Deciphering the TCF19/miR-199a-5p/SP1/LOXL2 pathway: Implications for breast cancer metastasis and epithelial-mesenchymal transition.

Globally, breast cancer (BC) is the predominant malignancy with a significant death rate due to metastasis. The epithelial-mesenchymal transition (EMT) is a fundamental initiator for metastatic progression. Through advanced computational strategies, TCF19 was identified as a critical EMT-associated gene with diagnostic and prognostic significance in BC, based on a novel EMT score. Molecular details and the pro-EMT impact of the TCF19/miR-199a-5p/SP1/LOXL2 axis were explored in BC cell lines through in vitro validations, and the oncogenic and metastatic potential of TCF19 and LOXL2 were investigated using subcutaneous and tail-vein models. Additionally, BC-specific enrichment of TCF19 and LOXL2 was measured using a distribution landscape driven by diverse genomic analysis techniques. Molecular pathways revealed that TCF19-induced LOXL2 amplification facilitated migratory, invasive, and EMT activities of BC cells in vitro, and promoted the growth and metastatic establishment of xenografts in vivo. TCF19 decreases the expression of miR-199a-5p and alters the nuclear dynamics of SP1, modulating SP1's affinity for the LOXL2 promoter, leading to increased LOXL2 expression and more malignant characteristics in BC cells. These findings unveil a novel EMT-inducing pathway, the TCF19/miR-199a-5P/SP1/LOXL2 axis, highlighting the pivotal role of TCF19 and suggesting potential for novel therapeutic approaches for more focused BC interventions.

FFAR2 expressing myeloid-derived suppressor cells drive cancer immunoevasion.

BACKGROUND: Emerging evidences suggest that aberrant metabolites contributes to the immunosuppressive microenvironment that leads to cancer immune evasion. Among tumor immunosuppressive cells, myeloid-derived suppressor cells (MDSCs) are pathologically activated and extremely immunosuppressive, which are closely associated with poor clinical outcomes of cancer patients. However, the correlation between MDSCs mediated immunosuppression and particular cancer metabolism remained elusive. METHODS: Spontaneous lung adenocarcinoma and subcutaneous mouse tumor models, gas chromatography-mass spectrometry (GC-MS) and immunofluorescence assay of patient-derived lung adenocarcinoma tissues, and flow cytometry, RNA sequencing and Western blotting of immune cells, were utilized. RESULTS: Metabolite profiling revealed a significant accumulation of acetic acids in tumor tissues from both patients and mouse model, which contribute to immune suppression and cancer progression significantly through free fatty acid receptor 2 (FFAR2). Furthermore, FFAR2 is highly expressed in the myeloid-derived suppressor cells (MDSCs) from the tumor of lung adenocarcinoma (LUAD) patients which is greatly associated with poor prognosis. Surprisingly, whole or myeloid Ffar2 gene deletion markedly inhibited urethane-induced lung carcinogenesis and syngeneic tumor growth with reduced MDSCs and increased CD8+ T cell infiltration. Mechanistically, FFAR2 deficiency in MDSCs significantly reduced the expression of Arg1 through Gαq/Calcium/PPAR-γ axis, which eliminated T cell dysfunction through relieving L-Arginine consumption in tumor microenvironment. Therefore, replenishment of L-Arginine or inhibition to PPAR-γ restored acetic acids/FFAR2 mediated suppression to T cells significantly. Finally, FFAR2 inhibition overcame resistance to immune checkpoint blockade through enhancing the recruitment and cytotoxicity of tumor-infiltrating T cells. CONCLUSION: Altogether, our results demonstrate that the acetic acids/FFAR2 axis enhances MDSCs mediated immunosuppression through Gαq/calcium/PPAR-γ/Arg1 signaling pathway, thus contributing to cancer progression. Therefore, FFAR2 may serve as a potential new target to eliminate pathologically activated MDSCs and reverse immunosuppressive tumor microenvironment, which has great potential in improving clinical outcomes of cancer immunotherapy.

