Association of Cystatin C Level with All-cause Mortality in Patients with Liver Cirrhosis: A Meta-analysis.

BACKGROUND AND OBJECTIVE: Blood cystatin C level has been introduced as a promising biomarker to detect early kidney injury in cirrhotic patients. The purpose of this meta-analysis was to investigate the association of blood cystatin C level with all-- cause mortality in patients with liver cirrhosis. METHODS: PubMed, ScienceDirect, and Embase databases were searched from the inception to November 15, 2022. Observational studies evaluating the value of blood cystatin C level in predicting all-cause mortality in patients with ACS were selected. The pooled hazard risk (HR) with 95% confidence intervals (CI) was calculated using a random effect model meta-analysis. RESULTS: Twelve studies with 1983 cirrhotic patients were identified. The pooled adjusted HR of all-cause mortality was 3.59 (95% CI 2.39-5.39) for the high versus low group of cystatin C level. Stratified analysis by study design, characteristics of patients, geographical region, sample size, and length of follow-up further supported the predictive value elevated cystatin C level. CONCLUSION: Elevated cystatin C level was an independent predictor of poor survival in patients with liver cirrhosis. Detection of blood cystatin C level may provide important prognostic information in cirrhotic patients.

Development and validation of cuproptosis-related lncRNAs associated with pancreatic cancer immune microenvironment based on single-cell.

Background: Cuproptosis, a novel mode of cell death associated with the tricarboxylic acid (TCA) cycle, is relevant to the development of cancer. However, the impact of single-cell-based Cuproptosis-associated lncRNAs on the Tumor immune microenvironment (TIME) of Pancreatic adenocarcinoma (PAAD) and its potential value for individualized immunotherapy has not been clarified. Methods: 14 immune-related CRGs were screened by exploring the interaction between differentially expressed Immune-Related Genes (IRGs) and Cuproptosis-Related Genes (CRGs) in PAAD. Next, the expression amount and expression distribution of CRGs in single-cell samples were analyzed by focusing on 7-CRGs with significant expressions. On the one hand, MAP2K2, SOD1, and VEGFA, which were significantly differentially expressed between PAAD sites and normal tissues adjacent to them, were subjected to immunohistochemical validation and immune landscape analysis. On the other hand, from these 7-CRGs, prognostic signatures of lncRNAs were established by co-expression and LASSO-COX regression analysis, and their prognostic value and immune relevance were assessed. In addition, this study not only validated the hub CRGs and the lncRNAs constituting the signature in a PAAD animal model treated with immunotherapy-based combination therapy using immunohistochemistry and qRT-PCR but also explored the potential value of the combination of targeted, chemotherapy and immunotherapy. Results: Based on the screening of 7-CRGs significantly expressed in a PAAD single-cell cohort and their co-expressed Cuproptosis-Related lncRNAs (CRIs), this study constructed a prognostic signature of 4-CRIs named CIR-score. A Nomogram integrating the CIR-score and clinical risk factors was constructed on this basis to predict the individualized survival of patients. Moreover, high and low-risk groups classified according to the median of signatures exhibited significant differences in clinical prognosis, immune landscape, bioenrichment, tumor burden, and drug sensitivity. And the immunohistochemical and qRT-PCR results of different mouse PAAD treatment strategies were consistent with the trend of inter-group variability in drug sensitivity of hub CRGs and CIR-score. The combination of immunotherapy, targeted therapy, and chemotherapy exhibited a better tumor suppression effect. Conclusion: CIR-score, as a Cuproptosis-related TIME-specific prognostic signature based on PAAD single cells, not only predicts the prognosis and immune landscape of PAAD patients but also provides a new strategy for individualized immunotherapy-based combination therapy.

Pseudogene TDGF1P3 regulates the proliferation and metastasis of colorectal cancer cells via the miR-338-3p-PKM2 axis.

