Explore the vast range of titles available.

Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer (CRC) patients. The role of the differentially expressed lncRNAs in 5-Fluorouracil chemoresistance has not fully explained. Here, we observed lncRNA H19 was associated with the 5-Fu resistance in CRC. Quantitative analysis indicated that H19 was significantly increased in recurrent CRC patient samples. Kaplan–Meier survival analysis indicated that high H19 expression in CRC tissues was significantly associated with poor recurrent free survival. Our functional studies demonstrated that H19 promoted colorectal cells 5-Fu resistance. Mechanistically, H19 triggered autophagy via SIRT1 to induce cancer chemoresistance. Furthermore, bioinformatics analysis showed that miR-194–5p could directly bind to H19, suggesting H19 might work as a ceRNA to sponge miR-194–5p, which was confirmed by Dual-luciferase reporter assay and Immunoprecipitation assay. Extensively, our study also showed that SIRT1 is the novel direct target of miR-194–5p in CRC cells. Taken together, our study suggests that H19 mediates 5-Fu resistance in CRC via SIRT1 mediated autophagy. Our finding provides a novel mechanistic role of H19 in CRC chemoresistance, suggesting that H19 may function as a marker for prediction of chemotherapeutic response to 5-Fu.

Background Early detection of colorectal cancer (CRC) significantly enhances patient outcomes. Conventional CRC screening tools, like endoscopy and stool-based tests, have constraints due to their invasiveness or suboptimal patient adherence. Recently, liquid biopsy employing plasma cell-free DNA (cfDNA) has emerged as a potential noninvasive screening technique for various malignancies. Methods In this research, we harnessed the Mutation Capsule Plus (MCP) technology to profile an array of genomic characteristics from cfDNA procured from a single blood draw. This profiling encompassed DNA methylation, the 5’ end motif, copy number variation (CNV), and genetic mutations. An integrated model built upon selected multiomics biomarkers was trained using a cohort of 93 CRC patients and 96 healthy controls. Results This model was subsequently validated in another cohort comprising 89 CRC patients and 95 healthy controls. Remarkably, the model achieved an area under the curve (AUC) of 0.981 (95% confidence interval (CI), 0.965–0.998) in the validation set, boasting a sensitivity of 92.1% (95% CI, 84.5%-96.8%) and a specificity of 94.7% (95% CI, 88.1%-98.3%). These numbers surpassed the performance of any single genomic feature. Importantly, the sensitivities reached 80% for stage I, 89.2% for stage II, and were 100% for stages III and IV. Conclusion Our findings underscore the clinical potential of our multiomics liquid biopsy test, indicating its prospective role as a noninvasive method for early-stage CRC detection. This multiomics approach holds promise for further refinement and broader clinical application.

Liver metastasis is the main cause of death in patients with colorectal cancer (CRC); thus, necessitating effective biomarkers and therapeutic targets for colorectal cancer liver metastasis (CRLM). Fibroblast growth factor 19 (FGF19) is a protumorigenic gene in numerous human malignancies. In this study, it is shown that FGF19 plays an indispensable role in CRLM. FGF19 expression and secretion are markedly correlated with liver metastasis and lower overall survival rates of patients with CRC. An in vivo metastasis model shows that FGF19 overexpression confers stronger liver‐metastatic potential in CRC cells. Mechanistically, FGF19 exerts an immunomodulatory function that creates an environment conducive for metastasis in CRLM. FGF19 mediates the polarization of hepatic stellate cells to inflammatory cancer‐associated fibroblasts (iCAFs) by activating the autocrine effect of IL‐1α via the FGFR4‐JAK2‐STAT3 pathway. FGF19‐induced iCAFs promote neutrophil infiltration and mediate neutrophil extracellular trap (NET) formation in liver metastatic niches via the production of complement C5a and IL‐1β, which in turn accelerates the liver colonization of CRC cells. Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19‐induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention. Liver metastasis is the main cause of colorectal cancer (CRC)‐related deaths in humans. Tumor‐secreted FGF19 mediates the polarization of hepatic stellate cells to inflammatory cancer‐associated fibroblasts (iCAFs), thereby modulating neutrophil infiltration and the metastasis‐supporting neutrophil extracellular traps (NETs) in liver metastatic niches. These promote liver colonization of CRC cells and support FGF19‐targeting therapy for colorectal cancer liver metastasis.