Identification of S1PR4 as an immune modulator for favorable prognosis in HNSCC through machine learning.

G protein-coupled receptors (GPCRs) are the largest family of membrane proteins and play a critical role as pharmacological targets. An improved understanding of GPCRs' involvement in tumor microenvironment may provide new perspectives for cancer therapy. This study used machine learning to classify head and neck squamous cell carcinoma (HNSCC) patients into two GPCR-based subtypes. Notably, these subtypes showed significant differences in prognosis, gene expression, and immune microenvironment, particularly CD8+ T cell infiltration. S1PR4 emerged as a key regulator distinguishing the subtypes, positively correlated with CD8+ T cell proportion and cytotoxicity in HNSCC. It was predominantly expressed in CX3CR1+CD8+ T cells among T cells. Upregulation of S1PR4 enhanced T cell function during CAR-T cell therapy, suggesting its potential in cancer immunotherapy. These findings highlight S1PR4 as an immune modulator for favorable prognosis in HNSCC, and offer a potential GPCR-targeted therapeutic option for HNSCC treatment.

LIGHT/TNFSF14 promotes CAR-T cell trafficking and cytotoxicity through reversing immunosuppressive tumor microenvironment.

Tertiary lymphoid structures (TLSs) in tumor tissues facilitate immune cell trafficking and cytotoxicity, which benefits survival and favorable responses in immune therapy. Here, we observed a high correlation of tumor necrosis factor superfamily member 14 (LIGHT) expression with TLS signature genes, which are all markers for immune cell accumulation and better prognosis, through retrieving RNA sequencing (RNA-seq) data from patients with cancer, suggesting the potential of LIGHT in reconstituting a high immune-infiltrated tumor microenvironment. Accordingly, LIGHT co-expressed chimeric antigen receptor T (LIGHT CAR-T) cells not only showed enhanced cytotoxicity and cytokine production but also improved CCL19 and CCL21 expression by surrounding cells. And the supernatant of LIGHT CAR-T cells promoted T cell migration in a paracrine manner. Furthermore, LIGHT CAR-T cells showed superior anti-tumor efficacy and improved infiltration in comparison with conventional CAR-T cells in immunodeficient NSG mice. Accordingly, murine LIGHT-OT-1 T cells normalized tumor blood vessels and enforced intratumoral lymphoid structures in C57BL/6 syngeneic tumor mouse models, implying the potential of LIGHT CAR-T in clinical application. Taken together, our data revealed a straightforward strategy to optimize trafficking and cytotoxicity of CAR-T cells by redirecting TLSs through LIGHT expression, which has great potential to expand and optimize the application of CAR-T therapy in solid tumors.

Tranditional Roux-en-Y vs Uncut Roux-en-Y in Laparoscopic Distal Gastrectomy: a Randomized Controlled Study.

BACKGROUND: Traditional Roux-en-Y may cause Roux-en-Y stasis syndrome (RSS), and Uncut Roux-en-Y was proposed to solve this problem. However, because afferent loop recanalization may occur after surgery, its clinical application remains controversial. The purpose of this study was to compare the long-term outcomes of these two gastrointestinal reconstruction methods. METHODS: A total of 108 patients who received laparoscopic-assisted distal gastrectomy (LADG) were enrolled; 57 were randomly divided into the Uncut Roux-en-Y (URY) group, and 51 were divided into the Roux-en-Y (RY) group. Patients were followed up for 1 year to evaluate variables, including the following: (1) Assessments for RSS; (2) Preoperative and postoperative Gastrointestinal Symptom Rating Scale (GSRS) scores; (3) Postoperative gastroscopy to assess the occurrence of reflux esophagitis (Los Angeles classification), residual gastritis and bile reflux 1 year after surgery; and (4) Upper gastrointestinal radiography to evaluate whether recanalization occurred in patients in the URY group after surgery. RESULTS: At 1 year after surgery, a total of 42 patients (73.7%) developed afferent loop recanalization. The incidence of RSS was not different between the two groups (OR, 1.301 [95% CI, 0.482 to 3.509]; P = 0.603P = 0.603). The GSRS score was higher in the URY group (P < 0.001). Postoperative gastroscopy showed that the incidence of bile reflux (P < 0.001) and the grade of residual gastritis (P < 0.001) were significantly higher in the URY group, but the grade of reflux esophagitis was not significantly different (P = 0.447, [95% CI, 0.437 to 0.457]P = 0.397). CONCLUSIONS: Compared with traditional Roux-en-Y anastomosis, due to the high recanalization rate, the URY group developed more severe gastrointestinal symptoms, the incidence of bile reflux and the grade of residual gastritis increased and the incidence of postoperative RSS was not reduced.