Research in the past decade has revealed significant roles of pseudogenes in colorectal cancer (CRC). Here, the role of teratocarcinoma-derived growth factor 1 pseudogene 3 (TDGF1P3) in regulating the proliferation and invasion of CRC cells was investigated; in addition, its downstream targets were analyzed, and the underlying mechanisms were elucidated. TDGF1P3 was determined to be upregulated in CRC cells and tissues. Silencing TDGF1P3 substantially repressed cell proliferation, migration, and invasion in vitro. Similarly, in vivo assays showed that TDGF1P3 knockdown attenuated tumor growth in nude mice. Mechanistic investigations revealed that TDGF1P3 directly bound to miR-338-3p, thereby preventing miR-338-3p from binding to its target mRNA pyruvate kinase M2 (PKM2). Functional rescue tests indicated that TDGF1P3 regulates CRC cell proliferation and invasion by restraining the miR-338-3p-PKM2 axis. Thus, these data illustrated that TDGF1P3 exerts its oncogenic activity by upregulating PKM2 via competitively binding miR-338-3p, which may be a therapeutic target for CRC.

ARHGEF16 expression correlates with proliferation, migration and invasion of colon cancer cells.

Background: Rho guanine nucleotide exchange factor 16 (ARHGEF16) is a newly discovered Rho-family guanine nucleotide exchange factor (GEF) involved in the activation of Rho-family GTPases. However, its roles in colon cancer cell proliferation, migration, and invasion remain unknown. This study analyzed the expression of ARHGEF16 in colon cancer and explored its biological effects on colon cancer cells, so as to find new therapeutic targets for the treatment of colon cancer. Methods: The expression of ARHGEF16 in colon cancer tissues and cells was detected by bioinformatics analysis, western blot, and quantitative real time polymerase chain reaction (qRT-PCR) assays. The effects of overexpression and silencing of ARHGEF16 on the biological behavior of colon cancer cells were examined by Cell Counting Kit-8 (CCK-8), cell scratching and Transwell assays. Results: The database showed that ARHGEF16 was highly expressed in colon cancer tissues. Validation with clinical fresh tissue specimens and colon cancer cell lines revealed that ARHGEF16 was highly expressed in both. The proliferation, growth, migration, and invasion ability of colon cancer cell lines increased significantly with the overexpression of ARHGEF16, while silencing ARHGEF16 showed the opposite effect. Conclusions: The expression of ARHGEF16 is closely related to the migration and invasive ability of colon cancer cells, and overexpression of ARHGEF16 promotes the migration and invasion of colon cancer cells and correlates with the metastatic potential of colon cancer.

Integrating the Ecological Security Pattern and the PLUS Model to Assess the Effects of Regional Ecological Restoration: A Case Study of Hefei City, Anhui Province.

Most studies in the field of ecological restoration have only focused on repairing damaged land and have made no attempt to account for the impact of high-intensity land use on future landscape patterns. The purpose of this study was to propose a framework for evaluating the expected effects of ecological restoration based on land-use change and the ecological security pattern. Therefore, we integrated the PLUS model with the ecological security pattern and used Hefei City as a case study to conduct research. The results showed that from 2020 to 2030, land-use changes would occur primarily in the main urban area of Hefei and along the eastern shore of the Chaohu Lake watershed. Under the ecological protection scenario, arable land would be converted to construction land and woodland. Additionally, there would be an increase in ecological sources and pinch points in the area, and the number and area of the barriers would show a certain degree of reduction. The ecosystem quality, ecological integrity, and landscape connectivity of Hefei would be improved. This study offers a novel perspective for evaluating the expected effects of regional ecological restoration and provides an important reference for the dynamic formulation of multilevel ecological restoration policies.

CCL2-mediated monocytes regulate immune checkpoint blockade resistance in pancreatic cancer.

The immunosuppressive microenvironment of pancreatic ductal adenocarcinoma (PDAC) contributes to resistance to immune checkpoint blockade. C-C motif chemokine ligand 2 (CCL2) is believed to participate in pancreatic tumorigenesis, but its role in PDAC progression and resistance to immune checkpoint blockade remains unclear. We hypothesized that CCL2 contributes to the pancreatic immunosuppressive microenvironment. In this study, we found that CCL2 recruits monocytes to and decrease CD8+ T cell infiltration in pancreatic tumors. CCL2 inhibition and monocyte neutralization increased the sensitivity of PDAC to immune checkpoint blockade. The findings of our study suggest the potential of CCL2-mediated monocytes as a target for PDAC treatment.

