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Ovarian cancer (OC) is a significant cause of cancer-related mortality in women worldwide. Despite advances in treatment modalities, including surgery and chemotherapy, the overall prognosis for OC patients remains poor, particularly for patients with advanced or recurrent disease. Immunotherapy, particularly immune checkpoint blockade (ICB), has revolutionized cancer treatment in various malignancies but has shown limited efficacy in treating OC, which is primarily attributed to the immunologically. Tertiary lymphoid structures (TLSs), which are ectopic aggregates of immune cells, have emerged as potential mediators of antitumor immunity. This review explores the composition, formation, and induction of tumor associated TLS (TA-TLS) in OC, along with their role and therapeutic implications in disease development and treatment. By elucidating the roles TA-TLSs and their cellular compositions played in OC microenvironment, novel therapeutic targets may be identified to overcome immune suppression and enhance immunotherapy efficacy in ovarian cancer. [ABSTRACT FROM AUTHOR]

Carotid atherosclerosis is a major cause of stroke. Hemodynamic forces, such as shear stress and oscillatory shear, play an important role in the initiation and progression of atherosclerosis. The alteration of the immune microenvironment is the fundamental pathological mechanism by which diverse external environmental factors impact the formation and progression of plaques. However, Current research on the relationship between hemodynamics and immunity in atherosclerosis still lack of comprehensive understanding. In this study, we combined computational fluid dynamics (CFD) and Mass cytometry (CyTOF) technologies to explore the changes in the immune microenvironment within plaques under different hemodynamic conditions. Our results indicated that neutrophils were enriched in adverse flow environments. M2-like CD163+CD86+ macrophages were predominantly enriched in high WSS and low OSI environments, while CD163-CD14+ macrophages were enriched in low WSS and high OSI environments. Functional analysis further revealed T cell pro-inflammatory activation and dysregulation in modulation, along with an imbalance in M1-like/M2-like macrophages, suggesting their potential involvement in the progression of atherosclerotic lesions mediated by adverse flow patterns. Our study elucidated the potential mechanisms by which hemodynamics regulated the immune microenvironment within plaques, providing intervention targets for future precision therapies. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disease characterized by cartilage, bone damage, synovial inflammation, hyperplasia, autoantibody production, and systemic features. To obtain an overall profile of the immune environment in RA patients and its association with clinical features, we performed single-cell transcriptome and T-cell receptor sequencing of mononuclear cells from peripheral blood (PBMC) and synovial fluid (SF) from RA patients, integrated with two large cohorts with bulk RNA sequencing for further validation and investigation. Dendritic cells (DCs) exhibited relatively high functional heterogeneity and tissue specificity in relation to both antigen presentation and proinflammatory functions. Peripheral helper T cells (TPHs) are likely to originate from synovial tissue, undergo activation and exhaustion, and are subsequently released into the peripheral blood. Notably, among all immune cell types, TPHs were found to have the most intense associations with disease activity. In addition, CD8 effector T cells could be clustered into two groups with different cytokine expressions and play distinct roles in RA development. By integrating single-cell data with bulk sequencing from two large cohorts, we identified interactions among TPHs, CD8 cells, CD16 monocytes, and DCs that strongly contribute to the proinflammatory local environment in RA joints. Of note, the swollen 28-joint counts exhibited a more pronounced association with this immune environment compared to other disease activity indexes. The immune environment alternated significantly from PBMCs to SF, which indicated that a series of immune cells was involved in proinflammatory responses in the local joints of RA patients. By integrating single-cell data with two large cohorts, we have uncovered associations between specific immune cell populations and clinical features. This integration provides a rapid and precise methodology for assessing local immune activation, offering valuable insights into the pathophysiological mechanisms at play in RA. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is a significant cause of cancer-related mortality in women worldwide. Despite advances in treatment modalities, including surgery and chemotherapy, the overall prognosis for OC patients remains poor, particularly for patients with advanced or recurrent disease. Immunotherapy, particularly immune checkpoint blockade (ICB), has revolutionized cancer treatment in various malignancies but has shown limited efficacy in treating OC, which is primarily attributed to the immunologically. Tertiary lymphoid structures (TLSs), which are ectopic aggregates of immune cells, have emerged as potential mediators of antitumor immunity. This review explores the composition, formation, and induction of tumor associated TLS (TA-TLS) in OC, along with their role and therapeutic implications in disease development and treatment. By elucidating the roles TA-TLSs and their cellular compositions played in OC microenvironment, novel therapeutic targets may be identified to overcome immune suppression and enhance immunotherapy efficacy in ovarian cancer.

Ischemic stroke (IS) is a severe condition regulated by complex molecular alterations. This study aimed to identify potential nicotinamide adenine dinucleotide (NAD+) metabolism-associated diagnostic markers of IS and explore their associations with immune dynamics. Weighted Gene Co-expression Network Analysis and single-sample gene set enrichment analysis (ssGSEA) were employed to identify key gene modules on the GEO dataset (GSE16561). LASSO regression was used to identify diagnostic genes. A diagnostic model was then developed using the training dataset, and its performance was assessed using a validation dataset (GSE22255 dataset). Associations between hub genes and immune cells, immune response genes, and human leukocyte antigen (HLA) genes were assessed by ssGSEA. A regulatory network was constructed using mirBase and TRRUST databases. A total of 20 NAD+ metabolic genes exhibited noteworthy expression variations. Within the module notably associated with NAD+ metabolism, 19 specific genes were included in the diagnostic model, which was validated on the GSE22255 dataset (AUC: 0.733). There were significant disparities in immune cell populations, immune response genes, and HLA gene expression, all of which were associated with the hub genes. A regulatory network composed of 153 edges and 103 nodes was constructed. This study advances our understanding of IS by providing insights into NAD+ metabolism and gene interactions, contributing to potential diagnostic innovations in IS.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with high probability of recurrence and distant metastasis. Liver metastasis is the predominant metastatic mode developed in most pancreatic cancer cases, which seriously affects the overall survival rate of patients. Abnormally activated endoplasmic reticulum stress and lipid metabolism reprogramming are closely related to tumor growth and metastasis. This study aims to construct a prognostic model based on endoplasmic reticulum stress and lipid metabolism for pancreatic cancer, and further explore its correlation with tumor immunity and the possibility of immunotherapy. Methods Transcriptomic and clinical data are acquired from TCGA, ICGC, and GEO databases. Potential prognostic genes were screened by consistent clustering and WGCNA methods, and the whole cohort was randomly divided into training and testing groups. The prognostic model was constructed by machine learning method in the training cohort and verified in the test, TCGA and ICGC cohorts. The clinical application of this model and its relationship with tumor immunity were analyzed, and the relationship between endoplasmic reticulum stress and intercellular communication was further explored. Results A total of 92 characteristic genes related to endoplasmic reticulum stress, lipid metabolism and liver metastasis were identified in pancreatic cancer. We established and validated a prognostic model for pancreatic cancer with 7 signatures, including ADH1C, APOE, RAP1GAP, NPC1L1, P4HB, SOD2, and TNFSF10. This model is considered to be an independent prognosticator and is a more accurate predictor of overall survival than age, gender, and stage. TIDE score was increased in high-risk group, while the infiltration levels of CD8+ T cells and M1 macrophages were decreased. The number and intensity of intercellular communication were increased in the high ER stress group. Conclusions We constructed and validated a novel prognostic model for pancreatic cancer, which can also be used as an instrumental variable to predict the prognosis and immune microenvironment. In addition, this study revealed the effect of ER stress on cell–cell communication in the tumor microenvironment.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with high probability of recurrence and distant metastasis. Liver metastasis is the predominant metastatic mode developed in most pancreatic cancer cases, which seriously affects the overall survival rate of patients. Abnormally activated endoplasmic reticulum stress and lipid metabolism reprogramming are closely related to tumor growth and metastasis. This study aims to construct a prognostic model based on endoplasmic reticulum stress and lipid metabolism for pancreatic cancer, and further explore its correlation with tumor immunity and the possibility of immunotherapy. Methods: Transcriptomic and clinical data are acquired from TCGA, ICGC, and GEO databases. Potential prognostic genes were screened by consistent clustering and WGCNA methods, and the whole cohort was randomly divided into training and testing groups. The prognostic model was constructed by machine learning method in the training cohort and verified in the test, TCGA and ICGC cohorts. The clinical application of this model and its relationship with tumor immunity were analyzed, and the relationship between endoplasmic reticulum stress and intercellular communication was further explored. Results: A total of 92 characteristic genes related to endoplasmic reticulum stress, lipid metabolism and liver metastasis were identified in pancreatic cancer. We established and validated a prognostic model for pancreatic cancer with 7 signatures, including ADH1C, APOE, RAP1GAP, NPC1L1, P4HB, SOD2, and TNFSF10. This model is considered to be an independent prognosticator and is a more accurate predictor of overall survival than age, gender, and stage. TIDE score was increased in high-risk group, while the infiltration levels of CD8+ T cells and M1 macrophages were decreased. The number and intensity of intercellular communication were increased in the high ER stress group. Conclusions: We constructed and validated a novel prognostic model for pancreatic cancer, which can also be used as an instrumental variable to predict the prognosis and immune microenvironment. In addition, this study revealed the effect of ER stress on cell–cell communication in the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is a common underlying pathology of coronary artery disease, peripheral artery disease, and stroke. The characteristics of immune cells within plaques and their functional relationships with blood are crucial in AS. In this study, Mass cytometry (CyTOF), RNA-sequencing and immunofluorescence were combined to comprehensively analyze plaque tissues and peripheral blood from 25 AS patients (22 for Mass cytometry and 3 for RNA-sequencing), as well as blood from 20 healthy individuals. The study identified a complexity of leukocytes in the plaque, including both defined anti-inflammatory and pro-inflammatory subsets such as M2-like CD163+ macrophages, Natural killer T cells (NKT), CD11b+ CD4+ T effector memory cells (Tem), and CD8+ terminally differentiated effector memory cells (TEMRA). Functionally activated cell subsets were also found in peripheral blood in AS patients, highlighting the vivid interactions between leukocytes in plaque and blood. The study provides an atlas of the immune landscape in atherosclerotic patients, where proinflammatory activation was found to be a major feature of peripheral blood. The study identified NKT, CD11b+ CD4+ Tem, CD8+ TEMRA and CD163+ macrophages as key players in the local immune environment. [ABSTRACT FROM AUTHOR]

