PD-1 inhibitor plus concurrent chemoradiotherapy for high-risk locally advanced cervical cancer.

Aim: The prognosis of high-risk, locally advanced cervical cancer (LACC) remains poor following concurrent chemoradiotherapy (CCRT). We investigated whether the effect of CCRT can be enhanced by programmed cell death protein 1 (PD-1) inhibitor. Methods: A retrospective cohort study was conducted to compare the efficacy and safety of CCRT group (n = 82) and PD-1 inhibitor plus CCRT group (n = 70). Results: Compared with the CCRT group, the PD-1 inhibitor plus CCRT group had significantly higher objective response rate, median progression-free survival, leukopenia and fatigue. The addition of PD-1 inhibitor to CCRT showed a favorable trend in overall survival without statistical significance. Conclusion: PD-1 inhibitor plus CCRT presented a significant survival benefit and a manageable safety profile in high-risk LACC.

[Box: see text].

Norepinephrine inhibits CD8+ T-cell infiltration and function, inducing anti-PD-1 mAb resistance in lung adenocarcinoma.

BACKGROUND: Mental stress-induced neurotransmitters can affect the immune system in various ways. Therefore, a better understanding of the role of neurotransmitters in the tumour immune microenvironment is expected to promote the development of novel anti-tumour therapies. METHODS: In this study, we analysed the plasma levels of neurotransmitters in anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb)-resistance patients and sensitive patients, to identify significantly different neurotransmitters. Subsequently, animal experiments and experiments in vitro were used to reveal the specific mechanism of norepinephrine's (NE) effect on immunotherapy. RESULTS: The plasma NE levels were higher in anti-PD-1 mAb-resistance patients, which may be the main cause of anti-PD-1 mAb resistance. Then, from the perspective of the immunosuppressive microenvironment to explore the specific mechanism of NE-induced anti-PD-1 mAb resistance, we found that NE can affect the secretion of C-X-C Motif Chemokine Ligand 9 (CXCL9) and adenosine (ADO) in tumour cells, thereby inhibiting chemotaxis and function of CD8+ T cells. Notably, the WNT7A/ß-catenin signalling pathway plays a crucial role in this progression. CONCLUSION: NE can affect the secretion of CXCL9 and ADO in tumour cells, thereby inhibiting chemotaxis and the function of CD8+ T cells and inducing anti-PD-1 mAb resistance in lung adenocarcinoma (LUAD).

Molecular mechanism study of HGF/c-MET pathway activation and immune regulation for a tumor diagnosis model.

BACKGROUND: Hepatocyte growth factor (HGF) binds to the c-mesenchymal-epithelial transition (C-MET) receptor and activates downstream signaling pathways, playing an essential role in the development of various cancers. Given the role of this signaling pathway, the primary therapeutic direction focuses on identifying and designing HGF inhibitors, antagonists and other molecules to block the binding of HGF to C-MET, thereby limiting the abnormal state of other downstream genes. METHODS: This study focuses on the analysis of immune-related genes and corresponding immune functions that are significantly associated with the HGF/c-MET pathway using transcriptome data from 11 solid tumors. RESULTS: We systematically analyzed 11 different cancers, including expression correlation, immune infiltration, tumor diagnosis and survival prognosis from HGF/c-MET pathway and immune regulation, two biological mechanisms having received extensive attention in cancer analysis. CONCLUSION: We found that the HGF/c-MET pathway affected the tumor microenvironment mainly by interfering with expression levels of other genes. Immune infiltration is another critical factor involved in changes to the tumor microenvironment. The downstream immune-related genes activated by the HGF/c-MET pathway regulate immune-related pathways, which in turn affect the degree of infiltration of immune cells. Immune infiltration is significantly associated with cancer development and prognosis.

Identification of esophageal cancer pathway deviation and construction of a diagnosis model using three kernel genes.