Case-control study on TP73 rs1801173 C > T gene polymorphism and susceptibility to gastric cancer in a Chinese Han population.

BACKGROUND: This study investigated the role of TP73 gene polymorphism, rs1801173on risk of gastric cancer. METHODS: We conducted a case-controlled study including 577 primary gastric cancer and 678 normal control cases. The target gene fragment was amplified using PCR using blood samples collected from patients. Allele analysis and genotyping were performed using snapshot method. RESULTS: The findings showed that the control group had consistent genotype frequency distribution and presented Hardy-Weinberg equilibrium. The results showed no significant differences in sex, drinking history and age distributions between subjects with the polymorphism and subjects in the control group. Smoking status was correlated with incidence of gastric cancer (P = 0.006). The rs1801173 locus of TP73 gene contained 3 genotypes including: TT, CT, and CT. Logistic regression analysis showed that distribution of recessive model and dominant model was comparable between the two groups before (P = 0.688; 0.937) or after (P = 0.703; 0.990) adjusting for confounders. The distribution frequency in case group was not significantly different relative to that of the control group (P = 0.763). CONCLUSION: Smoking can independently influence the risk of gastric cancer. TP73 gene rs1801173 polymorphism was not significantly correlated with risk of gastric cancer.

In Hepatocellular Carcinoma, miRNA-296-3p Targets MSL2 and Suppresses Cell Proliferation and Invasion.

Hepatocellular carcinoma (HCC) is the third-highest cause of cancer-related death in the world. miRNAs have a role in cell division, differentiation, and death biological processes. They are typically dysregulated in cancers, affecting tumor progression. miRNA-296-3p appears to play a crucial role in cancer control, according to new research. However, its expression and roles in HCC are unknown. This study used qRT-PCR and western blotting to detect the miRNA-296-3p and male-specific lethal 2 (MSL2) expression. In addition, cell proliferation, migration, invasion, and apoptosis were studied using CCK-8, flow cytometric analysis, colony formation assay, wound healing test, and transwell assays. The results show that miRNA-296-3p is underexpressed in HCC cell lines, particularly in Huh-7 and HepG2 cells. miRNA-296-3p overexpression lowers the ability of HCC cells to proliferate, migrate, and invade while increasing cell death. Luciferase reporter experiments revealed that the MSL2 is a direct target of miRNA-296-3p. Furthermore, overexpression of miRNA-296-3p reduced MSL2 mRNA and protein levels considerably, according to our findings. Furthermore, the rescue experiments showed that the MSL2 overexpression partially blocked the inhibition effects of miRNA-296-3p mimic on the proliferation and migration of HCC cells. The above results show that miRNA-296-3p may have a repressive effect in HCC by targeting MSL2 and could be used as a therapeutic target for HCC treatment.

Inactivation of Pancreatic Stellate Cells by Exendin-4 Inhibits the Migration and Invasion of Pancreatic Cancer Cells.

BACKGROUND: Pancreatic stellate cells (PSCs) are precursor cells of cancer-associated fibroblasts that promote tumor proliferation, invasion, and metastasis. The glucagon-like peptide-1 receptor agonist exendin-4 has been reported to exhibit anticancer effects against several tumor cells; however, the function and mechanism underlying the effects of exendin-4 on pancreatic cancer cells remain unclear. METHODS: Gene expression levels were determined using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assay. Cell viability, migration and invasion were assessed using the cell counting kit-8 (CCK-8), wound healing, and transwell assays, respectively. A xenografted tumor model was established in mouse to evaluate the effects of exendin-4 in vivo. RESULTS: Exendin-4 treatment led to the inactivation of PSCs and suppressed their proliferation and migration. Moreover, we also found that exendin-4 attenuated NF-κB-dependent SDF-1 secretion. Furthermore, pancreatic cancer cells incubated with conditioned medium obtained from exendin-4-treated PSCs showed a decreased ability to proliferate, migrate, and invade as compared to the control cells, which is similar to the effects induced by the CXCR4 inhibitor, AMD3100. Consistent with in vitro results, we also confirmed that exendin-4 indirectly targeted pancreatic cancer cells in vivo by attenuating the function of PSCs and suppressing the deposition of extracellular matrix. CONCLUSION: These results revealed that exendin-4-treated PSCs could suppress pancreatic cancer cell proliferation and invasion, offering a potential strategy for the treatment of pancreatic cancer.

