Integrative Omics Uncovers Low Tumorous Magnesium Content as A Driver Factor of Colorectal Cancer.

Magnesium (Mg) deficiency is associated with increased risk and malignancy in colorectal cancer (CRC), yet the underlying mechanisms remain elusive. Here, we used genomic, proteomic, and phosphoproteomic data to elucidate the impact of Mg deficiency on CRC. Genomic analysis identified 160 genes with higher mutation frequencies in Low-Mg tumors, including key driver genes such as KMT2C and ERBB3. Unexpectedly, initiation driver genes of CRC, such as TP53 and APC, displayed higher mutation frequencies in High-Mg tumors. Additionally, proteomic and phosphoproteomic data indicated that low Mg content in tumors may activate epithelial-mesenchymal transition (EMT) by modulating inflammation or remodeling the phosphoproteome of cancer cells. Notably, we observed a negative correlation between the phosphorylation of DBN1 at S142 (DBN1S142p) and Mg content. A mutation in S142 to D (DBN1S142D) mimicking DBN1S142p upregulated MMP2 and enhanced cell migration, while treatment with MgCl2 reduced DBN1S142p, thereby reversing this phenotype. Mechanistically, Mg2+ attenuated the DBN1-ACTN4 interaction by decreasing DBN1S142p, which in turn enhanced the binding of ACTN4 to F-actin and promoted F-actin polymerization, ultimately reducing MMP2 expression. These findings shed new light on the crucial role of Mg deficiency in CRC progression and suggest that Mg supplementation may be a promising preventive and therapeutic strategy for CRC.

Laparoscopic assisted colectomy versus laparoscopic complete colectomy: a cost analysis.

To compare the short-term outcomes and explore the potential economic benefits of laparoscopic-assisted colectomy with extracorporeal anastomosis (LAC/EA) vs. laparoscopic complete colectomy with intracorporeal anastomosis (LCC/IA) for patients with non-metastatic resectable colon cancer. Data of patients who underwent laparoscopic hemicolectomy from January 2017 to March 2023 were collected and analyzed. Propensity score matching (PSM) analyses was carried out to minimize the selection bias. Before PSM, a total of 113 patients met the inclusion criteria (39 in the LCC/IA vs. 74 in the LAC/EA). Clinicopathologic characteristics were comparable except for the median number of removed lymph nodes (P = 0.023). LCC/IA was associated with longer operative time, less intraoperative blood loss, and shorter incision length. The rate of 30-day postoperative complications was similar, but the time to first flatus and soft diet was shorter in the LCC/IA. No deaths were reported in either group within 30 days after surgery. Costs of surgical instruments (25,945.8 ± 1,918.0 vs. 23,551.9 ± 2,665.5 RMB; P < 0.01) were higher for the LCC/IA but overall costs were similar (LCC/IA, 43,220.0 ± 4,954.0 vs. LAC/EA, 41,269.2 ± 6,685.9 RMB; P = 0.112). After PSM, 38 patients in the LCC/IA and 63 patients in the LAC/EA were compared. LCC/IA was superior in terms of intraoperative blood loss, incision length, and postoperative functional recovery. There was an extra charge of 2385.0 RMB regarding surgical instruments in the LCC/IA but the overall cost did not reach statistical significance. LCC/IA is a feasible, safe, and cost-effective surgical treatment for patients with non-metastatic resectable colon cancer.

PD-L1 blockade in mitigating severe acute pancreatitis induced pancreatic damage through modulation of immune cell apoptosis.

Acute pancreatitis (AP) is a prevalent gastrointestinal disorder. The immune response plays a crucial role in AP progression. However, the impact of immune regulatory checkpoint PD-L1 on severe acute pancreatitis (SAP) remains uncertain. Hence, this study aimed to examine the influence of PD-L1 on SAP. We assessed PD-L1 expression in neutrophils and monocytes obtained from SAP patients. We induced SAP in C57BL/6J mice, PD-L1 gene-deficient mice, and PD-L1 humanized mice using intraperitoneal injections of cerulein plus lipopolysaccharide. Prior to the initial cerulein injection, a PD-L1 inhibitor was administered. Pancreatic tissues were collected for morphological and immunohistochemical evaluation, and serum levels of amylase, lipase, and cytokines were measured. Flow cytometry analysis was performed using peripheral blood cells. The expression of PD-L1 in neutrophils and monocytes was significantly higher in SAP patients compared to healthy individuals. Likewise, the expression of PD-L1 in inflammatory cells in the peripheral blood of SAP-induced C57BL/6J mice was notably higher than in the control group. In mice with PD-L1 deficiency, SAP model exhibited lower pancreatic pathology scores, amylase, lipase, and cytokine levels compared to wild-type mice. PD-L1 deletion resulted in reduced neutrophil apoptosis, leading to an earlier peak in neutrophil apoptosis. Furthermore, it decreased early monocyte apoptosis and diminished the peak of T lymphocyte apoptosis. Within the SAP model, administration of a PD-L1 inhibitor reduced pancreatic pathology scores, amylase, lipase, and cytokine levels in both C57BL/6J mice and PD-L1 humanized mice. These findings suggest that inhibiting PD-L1 expression can alleviate the severity of SAP.