Background: Lymphocyte antigen 96 (LY96) plays an important role in innate immunity and has been reported to be associated with various neurological diseases. However, its role in Parkinson's disease (PD) remains unclear. Methods: Transcriptome data from a total of 49 patients with PD and 34 healthy controls were downloaded from the Gene Expression Omnibus (GEO) database to analyse the expression pattern of LY96 and its relationship with gene function and immune-related markers. In addition, peripheral blood samples were collected from clinical patients to validate LY96 mRNA expression levels. Finally, an in vitro cell model of PD based on highly differentiated SH-SY5Y cells was constructed, with small interfering RNA-silenced LY96 expression, and LY96 mRNA level, cell viability, flow cytometry, and mitochondrial membrane potential assays were performed. Results: The results of the analyses of the GEO database and clinical samples revealed significantly abnormally high LY96 expression in patients with PD compared with healthy controls. The results of cell experiments showed that inhibiting LY96 expression alleviated adverse cellular effects by increasing cell viability, reducing apoptosis, and reducing oxidative stress. Gene set enrichment analysis showed that LY96 was positively correlated with T1 helper cells, T2 helper cells, neutrophils, natural killer T cells, myeloid-derived suppressor cells, macrophages, and activated CD4 cells, and may participate in PD through natural killer cell-mediated cytotoxicity pathways and extracellular matrix receptor interaction pathways. Conclusion: These findings suggested that LY96 might be a novel potential biomarker for PD, and offer insights into its immunoregulatory role.

Objective: This research aims to examine the involvement of lymphocyte subsets and inflammatory cytokines in the development and progression of COVID-19. Methods: 164 COVID-19 patients were admitted to hospital between December 2022 and January 2023. Based on lung CT scans and whether it is necessary for intensive care unit (ICU) admission, they were categorized into: severe groups (84) and mild disease groups (80). Peripheral blood were also collected from 101 healthy examinees and 164 patients. Flow cytometry (FCM) was used to measure the absolute and relative counts of lymphocyte subsets, while chemiluminescence was used to detect the level of inflammatory cytokines. Results: The COVID-19 patient group exhibited lower count of lymphocytes subsets than healthy control group. Moreover, COVID-19 patient case presented higher content of cytokines (IL-6, IL-4, IL-8, IL-10, and TNF-α) expression compared to healthy control case. Within the COVID-19 patient group, individuals with severe disease showed lower counts of lymphocytes subsets than the mild disease case. Furthermore, IL-6 levels in severe case were higher than the mild disease patients case. Multi-variate logistic regression analysis confirmed IL-6 (odds ratio: 0.985 [0.977–0.993]), CD3+ T cells (odds ratio:1.007 [1.004–1.010]), CD8+ T cells (odds ratio:1.016 [1.009–1.023]), and CD19+ B cells (odds ratio:1.011 [1.002–1.020]) independently predicted severe progression. ROC curve results indicated AUC for lymphocytes in patients with severe COVID-19 was 0.8686 (0.8112–0.9260), CD3+ T cells was 0.8762 (0.8237–0.9287), CD8+ T cells was 0.7963 (0.7287–0.8638), CD4+ T cells was 0.8600 (0.8036–0.9164), CD19+ B cells was 0.7217 (0.6434–0.8001), NK cells was 0.6492 (0.5627–0.7357), age was 0.6699 (0.5877–0.7521), diabetes was 0.5991 (0.5125–0.6857), and IL-6 was 0.7241 (0.6479–0.8003). Furthermore, the ROC curves for different factors (CD3+ T cells, age, IL-6) yielded an AUC of 0.9031 (0.8580–0.9483). Conclusions: The research indicated that COVID-19 patients experience a decrease in lymphocytes subset and an increase in the inflammatory factor IL-6, particularly in the severe case group. As a result, the count of lymphocyte subset (CD3+ T cells) and the content of inflammatory cytokine (IL-6) can serve as predictive markers for assessing the severity of COVID-19 and developing treatment plans efficacy.

Amino acids are essential for the survival of all living organisms and living cells. Amino acid transporters mediate the transport and absorption of amino acids, and the dysfunction of these proteins can induce human diseases. Cationic amino acid transporters (CAT family, SLC7A1-4, and SLC7A14) are considered to be a group of transmembrane transporters, of which SLC7A1-3 are essential for arginine transport in mammals. Numerous studies have shown that CAT family-mediated arginine transport is involved in signal crosstalk between malignant tumor cells and immune cells, especially T cells. The modulation of extracellular arginine concentration has entered a number of clinical trials and achieved certain therapeutic effects. Here, we review the role of CAT family on tumor cells and immune infiltrating cells in malignant tumors and explore the therapeutic strategies to interfere with extracellular arginine concentration, to elaborate its application prospects. CAT family members may be used as biomarkers for certain cancer entities and might be included in new ideas for immunotherapy of malignant tumors. [ABSTRACT FROM AUTHOR]

Background: Many researches proved that non-coding RNAs are important in glioma development. We screened the differentially expressed genes through The Cancer Genome Atlas (TCGA) database and identified the molecule LYRM4-AS1 associated with prognosis. As a lncRNA, the expression level and role of LYRM4-AS1 in glioma are inconclusive. Therefore, we attempted to assess the clinical significance, expression and related mechanisms of LYRM4-AS1 in glioma by employing cell experiments and an integrative in silico methodology. Methods: RNA-seq data were obtained from UCSC XENA and TCGA datasets. The Gene Expression Omnibus (GEO) database was used to download glioma-related expression profile data. The LYRM4-AS1 expression level was evaluated. Survival curves were constructed by the Kaplan--Meier method. Cox regression analysis was used to analyze independent variables. Patients were divided into high and low expression group base on the median LYRM4-AS1 expression value in glioma tissues. The DESeq2 R package was used to identify differentially expressed genes (DEGs) between two different expression LYRM4-AS1 groups. Gene set enrichment analysis (GSEA) was conducted. Next, the single-sample Gene Set Enrichment Analysis (ssGSEA) was done to quantify the immune infiltration of immune cells in glioma tissues. Gene expression profiles for glioma tumor tissues were used to quantify the relative enrichment score for each immune cell. Spearman correlation analysis was used to analyze the correlation between LYRM4-AS1 and biomarkers of immune cells as well as immune checkpoints in glioma. Finally, assays for cell apoptosis, cell viability and wound healing were conducted to evaluate the function on U87 MG and U251 cells after knocking down LYRM4-AS1. Results: We found that LYRM4-AS1 was upregulated and related to the grade and malignancy of glioma. Survival analyses showed that high expression LYRM4-AS1 patients had poor clinical outcomes (P < 0.01). Cox regression analyses demonstrated that LYRM4-AS1 was an independent risk factor for overall survival (OS) in glioma (HR: 274 1.836; CI [1.278-2.639]; P = 0.001). Enrichment and immune infiltration analysis showed interferon signaling and cytokine-cytokine receptor interaction enriched in the LYRM4-AS1 high-expression phenotype, and LYRM4-AS1 showed significantly positively related to immune infiltration as well as immune checkpoints (P < 0.01). The knockdown of LYRM4-AS1 in U87 MG and U251 cells can inhibit migration and proliferation of cells (P < 0.05). Conclusions: These findings indicated that the increased LYRM4-AS1 may be useful for the diagnosis and prognosis of glioma and might participate in the immune infiltration. [ABSTRACT FROM AUTHOR]

Abstract Increasing evidences have demonstrated that pyroptosis exerts key roles in the occurrence, development of chronic obstructive pulmonary disease. However, the mechanisms of pyroptosis in COPD remain largely unknown. In our research, Statistics were performed using R software and related packages in this study. Series matrix files of small airway epithelium samples were downloaded from the GEO database. Differential expression analysis with FDR