Association of Genetic Polymorphisms in TNFRSF11 with the Progression of Genetic Susceptibility to Gastric Cancer.

OBJECTIVE: To investigate the relationship between polymorphism of TNFRSF11 gene rs9533156 and rs2277438 and susceptibility to gastric cancer. METHODS: A case-control study was conducted to select 577 cases of primary gastric cancer and 678 cases of normal control. We extracted whole blood genomic DNA and amplified the target gene fragment by PCR. The genotyping and allele were tested through the snapshot method. RESULTS: In this case-control study, we observed that there was a difference in the genotype distribution of TNFRSF11 gene rs9533156 between the case group and the control group. The frequency distribution of TC heterozygous mutation in the case group was higher than that in the control group. The smoking rate in the case group (34.49%) was higher than that in the control group (27.29%), and the difference in frequency distribution between the two groups was statistically significant (P=0.006). Our findings suggest that TNFRSF11 rs9533156 is associated with susceptibility to GC, which is more evident among elderly patients (>62 years), nonsmokers, and patients who do not consume alcohol. The analysis of the relationship between the TNFSF11 gene rs9533156 site variant and clinical factors of gastric cancer showed that, compared with the tumor size <2 cm group, patients with tumor size ≥2 cm and whom carrying rs9533156 site mutations had a higher frequency distribution, and the difference was statistically significant (P=0.022). Compared with the nonhyperglycemic group, the frequency distribution of patients with rs9533156 site mutations in the diabetes group was higher, and the difference was statistically significant (P < 0.001). CONCLUSION: This study shows that there is a correlation between smoking and the occurrence of gastric cancer. Based on our research, the functional SNP TNFRSF11 TC genotype may be an indicator of individual susceptibility to GC. The mutation at rs9533156 may be related to the size of gastric cancer. The mutation rate of rs9533156 of TNFSF11 gene is higher in diabetic gastric cancer patients.

Pretreatment C-reactive protein/albumin ratio for predicting overall survival in pancreatic cancer: A meta-analysis.

BACKGROUND: Inconsistent findings have been reported regarding the association of C-reactive protein to albumin ratio (CAR) with survival outcome in patients with pancreatic cancer. We conducted the current meta-analysis to assess the prognostic utility of elevated baseline CAR in predicting overall survival (OS) in pancreatic cancer patients. METHODS: A comprehensively literature search was performed in the PubMed and Embase database until February 10, 2019. Studies evaluating the association between pretreatment CAR and OS among pancreatic cancer were selected. Study quality was evaluated by using the Newcastle-Ottawa Scale. RESULTS: Nine retrospective studies involving 1534 pancreatic cancer patients were identified. A meta-analysis using a random-effect model indicated that elevated CAR was associated with poor OS (hazard ratio 1.98; 95% confidence interval 1.58-2.48). Subgroup analysis produced similar prognostic values for OS in different geographical regions, sample sizes, thresholds of CAR, treating methods, and Newcastle-Ottawa Scale points. CONCLUSION: Elevated pretreatment CAR may independently predict poor OS in pancreatic cancer patients. Pretreatment CAR is possibly a simple and cost-effective blood-derived indicator for predicting survival outcome in patients with pancreatic cancer.

N6-methyladenosine (m6A) RNA modification in gastrointestinal tract cancers: roles, mechanisms, and applications.

Analogous to DNA methylation and histone modification, RNA modification, as another epigenetic layer, plays an important role in many diseases, especially in tumours. As the most common form of RNA modification, m6A methylation has attracted increasing research interest in recent years. m6A is catalysed by RNA methyltransferases METTL3, METTL14 and WTAP (writers), m6A is removed by the demethylases FTO and ALKBH5 (erasers) and interacts with m6A-binding proteins, such as YT521-B homology (YTH) domain-containing proteins. This article reviews recent studies on methylation modification of m6A in gastrointestinal tract cancers.

