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.

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.

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.

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.

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.

Genetically predicted thyroid function and risk of colorectal cancer: a bidirectional Mendelian randomization study.

BACKGROUND: Observational studies have reported an association between thyroid function and colorectal cancer (CRC), with conflicting results. Elucidating the causal relationship between thyroid function and CRC facilitates the development of new preventive strategies to reduce CRC incidence. METHOD: We applied a two-sample Mendelian randomization (MR) method to evaluate the causal relationship between five thyroid-related indexes, including hyperthyroidism, hypothyroidism, thyroid stimulating hormone (TSH), free thyroxine (FT4) and basal metabolic rate (BMR), and CRC. Genome-wide association study statistics for thyroid-related phenotypes were obtained from the ThyroidOmics consortium, and summary statistics for genetic associations with CRC were obtained from the FinnGen consortium. We set a series of criteria to screen single nucleotide polymorphisms (SNPs) as instrumental variables and then performed bidirectional MR analysis, stratified analysis and extensive sensitivity analysis. Multiplicative random-effects inverse variance weighted was the primary analysis method, supplemented by weighted median and MR-Egger. RESULT: We identified 12 SNPs for hyperthyroidism, 10 SNPs for hypothyroidism, 41 SNPs for TSH, 18 SNPs for FT4, and 556 SNPs for BMR. Genetically predicted hyperthyroidism, hypothyroidism, TSH, and FT4 were not associated with CRC risk (all P > 0.05). Sensitivity analysis revealed no heterogeneity or pleiotropy. Genetically predicted BMR was significantly associated with increased CRC risk after removing outlier (OR = 1.30, P = 0.0029). Stratified analysis showed that BMR was significantly associated with colon cancer (OR = 1.33, P = 0.0074) but not rectal cancer. In the reverse analysis, there was no evidence of an effect of CRC on thyroid function (all P > 0.05). CONCLUSION: Our bidirectional MR analysis provides new insights into the relationship between thyroid function and CRC. CRC prevention may benefit from enhanced screening of high BMR populations.

MRI-based deep learning model for differentiation of hepatic hemangioma and hepatoblastoma in early infancy.

Hepatic hemangioma (HH) and hepatoblastoma (HBL) are common pediatric liver tumors and present with similar clinical manifestations with limited distinguishing value of serum AFP in early infancy. An accurate differentiation diagnostic tool is warranted for optimizing treatments and improving prognosis. The present study aimed to develop an innovative and cost-effective diagnostic tool to differentiate HH and HBL in early infancy using advanced deep learning (DL) techniques. One hundred forty patients ≤4 months old diagnosed as HH or HBL with histological specimens were recruited from two institutions assigned into a training set with cross-validation and a testing set for external validation, respectively. Based on MRI images, imaging diagnoses were interpreted by two radiologists, and imaging-derived radiomic features were extracted by pretrained convolutional neural networks (CNNs)-Xception extractor via DL analysis. A nomogram model was constructed integrating predictive clinical variables, radiologist-based interpretation, and DL features, evaluated comprehensively on diagnostic and calibration accuracy. The DL-based model performed an area under the receiver operating characteristic curve (AUC) of 0.966 for the training cohort and 0.864 for the testing cohort. The radiologist-interpreted differentiation model showed an AUC of 0.837 in the testing cohort. The integrated nomogram model represented an increasing performance with an AUC of 0.887, accuracy of 78.57%, sensitivity of 76.19%, and specificity of 80.95% in the testing cohort. CONCLUSION:  The MRI-based integrated model, a noninvasive preoperative diagnostic tool, yielded favorable efficacy for differentiating HH and HBL in early infancy, which might reduce the patients' costs of repetitive and unnecessary examinations or over-treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05170282. WHAT IS KNOWN: • Hepatic hemangioma (HH) and hepatoblastoma (HBL) are common pediatric liver tumors and present with similar clinical manifestations with limited distinguishing value of serum AFP in early infancy. • Considering the rare incidence of infantile hepatic tumors, the distinguishing accuracy between HBL and HH for cases in early infancy is unsatisfactory for radiologists' recognition solely. WHAT IS NEW: • The MRI-based integrated model, a noninvasive preoperative diagnostic tool yielded favorable efficacy for differentiating HH and HBL in early infancy, which might reduce the patients' costs of repetitive and unnecessary examinations or over-treatment.

A U-tie technique simplifies the intracorporeal anastomosis of totally laparoscopic colectomy.