The purpose of this study is to better understand the role of interleukin 35 (IL35) in esophageal carcinoma by comparing the mRNA level in Barrett's esophageal mucosa and in matched normal squamous mucosa and to understand how the diagnosis model works with two other genes: hepatocyte nuclear factor 1B (HNF1B) and cAMP responsive element binding protein 3-like 1 (CREB3L1). By comparing carcinoma tissue and normal tissue samples, we extracted all the differentially expressed mRNAs. The bioinformatics analysis resulted in the discovery of three prominent genes. Eventually, the three genes were utilized to train a deep-learning model. An additional wet experiment was conducted to validate the effect of IL35. All the differentially expressed genes were enriched into nine groups, each of which has specific biological functions. Given that the three significant genes HNF1B, CREB3L1, and IL35 as diagnostic features, a deep-learning model was constructed, reaching an accuracy of 93% in the training set and 87% in the test set. Our findings suggest that IL35, along with the other two signatures, can distinguish esophageal tumor samples from normal samples precisely.

Lung adenocarcinoma-intrinsic GBE1 signaling inhibits anti-tumor immunity.

BACKGROUND: Changes in glycogen metabolism is an essential feature among the various metabolic adaptations used by cancer cells to adjust to the conditions imposed by the tumor microenvironment. Our previous study showed that glycogen branching enzyme (GBE1) is downstream of the HIF1 pathway in hypoxia-conditioned lung cancer cells. In the present study, we investigated whether GBE1 is involved in the immune regulation of the tumor microenvironment in lung adenocarcinoma (LUAD). METHODS: We used RNA-sequencing analysis and the multiplex assay to determine changes in GBE1 knockdown cells. The role of GBE1 in LUAD was evaluated both in vitro and in vivo. RESULTS: GBE1 knockdown increased the expression of chemokines CCL5 and CXCL10 in A549 cells. CD8 expression correlated positively with CCL5 and CXCL10 expression in LUAD. The supernatants from the GBE1 knockdown cells increased recruitment of CD8+ T lymphocytes. However, the neutralizing antibodies of CCL5 or CXCL10 significantly inhibited cell migration induced by shGBE1 cell supernatants. STING/IFN-I pathway mediated the effect of GBE1 knockdown for CCL5 and CXCL10 upregulation. Moreover, PD-L1 increased significantly in shGBE1 A549 cells compared to those in control cells. Additionally, in LUAD tumor tissues, a negative link between PD-L1 and GBE1 was observed. Lastly, blockade of GBE1 signaling combined with anti-PD-L1 antibody significantly inhibited tumor growth in vivo. CONCLUSIONS: GBE1 blockade promotes the secretion of CCL5 and CXCL10 to recruit CD8+ T lymphocytes to the tumor microenvironment via the IFN-I/STING signaling pathway, accompanied by upregulation of PD-L1 in LUAD cells, suggesting that GBE1 could be a promising target for achieving tumor regression through cancer immunotherapy in LUAD.

A cycle involving HMGB1, IFN-γ and dendritic cells plays a putative role in anti-tumor immunity.

An important subset in regulating antitumor immunity is the maturation and accumulation of intratumor dendritic cells (DCs), inducing potent T cell cytotoxicity. In this study, we explored how the soluble abundant high-mobility group box 1 protein (HMGB1) affected DC activation and retention within lung cancers, and in which way the resultant interferon-γ (IFN-γ) further enhanced DC maturation and accumulation. It was discovered that HMGB1 was correlated with DC markers HLA-DR and CD86 in lung cancers at both mRNA and protein level. Further analyses showed HMGB1 enhanced the maturation of DCs, indicated by upregulated IFN-γ in CD8+ T cells. Additionally, HMGB1 increased the accumulation of DCs by promoting CCR5 and CXCR3 production. Moreover, the resultant IFN-γ elevated the levels of HMGB1 and DC-associated chemokines, CCL5, CXCL10 and CXCL11 in tumor cells. Hence, the HMGB1-IFN-γ cycle may represent an important mechanism underlying DC-mediated anti-tumor immune response.

An immune checkpoint-based signature predicts prognosis and chemotherapy response for patients with small cell lung cancer.