Exosome-mediated transfer of miR-1290 promotes cell proliferation and invasion in gastric cancer via NKD1.

Currently, exosomes rich in RNAs and proteins are regarded as vital mediators of intercellular communication. Here, we aimed to explore the effects of exosomal miR-1290 in gastric cancer (GC) and understand its mechanism of action on GC progression. We first isolated exosomes from serum samples of GC patients and healthy people and characterized them by transmission electron microscopy. Then, we examined the expression level of miR-1290 contained in the exosomes by quantitative reverse-transcription polymerase chain reaction and found that exosomal miR-1290 was overexpressed in GC patients and cell lines. Promotion of proliferation, migration, and invasiveness of GC cells was noted after they were incubated with the isolated miR-1290-rich exosomes compared with incubation with a negative control. Furthermore, we predicted that naked cuticle homolog 1 (NKD1) mRNA is a direct target of miR-1290 and confirmed their interaction by a dual luciferase reporter assay. NKD1 overexpression attenuated the stimulatory effects of miR-1290 on GC cells. Collectively, our results suggest that exosomal miR-1290 enhances GC cell proliferation and invasion by targeting NKD1 mRNA and downregulating NKD1 expression. A better understanding of this process may facilitate the development of novel therapeutic agents for GC.

Prognostic significance of C-reactive protein to albumin ratio in colorectal cancer patients: a meta-analysis.

PURPOSE: Inconsistent results on the prognostic significance of C-reactive protein to albumin ratio (CAR) in colorectal cancer patients have been reported. This meta-analysis sought to assess the prognostic value of pretreatment CAR for survival outcomes in colorectal cancer patients. METHODS: We conducted a systematic literature search of PubMed and Embase databases until February 16, 2019. Observational studies investigating the prognostic role of pretreatment CAR for survival outcome in patients with colorectal cancer were included. Outcome measures included overall survival (OS), disease-free survival (DFS), or progression-free survival (PFS). Pooled hazard ratio (HR) with 95% confidence interval (CI) was utilized to summarize the prognostic significance of CAR for patient survival. RESULTS: Nine retrospective studies involving 2492 colorectal cancer patients were identified. A fixed-effect model meta-analysis showed that high pretreatment CAR was an independent predictor of poor OS (HR 2.25; 95% CI 1.84-2.76) and DFS (HR 2.49; 95% CI 1.43-4.33). On the other hand, no significant association was observed between high CAR and PFS (HR 1.71; 95% CI 0.44-6.60). The predictive values of OS with high pretreatment CAR caused no significant changes in different sample sizes, countries, cut-off values of CAR, treatment methods, and study quality of subgroups. CONCLUSION: This meta-analysis suggests that CAR may be a powerful prognostic indicator for colorectal cancer prognosis. High pretreatment CAR is associated with poor OS and DFS in patients with colorectal cancer.

Meta-analysis of the association between the inflammatory potential of diet and colorectal cancer risk.

OBJECTIVES: The inflammatory potential of diet has been inconsistently linked to colorectal cancer (CRC) risk. This meta-analysis aimed to evaluate the association of the inflammatory potential of diet, as estimated by the dietary inflammatory index (DII) score, with CRC risk. MATERIALS AND METHODS: The PubMed and Embase databases were searched for relevant studies from inception to February 2017. All cohort and case-control studies investigating the association of the DII score with CRC risk were selected. RESULTS: Four prospective cohorts and four case-control studies, which enrolled a total of 880,380 participants, were included. The pooled adjusted risk ratio (RR) of CRC for the highest DII score versus the lowest category was 1.43 (95% confidence interval [CI]: 1.26-1.62). When stratified by study design, the RRs for the case-control and cohort studies were 1.27 (95% CI: 1.16-1.38) and 1.81 (95% CI: 1.48-2.22), respectively. Subgroup analysis showed that individuals with the highest category of DII score were independently associated with CRC risk in men (RR=1.51; 95% CI: 1.29-1.76), women (RR=1.25; 95% CI: 1.10-1.41), colon cancer (RR=1.39; 95% CI: 1.19-1.62), and rectal cancer (RR=1.32; 95% CI: 1.01-1.74). However, the pooled RR was 1.07 (95% CI: 0.87-1.31) for rectal cancer among the prospective cohort studies. CONCLUSIONS: As estimated by a high DII score, pro-inflammatory diet is independently associated with increased CRC risk. This finding confirms that low inflammatory potential diet may reduce CRC risk. However, the gender- and cancer site-specific associations of the DII score with CRC risk need to be further investigated.

