas (TCGA). The least absolute shrinkage and selection operator (LASSO) model was used to construct a risk prediction score model. Patients with lung adenocarcinoma from TCGA were classified into high- or low-risk groups based on the scores. The differences in clinicopathologic, genomic, and immune characteristics between the two groups were analyzed. The prognosis of the genes in the model was verified with immunohistochemical staining in 100 samples from the Department of Thoracic Surgery, Zhongshan Hospital, and the alteration in the proliferation rate was checked after these genes were knocked down in lung adenocarcinoma cells (A549 and H358). RESULTS: A total of 55 genes were found to be significantly related to survival by combined methods, which were crucial to tumor progression in functional enrichment analysis. A six-gene-based risk prediction score, including the proteasome subunit beta type-6 (PSMB6), the heat shock protein family A member 9 (HSPA9), the deoxyuridine triphosphatase (DUT), the cyclin-dependent kinase 7 (CDK7), the polo-like kinases 1 (PLK1), and the folate receptor beta 2 (FOLR2), was built using the LASSO method. The high-risk group classified with the score model was characterized by poor overall survival (OS), immune infiltration, and relatively higher mutation load. A total of 9864 differentially expressed genes and 138 differentially expressed miRNAs were found between the two groups. Also, a nomogram comparing score model, age, and the stage was built to predict OS for patients with lung adenocarcinoma. Using immunohistochemistry, the expression levels of PSMB6, HSPA9, DUT, CDK7, and PLK1 were found to be higher in lung adenocarcinoma tissues of patients, while the expression of FOLR2 was low, which was consistent with survival prediction. The knockdown of PSMB6 and HSPA9 by siRNA significantly downregulated the proliferation of A549 and H358 cells. CONCLUSION: The proposed score model may function as a promising risk prediction tool for patients with lung adenocarcinoma and provide insights into the molecular regulation mechanism of lung adenocarcinoma.

The tumor environment immune phenotype of LUSC by genome-wide analysis.

PURPOSE: To compare the landscape of tumor microenvironment (TME) of lung squamous carcinoma (LUSC) in different immune pattern and explore potential factors on immune therapy and prognosis. METHOD AND MATERIALS: We have obtained the LUSC data from TCGA, GEO, and our department and classified them into 2 TME clusters by random forest model based on the infiltration pattern of 24 immune cell populations. We systemically compared the genomic significance, clinical characteristics, and immune infiltration pattern in 2 TME clusters. RESULTS: Samples were divided into 2 TME clusters based on the relative abundance of 24 immune cells, and a random forest classifier model was constructed. TME cluster B was a higher immune infiltration group with lower mutation load, richer co-infiltrate immune cells, upregulated immune-related cytokines, immune checkpoint molecules, and higher active immune cells. TME cluster was also an independent predictor in prognosis (B vs. A, p < 0.05) in patients from TCGA, GEO, and our department. CONCLUSIONS: Our study has described the microenvironment landscape of LUSC in different immune infiltration patterns and systemically analyzed genomic and clinical characteristics with distinct immunophenotypes, thus partly revealed the interaction between tumors and the immune microenvironment, which may guide a more precise and personalized immune therapeutic strategy for LUSC patients.

Multi-omics characterization and validation of MSI-related molecular features across multiple malignancies.

HEADINGS AIMS: To establish a microsatellite instability (MSI) predictive model in pan-cancer and compare the multi-omics characterization of MSI-related molecular features. MATERIALS AND METHODS: We established a 15-gene signature for predicting MSI status and performed a systematic assessment of MSI-related molecular features including gene and miRNA expression, DNA methylation, and somatic mutation, in approximately 10,000 patients across 30 cancer types from The Cancer Genome Atlas, Gene Expression Omnibus database, and our institution. Then we identified common MSI-associated dysregulated molecular features across six cancers and explored their mutual interfering relationships and the drug sensitivity. KEY FINDINGS: we demonstrated the model's high prediction performance and found the samples with high-MSI were mainly distributed in six cancers: BRCA, COAD, LUAD, LIHC, STAD, and UCEC. We found RPL22L1 was up-regulated in the high-MSI group of 5/6 cancer types. CYP27A1 and RAI2 were down-regulated in 4/6 cancer types. More than 20 miRNAs and 39 DMGs were found up-regulated in MSI-H at least three cancers. We discovered some drugs, including OSI-027 and AZD8055 had a higher sensitivity in the high MSI-score group. Functional enrichment analysis revealed the correlation between MSI score and APM score, HLA score, or glycolysis score. The complicated regulatory mechanism of tumor MSI status in multiple dimensions was explored by an integrated analysis of the correlations among MSI-related genes, miRNAs, methylation, and drug response data. SIGNIFICANCE: Our pan-cancer study provides a valuable predictive model and a comprehensive atlas of tumor MSI, which may guide more precise and personalized therapeutic strategies for tumor patients.