BACKGROUND: Therapeutic options for small cell lung cancer (SCLC), a particularly lethal malignancy, remain limited. Members of the B7-CD28 family are compelling targets for immune checkpoint blockade strategies, which involve activating, inhibiting, and fine-tuning the T cell immune response. However, their clinical features and significance have not been explored comprehensively. METHOD: We enrolled 228 patients with an initial diagnosis of SCLC, including 77 cases from Cbioportal and a validation cohort of 151 cases with qPCR data. Kaplan-Meier analysis and LASSO Cox model were used to identify a signature based on the B7-CD28 family, which was applied for accurate prediction of chemotherapy benefit and prognosis for SCLC patients. In addition, we applied bioinformatics analysis to explore potential signature-related molecular mechanisms and the immune landscape. RESULTS: The mutation profiles of healthy tissues and SCLC tissues were distinct. A signature consisting of seven genes (CD86, ICOSLG, CD276, CD28, CTLA-4, PDCD1, and TMIGD2) was identified and applied to group patients based on risk level (high-risk and low-risk), producing two groups for which survival outcomes differed significantly (HR = 3.81, 95% CI: 2.16-6.74, P < 0.001). The immune checkpoint-based signature accurately predicted patient outcomes for the selected training and validation sets. Notably, low-risk patients were more likely to benefit from chemotherapy and showed greater immune activation. Additionally, time-dependent ROC curves and C-index analysis confirmed that the immune checkpoint-based signature has excellent predictive power for prognosis and chemotherapy benefit compared to clinically recognized parameters. Finally, multivariate analysis confirmed the identified signature as an independent risk factor for prognosis and chemotherapeutic response. CONCLUSION: We systematically obtained a comprehensive molecular profile for B7-CD28 family members in SCLC patients, from which we produced a reliable and robust prognostic immune checkpoint-based signature with the potential to improve prognostic stratification and therapy strategies for SCLC patients.

Immunogenomic-Based Analysis of Hierarchical Clustering of Diffuse Large Cell Lymphoma.

Diffuse large B cell lymphoma (DLBCL) is one of the most usual types of adult lymphoma with heterogeneousness in histological morphology, prognosis, and clinical indications. Prior to this, several studies were carried out to determine the DLBCL subtype based on the analysis of the genome profile. However, classification based on assessment of genes related to the immune system has limited clinical significance for DLBCL. We systematically explored the DLBCL gene expression dataset and provided publicly available clinical information on patients with GEO. In this research, 928 DLBCL samples were applied, and we calculated 29 immune-related genomes' enrichment levels in each sample and stratified them into high immunity (Immunity_H, n = 135, 28.7%), moderate immunity (Immunity_M, n = 135, 28.7%), and low immunity (Immunity_L, n = 12, 2.6%) that was based on ssGSEA score. The ESTIMATE algorithm was used to calculate stromal scores (range 586.88 to 1982.43), immune scores, estimated scores (range 2,618.2 to 8,098.14), and tumor purity (range 0.216 to 0.976). All of them were significantly correlated with immune subtypes (Kruskal-Wallis test, p < 0.001). At the same time, the correlation of related genes was analyzed by immunohistochemistry staining. In addition, DLBCL cells were cultured in transfected and in vitro with siRNA to verify correlation analysis and gene expression. Finally, human peripheral blood lymphocytes were incubated with DLBCL cells and stained. Flow cytometry was applied to analyze genes' influence on immune function. By analysis, immune checkpoint and HLA gene expression levels were higher in the Immunity_H group (Kruskal-Wallis test, p < 0.05). The levels of Tfhs (follicular helper T cells), monocytes, CD8+ T cells, M1 macrophages, M2 macrophages, and CD4+ memory-activated T cells were the most excellent in Immunity_H, and the total survival rate was higher in the Immunity_L. Through analysis, IRF4 (MUM1) was identified by us as immunotherapeutic target and a potential prognostic marker for DLBCL, which was made sure by using molecular biology experimentations. To conclude, immunosignature made a connection between DLBCL subtypes playing a position in DLBCL prognostic stratification. Immunocharacteristics-related DLBCL subtypes' construction predicts expected patient results and supplies conceivable immunotherapy candida.

Inhibition of USP1 activates ER stress through Ubi-protein aggregation to induce autophagy and apoptosis in HCC.