Background In this study, we aimed to identify the risk factors in patients with rectal anastomotic re-leakage and develop a prediction model to predict the probability of rectal anastomotic re-leakage after stoma closure. Methods This study was a single-center retrospective analysis of patients with rectal cancer who underwent surgery between January 2010 and December 2020. Among 3225 patients who underwent Total or Partial Mesorectal Excision (TME/PME) surgery for rectal cancer, 129 who experienced anastomotic leakage following stoma closure were enrolled. Risk factors for rectal anastomotic re-leakage were analyzed, and a prediction model was established for rectal anastomotic re-leakage. Results Anastomotic re-leakage after stoma closure developed in 13.2% (17/129) of patients. Multivariable analysis revealed that neoadjuvant chemoradiotherapy (odds ratio, 4.07; 95% confidence interval, 1.17–14.21; p =  0.03), blood loss > 50 ml (odds ratio, 4.52; 95% confidence interval, 1.31–15.63; p  = 0.02), and intersphincteric resection (intersphincteric resection vs. low anterior resection: odds ratio, 6.85; 95% confidence interval, 2.01–23.36; p  = 0.002) were independent risk factors for anastomotic re-leakage. A nomogram was constructed to predict the probability of anastomotic re-leakage, with an area under the receiver operating characteristic curve of 0.828 in the cohort. Predictive results correlated with the actual results according to the calibration curve. Conclusions Neoadjuvant chemoradiotherapy, blood loss > 50 ml, and intersphincteric resection are independent risk factors for anastomotic re-leakage following stoma closure. The nomogram can help surgeons identify patients at a higher risk of rectal anastomotic re-leakage.

The epidermal growth factor receptor (EGFR) gene copy number (GCN) has been previously demonstrated to correlate with the clinical outcome of colorectal cancer (CRC) treated with anti-EGFR monoclonal antibodies (mAbs), although it remains controversial. We conducted a systematic review and meta-analysis to assess EGFR GCN as a potential biomarker of survival for patients with advanced CRC receiving treatment with anti-EGFR mAbs. We systematically identified articles investigating EGFR GCN by fluorescent or chromogenic in situ hybridization or other detection techniques in patients with metastatic CRC treated with panitumumab or cetuximab, (last search: 10 August 2012). Eligible studies had to report on overall survival (OS), progression-free survival (PFS) or time-to-progression (TTP), stratified by EGFR GCN. Summary hazard ratios (HRs) were calculated using random-effects models. Among 13 identified studies, 10 (776 patients, 302 with increased GCN), 8 (893 patients, 282 with increased GCN) and 3 (149 patients, 66 with increased GCN) were eligible for the OS, PFS and TTP meta-analyses, respectively. Increased EGFR GCN was associated with increased OS (HR = 0.62; 95% CI 0.50-0.77; P<0.001), PFS (HR = 0.65; 95% CI 0.47-0.89; P = 0.008) but not TTP (HR = 0.71; 95% CI 0.44-1.14; P = 0.157). It was also shown that EGFR GCN is independent of other factors such as KRAS status. Among those populations received second-line or higher treatment, increased EGFR GCN was strongly associated with improved survival (for OS, HR = 0.60; 95% CI 0.47-0.75; P<0.001; for PFS, HR = 0.59; 95% CI 0.47-0.75; P<0.001), whereas it did not influence survival in patients that received first-line therapy. Among the anti-EGFR-treated patients, increased EGFR GCN appears to be associated with improved survival outcomes. The effect on survival appears to be related to patients receiving the line of treatment.

Background There have been previously reported associations between the gut microbiota, immune cells, and colorectal cancer; however, the specific mechanisms underlying these relationships remain largely unexplored and require further research. Therefore, in this study, we aimed to unravel the interactions between the gut microbiota, immune cells, and colorectal cancer. Methods The analysis used genome-wide association study (GWAS) data encompassing 207 microbial taxa and 205 functional pathways and data on 731 immune cell phenotypes. Colorectal cancer data on 6 581 cases and 463 421 controls were sourced from the Integrative Epidemiology Unit Open GWAS Project. Univariate inverse-variance weighted Mendelian randomization analysis was used to identify gut microbial taxa associated with colorectal cancer. Mediation analysis was used to identify the mediating role of specific immune cells in the link between gut bacteria and colorectal cancer. Results Univariate inverse-variance weighted Mendelian randomization analysis revealed that several microbial taxa from the Actinobacteria and Firmicutes phyla were significantly associated with colorectal cancer. Coriobacteriaceae (odds ratio [OR]: 0.84, 95% confidence interval [CI]: 0.72–0.97), Sutterellaceae (OR: 0.88, 95% CI: 0.78–0.99), Eggerthella (OR: 0.91, 95% CI: 0.84–0.99), Coriobacteriales (OR: 0.84, 95% CI: 0.72–0.97), Collinsella aerofaciens (OR: 0.85, 95% CI: 0.74–0.99), and Ruminococcus bromii (OR: 0.91, 95% CI: 0.83–0.99) were negatively associated with colorectal cancer, whereas Lactobacillales (OR: 1.11, 95% CI: 1.03–1.20), Veillonella (OR: 1.08, 95% CI: 1.01–1.15), and Bifidobacterium bifidum (OR: 1.05, 95% CI: 1.00–1.09) were positively associated with colorectal cancer. Mediation analysis revealed that in the causal pathway from Collinsella aerofaciens to colorectal cancer, CD127 on CD28 + CD45RA − CD8br and human leukocyte antigen (HLA) DR on CD33 − HLA DR + , mediated 11.30% and − 6.52% of the effect, respectively, and that in the causal pathway from Ruminococcus bromii to colorectal cancer, IgD − CD38dim %lymphocyte mediated − 14.80% of the effect. Conclusions These results highlight the potential of gut microbiota and immune cell phenotypes as novel treatment strategies for colorectal cancer.

