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Digestive system diseases arise primarily through the interplay of genetic and environmental influences; there is an urgent need in elucidating the pathogenic mechanisms of these diseases and deploy personalized treatments. Traditional and long-established model systems rarely reproduce either tissue complexity or human physiology faithfully; these shortcomings underscore the need for better models. Organoids represent a promising research model, helping us gain a more profound understanding of the digestive organs; this model can also be used to provide patients with precise and individualized treatment and to build rapid in vitro test models for drug screening or gene/cell therapy, linking basic research with clinical treatment. Over the past few decades, the use of organoids has led to an advanced understanding of the composition of each digestive organ and has facilitated disease modeling, chemotherapy dose prediction, CRISPR-Cas9 genetic intervention, high-throughput drug screening, and identification of SARS-CoV-2 targets, pathogenic infection. However, the existing organoids of the digestive system mainly include the epithelial system. In order to reveal the pathogenic mechanism of digestive diseases, it is necessary to establish a completer and more physiological organoid model. Combining organoids and advanced techniques to test individualized treatments of different formulations is a promising approach that requires further exploration. This review highlights the advancements in the field of organoid technology from the perspectives of disease modeling and personalized therapy.

This study aimed to improve the American Joint Committee on Cancer (AJCC) Tumor Node Metastases (TNM) staging system and demonstrate the improvement in prognostic accuracy and clinical management guidance in colon cancer using the novel prognostic score (P score). Eligible patients were identified using the Surveillance, Epidemiology, and End Results database. A P score (based on age, tumor size, and tumor grade) was assigned to each patient. The Cox proportional hazards regression analyses were performed to identify independent factors associated with prognosis. The Kaplan–Meier survival curves were used to analyze the prognosis of patients with colon cancer with different P scores. The TNM staging system was compared with the P score in stages I–IV by calculating the concordance index. The multivariate Cox analysis indicated that a higher P score was independently associated with a higher risk of cancer-specific mortality. The Kaplan–Meier survival curves showed that the survival benefit gradually increased as the P score decreased. The concordance index rose from 0.5, 0.593, 0.633, and 0.551 of AJCC TNM staging system to 0.709, 0.651, 0.691, and 0.623 of P score in stages I–IV, respectively. The P score was an independent prognostic factor of colon cancer and had a much better prognostic accuracy than the AJCC TNM staging system in all patients with colon cancer. It may help in identifying patients with high-risk stage II colon cancer who were candidates for adjuvant therapy and differentiating patients with stage III colon cancer for adjuvant therapy.

In the intestinal epithelium, the aberrant regulation of cell/cell junctions leads to intestinal barrier defects, which may promote the onset and enhance the severity of inflammatory bowel disease (IBD). However, it remains unclear how the coordinated behaviour of cytoskeletal network may contribute to cell junctional dynamics. In this report, we identified ACF7, a crosslinker of microtubules and F-actin, as an essential player in this process. Loss of ACF7 leads to aberrant microtubule organization, tight junction stabilization and impaired wound closure in vitro. With the mouse genetics approach, we show that ablation of ACF7 inhibits intestinal wound healing and greatly increases susceptibility to experimental colitis in mice. ACF7 level is also correlated with development and progression of ulcerative colitis (UC) in human patients. Together, our results reveal an important molecular mechanism whereby coordinated cytoskeletal dynamics contributes to cell adhesion regulation during intestinal wound repair and the development of IBD.

The cumulative lifetime risk for the development of colorectal cancer in the general population is 6 %. In many cases, early detection by fecal occult blood test is limited regarding sensitivity. Therefore, there is an urgent need for improved diagnostic tests in colorectal cancer. The recent development of high-throughput molecular analytic techniques should allow the rapid evaluation of new diagnostic markers. However, researchers are faced with an overwhelming number of potential markers form numerous colorectal cancer protein expression profiling studies. To address the challenge, we have carried out a comprehensive systematic review of colorectal cancer biomarkers from 13 published studies that compared the protein expression profiles of colorectal cancer and normal tissues. A protein ranking system that considers the number of comparisons in agreement, total sample sizes, average fold-change and direction of differential expression was devised. We observed that some proteins were consistently reported by multiple studies as differentially expressed with a statistically significant frequency (P < 0.05) in cancer versus normal tissues comparison. Our systematic review method identified proteins that were consistently reported as differentially expressed. A review of the top four candidates revealed proteins described previously as having diagnostic value as well as novel candidate biomarkers. These candidates should help to develop a panel of biomarkers with sufficient sensitivity and specificity for the diagnosis of colorectal cancer in a clinical setting.