The deubiquitinating enzyme USP1 (ubiquitin-specific protease 1) plays a role in the progression of various tumors, emerging as a potential therapeutic target. This study aimed to determine the role of USP1 as a therapeutic target in hepatocellular carcinoma (HCC). We detected USP1 expression in the tumor and adjacent tissues of patients with HCC using immunohistochemical staining. We evaluated the effect of the USP1 inhibitor ML-323 on HCC cell proliferation and cell cycle using a CCK-8 cell-counting kit and plate cloning assays, and propidium iodide, respectively. Apoptosis was detected by annexin V-FITC/Propidium Iodide (PI) staining and caspase 3 (casp3) activity. Transmission electron microscopy and LC3B immunofluorescence were used to detect autophagy. Western blotting was used to detect the accumulation of ubiquitinated proteins, the expression of endoplasmic reticulum (ER) stress-related proteins, and the AMPK-ULK1/ATG13 signaling pathway. We demonstrated that ML-323 inhibits the growth of HCC cells and induces G1 phase cell cycle arrest by regulating cyclin expression. ML-323 treatment resulted in the accumulation of ubiquitinated proteins, induced ER stress, and triggered Noxa-dependent apoptosis, which was regulated by the Activating Transcription Factor 4(ATF4). Moreover, active ER stress induces protective autophagy by increasing AMPK phosphorylation; therefore, we inhibited ER stress using 4-Phenylbutyric acid (4-PBA), which resulted in ER stress reduction, apoptosis, and autophagy in ML-323-treated HCC cells. In addition, blocking autophagy using the AMPK inhibitor compound C (CC), chloroquine (CQ), or bafilomycin A1 (BafA1) enhanced the cytotoxic effect of ML-323. Our findings revealed that targeting USP1 may be a potential strategy for the treatment of HCC.

COL1A1 is a prognostic biomarker and correlated with immune infiltrates in lung cancer.

OBJECTIVE: Lung cancer (LC) is one of the top ten malignant tumors and the first leading cause of cancer-related death among both men and women worldwide. It is imperative to identify immune-related biomarkers for early LC diagnosis and treatment. METHODS: Three Gene Expression Omnibus (GEO) datasets were selected to acquire the differentially expressed genes(DEGs) between LC and normal lung samples through GEO2R tools of NCBI. To identify hub genes, the DEGs were performed functional enrichment analysis, the protein-protein interaction (PPI) network construction, and Lasso regression. Then, a nomogram was constructed to predict the prognosis of patients with carcinoma based on hub genes. We further evaluated the influence of COL1A1 on clinical prognosis using GSE3141, GSE31210, and TCGA database. Also, the correlations between COL1A1 and cancer immune infiltrates and the B7-CD28 family was investigated via TIMER and GEPIA. Further analysis of immunohistochemistry shown that the COL1A1 expression level is positively correlated with CD276 expression level. RESULTS: By difference analysis, there were 340 DEGs between LC and normal lung samples. Then, we picked out seven hub genes, which were identified as components of the risk signature to divide LC into low and high-risk groups. Among them, the expression of COL1A1 is highly correlated with overall survival(OS) and progression-free survival (PFS) (p < 0.05). Importantly, there is a moderate to strong positive relationships between COL1A1 expression level and infiltration level of CD4+ T cells, Macrophage, Neutrophil, and Dendritic cell, as well as CD276 expression level. CONCLUSION: These findings suggest that COL1A1 is correlated with prognosis and immune infiltrating levels, including CD4+ T cells, Macrophage, Neutrophil, and Dendritic cell, as well as CD276 expression level, indicating COL1A1 can be a potential immunity-related biomarker and therapeutic target in LC.

Long non-coding RNAs MACC1-AS1 and FOXD2-AS1 mediate NSD2-induced cisplatin resistance in esophageal squamous cell carcinoma.