TECHNIQUE: We propose a small improvement termed "U-tied functional end-to-end anastomosis", aiming to promote the standardization of totally laparoscopic colectomy. After bowel mobilization and vascular ligation, the proximal and distal bowel regions are tied in parallel using a ligature. Anastomosis is completed using a linear stapler through the common enterotomies. Resection of the bowel and closure of the stump are then performed simultaneously with one cartridge following the bowel anastomosis. RESULTS: Thirty patients underwent U-tied anastomosis from December 2019 to October 2022. In all cases, two cartridges were used to complete the U-tied procedure. There were no major complications or mortality within 30 days after the operation, and only one patient developed mild surgical site infection. CONCLUSIONS: The U-tied intracorporeal anastomosis is safe and effective, simplifying the reconstruction process and reducing the discrepancy between the operators' experience on the anastomotic outcomes. Thus, this procedure may promote homogeneity of intracorporeal anastomosis and reduce the use of cartridges.

Colorectal cancer liver metastasis: genomic evolution and crosstalk with the liver microenvironment.

Colorectal cancer (CRC) patients frequently develop liver metastases, which are the major cause of cancer-related mortality. The molecular basis and management of colorectal liver metastases (CRLMs) remain a challenging clinical issue. Recent genomic evidence has demonstrated the liver tropism of CRC and the presence of a stricter evolutionary bottleneck in the liver as a target organ compared to lymph nodes. This bottleneck challenging CRC cells in the liver is organ-specific and requires adaptation not only at the genetic level, but also at the phenotypic level to crosstalk with the hepatic microenvironment. Here, we highlight the emerging evidence on the clonal evolution of CRLM and review recent insights into the molecular mechanisms orchestrating the bidirectional interactions between metastatic CRC cells and the unique liver microenvironment.

Deciphering the Clinical Significance and Kinase Functions of GSK3α in Colon Cancer by Proteomics and Phosphoproteomics.

GSK3α and GSK3ß are two GSK3 isoforms with 84% overall identity and 98% identity in their catalytic domains. GSK3ß plays important roles in the pathogenesis of cancer, while GSK3α has long been considered a functionally redundant protein of GSK3ß. Few studies have specifically investigated the functions of GSK3α. In this study, unexpectedly, we found that the expression of GSK3α, but not GSK3ß, was significantly correlated with the overall survival of colon cancer patients in 4 independent cohorts. To decipher the roles of GSK3α in colon cancer, we profiled the phosphorylation substrates of GSK3α and uncovered 156 phosphosites from 130 proteins specifically regulated by GSK3α. A number of these GSK3α-mediated phosphosites have never been reported before or have been incorrectly identified as substrates of GSK3ß. Among them, the levels of HSF1S303p, CANXS583p, MCM2S41p, POGZS425p, SRRM2T983p, and PRPF4BS431p were significantly correlated with the overall survival of colon cancer patients. Further pull-down assays identified 23 proteins, such as THRAP3, BCLAF1, and STAU1, showing strong binding affinity to GSK3α. The interaction between THRAP3 and GSK3α was verified by biochemical experiments. Notably, among the 18 phosphosites of THRAP3, phosphorylation at S248, S253, and S682 is specifically mediated by GSK3α. Mutation of S248 to D (S248D), which mimics the effect of phosphorylation, obviously increased cancer cell migration and the binding affinity to proteins related to DNA damage repair. Collectively, this work not only discloses the specific function of GSK3α as a kinase but also suggests GSK3α as a promising therapeutic target for colon cancer.

Phenotypic Heterogeneity Analysis of APC-Mutant Colon Cancer by Proteomics and Phosphoproteomics Identifies RAI14 as a Key Prognostic Determinant in East Asians and Westerners.

Adenomatous polyposis coli (APC) is an important tumor suppressor and is mostly linked to the regulation of the Wnt/ß-catenin signaling pathway. APC mutation has been identified as an early event in more than 80% of sporadic colorectal cancers (CRCs). Moreover, prognostic differences are observed in CRC patients with APC mutations. Although previous genomics studies have investigated the roles of concomitant gene mutations in determining the phenotypic heterogeneity of APC-mutant tumors, valuable prognostic determinants for APC-mutant CRC patients are still lacking. Based on the proteome and phosphoproteome data, we classified APC-mutant colon cancer patients and revealed genomic, proteomic, and phosphoproteomic heterogeneity in APC-mutant tumors. More importantly, we identified RAI14 as a key prognostic determinant for APC-mutant but not APC-wildtype colon cancer patients. The heterogeneity and the significance of prognostic biomarkers in APC-mutant tumors were further validated in the Clinical Proteomic Tumor Analysis Consortium (CPTAC) colon cancer cohort. In addition, we found that colon cancer patients with high expression of RAI14 were less responsive to chemotherapy. Knockdown of RAI14 in cell lines led to reduced cell migration and changes in epithelial-mesenchymal transition (EMT)-related markers. Mechanistically, knockdown of RAI14 remodeled the phosphoproteome associated with cell adhesion, which might affect EMT marker expression and promote F-actin degradation. Collectively, this work describes the phenotypic heterogeneity of APC-mutant tumors and identifies RAI14 as an important prognostic determinant for APC-mutant colon cancer patients. The prognostic utility of RAI14 in APC-mutant colon cancer will provide early warning and increase the chance of successful treatment.

circNEIL3 inhibits tumor metastasis through recruiting the E3 ubiquitin ligase Nedd4L to degrade YBX1.