Various biomarkers currently used for the diagnosis of intestinal mucosal injury (IMI) in patients with acute intestinal obstruction have low sensitivity and specificity. In the present study, IMI, as indicated by the impaired expression of tight junction proteins, including zonula occludens-1, occludin and claudin-1, and inflammation were determined in colonic tissues of patients with 45 strangulated intestinal obstruction (STR-IO) and the adjacent “normal” colonic tissues of 35 patients with colon cancers by quantitative real-time polymerase chain reaction (QRT-PCR), Western blotting, immunohistochemistry and histological examination, respectively. Then, two-dimensional fluorescent difference gel electrophoresis coupled with linear trap quadrupole mass spectrometry was used to screen for potential biomarkers of IMI in the serum samples of 10 STR-IO, 10 simple intestinal obstruction (SIM-IO) and 10 normal healthy controls. A total of 35 protein spots were differentially expressed among the serum samples, and six of the proteins were identified as potential biomarkers. Among the six proteins, histidine decarboxylase (HDC) and ceruloplasmin (CP) were elevated significantly in patients with STR-IO, compared with patients with SIM-IO and healthy controls. Thus, HDC and CP were further validated by QRT-PCR, Western blotting, immunohistochemistry and enzyme-linked immunosorbent assay, respectively, in colonic tissues, serum and urine samples. Finally, the receiver operating characteristic curves were used to show the area under the curves of HDC, CP and several established biomarkers, followed by the determination of the appropriate cutoff values and their sensitivities and specificities. It was shown that for serum and urine, HDC levels achieved sensitivities and specificities compatible to or even greater than those of established biomarkers for the diagnosis of IMI in patients with acute intestinal obstruction, although further validation in a larger cohort is required.

Accumulating evidence has demonstrated that miRNAs play important roles in the occurrence and development of colorectal cancer (CRC). However, whether miRNAs are associated with the metastasis of CRC remains largely unexplored. The aim of the current study is to profile miRNAs in different CRC metastatic cell lines to identify the biomarkers in CRC metastasis. Gene and miRNA expression profiling was performed to analyze the global expression of mRNAs and miRNAs in the four human CRC cell lines (LoVo, SW480, HT29 and Caco-2) with different potential of metastasis. Expression patterns of mRNAs and miRNAs were altered in different CRC cell lines. By developing an integrated bioinformatics analysis of gene and miRNA expression patterns, hsa-let-7i was identified to show the highest degree in the microRNA-GO-network and microRNA-Gene-network. The expression level of hsa-let-7i was further validated by qRT-PCR in CRC cells. In addition, the targets of hsa-let-7i were predicted by two programs TargetScan and PicTar, and target genes were validated by expression profiling in the most epresentative LoVo and Caco-2 cell lines. Eight genes including TRIM41, SOX13, SLC25A4, SEMA4F, RPUSD2, PLEKHG6, CCND2, and BTBD3 were identified as hsa-let-7i targets. Our data showed the power of comprehensive gene and miRNA expression profiling and the application of bioinformatics tools in the identification of novel biomarkers in CRC metastasis.

Our previous study established the human multi-drug-resistant cholangiocarcinoma cell line QBC939/ADM. In this study, we investigate further the ability of tamoxifen (TAM) to reverse drug-resistance to chemotherapeutics using QBC939/ADM cells. Cell growth inhibition was determined by the MTT assay, while cell cycle progression, apoptosis and the intra-cellular concentration of adriamycin (ADM) were all determined by flow cytometry. P-glycoprotein (P-gp) protein and mRNA expression was determined by Western blotting and real-time PCR. Growth inhibition and apoptosis induced by ADM, mitomycin (MMC), or vindesine (VDS) were enhanced after pre-treatment with 5 or 10 μM TAM, while only VDS increased cell numbers in the G(2)/M phase. The intra-cellular concentration of ADM rose after pre-treatment with 10 μM TAM, but not 5 μM TAM. Furthermore, real-time PCR and western blot analysis revealed down-regulation of P-gp expression in QBC939/ADM cells after TAM pre-treatment. The enhanced effects of TAM on growth inhibition, apoptosis, and intra-cellular concentration and the down-regulation of P-gp expression were blocked by an anti-P-gp antibody. TAM (10 μM) may reverse the multi-drug-resistance (MDR) of QBC939/ADM and enhance the chemotherapeutic effects on cholangiocarcinoma, by competitively inhibiting over-expressed P-gp.