The nuclear receptor-binding SET domain (NSD) protein family encoding histone lysine methyltransferases is involved in cancer progression. However, the role of NSDs in esophageal squamous cell carcinoma (ESCC) remains unclear. Here we examined the expression of NSDs in cisplatin-resistant and parental ESCC cells and revealed the upregulation of NSD2 in cisplatin-resistant cells. Ectopic expression of NSD2 increased cisplatin resistance and attenuated cisplatin-induced apoptosis. Colony formation assay indicated that NSD2 overexpression enhanced long-term survival of ESCC cells after treatment with cisplatin. In contrast, knockdown of NSD2 inhibited ESCC cell proliferation and sensitized ESCC cells to cisplatin. Depletion of NSD2 augmented the cytotoxic effect of cisplatin on EC109 xenograft tumors. NSD2 stimulated long non-coding RNA MACC1-AS1 in ESCC cells. Knockdown of MACC1-AS1 impaired NSD2-induced cisplatin resistance. Moreover, MACC1-AS1 overexpression promoted ESCC cell proliferation and cisplatin resistance. Clinically, MACC1-AS1 was upregulated in ESCC relative to adjacent noncancerous tissues. High MACC1-AS1 levels were significantly associated with reduced overall survival of ESCC patients. There was a positive correlation between MACC1-AS1 and NSD2 expression in ESCC specimens. Taken together, MACC1-AS1 induced by NSD2 mediates resistance to cisplatin in ESCC and may represent a novel target to improve cisplatin-based chemotherapy.

Identification of risk genes related to myocardial infarction and the construction of early SVM diagnostic model.

BACKGROUND: Myocardial Infarction (MI) is a fatal cardiovascular system disease. At present, the diagnosis of MI patients is mainly based on the patient's clinical manifestations, dynamic changes in electrocardiogram (ECG), and changes in myocardial enzymes. ECG is insufficient to diagnose an acute coronary syndrome or acute myocardial infarction, since ST-segment deviation might be also present in other conditions, such as acute pericarditis and early repolarization patterns. Given the low specificity and effectiveness of the current diagnostic strategies, an accurate diagnostic approach based on the level of gene expression is urgently needed in the clinic. METHODS AND RESULTS: We compared the gene's expression between MI patients and normal samples. The RNAseq data were downloaded from the GEO database. Differentially expressed genes underwent a feature selection process, and the signatures were selected to train a machine-learning model. In this study, we identified the risk genes associated with MI as signatures and uses the SVM to establish a diagnostic model. The accuracy of the model on discovery data is 0.87, which significantly improves the diagnostic efficiency of early detection of MI patients (MIPs). Two independent datasets were applied to verify the diagnostic model. Our model can effectively distinguish the control group from the disease group. CONCLUSIONS: We used risk genes to construct a diagnostic model for MI diagnosis, which can effectively distinguish MIPs from normal samples in the both of the discovery data and validation data. In the validation data, we found that percutaneous coronary intervention could indeed reverse MI to a certain extent, and the gene expression level of patients treated with percutaneous coronary intervention (PCI) was closer to the normal state.

Precise medication for tumor patients in the context of mental stress.

Cancer is the leading cause of disease-related death worldwide due to its late diagnosis and poor outcomes. Precision medicine plays an important role in the treatment of tumors. As found for many types of tumors, mental stress plays a vital role in the promotion and progression of tumors. In this paper, we briefly introduce the manifestation and effects of mental symptoms in tumor patients. We next specifically discuss the multiple roles of precision medicine in the tumor therapy. Finally, we also highlight the precision medicine strategy for psychiatric symptoms in tumor patients, which promises to enhance the efficacy of tumor therapy.

Comprehensive Analysis of the Prognostic Value and Immune Infiltrates of the Three-m5C Signature in Colon Carcinoma.

BACKGROUND: The 5-methylcytosine (m5C) is one of the important forms of RNA post modification, and its regulatory mechanism in tumors has received increasing attention. However, its potential role in colorectal cancer remains unclear. MATERIALS AND METHODS: Here, we systematically investigated the genetic variation and prognostic value of the 14 m5c RNA methylation regulators in colon cancer. The prognostic risk score was constructed using three m5C regulators, which was verified in the GSE17536 (N=177), GSE41258 (N=248) and GSE38832 (N=122) datasets. RESULTS: The risk score developed from the three-m5C signature represents an independent prognostic factor, which can accurately predict the prognosis of patients with colon cancer in multiple datasets. The cytokine-cytokine receptor interaction and chemokine signaling pathway were significantly enriched in the low-risk score group. Further analysis showed that the three-m5C signature was related to tumor immune microenvironment (TIME), affecting the abundance of tumor-infiltrating immune cells. Especially, patients with low risk score had higher immune score than those with high risk score. In addition, gene set enrichment analysis (GSEA) confirmed that all three regulatory factors are associated with the MAPK/p38 signaling pathway. CONCLUSION: In conclusion, our study illustrates that the three-m5C signature may be involved in the regulation of colon cancer immune microenvironment in synergy with the MAPK signaling pathway. Therefore, further studying the three-m5C signature regulatory mechanisms might provide promising targets for improving the responsiveness of colon cancer to immunotherapy.