Immune checkpoint inhibitors highlight the importance of anticancer immunity. However, their clinical utility and safety are limited by the low response rates and adverse effects. We focused on progesterone (P4), a hormone produced by the placenta during pregnancy, because it has multiple biological activities related to anticancer and immune regulation effects. P4 has a reversible immune regulatory function distinct from that of the stress hormone cortisol, which may drive irreversible immune suppression that promotes T cell exhaustion and apoptosis in patients with cancer. Because the anticancer effect of P4 is induced at higher than physiological concentrations, we aimed to develop a new anticancer drug by encapsulating P4 in liposomes. In this study, we prepared liposome-encapsulated anti-programmed death ligand 1 (PD-L1) antibody-conjugated P4 (Lipo-anti-PDL1-P4) and evaluated the effects on the growth of MDA-MB-231 cells, a PD-L1-expressing triple-negative breast cancer cell line, in vitro and in NOG-hIL-4-Tg mice transplanted with human peripheral blood mononuclear cells (humanized mice). Lipo-anti-PD-L1-P4 at physiological concentrations reduced T cell exhaustion and proliferation of MDA-MB-231 in vitro. Humanized mice bearing MDA-MB-231 cells expressing PD-L1 showed suppressed tumor growth and peripheral tissue inflammation. The proportion of B cells and CD4+ T cells decreased, whereas the proportion of CD8+ T cells increased in Lipo-anti-PDL1-P4-administrated mice spleens and tumor-infiltrated lymphocytes. Our results suggested that Lipo-anti-PD-L1-P4 establishes a systemic anticancer immune environment with minimal toxicity. Thus, the use of P4 as an anticancer drug may represent a new strategy for cancer treatment. [ABSTRACT FROM AUTHOR]

Abstract Background PI3K pathway is the most frequently mutated pathway in head and neck squamous cell carcinoma (HNSC), which plays a crucial role in tumorigenesis and progression. In the present study, we aimed to investigate the role of PI3K pathway mutation in clinical prognosis prediction and the relationship with immune microenvironment and response rate to immunotherapy. Methods We collected 129 samples with immunotherapy information from MSKCC-2019 cohort as well as 501 and 40 samples from TCGA-HNSC and MD-Anderson non-immunotherapy cohorts, respectively. Somatic mutation data was utilized to characterize the mutational status of the PI3K pathway. Subsequently, we further analyzed the differences in prognosis, immunotherapy response, genomic alterations, functional characteristics, and immune microenvironment between the mutation and wild groups. Results The Kaplan-Meier survival curves displayed that PI3K pathway mutation predicted observably prolonged overall survival (OS) in the immunotherapy cohort MSKCC-2019 (p = 0.012) but did not reach statistical significance in the non-immunotherapy cohorts TCGA-HNSC (p = 0.68) and MD-Anderson (p = 0.68). After incorporating several clinicopathologic features such as age, gender, and tumor mutation burden (TMB), the results of multivariate Cox regression analysis also demonstrated that the PI3K pathway mutation could indicate better immunotherapy outcomes in HNSC patients with a hazard ratio (HR) of 0.533 (95% CI: 0.313–0.910; p = 0.021) in the immunotherapy cohort MSKCC-2019, compared with 0.888 (95% CI: 0.636–1.241; p = 0.487) and 1.939 (95% CI: 0.483–7.781; p = 0.351) in the non-immunotherapy cohorts TCGA-HNSC and MD-Anderson. In addition, the results of the subclass mapping (SubMap) and the tumor immune dysfunction and exclusion (TIDE) also consistently suggested that patients in the mutation group are more likely to benefit from immunotherapy. And further studies showed that the mutation group owned significantly higher TMB, activated immune-related pathways, richer abundance of immune cells, and higher expression levels of immunomodulators. To improve the prognosis of the wild group, we identified five relatively sensitive potential drugs for the wild group, including “BMS-536924,” “linsitinib,” “NVP-TAE684,” “PLX-4720,” and “clonazepam.” Conclusions The PI3K pathway mutation status could be considered as a potential biomarker to predict better immunotherapeutic efficacy and clinical outcomes after immunotherapy in HNSC patients.

Yu Zhang,1,&ast; Xue-Li Wang,2,&ast; Jing-Jing Liu,3 Zhen-Yuan Qian,4 Zheng-Yang Pan,5 Ni-Ping Song,5 Hui-Yan Chen,6 Wei Zhang,7 Xin Zhang8 1Cancer Center, Department of Gastroenterology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People’s Republic of China; 2College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, Zhejiang, People’s Republic of China; 3Bengbu Medical College, Bengbu, Anhui, People’s Republic of China; 4General Surgery, Cancer Center, Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People’s Republic of China; 5The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 6Clinical Laboratory, Tongxiang First People’s Hospital, Tongxiang, Zhejiang, People’s Republic of China; 7Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 8Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin Zhang, Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), No. 158 Shangtang Road, Hangzhou, Hangzhou, Zhejiang, 310014, People’s Republic of China, Tel +86 13758197690, Fax +86 057185893288, Email zhangxin120189@163.com Wei Zhang, Department of Gastrointestinal surgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310005, People’s Republic of China, Email zhangweils1968@163.comPurpose: This study aimed to investigate the expression of inducible T-cell co-stimulator (ICOS) and its ligand (ICOSLG), along with their association with clinicopathological features and influence on the immune profile in colorectal cancer (CRC).Patients and Methods: The Cancer Genome Atlas Colorectal Adenocarcinoma cohorts were used. We also analyzed 131 clinical samples of colon lesions, including precancerous lesions (hyperplastic polyps, low-grade dysplasia, and high-grade dysplasia) and CRC tissues. We conducted immunohistochemical (IHC) assays and multiple IHC (mIHC) of CD4+, Foxp3+ tumor-infiltrating lymphocytes (TILs), and PD-1/PD-L1 immune checkpoints in precancerous lesions and CRC samples from our patient subsets to determine changes and correlations in ICOS and ICOSLG expression during progression through the adenoma–carcinoma pathway.Results: High expression of ICOS and ICOSLG was a significant factor in CRC in multiple analyses and was positively correlated with CD4+/Foxp3+ TIL density and PD-1/PD-L1 expression, which increased with the sequential progression of lesions from precancerous tissues to carcinoma. Multivariable logistic regression analysis suggested that the location and expression level of ICOS/ICOSLG may be involved in precancerous–carcinoma progression. The co-expression status of PD-1 and ICOS/ ICOSLG could stratify patients with colorectal lesions into three groups of low, moderate, and high risk of progression. According to this classification and mIHC assays, we found a strong correlation between increased PD-1+ICOS+ or PD-1+ICOSLG+ co-expression and CRC, which might be deemed an independent factor in carcinogenesis.Conclusion: Increased ICOS/ICOSLG expression may be associated with the progressive formation of Foxp3+ TILs in the immune microenvironment and may further promote the development of the abnormal cytology of colorectal lesions from precancerous neoplasia to CRC. Our findings support the interpretation that enhanced co-expression of PD-1+ICOS+ or PD-1+ICOSLG+ contributes to the immune-active microenvironment of the colorectal adenoma-carcinoma sequence.Keywords: precancerous-carcinoma, immune environment, ICOS/ICOSLG, PD-1/PD-L1, tumor-infiltrating lymphocytes

Cells utilize different metabolic processes to maintain their growth and differentiation. Tumor cells have made some metabolic changes to protect themselves from malnutrition. These metabolic alterations affect the tumor microenvironment and macroenvironment. Developing drugs targeting these metabolic alterations could be a good direction. In this review, we briefly introduce metabolic changes/regulations of the tumor macroenvironment and microenvironment and summarize potential drugs targeting the metabolism in diffuse large B-cell lymphoma. [ABSTRACT FROM AUTHOR]

Increasing evidences have demonstrated that pyroptosis exerts key roles in the occurrence, development of chronic obstructive pulmonary disease. However, the mechanisms of pyroptosis in COPD remain largely unknown. In our research, Statistics were performed using R software and related packages in this study. Series matrix files of small airway epithelium samples were downloaded from the GEO database. Differential expression analysis with FDR < 0.05 was performed to identify COPD-associated pyroptosis-related genes. 8 up-regulated genes (CASP4, CASP5, CHMP7, GZMB, IL1B, AIM2, CASP6, GSDMC) and 1 down-regulated genes (PLCG1) was identified as COPD-associated pyroptosis-related genes. Twenty-six COPD key genes was identified by WGCNA analysis. PPI analysis and gene correlation analysis showed their relationship clearly. KEGG and GO analysis have revealed the main pyroptosis-related mechanism of COPD. The expression of 9 COPD-associated pyroptosis-related genes in different grades was also depicted. The immune environment of COPD was also explored. Furthermore, the relationship of pyroptosis-related genes and the expression of immune cells was also be shown in the end. In the end, we concluded that pyroptosis influences the development of COPD. This study may provide new insight into the novel therapeutic targets for COPD clinical treatment. [ABSTRACT FROM AUTHOR]