Unveiling the hidden: identification and management of overlooked blood vessels in laparoscopic left hemicolectomy for splenic flexure cancer.

BACKGROUND: During laparoscopic left hemicolectomy procedures, a previously overlooked consistently thick blood vessel within the gastrocolic ligament near the splenic hilum may contribute to post-operative bleeding complications. The purpose of this study was to investigate the identification and management of the previously overlooked blood vessel. METHODS: This is a retrospective descriptive study of patients undergoing laparoscopic left colectomy for splenic fexure cancer conducted at a national gastrointestinal surgery centre in China. Consecutive patients with splenic fexure cancer who underwent laparoscopic left colectomy using our"five-step process"(n = 34) between January 2021 and July 2023 were included. RESULTS: The vessels can be effectively exposed using the aforementioned "five-step process." It was observed that the overlooked vessels consistently present in all patients were identified as the omental branch of the left gastroepiploic artery and vein. CONCLUSION: We have identified the origin of previously overlooked blood vessels and recommended a safe method for their management. This may offer advantages to colorectal surgeons performing laparoscopic left colectomy for splenic flexure cancer.

A novel U-tied semi-manual anastomosis in totally laparoscopic colectomy.

TECHNIQUE: We describe improvements to the previously proposed "U-tied anastomosis" with the aim of broadening its indications, especially in left hemicolectomy. After bowel mobilization and vascular ligation, the proximal and distal colon were aligned in a U-shape using a ligature. An anastomosis was constructed using a linear stapler through the common enterotomies. Following resection of the bowel using laparoscopic coagulation shears, the common opening was closed using 3-0 barbed sutures. RESULTS: Eight consecutive patients underwent colectomy using the U-tied semi-manual technique between May and July 2023. In all cases, the U-tied procedures were completed using one cartridge and two sutures. No complications or mortality were observed after one month of follow-up. CONCLUSIONS: The U-tied semi-manual anastomosis is a straightforward and effective method for intracorporeal anastomosis. The simplified reconstruction technique of U-tied series, together with the minimization of technique variability, results in consistent outcomes when performed by surgeons with different levels of experience. The streamlined process enhances the homogeneity of the intracorporeal anastomosis while reducing cartridge use.

Mismatch repair protein deficiency and its implications on distant metastasis in colorectal cancer: A comprehensive analysis.

BACKGROUND: While previous studies have indicated variability in distant metastatic potential among different mismatch repair (MMR) states in colorectal cancer (CRC), their findings remain inconclusive, especially considering potential differences across various ethnic backgrounds. Furthermore, the gene regulatory networks and the underlying mechanisms responsible for these variances in metastatic potential across MMR states have yet to be elucidated. METHODS: We collected 2058 consecutive primary CRC samples from the South West of China and assessed the expression of MMR proteins (MLH1, MSH2, MSH6, and PMS2) using immunohistochemistry. To explore the inconsistencies between different MMR statuses and recurrence, we performed a meta-analysis. To delve deeper, we employed Weighted Gene Co-expression Network Analysis (WGCNA), ClueGo, and iRegulon, pinpointing gene expression networks and key regulatory molecules linked to metastasis and recurrence in CRC. Lastly, both univariate and multivariate Cox regression analyses were applied to determine the impact of core regulatory molecules on metastasis. RESULTS: Of the samples, 8.2% displayed deficient MMR (dMMR), with losses of MLH1 and PSM2 observed in 40.8% and 63.9%, respectively. A unique 24.3% isolated loss of PMS2 without concurrent metastasis was identified, a result that diverges from established literature. Additionally, our meta-analysis further solidifies the reduced recurrence likelihood in dMMR CRC samples compared to proficient MMR (pMMR). Two gene expression networks tied to distant metastasis and recurrence were identified, with a majority of metastasis-related genes located on chromosomes 8 and 18. An IRF1 positive feedback loop was discerned in the metastasis-related network, and IRF1 was identified as a predictive marker for both recurrence-free and distant metastasis-free survival across multiple datasets. CONCLUSION: Geographical and ethnic factors might influence peculiarities in MMR protein loss. Our findings also highlight new gene expression networks and crucial regulatory molecules in CRC metastasis, enhancing our comprehension of the mechanisms driving distant metastasis.