Over-Expression and Prognostic Significance of FN1, Correlating With Immune Infiltrates in Thyroid Cancer.

BACKGROUND: Thyroid cancer (THCA) is a malignancy affecting the endocrine system, which currently has no effective treatment due to a limited number of suitable drugs and prognostic markers. METHODS: Three Gene Expression Omnibus (GEO) datasets were selected to identify differentially expressed genes (DEGs) between THCA and normal thyroid samples using GEO2R tools of National Center for Biotechnology Information. We identified hub gene FN1 using functional enrichment and protein-protein interaction network analyses. Subsequently, we evaluated the importance of gene expression on clinical prognosis using The Cancer Genome Atlas (TCGA) database and GEO datasets. MEXPRESS was used to investigate the correlation between gene expression and DNA methylation; the correlations between FN1 and cancer immune infiltrates were investigated using CIBERSORT. In addition, we assessed the effect of silencing FN1 expression, using an in vitro cellular model of THCA. Immunohistochemical(IHC) was used to elevate the correlation between CD276 and FN1. RESULTS: FN1 expression was highly correlated with progression-free survival and moderately to strongly correlated with the infiltration levels of M2 macrophages and resting memory CD4+ T cells, as well as with CD276 expression. We suggest promoter hypermethylation as the mechanism underlying the observed changes in FN1 expression, as 20 CpG sites in 507 THCA cases in TCGA database showed a negative correlation with FN1 expression. In addition, silencing FN1 expression suppressed clonogenicity, motility, invasiveness, and the expression of CD276 in vitro. The correlation between FN1 and CD276 was further confirmed by immunohistochemical. CONCLUSION: Our findings show that FN1 expression levels correlate with prognosis and immune infiltration levels in THCA, suggesting that FN1 expression be used as an immunity-related biomarker and therapeutic target in THCA.

Involvement of long non-coding RNAs in the progression of esophageal cancer.

Esophageal cancer (EC) is one of the most common malignant tumors of the digestive system with high incidence and mortality rate worldwide. Therefore, exploring the pathogenesis of EC and searching for new targeted therapies are the current research hotspot for EC treatment. Long non-coding RNAs (lncRNAs) are endogenous RNAs with more than 200 nucleotides, but without protein-coding function. In recent years, lncRNAs have gradually become the focuses in the field of non-coding RNA. Some lncRNAs have been proved to be closely related to the pathogenesis of EC. Many lncRNAs are abnormally expressed in EC and participate in many biological processes including cell proliferation, apoptosis, and metastasis by inhibiting or promoting target gene expression. LncRNAs can also regulate the progression of EC through epithelial-mesenchymal transformation (EMT), which is closely related to the occurrence, development, and prognosis of EC. In this article, we review and discuss the involvement of lncRNAs in the progression of EC.

Transcriptome sequencing and metabolome analysis reveal the mechanism of Shuanghua Baihe Tablet in the treatment of oral mucositis.

Oral mucositis (OM) caused by cancer therapy is the most common adverse reaction in the radiotherapy of head and neck tumors. In severe cases, it can lead to the interruption of treatment, which affects the control of the disease and the quality of life. Shuanghua Baihe Tablet (SBT) is a traditional Chinese medicine (TCM) formula, which is administerd to treat OM in China. It has been clinically effective for more than 30 years, but the underlying mechanism is not completely understood. With the development of multiple omics, it is possible to explore the mechanism of Chinese herbal compound prescriptions. Based on transcriptomics and metabolomics, we explored the underlying mechanism of SBT in the treatment of OM. An OM model of rats was established by 5-FU induction, and SBT was orally administered at dosages of 0.75 and 3 g·kg-1·d-1. In order to search for SBT targets and related metabolites, the dysregulated genes and metabolites were detected by transcriptomics and metabolomics. Immune related indicators such as interleukin-17 (IL-17) and tumor necrosis factor-α (TNF-α) were detected by ELISA. Treg cell disorders was analyzed by flow cytometry. Our results showed that SBT significantly alleviated the symptoms of OM rats and the inflammatory infiltration of ulcer tissues. After SBT administration, inflammatory related metabolic pathways including linoleic acid metabolism, valine, leucine and isoleucine biosynthesis were significantly altered. Furthermore, the production of proinflammatory factors like IL-17 and TNF-α, were also dramatically reduced after SBT administration. Besides, the infiltration degree of Treg cells in the spleen of OM modeling rats was significantly improved by SBT administration, thus maintaining the immune balance of the body. The current study demonstrates that SBT regulates inoleic acid metabolism, glycerophospholipid metabolism and amino acid metabolism, and inhibits IL-17/TNF signal transduction to restore Treg and Th17 cell homeostasis in OM rats, thereby alleviating chemotherapy-induced OM.