Background: Chromobox (CBX) proteins are essential components of polycomb group proteins and perform essential functions in bladder cancer (BLCA). However, research on CBX proteins is still limited, and the function of CBXs in BLCA has not been well illustrated. Methods and Results: We analyzed the expression of CBX family members in BLCA patients from The Cancer Genome Atlas database. By Cox regression analysis and survival analysis, CBX6 and CBX7 were identified as potential prognostic factors. Subsequently, we identified genes associated with CBX6/7 and performed enrichment analysis, and they were enriched in urothelial carcinoma and transitional carcinoma. Mutation rates of TP53 and TTN correlate with expression of CBX6/7. In addition, differential analysis indicated that the roles played by CBX6 and CBX7 may be related to immune checkpoints. The CIBERSORT algorithm was used to screen out immune cells that play a role in the prognosis of bladder cancer patients. Multiplex immunohistochemistry staining confirmed a negative correlation between CBX6 and M1 macrophages, as well as a consistent alteration in CBX6 and regulatory T cells (Tregs), a positive correlation between CBX7 and resting mast cells, and a negative correlation between CBX7 and M0 macrophages. Conclusions: CBX6 and CBX7 expression levels may assist in predicting the prognosis of BLCA patients. CBX6 may contribute to a poor prognosis in patients by inhibiting M1 polarization and promoting Treg recruitment in the tumor microenvironment, while CBX7 may contribute to a better prognosis in patients by increasing resting mast cell numbers and decreasing macrophage M0 content. [ABSTRACT FROM AUTHOR]

In hepatocellular carcinoma (HCC), the signal transducer and activator of transcription 3 (STAT3) is present in an overactive state that is closely related to tumour development and immune escape. STAT3 inhibition reshapes the tumour immune microenvironment, but the underlying mechanisms have not been fully clarified. We found that STAT3 inhibition could induce immunogenic cell death (ICD) of HCC cells via translocation of the “eat me” molecule calreticulin to the cell surface and a significant reduction in the expression of the “don’t eat me” molecule leucocyte surface antigen CD47. STAT3 inhibition promoted dendritic cell (DC) activation and enhanced the recognition and phagocytosis of HCC cells by macrophages. Furthermore, STAT3 inhibition prevented the expression of key glycolytic enzymes, facilitating the induction of ICD in HCC. Interestingly, STAT3 directly regulated the transcription of CD47 and solute carrier family 2 member 1 (SLC2A1; also known as GLUT1). In subcutaneous and orthotopic transplantation mouse tumour models, the STAT3 inhibitor napabucasin prevented tumour growth and induced the expression of calreticulin and the protein disulfide isomerase family A member 3 (PDIA3; also known as ERp57) but suppressed that of CD47 and GLUT1. Meanwhile, the amount of tumour‐infiltrated DCs and macrophages increased, along with the expression of costimulatory molecules. More CD4+ and CD8+ T cells accumulated in tumour tissues, and CD8+ T cells had lower expression of checkpoint molecules such as lymphocyte activation gene 3 protein (LAG‐3) and programmed cell death protein 1 (PD‐1). Significantly, the antitumour immune memory response was induced by treatment targeting STAT3. These findings provide a new mechanism for targeting STAT3‐induced ICD in HCC, and confirms STAT3 as a potential target for the treatment of HCC via reshaping the tumour immune microenvironment.

BackgroundThe occurrence of abdominal aortic aneurysms (AAAs) is related to the disorder of immune microenvironment. Cuprotosis was reported to influence the immune microenvironment. The objective of this study is to identify cuprotosis-related genes involved in the pathogenesis and progression of AAA.MethodsDifferentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) in mouse were identified following AAA through high-throughput RNA sequencing. The enrichment analyses of pathway were selected through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG). The validation of cuprotosis-related genes was conducted through immunofluorescence and western blot analyses.ResultsTotally, 27616 lncRNAs and 2189 mRNAs were observed to be differentially expressed (|Fold Change| ≥ 2 and q< 0.05) after AAA, including 10424 up-regulated and 17192 down-regulated lncRNAs, 1904 up-regulated and 285 down-regulated mRNAs. Gene ontology and KEGG pathway analysis showed that the DElncRNAs and DEmRNAs were implicated in many different biological processes and pathways. Furthermore, Cuprotosis-related genes (NLRP3, FDX1) were upregulated in the AAA samples compared with the normal one.ConclusionCuprotosis-related genes (NLRP3,FDX1) involved in AAA immune environment might be critical for providing new insight into identification of potential targets for AAA therapy.

BackgroundOvarian cancer (OC) is highly heterogeneous and has a poor prognosis. A better understanding of OC biology could provide more effective therapeutic paradigms for different OC subtypes.MethodsTo reveal the heterogeneity of T cell-associated subclusters in OC, we performed an in-depth analysis of single-cell transcriptional profiles and clinical information of patients with OC. Then, the above analysis results were verified by qPCR and flow cytometry examine.ResultsAfter screening by threshold, a total of 85,699 cells in 16 ovarian cancer tissue samples were clustered into 25 major cell groups. By performing further clustering of T cell-associated clusters, we annotated a total of 14 T cell subclusters. Then, four distinct single-cell landscapes of exhausted T (Tex) cells were screened, and SPP1 + Tex significantly correlated with NKT cell strength. A large amount of RNA sequencing expression data combining the CIBERSORTx tool were labeled with cell types from our single-cell data. Calculating the relative abundance of cell types revealed that a greater proportion of SPP1 + Tex cells was associated with poor prognosis in a cohort of 371 patients with OC. In addition, we showed that the poor prognosis of patients in the high SPP1 + Tex expression group might be related to the suppression of immune checkpoints. Finally, we verified in vitro that SPP1 expression was significantly higher in ovarian cancer cells than in normal ovarian cells. By flow cytometry, knockdown of SPP1 in ovarian cancer cells could promote tumorigenic apoptosis.ConclusionThis is the first study to provide a more comprehensive understanding of the heterogeneity and clinical significance of Tex cells in OC, which will contribute to the development of more precise and effective therapies.

Simultaneous spatio-temporal description of tumor microvasculature, blood-brain barrier, and immune activity is pivotal to understanding the evolution mechanisms of highly aggressive glioblastoma, one of the most common primary brain tumors in adults. However, the existing intravital imaging modalities are still difficult to achieve it in one step. Here, we present a dual-scale multi-wavelength photoacoustic imaging approach cooperative with/without unique optical dyes to overcome this dilemma. Label-free photoacoustic imaging depicted the multiple heterogeneous features of neovascularization in tumor progression. In combination with classic Evans blue assay, the microelectromechanical system based photoacoustic microscopy enabled dynamic quantification of BBB dysfunction. Concurrently, using self-fabricated targeted protein probe (αCD11b-HSA@A1094) for tumor-associated myeloid cells, unparalleled imaging contrast of cells infiltration associated with tumor progression was visualized by differential photoacoustic imaging in the second near-infrared window at dual scale. Our photoacoustic imaging approach has great potential for tumor-immune microenvironment visualization to systematically reveal the tumor infiltration, heterogeneity, and metastasis in intracranial tumors.

There is increasing evidence in a range of cancer types that the microbiome plays a direct role in modulating the anti-cancer immune response both at the gut level and systemically. Differences in the gut microbiota have been shown to correlate with differences in immunotherapy responses in a range of non-gastrointestinal tract cancers. DNA mismatch repair-deficient (dMMR) colorectal cancer (CRC) is radically different to DNA mismatch repair-proficient (pMMR) CRC in clinical phenotype and in its very good responses to immunotherapy. While this has usually been thought to be due to the high mutational burden in dMMR CRC, the gut microbiome is radically different in dMMR and pMMR CRC in terms of both composition and diversity. It is probable that differences in the gut microbiota contribute to the varied responses to immunotherapy in dMMR versus pMMR CRC. Targeting the microbiome offers a way to boost the response and increase the selection of patients who might benefit from this therapy. This paper reviews the available literature on the role of the microbiome in the response to immunotherapy in dMMR and pMMR CRC, explores the potential causal relationship and discusses future directions for study in this exciting and rapidly changing field. [ABSTRACT FROM AUTHOR]

Introduction: Endoplasmic reticulum stress (ERS) has sizeable affect on cancer proliferation, metastasis, immunotherapy and chemoradiotherapy resistance. However, the effect of ERS on the biochemical recurrence (BCR) of prostate cancer patients remains elusive. Here, we generated an ERS-related genes risk signature to evaluate the physiological function of ERS in PCa with BCR. Methods: We collected the ERS-related genes from the GeneCards. The edgeR package was used to screen the differential ERS-related genes in PCa from TCGA datasets. ERS-related gene risk signature was then established using LASSO and multivariate Cox regression models and validated by GEO data sets. Nomogram was developed to assess BCR-free survival possibility. Meanwhile, the correlations between ERS-related signature, gene mutations, drug sensitivity and tumor microenvironment were also investigated. Results: We obtained an ERS risk signature consisting of five genes (AFP, COL10A1, DNAJB1, EGF and PTGS2). Kaplan Meier survival analysis and ROC Curve analysis indicated that the high risk score of ERS-related gene signature was associated with poor BCR-free prognosis in PCa patients. Besides, immune cell infiltration and immune checkpoint expression levels differed between highand low-risk scoring subgroups. Moreover, drug sensitivity analyzed indicated that high-risk score group may be involved in apoptosis pathway. Discussion: This study comprehensively analyzed the characteristics of ERS related genes in PCa, and created a five-gene signature, which could effectively predict the BCR time of PCa patients. Targeting ERS related genes and pathways may provide potential guidance for the treatment of PCa. [ABSTRACT FROM AUTHOR]