Lactobacillus plantarum can exert additional probiotic effects via regulation of human immune system. However, the direct interaction between probiotics and the receptors of immune cells still needs to be further studied. To identify the receptor of dendritic cells during the interaction with L. plantarum. Dendritic cells were pretreated with L. plantarum and the antibody to dendritic cells specific intercellular adhesion molecule-grabbing nonintegrin (DC-SIGN), toll like receptor (TLR)-2 and TLR-4. The maturation of immature dendritic cells, cytokine production, and modulation of T cells were studied by flow cytometry. Adherence between L. plantarum and dendritic cells were studied by ELISA, flow cytometry, and Western blot. L. plantarum could mature dendritic cells by up-regulating MHC-II and CD80 and CD86. Anti-inflammatory interlectin (IL)-10 and IL-6 was up-regulated and pro-inflammatory IL-12p70 was retro-regulated by L. plantarum. L. plantarum may interact with DC-SIGN and modulate of T to differentiate into IL-4 producing T cells. The interaction of L. plantarum and DC-SIGN and the biological effects could be blocked by EDTA and antibody to DC-SIGN. Effects of L. plantarum were concentration-dependent. L. plantarum could bind to DC-SIGN to improve DC maturation at different ratios, regulate the secretion of anti-inflammatory and pro-inflammatory cytokines, and induce the polarization of interlectin-4-producing T cells.

It is reported that defects exist in the small intestinal epithelial barrier of inflammatory bowel disease, which might be associated with increased intestinal permeability at a very early stage. Our study aims to investigate the role of Lactobacillus plantarum on the decrease of epithelial permeability and the further protective effects on the intestinal epithelial barrier using the IL-10-deficient mouse model. Our study showed that tight junction associated proteins were increased after the pre-treatment of L. plantarum by fluorescence staining, western blot, real-time PCR and transmission electron microscope. Oral gavage of milk containing L. plantarum was effective in decreasing small intestinal permeability using methods of Ussing chamber assay and sugar probe. Assay of pro-inflammatory cytokines IFN-γ, TNF-α, MPO, and colonic histology by ELISA showed protective effects of L. plantarum on the intestinal epithelial barrier. Therefore, L. plantarum may prevent the development of colitis in IL-10-deficient mice by blocking changes in the expression of TJ proteins, TJ structure and intestinal permeability.

Conflicting data have been published as to the possible association between polymorphism in codon 72 of the TP53 tumor suppressor gene and the risk of developing breast cancer. In order to address this question, we carried out a meta-analysis of 21 studies of and this polymorphism and breast cancer risk, which collectively included 12,601 cases and 11,462 controls. Studies were identified by searching the Medline, PubMed, Embase, and ISI Web of Knowledge databases. The strength of association between the TP53 codon 72 polymorphism and breast cancer risk was assessed by calculating crude OR values with 95% CIs, with pooled OR values calculated separately for three genetic inheritance models. We found no significant association between TP53 codon 72 polymorphism and breast cancer risk for either the codominant inheritance model (Pro/Arg vs. Pro/Pro: OR = 1.063, 95% CI = 0.967-1.169; Arg/Arg vs. Pro/Pro: OR = 1.245, 95% CI = 0.997-1.554), the dominant model (OR = 1.146, 95% CI = 0.979-1.340), or the recessive model (OR = 1.179, 95% CI = 1.020-1.362). Stratified analysis by ethnicity and source of controls similarly revealed no significant association for any of the genetic models. In summary, this meta-analysis provides strong evidence that the TP53 codon 72 polymorphism is not associated with the risk of developing breast cancer.

The aim of this study was to compare the outcome of the overall complication, mortality, and recurrence rate between laparoscopic resection and open surgery for colorectal cancer. We searched the Medline, Embase, and Cochrane Library and systematically reviewed the randomized controlled trials by comparing the overall complication, mortality, and recurrence rate between laparoscopic resection and open surgery for colorectal cancer. Fifteen trials with 4,207 patients who reported long-term outcomes of the overall complication, mortality, and recurrence rate were included. The combined results of the individual trials showed no statistically significant difference in the odds ratio (OR) for overall recurrence (OR 0.92, 95% CI, 0.77–1.11, P = 0.34), local recurrence (OR 0.81, 95% CI, 0.59–1.12, P = 0.20), distant metastasis (OR 1.01, 95% CI, 0.78–1.30, P = 0.95), wound-site recurrence (OR 1.97, 95% CI, 0.77–5.02, P = 0.16), colorectal cancer-related mortality (OR 0.82, 95% CI, 0.66–1.02, P = 0.07), colon cancer-related mortality (OR 0.85, 95% CI, 0.66–1.09, P = 0.20), rectal cancer-related mortality (OR 0.76, 95% CI, 0.53–1.11, P = 0.16), and overall mortality (OR 0.87, 95% CI, 0.73–1.73, P = 0.11) between the laparoscopic surgery and open surgery groups. The overall complications in the laparoscopic surgery group were much lower than that in the open surgery group (OR 0.71, 95% CI, 0.58–0.87, P = 0.001). This meta-analysis showed that the successful laparoscopic colorectal resection for colorectal cancer was as effective as open surgery in terms of the oncological outcomes, thereby suggesting that laparoscopic surgery can be continued in patients with colorectal cancer.