Pancreatic stellate cells increase the invasion of human pancreatic cancer cells through the stromal cell-derived factor-1/CXCR4 axis.

AIM: Both pancreatic stellate cells (PSCs) and the stromal cell-derived factor-1(SDF-1)/CXCR4 receptor ligand system have important roles in pancreatic cancer progression. This study set out to detect if PSCs express SDF-1 and promote the invasion of pancreatic cancer through the SDF-1/CXCR4 receptor ligand axis. METHODS: RT-PCR was performed to detect the expression of SDF-1 and CXCR4 in PSCs, pancreatic cancer lines and cancer tissue samples. ELISA was used to investigate the concentration of SDF-1 in PSC supernatants. An MTT assay was applied to detect the proliferation of pancreatic cancer cells. A transwell chamber migration assay was employed to detect the migration of AsPC-1 cells. An in vitro invasion assay was used to detect the invasion of AsPC-1 cells. RESULTS: CXCR4 expression was detected in PSCs; AsPC-1, SW1990 and BxPC-3 cancer cells; and cancer tissues. SDF-1 was detected in PSCs and cancer tissues, but not in AsPC-1, SW1990 and BxPC-3 cells. SDF-1alpha protein was found in PSC supernatants. PSC-conditioned media can promote the proliferation, migration and invasion of pancreatic cancer cells. SDF-1 neutralizing antibody or AMD3100 can significantly inhibit these promotive and IAP.

Increase of mast cells may be associated with infiltration of eosinophils and proliferation of microvessels in gastric eosinophilic granuloma.

BACKGROUND: Gastric eosinophilic granuloma (GEG) is a rare disease. Recently this disease has begun to increase in China. In the present study, the function and the role of mast cells (MC) in the pathogenesis of GEG were investigated. METHODS: Paraffin-embedded tissue sections from 23 GEG patients and 15 gastric ulcer (GU) patients, were stained with antihuman mast cell tryptase for counting the MC and degranulated MC. Antihuman CD34 antibody was used for detecting the microvessel density (MVD) with immunohistochemical technique. Mast cell degranulation was also studied using electron microscopy. RESULTS: The quantity of both MC and degranulated MC were higher in both GEG and GU than in normal gastric mucosa. The proportion of degranulated MC was higher in the GEG but in GU it was similar to normal mucosa. The MVD was higher in both GU and GEG than that in the normal gastric mucosa and it was higher in the high-MC group than in the low-MC group in GEG. The positive correlation between eosinophil and MC was present only in GEG, not in GU. CONCLUSIONS: The infiltration of eosinophils and MVD may be associated with the increase of MC in GEG. This suggests that in addition to eosinophils, MC might be the important cells in the pathogenesis of GEG.

Gastric eosinophilic granuloma in China: case series.

AIM: Eosinophilic granulomas are benign localized lesions in the stomach that are distinct from eosinophilic gastritis. The aim of this study was to identify the potential etiological factors and clinical features of gastric eosinophilic granulomas (GEG). METHODS: Clinical manifestations, histopathological features, diagnosis and treatments of 48 hospitalized cases of GEG were analyzed retrospectively. A modified Giemsa staining was employed to detect Helicobacter pylori in 23 of these 48 patients. RESULTS: There was a significant gender difference among patients with GEG with male patients significantly more affected than female patients. The final diagnosis was made after operating the patients (the misdiagnosis level was rather high before resection). Lymphoid follicles were found in 68.6% of the tissues surrounding the lesion. H. pylori infection was detected in 69.6% of patients. In 11 patients eosinophilia in the peripheral blood was observed. CONCLUSION: The results suggest that H. pylori infection, estrogen status and local allergic reactions may be associated with the development of GEG.