Background: PI3K pathway is the most frequently mutated pathway in head and neck squamous cell carcinoma (HNSC), which plays a crucial role in tumorigenesis and progression. In the present study, we aimed to investigate the role of PI3K pathway mutation in clinical prognosis prediction and the relationship with immune microenvironment and response rate to immunotherapy. Methods: We collected 129 samples with immunotherapy information from MSKCC-2019 cohort as well as 501 and 40 samples from TCGA-HNSC and MD-Anderson non-immunotherapy cohorts, respectively. Somatic mutation data was utilized to characterize the mutational status of the PI3K pathway. Subsequently, we further analyzed the differences in prognosis, immunotherapy response, genomic alterations, functional characteristics, and immune microenvironment between the mutation and wild groups. Results: The Kaplan-Meier survival curves displayed that PI3K pathway mutation predicted observably prolonged overall survival (OS) in the immunotherapy cohort MSKCC-2019 (p = 0.012) but did not reach statistical significance in the non-immunotherapy cohorts TCGA-HNSC (p = 0.68) and MD-Anderson (p = 0.68). After incorporating several clinicopathologic features such as age, gender, and tumor mutation burden (TMB), the results of multivariate Cox regression analysis also demonstrated that the PI3K pathway mutation could indicate better immunotherapy outcomes in HNSC patients with a hazard ratio (HR) of 0.533 (95% CI: 0.313–0.910; p = 0.021) in the immunotherapy cohort MSKCC-2019, compared with 0.888 (95% CI: 0.636–1.241; p = 0.487) and 1.939 (95% CI: 0.483–7.781; p = 0.351) in the non-immunotherapy cohorts TCGA-HNSC and MD-Anderson. In addition, the results of the subclass mapping (SubMap) and the tumor immune dysfunction and exclusion (TIDE) also consistently suggested that patients in the mutation group are more likely to benefit from immunotherapy. And further studies showed that the mutation group owned significantly higher TMB, activated immune-related pathways, richer abundance of immune cells, and higher expression levels of immunomodulators. To improve the prognosis of the wild group, we identified five relatively sensitive potential drugs for the wild group, including "BMS-536924," "linsitinib," "NVP-TAE684," "PLX-4720," and "clonazepam." Conclusions: The PI3K pathway mutation status could be considered as a potential biomarker to predict better immunotherapeutic efficacy and clinical outcomes after immunotherapy in HNSC patients. [ABSTRACT FROM AUTHOR]

Nonalcoholic steatohepatitis (NASH) is one of the most common chronic liver diseases worldwide and no effective drugs or treatments have been approved for disease management. Recently, bariatric surgery (BS) is considered to be a novel disease-modifying therapy for NASH and liver metabolic diseases, according to clinical follow-up studies. Despite the revealment of physiopathological alterations, underlying mechanisms and key factors remain indeterminate. This study included multiple bulk RNA-sequencing datasets to investigate transcriptome variation in one-year follow-up BS and diet management (Diet) NASH patients' liver biopsies. Liver functions, fibrosis, and carcinogenesis were predicted in liver samples via hallmark-based function enrichment analysis. Key factors generated from multi-dataset comparison were further assessed with hepatocellular carcinoma (HCC) progression and prognosis. BS leads to active gene expression alterations in NASH liver in comparison to diet management (Diet). Both approaches reduce cell stress and immune response, whereas BS contributes to higher metabolic levels and lower apoptosis levels. The macrophage infiltration, adipose accumulation, and fibroblast activation were revealed to be lower in post-BS NASH livers, further demonstrating positive correlations mutually. Seven key genes (MNDA, ALOX5AP, PECAM1, SPP1, CD86, FGF21, CSTA) were screened out as potential macrophage-associated and carcinogenetic factors suppressed by BS. SPP1 was identified as a crucial factor participating in BS intervened NASH-HCC progression. This study determined that BS exerts potentially superior protective functions in NASH livers compared to diet management. SPP1 may serve as a novel factor to study the functionalities of BS on NASH patients. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) is a severe condition regulated by complex molecular alterations. This study aimed to identify potential nicotinamide adenine dinucleotide (NAD+) metabolism-associated diagnostic markers of IS and explore their associations with immune dynamics. Weighted Gene Co-expression Network Analysis and single-sample gene set enrichment analysis (ssGSEA) were employed to identify key gene modules on the GEO dataset (GSE16561). LASSO regression was used to identify diagnostic genes. A diagnostic model was then developed using the training dataset, and its performance was assessed using a validation dataset (GSE22255 dataset). Associations between hub genes and immune cells, immune response genes, and human leukocyte antigen (HLA) genes were assessed by ssGSEA. A regulatory network was constructed using mirBase and TRRUST databases. A total of 20 NAD+ metabolic genes exhibited noteworthy expression variations. Within the module notably associated with NAD+ metabolism, 19 specific genes were included in the diagnostic model, which was validated on the GSE22255 dataset (AUC: 0.733). There were significant disparities in immune cell populations, immune response genes, and HLA gene expression, all of which were associated with the hub genes. A regulatory network composed of 153 edges and 103 nodes was constructed. This study advances our understanding of IS by providing insights into NAD+ metabolism and gene interactions, contributing to potential diagnostic innovations in IS. • Identified NAD+ metabolism-associated markers for ischemic stroke (IS). • Used WGCNA and ssGSEA for key gene modules on GSE16561 dataset. • Constructed a diagnostic model using LASSO regression on GSE22255 dataset. • Explored associations between hub genes, immune dynamics, and HLA genes. • Created a regulatory network using mirBase and TRRUST databases. [ABSTRACT FROM AUTHOR]

Janus kinase/signal transduction and transcription activation (JAK/STAT) pathways were originally thought to be intracellular signaling pathways that mediate cytokine signals in mammals. Existing studies show that the JAK/STAT pathway regulates the downstream signaling of numerous membrane proteins such as such as G-protein-associated receptors, integrins and so on. Mounting evidence shows that the JAK/STAT pathways play an important role in human disease pathology and pharmacological mechanism. The JAK/STAT pathways are related to aspects of all aspects of the immune system function, such as fighting infection, maintaining immune tolerance, strengthening barrier function, and cancer prevention, which are all important factors involved in immune response. In addition, the JAK/STAT pathways play an important role in extracellular mechanistic signaling and might be an important mediator of mechanistic signals that influence disease progression, immune environment. Therefore, it is important to understand the mechanism of the JAK/STAT pathways, which provides ideas for us to design more drugs targeting diseases based on the JAK/STAT pathway. In this review, we discuss the role of the JAK/STAT pathway in mechanistic signaling, disease progression, immune environment, and therapeutic targets.

Genomic instability is a characteristic of tumors, and recent studies have shown that it is related to a poor prognosis of multiple cancers. Long non-coding RNAs (lncRNAs) have become a research hotspot in recent years, and many unknown biological functions are being explored. For example, some lncRNAs play a critical role in the initiation and progression of multiple cancer types by modulating genomic instability. However, the role of genomic instability-related lncRNAs in liver cancer remains unclear. Therefore, we screened genomic instability-related lncRNAs by combining somatic mutation data and RNA-Seq data in The Cancer Genome Atlas (TCGA) database. We established a genomic instability-related lncRNA model (GLncM) involving ZFPM2-AS1 and MIR210HG to predict the hepatocellular carcinoma (HCC) prognosis and further explore the clinical significance of these lncRNAs, and the robustness of the model was validated in the verification set. Thereafter, we calculated the immune score for each patient and explored the relationship between genome instability and the immune microenvironment. The analysis indicated that this model was better than the immune microenvironment in predicting the prognosis of HCC patients, suggesting that the GLncM may be an effective indicator of HCC prognosis and providing a new direction and strategy for estimating the prognosis of HCC patients.