Impact of endoscopic metallic stent placement and emergency surgery on detection of viable circulating tumor cells for acute malignant left-sided colonic obstruction.

BACKGROUND: Self-expanding metal stents (SEMS) served as a bridge to surgery (BTS). However, this method may be associated with worse long-term prognosis and relapse of CRC patients. Therefore, we attempted to clarify this in the angle of circulating tumor cells (CTCs). METHODS: A multicenter study was performed from March 2018 to January 2021. Thirty-two colorectal cancer patients with obstruction were selected, of which 21 patients were performed SEMS as a BTS while 11 patients were performed emergency surgery. Bloods samples were collected in two groups of patients for further detecting CTCs. In the SEMS group, the samples were collected before and after stent insert and after radical surgery performed. In the ES group, the samples were collected before stent insert and after emergency surgery performed. RESULTS: The number of CTCs did not show statistically significant differences before and after stent placement (34.90 vs 38.33, p=0.90), neither between the SEMS group and ES group in initial CTC levels (34.90 vs 58.09, p=0.394). No significant differences (38.33 vs 58.09, p=0.632) were observed after stent insert in the SMES group and the initial CTC levels in the ES group. Moreover, no major differences (24.17 vs 42.27, p=0.225) were observed after radical operation performed in both groups. CONCLUSION: The treatment of SEMS does not cause an increase in the number of CTC after stent insertion. Furthermore, there are may be other factors besides CTC to cause these poorer oncologic outcomes after SEMS placement.

Novel insight on predicting prognosis of gastric cancer based on inflammation.

Background: The tumor microenvironment (TME) and inflammation play vital roles in the development and progression of gastric cancer (GC). However, there are no inflammation-related models that can predict the prognosis and immunotherapy response of GC patients. We aimed to establish a prognostic model based on an inflammation-related gene (IRG) signature that can predict poor clinical outcomes in GC. Methods: We searched IRGs in The Cancer Genome Atlas (TCGA) database and identified genes differentially expressed in GC. The model was constructed using univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analysis and validated using Gene Expression Omnibus (GEO) database. Receiver operating characteristic (ROC) curve, principal component analysis (PCA), and t-distribution stochastic neighbor embedding (t-SNE) analysis were performed to evaluate model performance. Independent prognostic factor, immune infiltration, cancer stemness, immunotherapy response analysis and gene set enrichment analysis (GSEA) were performed for functional evaluation. Results: An inflammation-related risk model was established based on 8 genes (F2, LBP, SERPINE1, ADAMTS12, FABP4, PROC, TNFSF18, and CYSLTR1). Risk score significantly correlated with poor outcomes and independently predicted prognosis. It was also associated with immune infiltration and reflected immunotherapy response. Conclusions: We established and validated an inflammation-related prognostic model that predicts immune escape and patient prognosis in GC. Our model is expected to improve clinical outcomes by facilitating clinical decision making and the development of individualized treatments.

Multi-omics analysis for potential inflammation-related genes involved in tumour immune evasion via extended application of epigenetic data.