Lactobacillus consumption has been shown to attenuate the severity of experimental colitis. Whether the effects of Lactobacillus on colitis are related to modulation of leukocyte recruitment into the inflamed intestine is unclear.To investigate the effect of Lactobacillus plantarum daily intragastric administration on lymphocyte homing and intestinal inflammation in interleukin 10 (IL-10) knockout mice, an experimental model of colitis.Two groups of ten IL-10 knockout mice were fed phosphate buffered saline containing Lactobacillus plantarum 1258 or unmodified vehicle for 4 weeks. Two groups of ten wild-type mice were used as controls. At killing, the bowels were histologically scored and evaluated by transmission electron microscopy. Mucosal addressin cell adhesion molecule 1 (MAdCAM-1) and intercellular adhesion molecule 1 (ICAM-1) expression were determined by immunohistochemistry. The levels of proinflammatory cytokines, tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma) were determined by ELISA. In addition, levels of CD3, alpha4beta7, ICAM-1, and MAdCAM-1 were determined by reverse-transcription polymerase chain reaction and Western blot.L. plantarum treatment improved the histological damage score in KO mice compared to untreated KO mice. L. plantarum significantly attenuated the expression of MAdCAM-1, ICAM-1, CD3, and alpha4beta7, but did not affect the levels of TNF-alpha and IFN-gamma when treated KO mice were compared to untreated KO mice.L. plantarum interfered with the upregulation of adhesion molecules observed in IL-10 knockout mice compared to wild-type mice, attenuating the symptoms of colitis.

Colorectal cancer (CRC) is mainly depended on the radical operation, the changing energy metabolism after operation reflects the extent, the magnitude, and the degree of surgical trauma. The aim of this study was to analyse the biochemical perturbation in the serum of CRC after operation and to evaluate their involvement in the progression of CRC. Gas chromatograph-mass spectrometry (GC-MS) in combination with pattern recognition techniques (Partial least squares discriminant analysis, supervised clustering analysis) was used to analyze serum metabolome in 30 CRC patients. A 34 endogenous metabolites included amino acid, fatty acid, carbohydrate and other intermediate metabolites were identified. Partial least squares discriminant analysis based on these metabolites discriminated preoperative from postoperative CRC group. Compared with preoperative CRC patients group, decreases in L-valine, 5-oxo-L-proline, 1-Deoxyglucose, D-turanose, D-maltose, arachidonic acid and hexadecanoic acid levels and increases in L-tyrosine levels were observed in postoperative CRC patients group. The result demonstrated the GC-MS technique is an valuable tool for the characterization of the metabolic perturbation, and the metabolomic study will certainly benefit for monitoring the nutrition state of CRC patients, the prognosis and therapy evaluation of CRC patients after operation.

CD34, cytokeratin (CK) 19, cytokeratin (CK) 20, and Ki67 have been demonstrated to be involved in tumor invasion and angiogenesis. The aim of this study was to analyze the clinicopathological significance of CD34, CK19, CK20, and Ki67 expressions in colorectal cancer (CRC) and to evaluate their involvement in the progression of CRC. CD34, CK19, CK20, and Ki67 expressions were assessed in paraffin-embedded specimens collected from 152 cases of CRC and 30 paired normal colorectal tissues by immunohistochemistry. The relationships between CD34, CK19, CK20, and Ki67 expressions and CRC were evaluated. The association of CD34 and Ki67 protein expressions with the clinicopathological characteristics and the prognosis of CRC were subsequently assessed. CD34, CK19, CK20, and Ki67 expressed highly in CRC tissues relative to normal colorectal tissues. Using immunostaining scoring, a significant correlation of CD34 and Ki67 with the UICC staging and histo-differentiation of CRC was found (P0.05), but no such correlation of CK19 and CK20 with the UICC staging and histo-differentiation (P0.05). Meanwhile, no relationship of CD34, CK19, CK20, and Ki67 with the location of CRC was found (P0.05). Patients with high expressions of CD34 and Ki67 had the lowest survival (P0.05). The results suggest that concurrent expression of CD34 and Ki67 may be an important characteristic of CRC which may help in the prediction of CRC progression.

MicroRNAs (miRNAs) are essential for regulating normal embryonic development and carcinogenesis. Here we report that miR-17-5p, an oncofoetal miRNA, is a key regulator of colorectal cancer progression. We show that miR-17-5p is an oncogenic miRNA that regulates tumorigenesis and progression by targeting the gene encoding P130 and subsequently activating the Wnt/β-catenin pathway. Using specimens from two large cohorts of colorectal cancer patients, we found that patients whose tumours had high miR-17-5p expression had shorter overall survival rates but showed a better response to adjuvant chemotherapy than did patients whose tumours had low miRNA expression. We also observed a strong inverse correlation between miR-17-5p and P130 expression. The current findings suggest that miR-17-5p is a crucial determinant of colorectal cancer progression.