Immune environment plays an important role in the management of liver cancer. The current study aimed to explore the change of NK and NKT cells, IL-17A, CD4+ T and CD8+ T cells in refractory liver metastases patients before and after CalliSpheres® microspheres transarterial chemoembolization (CSM-TACE). Peripheral blood (PB) samples from 35 refractory liver metastases patients were collected before CSM-TACE (baseline), 2 days (D2) and 5 days (D5) after CSM-TACE. Then, NK and NKT cells, IL-17A, CD4+ T and CD8+ T cells from PB samples were detected. All enrolled patients successfully completed CSM-TACE procedure and achieved disease control rate of 100% after 1 month. NKT cells were increased from baseline to D2 and D5 [median (range): 5.88% (1.53%-12.05%) vs. 9.54% (5.19%-15.71%) vs. 7.12% (2.77%-13.29%)], NK cells were also enhanced from baseline to D2 and D5 [median (range): 14.35% (5.85%-20.52%) vs. 20.36% (15.88%-27.30%) vs. 30.82% (22.18%-37.72%)], while IL-17A was declined from baseline to D2 and D5 [median (range): 22.11 (9.46-39.18) pg/ml vs. 12.41 (3.24-26.84) pg/ml vs. 6.55 (1.11-20.98) pg/ml]. Furthermore, IL-17A was negatively correlated with the NK and NKT cells at baseline, D2 and D5 (all p <.05), respectively. Additionally, CD4+ T cells and CD4+ T/CD8+ T ratio were increased while CD8+ T cells were declined from baseline to D2 and D5 (all p <.05). NK cells, NKT cells, and CD4+ T cells are increased but IL-17A and CD8+ T cells are declined after CSM-TACE in refractory liver metastases. [ABSTRACT FROM AUTHOR]

Yu Zhang,1,2,&ast; Xin Zhang,3,&ast; Zhuoyi Jin,2 Huiyan Chen,4 Chenjing Zhang,2 wangyue Wang,2 Jiyong Jing,5 Wensheng Pan1,2 1Department of Clinical Medicine, Medical College of Soochow University, Suzhou, 215006, People’s Republic of China; 2Department of Gastroenterology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, People’s Republic of China; 3Department of Pathology, Laboratory Medicine Center, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, People’s Republic of China; 4School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, People’s Republic of China; 5Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wensheng PanDepartment of Gastroenterology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College; Institute of Gastrointestinal Diseases, Hangzhou Medical College; Zhejiang Provincial Engineering Laboratory of Diagnosis, Treatment and Pharmaceutical Development of Gastrointestinal Tract Tumors, No. 158 Shangtang Road, Hangzhou, 310014, People’s Republic of ChinaTel/Fax +86 57685893430Email wspan223@163.comJiyong JingZhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, No. 158 Shangtang Road, Hangzhou, 310014, People’s Republic of ChinaEmail jiyong_jing@126.comPurpose: Colorectal cancer (CRC) can develop via a hypermutagenic pathway characterized by frequent somatic DNA base-pair mutations. Alternatively, the immunogenicity of tumor cells themselves may influence the anticancer activity of the immune effector cells. Impaired DNA repair mechanisms drive mutagenicity, which then increase the neoantigen load and immunogenicity. However, no studies have analyzed immune checkpoint protein expression, particularly programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1), in adenoma–carcinoma progression and its relationship with the emergence of other DNA repair gene mutation.Materials and Methods: We investigated mutations of 10 genes involved in DNA repair function: XRCC1, TP53, MLH1, MSH, KRAS, GSTP, UMP, MTHF, DPYD, and ABCC2. We performed sequencing to determine mutations and immunohistochemistry of immune checkpoints in clinical samples and determined changes in XRCC1 expression during progression through the adenoma–carcinoma pathway. We further investigated the prognostic associations of gene XRCC1 according to the expression, mutational profile, and immune profile using The Cancer Genome Atlas-colon adenocarcinoma (TCGA-COAD) dataset.Results: From clinical samples, XRCC1 mutation demonstrated the strongest association with adenomas with a mutation frequency of 56.2% in adenomas and 34% in CRCs (p =0.016). XRCC1 was abnormally expressed and altered by mutations contributing to adenoma carcinogenesis. High expression of XRCC1, CD4, FOXP3, and PD-1/PD-L1 showed an overall upward trend with increased lesion severity (all p < 0.01). PD-1/PD-L1 expression and CD4+ intraepithelial lymphocytes (IELs) correlated with cytological dysplasia progression, specifically in patients with wild-type XRCC1 (all p < 0.01), whereas FOXP3 expression was independently associated with adenoma–carcinoma progression. From TCGA-COAD analysis, XRCC1 expression was associated with patients survival, tumor-infiltrating lymphocytes and immune marker expression.Conclusion: Increased IEL density and PD-1/PD-L1 expression correlate with cytological dysplasia progression and specifically with the XRCC1 mutation status in CRC. Our findings support a stepwise dysplasia-carcinoma sequence of adenoma carcinogenesis and an XRCC1 hypermutated phenotypic mechanism of lesions.Keywords: adenoma–carcinoma, immune environment, PD-1/PD-L1, tumor-infiltrating lymphocytes, XRCC1

Bladder cancer (BC) is the most common malignancy of the urinary system. Pyroptosis is a host programmed cell death. However, the effects of pyroptosis-related lncRNAs (PRLs) on BC have not yet been completely elucidated. In this study, a prognostic PRLs model and two ceRNA networks were established using sufficient bioinformatics analysis and preliminary RT-qPCR validation in vitro. 6 PRLs were identified to construct a prognostic model. Then, the prognostic model risk score was verified to be an effective independent factor (Training cohort: Univariate analysis: HR = 1.786, 95% Cl = 1.416-2.252, p < 0.001; multivariate analysis: HR = 1.664, 95% Cl = 1.308-2.116,p < 0.001; testing cohort: Univariate analysis: HR = 1.268, 95% Cl = 1.144-1.405, p < 0.001; multivariate analysis: HR = 1.141, 95% Cl = 1.018-1.280, p = 0.024). Moreover, ROC and nomogram were performed to assess the accuracy of this signature (1-year-AUC = 0.764, 3-years-AUC = 0.769, 5-years-AUC = 0.738). Consequently, we evaluated the survival curves of these 6 lncRNAs using Kaplan-Meier survival analysis, demonstrating that MAFG-DT was risk lncRNA, while OCIAD1-AS1, SLC25A25-AS1, SNHG18, PSMB8-AS1 and TRM31-AS1 were protective lncRNAs. We found a strong correlation between PRLs and tumor immune microenvironment by Pearson's correlation analysis. As for sensitivity of anti-tumor drugs, the high-risk group was more sensitive to Sorafenib, Bicalutamide and Cisplatin, while the low-risk group was more sensitive to AKT.inhibitor.VIII, Salubrinal and Lenalidomide, etc. Meanwhile, we identified lncRNA OCIAD1-AS1/miR-141-3p/GPM6B and lncRNA OCIAD1-AS1/miR-200a-3p/AKAP11 regulatory axes, which may play a potential role in the progression of BC. [ABSTRACT FROM AUTHOR]

Background: Abnormal chromosome segregation is identified to be a common hallmark of cancer. However, the specific predictive value of it in lung adenocarcinoma (LUAD) is unclear. Method: The RNA sequencing and the clinical data of LUAD were acquired from The Cancer Genome Atlas (TACG) database, and the prognosis-related genes were identified. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were carried out for functional enrichment analysis of the prognosis genes. The independent prognosis signature was determined to construct the nomogram Cox model. Unsupervised clustering analysis was performed to identify the distinguishing clusters in LUAD-samples based on the expression of chromosome segregation regulators (CSRs). The differentially expressed genes (DEGs) and the enriched biological processes and pathways between different clusters were identified. The immune environment estimation, including immune cell infiltration, HLA family genes, immune checkpoint genes, and tumor immune dysfunction and exclusion (TIDE), was assessed between the clusters. The potential small-molecular chemotherapeutics for the individual treatments were predicted via the connectivity map (CMap) database. Results: A total of 2,416 genes were determined as the prognosis-related genes in LUAD. Chromosome segregation is found to be the main bioprocess enriched by the prognostic genes. A total of 48 CSRs were found to be differentially expressed in LUAD samples and were correlated with the poor outcome in LUAD. Nine CSRs were identified as the independent prognostic signatures to construct the nomogram Cox model. The LUAD-samples were divided into two distinct clusters according to the expression of the 48 CSRs. Cell cycle and chromosome segregation regulated genes were enriched in cluster 1, while metabolism regulated genes were enriched in cluster 2. Patients in cluster 2 had a higher score of immune, stroma, and HLA family components, while those in cluster 1 had higher scores of TIDES and immune checkpoint genes. According to the hub genes highly expressed in cluster 1, 74 small-molecular chemotherapeutics were predicted to be effective for the patients at high risk. Conclusion: Our results indicate that the CSRs were correlated with the poor prognosis and the possible immunotherapy resistance in LUAD. [ABSTRACT FROM AUTHOR]

Cells utilize different metabolic processes to maintain their growth and differentiation. Tumor cells have made some metabolic changes to protect themselves from malnutrition. These metabolic alterations affect the tumor microenvironment and macroenvironment. Developing drugs targeting these metabolic alterations could be a good direction. In this review, we briefly introduce metabolic changes/regulations of the tumor macroenvironment and microenvironment and summarize potential drugs targeting the metabolism in diffuse large B-cell lymphoma.

