Radiotherapy constitutes a standard arm of therapy in the multimodal treatment of patients with glioblastoma (GBM). Ironically, studies have recently revealed that radiation can augment malignant progression, by promoting migration and invasion, which make the disease especially difficult to cure. Here, we investigated the anticancer effects of YM155, a purported radiosensitizer, in GBM cell lines.

Background: Ferroptosis is a novel process of programmed cell death driven by excessive lipid peroxidation that is associated with the development of lung adenocarcinoma. N6-methyladenosine (m6a) modification of multiple genes is involved in regulating the ferroptosis process, while the predictive value of N6-methyladenosine- and ferroptosis-associated lncRNA (FMRlncRNA) in the prognosis of patients remains with LUAD remains unknown. Methods: Unsupervised cluster algorithm was applied to generate subcluster in LUAD according to ferroptosis-associated lncRNA. Stepwise Cox analysis and LASSO algorithm were applied to develop a prognostic model. Cellular location was detected by single-cell analysis. Also, we conducted Gene set enrichment analysis (GSEA) enrichment, immune microenvironment and drug sensitivity analysis. In addition, the expression and function of the LINC01572 were investigated by several in vitro experiments including qRT-PCR, cell viability assays and ferroptosis assays. Results: A novel ferroptosis-associated lncRNAs-based molecular subtype containing two subclusters were determined in LUAD. Then, we successfully created a risk model according to five ferroptosis-associated lncRNAs (LINC00472, MBNL1-AS1, LINC01572, ZFPM2-AS1, and TMPO-AS1). Our nominated model had good stability and predictive function. The expression patterns of five ferroptosis-associated lncRNAs were confirmed by polymerase chain reaction (PCR) in LUAD cell lines. Knockdown of LINC01572 significantly inhibited cell viability and induced ferroptosis in LUAD cell lines. Conclusion: Our data provided a risk score system based on ferroptosis-associated lncRNAs with prognostic value in LUAD. Moreover, LINC01572 may serve as a novel ferroptosis suppressor in LUAD.

Immune checkpoint blockade (ICB) therapy has achieved breakthroughs in the treatment of advanced non-small cell lung cancer (NSCLC). Nevertheless, the low response due to immuno-cold (i.e., tumors with limited tumor-infiltrating lymphocytes) tumor microenvironment (TME) largely limits the application of ICB therapy. Based on the glycolytic/cholesterol synthesis axis, a stratification framework for EGFR-WT NSCLC was developed to summarize the metabolic features of immuno-cold and immuno-hot tumors. The cholesterol subgroup displays the worst prognosis in immuno-cold NSCLC, with significant enrichment of the cholesterol gene signature, indicating that targeting cholesterol synthesis is essential for the therapy for immuno-cold NSCLC. Statin, the inhibitor for cholesterol synthesis, can suppress the aggressiveness of NSCLC in vitro and in vivo and can also drastically reverse the phenotype of immuno-cold to an inflamed phenotype in vivo. This change led to a higher response to ICB therapy. Moreover, both our in-house data and meta-analysis further support that statin can significantly enhance ICB efficacy. In terms of preliminary mechanisms, statin could transcriptionally inhibit PD-L1 expression and induce ferroptosis in NSCLC cells. Overall, we reveal the significance of cholesterol synthesis in NSCLC and demonstrate the improved therapeutic efficacy of ICB in combination with statin. These findings could provide a clinical insight to treat NSCLC patients with immuno-cold tumors.