Accumulating evidence suggests that inflammation-related genes may play key roles in tumour immune evasion. Programmed cell death ligand 1 (PD-L1) is an important immune checkpoint involved in mediating anti-tumour immunity. We performed multi-omics analysis to explore key inflammation-related genes affecting the transcriptional regulation of PD-L1 expression. The open chromatin region of the PD-L1 promoter was mapped using the assay for transposase-accessible chromatin using sequencing (ATAC-seq) profiles. Correlation analysis of epigenetic data (ATAC-seq) and transcriptome data (RNA-seq) were performed to identify inflammation-related transcription factors (TFs) whose expression levels were correlated with the chromatin accessibility of the PD-L1 promoter. Chromatin immunoprecipitation sequencing (ChIP-seq) profiles were used to confirm the physical binding of the TF STAT2 and the predicted binding regions. We also confirmed the results of the bioinformatics analysis with cell experiments. We identified chr9 : 5449463-5449962 and chr9 : 5450250-5450749 as reproducible open chromatin regions in the PD-L1 promoter. Moreover, we observed a correlation between STAT2 expression and the accessibility of the aforementioned regions. Furthermore, we confirmed its physical binding through ChIP-seq profiles and demonstrated the regulation of PD-L1 by STAT2 overexpression in vitro. Multiple databases were also used for the validation of the results. Our study identified STAT2 as a direct upstream TF regulating PD-L1 expression. The interaction of STAT2 and PD-L1 might be associated with tumour immune evasion in cancers, suggesting the potential value for tumour treatment.

Neuroendocrine Regulation of Stress-Induced T Cell Dysfunction during Lung Cancer Immunosurveillance via the Kisspeptin/GPR54 Signaling Pathway.

Emerging evidence suggests that physiological distress is highly correlated with cancer incidence and mortality. However, the mechanisms underlying psychological challenges-mediated tumor immune evasion are not systematically explored. Here, it is demonstrated that acute restraint (AR) increases the level of the plasma neuropeptide hormones, kisspeptin, and the expression levels of its receptor, Gpr54, in the hypothalamus, splenic and tumor-infiltrating T cells, suggesting a correlation between the neuroendocrine system and tumor microenvironment. Accordingly, administration of kisspeptin-10 significantly impairs T cell function, whereas knockout of Gpr54 in T cells inhibits lung tumor progression by suppressing T cell dysfunction and exhaustion with or without AR. In addition, Gpr54 defective OT-1 T cells show superior antitumor activity against OVA peptide-positive tumors. Mechanistically, ERK5-mediated NR4A1 activation is found to be essential for kisspeptin/GPR54-facilitated T cell dysfunction. Meanwhile, pharmacological inhibition of ERK5 signaling by XMD8-92 significantly reduces the tumor growth by enhancing CD8+ T cell antitumor function. Furthermore, depletion of GPR54 or ERK5 by CRISPR/Cas9 in CAR T cells intensifies the antitumor responses to both PSMA+ and CD19+ tumor cells, while eliminating T cell exhaustion. Taken together, these results indicate that kisspeptin/GPR54 signaling plays a nonredundant role in the stress-induced tumor immune evasion.

Recanalization in Uncut Roux-en-Y Reconstruction: An Animal Experiment and a Clinical Study.

Background: Because of the challenge of jejunal closure recanalization, uncut Roux-en-Y reconstruction remains controversial. This study aimed to investigate the incidence of recanalization after uncut Roux-en-Y reconstruction in pigs and a small number of patients. Methods: Twenty miniature pigs were subjected to distal gastrectomy and uncut Roux-en-Y reconstruction using various rows of linear staplers to block the intestine. The pigs were sacrificed, and the incidence of recanalization was investigated 1 month after the operation. From December 2018 to June 2019, 10 patients with gastric cancer who had undergone elective laparoscopy-assisted distal gastrectomy and uncut Roux-en-Y reconstruction were included in this study. The primary study outcome was recanalization of the afferent limb, demonstrated by gastrointestinal radiography 1, 3, and 6 months after surgery. Various numbers of staple lines across the afferent jejunal limb were applied for closure: 2 staple lines in 2 pigs, 4 staple lines in 6 pigs, 6 staple lines in 8 pigs, and 8 staple lines in 4 pigs. Results: Complete recanalization was detected in all 20 pigs 1 month postoperatively. Recanalization was detected in five cases (50%) by gastrointestinal radiography. Among them, 1 case of recanalization was found in the 1st month after the operation, 2 cases were found in the 3rd month, and another 2 cases were found in the 6th month. Bile reflux was detected by endoscopy in 2 patients with recanalization. Conclusions: The occurrence of afferent limb recanalization after uncut Roux-en-Y reconstruction is high, and using additional staplers alone cannot decrease the incidence of recanalization. Based on our study, uncut Roux-en-Y reconstruction is not recommended.