Over-Expression and Prognostic Significance of FATP5, as a New Biomarker, in Colorectal Carcinoma.

Background: Fatty acid transporters (FATPs) family play an important role in the uptake and metabolism regulation of long-chain fatty acids, which influence the occurrence and developing of multiple tumors. Fatty acid transporter 5(FATP5), a member of FATPs family, participates in fatty acid transport and lipid metabolism and is related to tumor development, whose mechanism in colorectal cancer (CRC) remains unclear. Methods: In this study, we comprehensively utilized a range of relevant bioinformatic tools along with multiple databases to analyze the expression of FATPs family and investigate the biological function and prognostic value of FATP5 in CRC. Besides, cell proliferation and cell cycle distribution analysis, western blotting and immunohistochemistry (IHC) further validated the conclusion of bioinformatics analysis. Results: FATP5 is the only member of FATPs family which was overexpressed in CRC. In the survival analysis based on the GSE39582 databases, the low expression of FATP5 predicts poor prognosis in CRC. Similar results were also observed in GSE17536, GSE28814 and TCGA colon cohorts. The potential function of DNA methylation regulated the abnormal expression of FATP5 in CRC. In addition, enrichment analysis indicated that FATP5 also participates in the regulation of cell cycle. Furthermore, Gene Set Enrichment Analysis (GSEA) showed a strong negative correlation between FATP5 and cell growth, implying that it may participate in regulating cancer cell proliferation by the regulation of cell cycle G2/M transition. At last, we identified that FATP5 was overexpressed in colorectal carcinoma tissues through immunohistochemistry staining, and played an important role in cell cycle by cell proliferation and cell cycle distribution analysis. Conclusion: This study suggested that FATP5 was overexpression in colorectal carcinoma and predicted favorable prognosis, indicating it as a novel appealing prognostic marker for CRC.

A Cereblon Modulator CC-885 Induces CRBN- and p97-Dependent PLK1 Degradation and Synergizes with Volasertib to Suppress Lung Cancer.

Therapeutic targeting of advanced or metastatic non-small-cell lung cancer (NSCLC) represents a major goal of clinical treatment. Polo-like kinase 1 (PLK1) is an essential mitotic kinase in cell cycle progression and is associated with oncogenesis in a large spectrum of cancer types, including NSCLC. Volasertib (BI 6727) is a potent, selective, PLK1 inhibitor that is currently under phase 2 clinical trials with modest antitumor activity against solid tumors. As the combination of volasertib with pemetrexed does not improve efficacy for NSCLC treatment, it is crucial to identify compounds that could enhance efficacy with volasertib. Immunomodulatory drugs (IMiDs) bind to E3 ligase CRBN and repurposes it to ubiquitinate other proteins as neo-substrates, representing an effective treatment for hematologic malignancies. In this study, by screening IMiDs, we found that a novel CRBN modulator, CC-885, can synergistically inhibit NSCLC with volasertib both in vitro and in vivo. This synergistic effect overcomes volasertib resistance caused by PLK1 mutations and is compromised in CRBN-or p97-depleted cells. Mechanistically, CC-885 selectively promotes CRBN- and p97-dependent PLK1 ubiquitination and degradation, thereby enhancing the sensitivity of NSCLC to volasertib. In conclusion, our findings reveal that PLK1 is a neo-substrate of CUL4-CRBN induced by CC-885 and represent a combinational approach for treating NSCLC.