Neutrophils play an important role in the occurrence and development of acute lung injury (ALI). Leukotriene B4 (LTB4), a hydrolysis product of epoxide leukotriene A4 (LTA4) catalyzed by LTA4 hydrolase (LTA4H), is one of the most potent chemoattractants for neutrophil. Bufexamac is a drug widely used as an anti-inflammatory agent on the skin, however, the mechanism of action is still not fully understood. In this study, we found bufexamac was capable of specifically inhibiting LTA4H enzymatic activity and revealed the mode of interaction of bufexamac and LTA4H using X-ray crystallography. Moreover, bufexamac significantly prevented the production of LTB4 in neutrophil and inhibited the fMLP-induced neutrophil migration through inhibition of LTA4H. Finally, bufexamac significantly attenuated lung inflammation as reflected by reduced LTB4 levels and weakened neutrophil infiltration in bronchoalveolar lavage fluid from a lipopolysaccharide-induced ALI mouse model. In summary, our study indicates that bufexamac acts as an inhibitor of LTB4 biosynthesis and may have potential clinical applications for the treatment of ALI.

Mechanistic studies in human cancer have relied heavily on cell lines and mouse models, but are limited by in vitro adaptation and species context issues, respectively. More recent efforts have utilized patient-derived xenografts; however, these are hampered by variable genetic background, inability to study early events, and practical issues with availability/reproducibility. We report here an efficient, reproducible model of T-cell leukemia in which lentiviral transduction of normal human cord blood yields aggressive leukemia that appears indistinguishable from natural disease. We utilize this synthetic model to uncover a role for oncogene-induced HOXB activation which is operative in leukemia cells-of-origin and persists in established tumors where it defines a novel subset of patients distinct from other known genetic subtypes and with poor clinical outcome. We show further that anterior HOXB genes are specifically activated in human T-ALL by an epigenetic mechanism and confer growth advantage in both pre-leukemia cells and established clones.

In this work, we aimed to investigate the effect of the combination of starch nanoparticles (SNPs) and Tween 80 (TW) on the stability of oil-in-water emulsions. The emulsions prepared under different SNPs/TW ratios and different oil fraction values were characterized by means of photography, optical microscopy, laser particle size analysis, rheological measurement, quartz crystal microbalance analysis, and confocal laser scanning microscopy. At an oil fraction value of 0.4, the emulsions with a 3: 1 ratio of SNPs (1.5%, w/v) to TW (0.5%, w/v) exhibited excellent storage stability over a long period of 30 d, which was significantly better than the 2% TW stabilized emulsion and the 2% SNPs stabilized emulsion. Compared with the SNPs stable emulsions, the presence of TW decreased the emulsion droplets size, which was beneficial to reduce the aggregation of droplets. Emulsions co-stabilized by SNPs and TW can maintain good performance under harsh conditions. The results of quartz crystal microbalance analysis and isothermal titration calorimetry revealed non-covalent interactions between SNPs and TW. The results showed that SNPs and TW co-existed at the oil-water interface and improved the performance of the emulsion.

Follicular lymphoma (FL) is an indolent cancer of mature B-cells but with ongoing risk of transformation to more aggressive histology over time. Recurrent mutations associated with transformation have been identified; however, prognostic features that can be discerned at diagnosis could be clinically useful. We present here comprehensive profiling of both tumor and immune compartments in 155 diagnostic FL biopsies at single-cell resolution by mass cytometry. This revealed a diversity of phenotypes but included two recurrent patterns, one which closely resembles germinal center B-cells (GCB) and another which appears more related to memory B-cells (MB). GCB-type tumors are enriched for EZH2, TNFRSF14, and MEF2B mutations, while MB-type tumors contain increased follicular helper T-cells. MB-type and intratumoral phenotypic diversity are independently associated with increased risk of transformation, supporting biological relevance of these features. Notably, a reduced 26-marker panel retains sufficient information to allow phenotypic profiling of future cohorts by conventional flow cytometry.