According to Japanese guidelines, localized forms of colon cancer can be resected within 10-cm resection margins, depending on the feeding branch inflow pattern. [...]the results of NOSES should be analyzed in the context of segmental colon resection. [...]patients were filtered based on sex, then age was considered (a 5-year difference was acceptable), and lastly, height and weight were matched. [...]we showed that NOSES decreases the length of operations. [...]NOSES resulted in less blood loss in our study. [...]no positive resection margins were observed in this group. [...]segmental resections with natural orifice specimen extraction can be adopted.

Background Immune checkpoint inhibitors have traditionally been understood to exert their effects primarily within the tumor microenvironment, particularly targeting CD8 + T cells. However, recent studies have highlighted a pivotal role of tumor-draining lymph nodes in mediating responses to immune checkpoint inhibitor therapy. This study aimed to elucidate the specific mechanisms by which tumor-draining lymph nodes respond to immune checkpoint inhibitor therapy and regulate the tumor microenvironment in human colorectal cancer. Methods We performed single-cell RNA sequencing and T cell receptor sequencing on tumor-draining lymph nodes and tumor tissues from patients with colorectal cancer. Through in-depth analysis of the single-cell data, we established the connection between TDLNs and tumor, and explored the impact of immune checkpoint inhibitor therapy on the immune microenvironment of tumor-draining lymph nodes. In addition, we conducted animal experiments to validate these findings. Results Our findings revealed that immune checkpoint inhibitor treatment induced the expansion of tumor-specific CD8 + effector memory T cells within tumor-draining lymph nodes, which may serve as a source for the progenitor-exhausted CD8 + T cells in the tumor microenvironment. Moreover, conventional dendritic cells type 1 and macrophages within tumor-draining lymph nodes facilitated this process. We also observed that immune checkpoint inhibitor therapy promoted the expansion of tumor-specific CD4 + follicular helper T cells in tumor-draining lymph nodes, which may explain the increase of CD4 + follicular helper T cells in the tumor microenvironment after immune checkpoint inhibitor therapy. These hypotheses were corroborated through experiments in mice. Conclusions Our findings delineate the critical regulatory function of tumor-draining lymph nodes in modulating the tumor microenvironment during Immune checkpoint inhibitor therapy.

Fibroblast activation protein alpha (FAP) is a marker of cancer-associated fibroblast, which is also expressed in cancer epithelial cells. However, the role of FAP in colorectal cancer (CRC) cells remains to be elucidated. Here we investigate the expression pattern of FAP in CRC tissues and cells to prove that FAP is upregulated in CRC cells. Loss- of and gain-of-function assays identified FAP promotes migration and invasion instead of an effect on cell proliferation. Microarray assays are adopted to identify the different expressed genes after FAP knockdown and gene set enrichment analysis (GSEA) is used to exploit the involved signaling pathway. Our works reveal FAP exerts a function dependent on NF-κB signaling pathway and FAP expression is associated with NF-κB signaling pathway in clinical samples. Our work shows FAP is secreted by CRC cells and soluble FAP could promote metastasis. To investigate the mechanism of FAP influencing the NF-κB signaling pathway, LC/MS is performed to identify the proteins interacting with FAP. We find that FAP binds to ENO1 and activates NF-κB signaling pathway dependent on ENO1. Blocking ENO1 could partially reverse the pro-metastatic effect mediated by FAP. We also provide evidences that both FAP and ENO1 are associated with CRC stages, and high levels of FAP and ENO1 predict a poor survival in CRC patients. In summary, our work could provide a novel mechanism of FAP in CRC cells and a potential strategy for treatment of metastatic CRC.

Background Colorectal polyp is known a precursor of colorectal cancer (CRC) that holds an increased risk for progression to CRC. Circulating cell-free DNA (cfDNA) methylation has shown favorable performance in the detection and monitoring the malignant progression in a variety of cancers. Results To discover cfDNA methylation markers for the diagnosis of CRC, we first performed a genome-wide analysis between eight CRC and eight polyp tissues using the Infinium HumanMethylationEPIC BeadChip. We identified 7008 DMCs, and after filtering, we validated 39 DMCs by MethylTarget sequencing in 62 CRC and 56 polyp tissues. A panel of four CpGs (cg04486886, cg06712559, cg13539460, and cg27541454) was selected as the methylation marker in tissue by LASSO and random forest models. A diagnosis prediction model was built based on the four CpGs, and the methylation diagnosis score (md-score) can effectively discriminate tissues with CRC from polyp patients (AUROC > 0.9). Finally, the cg27541454 was confirmed hypermethylated in CRC (AUC = 0.85) in the plasma validation cohort. Conclusions Our findings suggest that the md-score could robustly detect CRC from polyp tissues, and cg27541454 may be a promising candidate noninvasive biomarker for CRC early diagnosis.