Colorectal cancer cells secreting DKK4 transform fibroblasts to promote tumour metastasis.

Wnt/ß-catenin signalling is aberrantly activated in most colorectal cancer (CRC) and is one key driver involved in the initiation and progression of CRC. However, mutations of APC gene in CRC patients retain certain activity of APC protein with decreased ß-catenin signalling and DKK4 expression significantly upregulates and represses Wnt/ß-catenin signalling in human CRC tissues, suggesting that a precisely modulated activation of the Wnt/ß-catenin pathway is essential for CRC formation and progression. The underlying reasons why a specifically reduced degree, not a fully activating degree, of ß-catenin signalling in CRC are unclear. Here, we showed that a soluble extracellular inhibitor of Wnt/ß-catenin signalling, DKK4, is an independent factor for poor outcomes in CRC patients. DKK4 secreted from CRC cells inactivates ß-catenin in fibroblasts to induce the formation of stress fibre-containing fibroblasts and myofibroblasts in culture conditions and in mouse CRC xenograft tissues, resulting in restricted expansion in tumour masses at primary sites and enhanced CRC metastasis in mouse models. Reduced ß-catenin activity by a chemical inhibitor MSAB promoted the CRC metastasis. Our findings demonstrate why reduced ß-catenin activity is needed for CRC progression and provide a mechanism by which interactions between CRC cells and stromal cells affect disease promotion.

Age-, sex- and proximal-distal-resolved multi-omics identifies regulators of intestinal aging in non-human primates.

The incidence of intestinal diseases increases with age, yet the mechanisms governing gut aging and its link to diseases, such as colorectal cancer (CRC), remain elusive. In this study, while considering age, sex and proximal-distal variations, we used a multi-omics approach in non-human primates (Macaca fascicularis) to shed light on the heterogeneity of intestinal aging and identify potential regulators of gut aging. We explored the roles of several regulators, including those from tryptophan metabolism, in intestinal function and lifespan in Caenorhabditis elegans. Suggesting conservation of region specificity, tryptophan metabolism via the kynurenine and serotonin (5-HT) pathways varied between the proximal and distal colon, and, using a mouse colitis model, we observed that distal colitis was more sensitive to 5-HT treatment. Additionally, using proteomics analysis of human CRC samples, we identified links between gut aging and CRC, with high HPX levels predicting poor prognosis in older patients with CRC. Together, this work provides potential targets for preventing gut aging and associated diseases.

[Construction and Exploration of Simulative Virtual Curriculum of Laparoscopy for Standardized Surgical Residency Training]. / å¤–ç§‘ä½é™¢åŒ»å¸ˆåŸ¹è®­çš„è ¹è ”é•œæ¨¡æ‹Ÿè™šæ‹Ÿè¯¾ç¨‹å»ºè®¾æŽ¢ç´¢.

Laparoscopic operations have become an indispensable therapeutic measure in surgical treatment due to the emerging trends of minimal invasiveness and precision in the field of surgery. Laparoscopic skills have gradually become part of the essential skills for young surgeons and hospitals at all levels are giving high priority to laparoscopic skills training. The innovation and development of simulative and virtual medical technology has given rise to effective ways and platforms for the training of laparoscopy surgeons in China. Based on the laparoscopy simulative virtual technology, our hospital gradually developed a systematic training and evaluation system for the laparoscopy training of surgical residents by offering theory courses on laparoscopy, conducting simulative and virtual systematic training, and developing assessment criteria for the training. Herein, we presented and shared our experience in applying laparoscopy simulative virtual technology in the training of surgical residents in order to promote the standardized residency training of laparoscopic skills in China and to provide reference for the implementation of standardized training of laparoscopic skills.