Myeloid leukemia factor 1-interacting protein (MLF1-IP) has been found to exert functions in mitosis, although studies have been conducted only in cell lines up to now. To understand its roles during ontogeny and immunity, we analyzed its mRNA expression pattern by in situ hybridization and generated MLF1-IP gene knockout (KO) mice. MLF1-IP was expressed at elevated levels in most rudimentary tissues during the mid-gestation stage, between embryonic day 9.5 (e9.5) and e15.5. It declined afterwards in these tissues, but was very high in the testes and ovaries in adulthood. At post-natal day 10 (p10), the retina and cerebellum still expressed moderate MLF1-IP levels, although these tissues do not contain fast-proliferating cells at this stage. MLF1-IP expression in lymphoid organs, such as the thymus, lymph nodes, spleen and bone marrow, was high between e15.5 and p10, and decreased in adulthood. MLF1-IP KO embryos failed to develop beyond e6.5. On the other hand, MLF1-IP(+/-) mice were alive and fertile, with no obvious anomalies. Lymphoid organ size, weight, cellularity and cell sub-populations in MLF1-IP(+/-) mice were in the normal range. The functions of MLF1-IP(+/-) T cells and naïve CD4 cells, in terms of TCR-stimulated proliferation and Th1, Th17 and Treg cell differentiation in vitro, were comparable to those of wild type T cells. Our study demonstrates that MLF1-IP performs unique functions during mouse embryonic development, particularly around e6.5, when there was degeneration of epiblasts. However, the cells could proliferate dozens of rounds without MLF1-IP. MLF1-IP expression at about 50% of its normal level is sufficient to sustain mice life and the development of their immune system without apparent abnormalities. Our results also raise an intriguing question that MLF1-IP might have additional functions unrelated to cell proliferation.

Hypopharyngeal squamous cell carcinoma (HSCC) is a common type of malignant tumor. Long non-coding RNAs (lncRNAs) are known to participate in HSCC development, while the role of lncRNA MALAT1 in HSCC remains largely unknown. We aimed to explore function of the lncRNA MALAT1/miR-429/ZEB1 axis in HSCC progression.

ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. We show that ARID1A orchestrates B cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD40 signaling. The absence of ARID1A tilts GC cell fate toward immature IgM+CD80-PD-L2- memory B cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas (FLs) in mice. Patients with FL with ARID1A-inactivating mutations preferentially display an immature memory B cell-like state with increased transformation risk to aggressive disease. These observations offer mechanistic understanding into the emergence of both indolent and aggressive ARID1A-mutant lymphomas through the formation of immature memory-like clonal precursors. Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4 inhibition, paving the way for potential precision therapy for high-risk patients.

Pno1 is a protein that plays a role in proteasome and ribosome neogenesis in yeast. So far, its functions in mammalian cells have not been investigated. To understand its function in mammals, we performed in situ hybridization analysis of Pno1 expression in different development stages and generated Pno1 gene knockout (KO) and transgenic (Tg) mice lineages. The results showed early lethality of homozygous Pno1 KO lineage caused, as demonstrated in parallel by ex vivo experiments, by arrest of embryo development before compaction stage. Though, heterozygous (HET) mice with 50% of normal Pno1 mRNA concentration were fertile and showed no obvious anomalies. The lymphoid organs of HET mice were normal in size, weight and cellularity, with normal T and B cell subpopulations. TCR-triggered activation and proliferation of HET T cells were normal. Proteasome activities in HET organs were uncompromised. Tg mice with actin promoter-driven Pno1 expression were also fertile, with no apparent anomalies, although they expressed 2-5-fold higher Pno1 mRNA levels. The lymphoid organs of Tg mice were of normal size, weight and cellularity with normal T and B cell sub-populations. TCR-triggered activation and proliferation of Tg T cells were normal. Tg organs and tissues presented normal proteasome activity as did their wild type counterparts. Tagged Pno1 over-expression in L cells and density gradient fractionation established that Pno1 existed in large complexes with sedimentation rates between 20S and 26S, bigger than mature 26S proteasomes. Pno1 in fractions did not coincide with 40S or 60S ribosome subunits. Our study indicates that Pno1 is essential for cellular functions, but only a small percentage of its normal level is sufficient, and excessive amounts are neither harmful nor useful. The nature of the large complexes it associates with remains to be identified, but it is certain that they are not mature proteasomes or ribosomes.