Background: Chromobox (CBX) proteins are essential components of polycomb group proteins and perform essential functions in bladder cancer (BLCA). However, research on CBX proteins is still limited, and the function of CBXs in BLCA has not been well illustrated. Methods and Results: We analyzed the expression of CBX family members in BLCA patients from The Cancer Genome Atlas database. By Cox regression analysis and survival analysis, CBX6 and CBX7 were identified as potential prognostic factors. Subsequently, we identified genes associated with CBX6/7 and performed enrichment analysis, and they were enriched in urothelial carcinoma and transitional carcinoma. Mutation rates of TP53 and TTN correlate with expression of CBX6/7. In addition, differential analysis indicated that the roles played by CBX6 and CBX7 may be related to immune checkpoints. The CIBERSORT algorithm was used to screen out immune cells that play a role in the prognosis of bladder cancer patients. Multiplex immunohistochemistry staining confirmed a negative correlation between CBX6 and M1 macrophages, as well as a consistent alteration in CBX6 and regulatory T cells (Tregs), a positive correlation between CBX7 and resting mast cells, and a negative correlation between CBX7 and M0 macrophages. Conclusions: CBX6 and CBX7 expression levels may assist in predicting the prognosis of BLCA patients. CBX6 may contribute to a poor prognosis in patients by inhibiting M1 polarization and promoting Treg recruitment in the tumor microenvironment, while CBX7 may contribute to a better prognosis in patients by increasing resting mast cell numbers and decreasing macrophage M0 content.

Brain-gut axis refers to the bidirectional functional connection between the brain and the gut, which sustains vital functions for vertebrates. This connection also underlies the gastrointestinal (GI) comorbidities associated with brain disorders. Using a mouse model of glioma, based on the orthotopic injection of GL261 cell line in syngeneic C57BL6 mice, we show that late-stage glioma is associated with GI functional alteration and with a shift in the level of some bacterial metabolites in the cecum. By performing cecal content transfer experiments, we further show that cancer-associated alteration in cecal metabolites is involved in end-stage disease progression. Antibiotic treatment results in a slight but significant delay in mice death and a shift in the proportion of myeloid cells in the brain tumor environment. This work rationally considers microbiota modulating strategies in the clinical management of patients with late-stage glioma. [ABSTRACT FROM AUTHOR]

Abstract Background Although the tumour immune microenvironment is known to significantly influence immunotherapy outcomes, its association with changes in gene expression patterns in hepatocellular carcinoma (HCC) during immunotherapy and its effect on prognosis have not been clarified. Methods A total of 365 HCC samples from The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) dataset were stratified into training datasets and verification datasets. In the training datasets, immune-related genes were analysed through univariate Cox regression analyses and least absolute shrinkage and selection operator (LASSO)-Cox analyses to build a prognostic model. The TCGA-LIHC, GSE14520, and Imvigor210 cohorts were subjected to time-dependent receiver operating characteristic (ROC) and Kaplan–Meier survival curve analyses to verify the reliability of the developed model. Finally, single-sample gene set enrichment analysis (ssGSEA) was used to study the underlying molecular mechanisms. Results Five immune-related genes (LDHA, PPAT, BFSP1, NR0B1, and PFKFB4) were identified and used to establish the prognostic model for patient response to HCC treatment. ROC curve analysis of the TCGA (training and validation sets) and GSE14520 cohorts confirmed the predictive ability of the five-gene-based model (AUC > 0.6). In addition, ROC and Kaplan–Meier analyses indicated that the model could stratify patients into a low-risk and a high-risk group, wherein the high-risk group exhibited worse prognosis and was less sensitive to immunotherapy than the low-risk group. Functional enrichment analysis predicted potential associations of the five genes with several metabolic processes and oncological signatures. Conclusions We established a novel five-gene-based prognostic model based on the tumour immune microenvironment that can predict immunotherapy efficacy in HCC patients.

Background. Sleep deprivation (SD)-induced cognitive impairment is highly prevalent worldwide and has attracted widespread attention. The temporal and spatial oscillations of circadian genes are severely disturbed after SD, leading to a progressive loss of their physiological rhythms, which in turn affects memory function. However, there is a lack of research on the role of circadian genes and memory function after SD. Therefore, the present study aims to investigate the relationship between circadian genes and memory function and provide potential therapeutic insights into the mechanism of SD-induced memory impairment. Methods. Gene expression profiles of GSE33302 and GSE9442 from the Gene Expression Omnibus (GEO) were applied to identify differentially expressed genes (DEGs). Subsequently, both datasets were subjected to Gene Set Enrichment Analysis (GSEA) to determine the overall gene changes in the hippocampus and brain after SD. A Gene Oncology (GO) analysis and Protein-Protein Interaction (PPI) analysis were employed to explore the genes related to circadian rhythm, with their relationship and importance determined through a correlation analysis and a receiver operating characteristic curve (ROC), respectively. The water maze experiments detected behavioral changes related to memory function in SD rats. The expression of circadian genes in several critical organs such as the brain, heart, liver, and lungs and their correlation with memory function was investigated using several microarrays. Finally, changes in the hippocampal immune environment after SD were analyzed using the CIBERSORT in R software. Results. The quality of the two datasets was very good. After SD, changes were seen primarily in genes related to memory impairment and immune function. Genes related to circadian rhythm were highly correlated with engagement in muscle structure development and circadian rhythm. Seven circadian genes showed their potential therapeutic value in SD. Water maze experiments confirmed that SD exacerbates memory impairment-related behaviors, including prolonged escape latencies and reduced numbers of rats crossing the platform. The expression of circadian genes was verified, while some genes were also significant in the heart, liver, and lungs. All seven circadian genes were also associated with memory markers in SD. The contents of four immune cells in the hippocampal immune environment changed after SD. Seven circadian genes were related to multiple immune cells. Conclusions. In the present study, we found that SD leads to memory impairment accompanied by changes in circadian rhythm-related genes. Seven circadian genes play crucial roles in memory impairment after SD. Naïve B cells and follicular helper T cells are closely related to SD. These findings provide new insights into the treatment of memory impairment caused by SD. [ABSTRACT FROM AUTHOR]

Papillary renal cell carcinoma (pRCC) is one of the epithelial renal cell carcinoma (RCC) histological subtypes. Ferroptosis is a new iron-dependent form of cell death that has been seen in a variety of clinical situations. Using differentially expressed ferroptosis-related long non-coding RNAs (lncRNAs) from patients with pRCC in The Cancer Genome Atlas; we built a prognostic lncRNA-based signature. We discovered seven different lncRNAs that were strongly linked to the prognosis of patients with pRCC. High-risk scores were linked to a poor prognosis for pRCC, which was confirmed by the findings of Kaplan–Meier studies. In addition, the constructed lncRNA signature has a 1-year area under the curve (AUC) of 0.908, suggesting that it has a high predictive value in pRCC. In the high-risk group, Gene set enrichment analyses (GSEA) analysis identified immunological and tumor-related pathways. Furthermore, single-sample GSEA (ssGSEA) revealed significant differences in T cell functions checkpoint, antigen presenting cell (APC) co-stimulation, inflammation promoting, and para inflammation between the two groups with different risk scores. In addition, immune checkpoints like PDCD1LG2 (PD-L2), LAG3, and IDO1 were expressed differently in the two risk groups. In summary, a novel signature based on ferroptosis-related lncRNAs could be applied in predicting the prognosis of patients with pRCC.

Traditional cell lines and xenograft models have been widely recognized and used in research. As a new research model, organoids have made significant progress and development in the past 10 years. Compared with traditional models, organoids have more advantages and have been applied in cancer research, genetic diseases, infectious diseases, and regenerative medicine. This review presented the advantages and disadvantages of organoids in physiological development, pathological mechanism, drug screening, and organ transplantation. Further, this review summarized the current situation of vascularization, immune microenvironment, and hydrogel, which are the main influencing factors of organoids, and pointed out the future directions of development.

Nonalcoholic steatohepatitis (NASH) is one of the most common chronic liver diseases worldwide and no effective drugs or treatments have been approved for disease management. Recently, bariatric surgery (BS) is considered to be a novel disease-modifying therapy for NASH and liver metabolic diseases, according to clinical follow-up studies. Despite the revealment of physiopathological alterations, underlying mechanisms and key factors remain indeterminate. This study included multiple bulk RNA-sequencing datasets to investigate transcriptome variation in one-year follow-up BS and diet management (Diet) NASH patients’ liver biopsies. Liver functions, fibrosis, and carcinogenesis were predicted in liver samples via hallmark-based function enrichment analysis. Key factors generated from multi-dataset comparison were further assessed with hepatocellular carcinoma (HCC) progression and prognosis. BS leads to active gene expression alterations in NASH liver in comparison to diet management (Diet). Both approaches reduce cell stress and immune response, whereas BS contributes to higher metabolic levels and lower apoptosis levels. The macrophage infiltration, adipose accumulation, and fibroblast activation were revealed to be lower in post-BS NASH livers, further demonstrating positive correlations mutually. Seven key genes (MNDA, ALOX5AP, PECAM1, SPP1, CD86, FGF21, CSTA) were screened out as potential macrophage-associated and carcinogenetic factors suppressed by BS. SPP1 was identified as a crucial factor participating in BS intervened NASH-HCC progression. This study determined that BS exerts potentially superior protective functions in NASH livers compared to diet management. SPP1 may serve as a novel factor to study the functionalities of BS on NASH patients.