Detecting Three-Dimensional Vascular Networks in the Mouse Embryonic Hindbrain.

Blood vessel formation is a fine-regulated process and interfering with blood vessel formation causes embryonic lethality as well as associated with many diseases in the adult, including inflammatory, ischemic, and cancer metastatic diseases. Brain contains abundant blood vessels and has some unique physiological functions, such as blood-brain barrier. Due to the thickness and opaque characters of the tissues, it is a challenge to visualize the three-dimensional structures of the brain blood vessels in the mouse. Therefore, establishing a protocol to display the three-dimensional structures in the brain is required for exploring the regulatory molecular mechanisms in brain blood vessel formation. In this manuscript, we introduced a whole-mount and a vibratome thick section of mouse embryonic hindbrain to display the three-dimensional structures of brain vascular system.

PLXNC1: A Novel Potential Immune-Related Target for Stomach Adenocarcinoma.

BACKGROUND: Gastric cancer is associated with tumor microenvironment and chronic inflammation, but the underlying tumor-promoting mechanisms still remain unknown. METHODS: The ATAC-seq was used to identify genes with chromatin accessibilities in promoter regions. The RNA-seq datasets were performed to identify differentially expressed genes (DEGs). Pearson correlation analysis with the mRNA expression of three families of tumor-related inflammation TFs was used to filter downstream DEGs. Cox univariate survival analysis was performed to identify the prognostic value. The ImmPort database and CIBERSORTx algorithm were used to investigate the regulatory relationship between hub DEGs and immune cells. Immunohistochemistry (IHC) and multidimensional database were performed to verification. RESULTS: In this case, we require 2,454 genes with chromatin accessibility in promoter regions by ATAC-seq. Based on the gene expression profiles (RNA-seq), we identified 365 genes with chromatin accessibility and differential expression. Combined with the Cox univariate survival analysis, we identified 32 survival-related DEGs with chromatin accessibility. According to ImmPort database, CXCL3, PLXNC1, and EDN2 were identified as immune- related genes in STAD. By applying the CIBERSORTx algorithm and Pearson correlation, PLXNC1 was the only gene correlated with various immune cells, significantly associated with M2 macrophages. Furthermore, gene set variation analysis (GSVA) suggests the "hallmark_interferon_gamma_response" pathway was most significantly correlated with PLXNC1. Immunohistochemistry results revealed that PLXNC1 protein level was significantly higher in STAD tissues than in normal tissues (p < 0.001). CONCLUSION: PLXNC1, regulated by IRF5, is an immune-related gene that was significantly associated with M2 macrophages and poor outcome in stomach adenocarcinoma.

Propensity score-matched comparison of stenting as a bridge to surgery and emergency surgery for acute malignant left-sided colonic obstruction.