To uncover the genes associated with the development of esophageal squamous cell carcinoma (ESCC), an ESCC microarray dataset was used to identify genes differentially expressed between ESCC and normal control tissues. The dataset GSE17351 was downloaded from the Gene Expression Omnibus, containing 5 tumor esophageal mucosa samples and 5 adjacent normal esophageal mucosa samples from 5 male patients with ESCC. The differentially expressed genes (DEGs) were identified using the Linear Models for Microarray Data R package. Then, a co-expression network was constructed using the Weighted Correlation Network Analysis (WGCNA) package, and co-expression network modules were obtained with a hierarchical clustering algorithm. Additionally, functional enrichment analyses for DEGs in the top 2 modules with the highest significance were respectively conducted using the WGCNA package and the cluster Profiler package. In total, 487 upregulated and 468 downregulated DEGs were identified. A total of 24 modules were obtained from the co-expression network, and the top 2 modules with the highest significance, designated as 'blue4' and 'magenta', were further analyzed. In the module blue4, DEGs were significantly enriched in a number of Gene Ontology terms, including 'spindle organization' [e.g., ubiquitin conjugating enzyme E2 C (UBE2C) and SAC3 domain containing 1] and 'cell cycle process' [e.g., UBE2C, minichromosome maintenance complex component 6 (MCM6) and cell division cycle 20 (CDC20)]. Furthermore, a number of DEGs (e.g., UBE2C, CDC20 and MCM6) were enriched in the 'cell cycle' and 'ubiquitin mediated proteolysis' pathways. In the module 'magenta', a number of DEGs [e.g., transferrin receptor (TFRC) and TEA domain transcription factor 4 (TEAD4)] were enriched in the primary metabolic process and intracellular membrane-bounded organelle. Additionally, 308 upregulated genes and 215 downregulated genes were differentially expressed in the same pattern in another dataset, GSE20347, including UBE2C, CDC20, MCM6, TFRC, TEAD4, protein phosphatase 1 regulatory subunit 3C and MAL, T-cell differentiation protein. These DEGs may function in the development of ESCC.

Our earlier study revealed that STRA6 (stimulated by retinoic acid gene 6) was up-regulated within 3 h of TCR stimulation. STRA6 is the high-affinity receptor for plasma retinol-binding protein (RBP) and mediates cellular vitamin A uptake. We generated STRA6 knockout (KO) mice to assess whether such up-regulation was critical for T-cell activation, differentiation and function. STRA6 KO mice under vitamin A sufficient conditions were fertile without apparent anomalies upon visual inspection. The size, cellularity and lymphocyte subpopulations of STRA6 KO thymus and spleen were comparable to those of their wild type (WT) controls. KO and WT T cells were similar in terms of TCR-stimulated proliferation in vitro and homeostatic expansion in vivo. Naive KO CD4 cells differentiated in vitro into Th1, Th2, Th17 as well as regulatory T cells in an analogous manner as their WT counterparts. In vivo experiments revealed that anti-viral immune responses to lymphocytic choriomeningitis virus in KO mice were comparable to those of WT controls. We also demonstrated that STRA6 KO and WT mice had similar glucose tolerance. Total vitamin A levels are dramatically lower in the eyes of KO mice as compared to those of WT mice, but the levels in other organs were not significantly affected after STRA6 deletion under vitamin A sufficient conditions, indicating that the eye is the mouse organ most sensitive to the loss of STRA6. Our results demonstrate that 1) in vitamin A sufficiency, the deletion of STRA6 in T cells does no affect the T-cell immune responses so-far tested, including those depend on STAT5 signaling; 2) STRA6-independent vitamin A uptake compensated the lack of STRA6 in lymphoid organs under vitamin A sufficient conditions in mice; 3) STRA6 is critical for vitamin A uptake in the eyes even in vitamin A sufficiency.