Lymphocyte antigen 96 (LY96) plays an important role in innate immunity and has been reported to be associated with various neurological diseases. However, its role in Parkinson's disease (PD) remains unclear. Transcriptome data from a total of 49 patients with PD and 34 healthy controls were downloaded from the Gene Expression Omnibus (GEO) database to analyse the expression pattern of LY96 and its relationship with gene function and immune-related markers. In addition, peripheral blood samples were collected from clinical patients to validate LY96 mRNA expression levels. Finally, an in vitro cell model of PD based on highly differentiated SH-SY5Y cells was constructed, with small interfering RNA-silenced LY96 expression, and LY96 mRNA level, cell viability, flow cytometry, and mitochondrial membrane potential assays were performed. The results of the analyses of the GEO database and clinical samples revealed significantly abnormally high LY96 expression in patients with PD compared with healthy controls. The results of cell experiments showed that inhibiting LY96 expression alleviated adverse cellular effects by increasing cell viability, reducing apoptosis, and reducing oxidative stress. Gene set enrichment analysis showed that LY96 was positively correlated with T1 helper cells, T2 helper cells, neutrophils, natural killer T cells, myeloid-derived suppressor cells, macrophages, and activated CD4 cells, and may participate in PD through natural killer cell-mediated cytotoxicity pathways and extracellular matrix receptor interaction pathways. These findings suggested that LY96 might be a novel potential biomarker for PD, and offer insights into its immunoregulatory role. • This study for the first time indicates that LY96 can serve as a potential diagnostic biomarker for Parkinson's disease; • This study extends the discovered biological functions of LY96 ; • This study explores the changes in the immune environment in Parkinson's disease; • This study investigated the abnormal expression of immune cells caused by LY96 in Parkinson's disease for the first time. [ABSTRACT FROM AUTHOR]

Introduction: The purpose of this study was to detect the expression of local cytokines in cervical mucosa between patients with transient and persistent HR-HPV infection with or without CIN. Methodology: A total of 150 patients who were diagnosed as HR-HPV infection in Tianjin Central Hospital of Obstetrics and Gynecology from January 2016 to December 2016 were included in this study. The expression levels of 9 cytokines in 150 patients with HR-HPV infection, including interleukin (IL)-1ß, IL-4, IL-6, IL-8, IL-10, IL-12, IL-12p70, IL-21, interferon (IFN)-γ and tumor necrosis factor (TNF)-a, were simultaneously measured by using a multiplex immunoassay. Moreover, HR-HPV genotype was performed by using pyrosequencing. The association between cytokines and HPV genotype was also investigated. Results: There was a statistically significant difference in IL-1ß level between patients with HPV transient infection and HPV persistent infection (p = 0.041). There were statistically significant differences in the levels of IL-1ß, IL-10, IL-21 and TNF-a between patients with low grade squamous intraepithelial lesion (LSIL) and high grade squamous intraepithelial lesion (HSIL) (p = 0.011, p = 0.008, p = 0.046 and p = 0.019, respectively). Conclusions: Pro-inflammatory cytokines, IL-1ß and TNF-a, and Th2 type cytokines, IL-10 and IL-21, became stronger in cervical mucosa with the progression of CIN. IL-1ß may be advantageous for HR-HPV persistent infection. [ABSTRACT FROM AUTHOR]

Background: Although the tumour immune microenvironment is known to significantly influence immunotherapy outcomes, its association with changes in gene expression patterns in hepatocellular carcinoma (HCC) during immunotherapy and its effect on prognosis have not been clarified.Methods: A total of 365 HCC samples from The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) dataset were stratified into training datasets and verification datasets. In the training datasets, immune-related genes were analysed through univariate Cox regression analyses and least absolute shrinkage and selection operator (LASSO)-Cox analyses to build a prognostic model. The TCGA-LIHC, GSE14520, and Imvigor210 cohorts were subjected to time-dependent receiver operating characteristic (ROC) and Kaplan-Meier survival curve analyses to verify the reliability of the developed model. Finally, single-sample gene set enrichment analysis (ssGSEA) was used to study the underlying molecular mechanisms.Results: Five immune-related genes (LDHA, PPAT, BFSP1, NR0B1, and PFKFB4) were identified and used to establish the prognostic model for patient response to HCC treatment. ROC curve analysis of the TCGA (training and validation sets) and GSE14520 cohorts confirmed the predictive ability of the five-gene-based model (AUC > 0.6). In addition, ROC and Kaplan-Meier analyses indicated that the model could stratify patients into a low-risk and a high-risk group, wherein the high-risk group exhibited worse prognosis and was less sensitive to immunotherapy than the low-risk group. Functional enrichment analysis predicted potential associations of the five genes with several metabolic processes and oncological signatures.Conclusions: We established a novel five-gene-based prognostic model based on the tumour immune microenvironment that can predict immunotherapy efficacy in HCC patients. [ABSTRACT FROM AUTHOR]

The accumulation of mutated somatic cells due to the incompetency of body’s immune system may lead to tumor onset. Therefore, enhancing the ability of the system to eliminate such cells should be the core of tumor therapy. The intrinsic antitumor immunity is triggered by tumor-specific antigens (TSA) or TSA-sensitized dendritic cells (DC). Once initiated, specific anti-tumor antibodies are produced and tumor-specific killer immune cells, including cytotoxic T lymphocytes (CTL), NK cells, and macrophages, are raised or induced. Several strategies may enhance antitumor action of immune system, such as supplying tumor-targeted antibody, activating T cells, enhancing the activity and tumor recognition of NK cells, promoting tumor-targeted phagocytosis of macrophages, and eliminating the immunosuppressive myeloid-derived suppressor cells (MDSCs) and Treg cells. Apart from the immune system, the removal of tumor burden still needs to be assisted by drugs, surgery or radiation. And the body’s internal environment and tumor microenvironment should be improved to recover immune cell function and prevent tumor growth. Multiple microenvironment modulatory therapies may be applied, including addressing hypoxia and oxidative stress, correcting metabolic disorders, and controlling chronic inflammation. Finally, to cure tumor and prevent tumor recurrence, repairing or supporting therapy that consist of tissue repair and nutritional supplement should be applied properly.

Radiotherapy is a standard of care for locally advanced stage III N2 non–small-cell lung carcinoma (NSCLC) combined with surgery/chemotherapy. Radiotherapy is hypothesised to induce tumour immunogenic cell death, to release neoantigen resulting in intra-tumoural immune infiltration and abscopal effect. Conversely, it has not been demonstrated if immune cells are necessary to drive radiotherapy efficacy and predict patient's survival. We retrospectively analysed tumour samples and clinical data from 113 patients, 89 resected (PORT) and 24 non-resected (DRC) N2-NSCLC treated with chemotherapy and radiotherapy (same radiotherapy department from 2002 to 2015). The immune environment was characterised with in situ multiplex staining (CD8, FoxP3, PD-L1 and cytokeratin) and correlated with clinical data and survival. High density of CD8+ T cells was associated with OS (p = 0.04, HR = 1.93 [0.99–3.78]) and DFS (p = 0.003, HR = 2.42 [1.31–4.47]) in the PORT. High density of CD8+/FoxP3+ double positive cells was associated with OS (p = 0.01, HR = 1.97 [1.11–3.48]) in the whole population, with OS (p = 0.05, HR = 1.92 [0.98–3.74]) and PFS (p = 0.03, HR = 1.83 [1.03–3.23]) in the PORT without reaching significance for the DRC. Intermediate PD-L1 expression in tumour cells (TPS = 1–49%) was associated with a higher survival in the PORT. Intra-tumoural CD8+ T cell and particularly CD8+/FoxP3+ double positive T cell densities predict survival in stage III N2-NSCLC suggesting the need for a pre-existing intra-tumour immunity to mediate the action of radiotherapy. Density of CD8+/FoxP3+ cells was the best predictor of patient's survival in multivariate analysis and could represent a biomarker of radiotherapy efficacy. • Radiotherapy efficacy needs a pre-existing intra-tumour immunity. • Radiotherapy does not turn a cold tumour into a hot tumour, but enhance or awake a pre-existing immune response. • PD-L1 TPS >1% is associated with longer survival after radiotherapy in N2-NSCLC. • High density of CD8+/FoxP3 double positive cells is a biomarker of survival after radiotherapy in N2-NSCLC. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most commonly diagnosed liver cancer, accounting for ~90% of all primary malignancy of the liver. Although various medical treatments have been used as systemic therapies, patient survival time may be extended by only a few months. Moreover, the underlying mechanisms of HCC development and progression remain poorly understood. In the present study, the single-cell transcriptome of one in vivo HCC tumor sample, two in vitro HCC cell lines and normal peripheral blood mononuclear cells were analysed in order to identify the potential mechanism underlying the development and progression of HCC. Interestingly, JunB proto-oncogene was identified to serve a role in the immune response and in development and progression of HCC, potentially contributing to the development of novel therapeutics for HCC patients. [ABSTRACT FROM AUTHOR]