BACKGROUND: Bridge to elective surgery (BTS) using self-expanding metal stents (SEMSs) is a common alternative to emergency surgery (ES) for acute malignant left-sided colonic obstruction (AMLCO). However, studies regarding the long-term impact of BTS are limited and have reported unclear results. METHODS: A multicenter observational study was performed at three hospitals from April 2012 to December 2019. Propensity score matching (PSM) was introduced to minimize selection bias. The primary endpoint was overall survival. The secondary endpoints included surgical approaches, primary resection types, total stent-related adverse effects (AEs), surgical AEs, length of hospital stay, 30-day mortality and tumor recurrence. RESULTS: Forty-nine patients in both the BTS and ES groups were matched. Patients in the BTS group more often underwent laparoscopic resection [31 (63.3%) vs. 8 (16.3%), p < 0.001], were less likely to have a primary stoma [13 (26.5%) vs. 26 (53.1%), p = 0.007] and more often had perineural invasion [25 (51.0 %) vs. 13 (26.5 %), p = 0.013]. The median overall survival was significantly lower in patients with stent insertion (41 vs. 65 months, p = 0.041). The 3-year overall survival (53.0 vs. 77.2%, p = 0.039) and 5-year overall survival (30.6 vs. 55.0%, p = 0.025) were significantly less favorable in the BTS group. In multivariate Cox regression analysis, stenting (hazard ratio(HR) = 2.309(1.052-5.066), p = 0.037), surgical AEs (HR = 1.394 (1.053-1.845), p = 0.020) and pTNM stage (HR = 1.706 (1.116-2.607), p = 0.014) were positively correlated with overall survival in matched patients. CONCLUSIONS: Self-expanding metal stents as "a bridge to surgery" are associated with more perineural invasion, a higher recurrence rate and worse overall survival in patients with acute malignant left-sided colonic obstruction compared with emergency surgery.

Multi-Omics Analysis for Transcriptional Regulation of Immune-Related Targets Using Epigenetic Data: A New Research Direction.

Background: Currently, a comprehensive method for exploration of transcriptional regulation has not been well established. We explored a novel pipeline to analyze transcriptional regulation using co-analysis of RNA sequencing (RNA-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), and chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq). Methods: The G protein-coupled receptors (GPCRs) possibly associated with macrophages were further filtered using a reduced-Cox regression model. ATAC-seq profiles were used to map the chromatin accessibility of the GPRC5B promoter region. Pearson analysis was performed to identify the transcription factor (TF) whose expression was correlated with open chromatin regions of GPRC5B promoter. ChIP-seq profiles were obtained to confirm the physical binding of GATA4 and its predicted binding regions. For verification, quantitative polymerase chain reaction (qPCR) and multidimensional database validations were performed. Results: The reduced-Cox regression model revealed the prognostic value of GPRC5B. A novel pipeline for TF exploration was proposed. With our novel pipeline, we first identified chr16:19884686-19885185 as a reproducible open chromatin region in the GPRC5B promoter. Thereafter, we confirmed the correlation between GATA4 expression and the accessibility of this region, confirmed its physical binding, and proved in vitro how its overexpression could regulate GPRC5B. GPRC5B was significantly downregulated in colon adenocarcinoma (COAD) as seen in 28 patient samples. The correlation between GPRC5B and macrophages in COAD was validated using multiple databases. Conclusion: GPRC5B, correlated with macrophages, was a key GPCR affecting COAD prognosis. Further, with our novel pipeline, TF GATA4 was identified as a direct upstream of GPRC5B. This study proposed a novel pipeline for TF exploration and provided a theoretical basis for COAD therapy.

Sclerosing encapsulating peritonitis as a rare cause of intestinal obstruction after the treatment of peritoneal mesothelioma: a case report and review of the literature.

Sclerosing encapsulating peritonitis (SEP) is a rare cause of intestinal obstruction that is characterized by a thick greyish-white fibrotic membrane encasing the small bowel. The clinical features are typically nonspecific, and they occasionally present with recurrent episodes of incomplete or complete intestinal obstruction. The etiology of SEP remains unclear, and the diagnosis is often delayed mainly due to the lack of specific symptoms. Here, we first report a patient who suffered from SEP after treatment for malignant mesothelioma (MM) with tumor resection supplemented with hyperthermic intraperitoneal chemotherapy (HIPEC) once and intraperitoneal chemotherapy (IPC) eight times. The patient was discharged ten days after surgery and was free of complications at the 4-month follow-up. In addition, we reviewed the published literature from PubMed, only 7 articles of 16 cases finally met the defined requirements. Nine cases of SEP after IPC and 7 cases of SEP after HIPEC were previously reported. We synthetically review the pathogenesis, treatments, and outcomes. In conclusion, SEP is a rare abdominal disease, which is difficult to diagnose preoperatively. CT scanning is the most helpful imaging method for the diagnosis of SEP. Surgery is the most effective method for diagnosis and treatment, if conservative treatment has no effect or abdominal symptoms are aggravated.