Radiotherapy is one of the most important methods in the treatment of patients with hypopharyngeal squamous cell carcinoma (HSCC). However, radioresistance will be developed after repeated irradiation. Among many key factors contributing to radioresistance, enhanced autophagy is recognized as one of the most important. The ultraviolent irradiation resistance-associated gene (UVRAG) is reported to be a crucial gene involved in the process of autophagy. Here, we test whether UVRAG has effect on the radioresistance of HSCC.

Celecoxib is an inhibitor of cyclooxygenase-2, a gene that is often aberrantly expressed in the lung squamous cell carcinoma (LSQCC). The present study aims to provide novel insight into chemoprevention by celecoxib treatment. The human LSQCC cell line SK‑MES‑1 was treated with or without celecoxib and RNA‑sequencing (RNA‑seq) was performed on the Illumina HiSeq 2000 platform. Expression levels of genes or long non‑coding RNAs (lncRNAs) were calculated by Cufflinks software. Subsequently, differentially expressed genes (DEGs) and differentially expressed lncRNAs (DE‑LNRs) between the two groups were selected using the limma package and LNCipedia 3.0, respectively; followed by co‑expression analysis based on their expression correlation coefficient (CC). Enrichment analysis for the DEGs and co‑expressed DE‑LNRs were performed. Protein‑protein interaction (PPI) network analysis for DEGs was performed using STRING database. A set of 317 DEGs and 25 DE‑LNRs were identified between celecoxib‑treated and non‑treated cell lines. A total of 12 pathways were enriched by the DEGs, including 'protein processing in endoplasmic reticulum' for activating transcription factor 4 (ATF4), 'mammalian target of rapamycin (mTOR) signaling pathway' for vascular endothelial growth factor A (VEGFA) and 'ECM‑receptor interaction' for fibronectin 1 (FN1). Genes such as VEGFA, ATF4 and FN1 were highlighted in the PPI network. VEGFA was linked with lnc‑AP000769.1‑2:10 (CC= ‑0.99227), whereas ATF4 and FN1 were closely correlated with lnc‑HFE2‑2:1 (CC=0.996159 and ‑0.98714, respectively). lncRNAs were also enriched in pathways such as 'mTOR signaling pathway' for lnc‑HFE2‑2:1. Several important molecules were identified in celecoxib‑treated LSQCC cell lines, such as VEGFA, ATF4, FN1, lnc‑AP000769.1‑2:10 and lnc‑HFE2‑2:1, which may enhance the anti‑cancer effects of celecoxib on LSQCC.

Recent advances in spatial proteomics technologies have enabled the profiling of dozens of proteins in thousands of single cells in situ. This has created the opportunity to move beyond quantifying the composition of cell types in tissue, and instead probe the spatial relationships between cells. However, most current methods for clustering data from these assays only consider the expression values of cells and ignore the spatial context. Furthermore, existing approaches do not account for prior information about the expected cell populations in a sample.

Cuproptosis is a recently found non-apoptotic cell death type that holds promise as an emerging therapeutic modality in lung adenocarcinoma (LUAD) patients who develop resistance to radiotherapy and chemotherapy. However, the Cuproptosis' role in the onset and progression of LUAD remains unclear.

Lung adenocarcinoma (LUAD) stands as the foremost histological subtype of non-small-cell lung cancer, accounting for approximately 40% of all lung cancer diagnoses. However, there remains a critical unmet need to enhance the prediction of clinical outcomes and therapy responses in LUAD patients. Keratins (KRTs), serving as the structural components of the intermediate filament cytoskeleton in epithelial cells, play a crucial role in the advancement of tumor progression. This study investigated the prognostic significance of the KRT family gene and developed a KRT gene signature (KGS) for prognostic assessment and treatment guidance in LUAD.