Distant metastasis is a major contributor to cancer-related mortality. However, the role of circRNAs in this process remains unclear. Herein, we profiled the circRNA expression in a cohort of 68 colorectal carcinoma (CRC) primary tumors and their paired liver metastatic lesions. By overlapping with the TGFß-responsive circRNAs, circNEIL3 (hsa_circ_0001460) was identified as a TGFß-repressive and metastasis-related circRNA. Functionally, circNEIL3 effectively inhibited tumor metastasis in both and in vivo and in vivo models of various cancer types. Mechanistically, circNEIL3 exerts its metastasis-repressive function through its direct interaction with oncogenic protein, Y-box-binding protein 1 (YBX1), which consequently promotes the Nedd4L-mediated proteasomal degradation of YBX1. Importantly, circNEIL3 expression was negatively correlated to YBX1 protein level and metastatic tendency in CRC patient samples. Collectively, our findings indicate the YBX1-dependent antimetastatic function of circNEIL3 and highlight the potential of circNEIL3 as a biomarker and therapeutic option in cancer treatment.

Oncologic outcomes of intersphincteric resection versus abdominoperineal resection for lower rectal cancer: a systematic review and meta-analysis.

BACKGROUND: The efficacy of intersphincteric resection (ISR) surgery for patients with lower rectal cancer remains unclear compared to abdominoperineal resection (APR). The aim of this study is to compare the oncologic outcomes for lower rectal cancer patients after ISR and APR through a systematic review and meta-analysis. MATERIALS AND METHODS: A systematic electronic search of the Cochrane Library, PubMed, EMBASE, and MEDLINE was performed through January 12, 2022. The primary outcomes included 5-year disease-free survival (5y-DFS) and 5-year overall survival. Secondary outcomes included circumferential resection margin involvement, local recurrence, perioperative outcomes, and other long-term outcomes. The pooled odds ratios, mean difference, or hazard ratios (HRs) of each outcome measurement and their 95% CIs were calculated. RESULTS: A total of 20 nonrandomized controlled studies were included in the qualitative analysis, with 1217 patients who underwent ISR and 1135 patients who underwent APR. There was no significant difference in 5y-DFS (HR: 0.84, 95% CI: 0.55-1.29; P=0.43) and 5-year overall survival (HR: 0.93, 95% CI: 0.60-1.46; P=0.76) between the two groups. Using the results of five studies that reported matched T stage and tumor distance, we performed another pooled analysis. Compared to APR, the ISR group had equal 5y-DFS (HR: 0.76, 95% CI: 0.45-1.30; P=0.31) and 5y-LRFS (local recurrence-free survival) (HR: 0.72, 95% CI: 0.29-1.78; P=0.48). Meanwhile, ISR had equivalent local control as well as perioperative outcomes while significantly reducing the operative time (mean difference: -24.89, 95% CI: -45.21 to -4.57; P=0.02) compared to APR. CONCLUSIONS: Our results show that the long-term survival and safety of patients is not affected by ISR surgery, although this result needs to be carefully considered and requires further study due to the risk of bias and limited data.

JMJD3 Is Required for Acute Pancreatitis and Pancreatitis-Associated Lung Injury.

Acute pancreatitis (AP) can be complicated by inflammatory disorders of remote organs, such as lung injury, in which Jumonji domain-containing protein 3 (JMJD3) plays a vital role in proinflammatory responses. Currently, we found that JMJD3 expression was upregulated in the pancreas and lung in an AP male mouse model, which was also confirmed in AP patients. Further experiments revealed that the upregulation of JMJD3 and proinflammatory effects were possibly exerted by mitochondrial DNA (mtDNA) or oxidized-mtDNA from tissue injury caused by AP. The release of mtDNA and oxidized-mtDNA contributed to the infiltration of inflammatory monocytes in lung injury through the stimulator of IFN genes (STING)/TLR9-NF-κB-JMJD3-TNF-α pathway. The inhibition of JMJD3 or utilization of Jmjd3-cKO mice significantly alleviated pulmonary inflammation induced by AP. Blocking mtDNA oxidation or knocking down the TLR9/STING pathway effectively alleviated inflammation. Therefore, inhibition of JMJD3 or STING/TLR9 pathway blockage might be a potential therapeutic strategy to treat AP and the associated lung injury.

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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.