Chromatin Accessibility Regulates Gene Expression and Correlates With Tumor-Infiltrating Immune Cells in Gastric Adenocarcinoma.

BACKGROUND: We explored key molecules affecting the prognosis of gastric adenocarcinoma (STAD) using co-analysis of chromatin accessibility (ATAC-seq), mRNA expression (RNA-seq), and overall survival. METHODS: We used the assay for transposase-accessible chromatin using sequencing (ATAC-seq) profiles to identify genes with chromatin accessibilities in their promoter regions. The RNA-seq profiles were processed for differentially expressed genes (DEGs) at mRNA level. The DEGs with chromatin accessibilities in promoter regions were further filtered using the Pearson correlation with TP53 expression. After co-analysis, genes were identified for the prognostic value using Kaplan-Meier method, followed by Pearson correlation analysis with significant pathways. For verification, we acquired clinical samples for qPCR and immunohistochemistry (IHC). Multidimensional database validations were performed to prevent the bias introduced by the use of a single database. RESULTS: We identified 11,557 DEGs and 57 genes with chromatin accessibilities. The co-analysis of ATAC-seq, RNA-seq, and clinical survival data revealed that interleukin-18 binding protein (IL18BP), with significant chromatin accessibility in its promoter region and differential mRNA expression, might be directly regulated by TP53 and influence STAD prognosis. Further, gene set variation analysis indicated that IL18BP may impact the survival of STAD patients in an immune-related manner. According to the CIBERSORT algorithm and Pearson correlation, the integration of IL18BP and CD4+ T memory cells may play an important role in the prognosis of STAD patients. CONCLUSION: IL18BP, regulated by TP53, may serve as a key molecule affecting STAD prognosis. And the mechanism is proposed to be the interaction between IL18BP and CD4+ T cells.

Prognostic role of podocalyxin-like protein expression in various cancers: A systematic review and meta-analysis.

Several studies were conducted to explore the prognostic significance of podocalyxin-like protein (PODXL) expression in various cancers, with contradictory. This study aims to summarize the prognostic significance of PODXL expression in cancers. PubMed, the Cochrane Library and Embase were completely retrieved. The prospective or retrospective studies focusing on the prognostic role of PODXL expression in cancers were eligible. The endpoints were overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS).12 studies involving a total of 5,309 patients were identified. The results indicated that high PODXL expression was significantly associated with worse OS when compared to the low PODXL expression (HR=1.76, 95%CI=1.53-2.04, p<0.00001; I2=41%, p=0.08). And similar results were detected in the subgroup analysis of analysis model, ethnicity, sample size, tumor type and antibody type. And the results also showed that high PODXL expression was obviously related to shorter DSS (HR=2.47, 95%CI=1.53-3.99, p=0.0002; I2=66%, p=0.03) and DFS (HR=2.12, 95%CI=1.58-2.85, p<0.00001; I2=19%, p=0.29). In conclusion, it was revealed that high PODXL expression is an unfavorable predictor of OS, DSS and DFS in patients with cancers, and high PODXL expression is a promising prognostic biomarker for cancers, especially for patients in European.

Prognostic role of platelet to lymphocyte ratio in hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Several studies were conducted to explore the prognostic significance of platelet to lymphocyte ratio (PLR) in hepatocellular carcinoma (HCC), however, contradictory results across most reports were documented. To this end, we present a systematic review that aims to summarize the prognostic significance of PLR in patients with HCC. RESULTS: A total of 10 studies involving a total of 2,315 patients were identified. The Newcastle-Ottawa Quality Assessment Scale (NOS) of each included study was greater than or equal to 5. The results indicated that high PLR was significantly associated with a worse OS when compared to the low PLR (HR = 1.60, 95% CI = 1.23-2.08, p = 0.0005; I2 = 88%, p < 0.00001). Similar results were detected in the subgroup analysis of the analysis model, cut-off value, ethnicity, sample size and therapy. However, no obvious correlation between the PLR and DFS/RFS in patients with HCC was observed (HR = 1.21, 95% CI = 0.87-1.67, p = 0.26; I2 = 61%, p = 0.07). MATERIALS AND METHODS: A complete literature search in the PubMed, Cochrane Library and Embase database was performed. Retrospective and prospective studies focusing on the role of PLR on the prognosis in HCC were all deemed as "suitable" for our scope. The endpoints determined were: the overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS) and the progress free survival (PFS). CONCLUSIONS: The study revealed that high PLR is an unfavorable predictor of OS in patients with HCC, and high PLR is a promising prognostic biomarker for HCC, especially for patients in Asia.

Relationship of bovine TNF-α gene polymorphisms with the risk of bovine tuberculosis in Holstein cattle.

Many studies suggest significant genetic variation in the resistance of cattle and humans to infection with Mycobacterium bovis (M. bovis), the causative agent of zoonotic tuberculosis. TNF-α promotes inflammation and induces apoptosis in response to mycobacterial infection. The aim of the present study was to investigate the influence of single nucleotide polymorphisms of the TNF-α gene on bovine tuberculosis (bTB) susceptibility. We genotyped the TNF-α gene in 74 bTB-infected Holstein cows and 90 healthy control animals. The influence in the exon 3 region of TNF-α polymorphisms on bTB susceptibility was subsequently investigated by association analysis. Our finding demonstrated that the g.27534932A>C polymorphism of the TNF-α is associated with bTB in Holstein cattle. The susceptibility of cattle with the g.27534932A>C genotype compared with the CC genotype was 4.11-fold (95% CI, 1.27-13.36; P=0.02) higher. The g.27534932A>C polymorphism located in exon 3 of the TNF-α gene, and the functional consequence was missense. The deduced amino acid sequence for the protein product revealed an arginine to serine conversion at position 159, which may affect initiation of protein synthesis and disrupt normal TNF-α function that protects animals against mycobacterial infection. A significant association was observed with the A allele as a risk factor for bTB susceptibility (OR, 3.84; 95% CI, 1.21-12.17; P=0.02). In conclusion, this is the first report showing that the g.27534932A>C polymorphism may contribute to TNF-α-mediated bTB susceptibility.

Relationship of bovine NOS2 gene polymorphisms to the risk of bovine tuberculosis in Holstein cattle.

Many studies suggest significant genetic variation in the resistance of cattle and humans to infection with Mycobacterium bovis, the causative agent of zoonotic tuberculosis. The inducible nitric oxide synthase (iNOS which is encoded by the NOS2 gene) plays a key role in the immunological control of a broad spectrum of infectious agents. This study aimed to investigate the influence of genetic variations in the promoter of the NOS2 gene on bovine tuberculosis (bTB) susceptibility. In this study, the NOS2 genes of 74 bTB-infected Holstein cows and 90 healthy controls were genotyped using PCR followed by nucleotide sequencing. Polymorphisms at rs207692718, rs109279434, rs209895548, rs385993919, rs433717754, rs383366213, rs466730386, rs715225976, rs525673647, rs720757654 and g.19958101T>G in the promoter region of the NOS2 gene were detected. The g.19958101T>G SNP produced two different conformation patterns (TT and TG) and the TG genotype was over-represented in the bTB group (20.27%) compared with the control group (2.22%). The TG genotype frequency of the g.19958101T>G variant was significantly higher in bTB cattle than in healthy controls (OR, 11.19; 95% CI, 2.47-50.73; P=0.0002). The G allele of the g.19958101T>G polymorphism was more frequent in bTB group when compared to control group (10.14% versus 1.11%). Furthermore, the G allele was a risk factor for bTB susceptibility (OR, 10.04; 95% CI, 2.26-44.65; P=0.0002). In conclusion, the g.19958101T>G polymorphism of the NOS2 gene may contribute to the susceptibility of Holstein cattle to bTB.