Single-cell profiling reveals differences between human classical adenocarcinoma and mucinous adenocarcinoma.

Colorectal cancer is a highly heterogeneous disease. Most colorectal cancers are classical adenocarcinoma, and mucinous adenocarcinoma is a unique histological subtype that is known to respond poorly to chemoradiotherapy. The difference in prognosis between mucinous adenocarcinoma and classical adenocarcinoma is controversial. Here, to gain insight into the differences between classical adenocarcinoma and mucinous adenocarcinoma, we analyse 7 surgical tumour samples from 4 classical adenocarcinoma and 3 mucinous adenocarcinoma patients by single-cell RNA sequencing. Our results indicate that mucinous adenocarcinoma cancer cells have goblet cell-like properties, and express high levels of goblet cell markers (REG4, SPINK4, FCGBP and MUC2) compared to classical adenocarcinoma cancer cells. TFF3 is essential for the transcriptional regulation of these molecules, and may cooperate with RPS4X to eventually lead to the mucinous adenocarcinoma mucus phenotype. The observed molecular characteristics may be critical in the specific biological behavior of mucinous adenocarcinoma.

Novel pharmacological inhibition of JMJD3 improves necrotizing enterocolitis by attenuating the inflammatory response and ameliorating intestinal injury.

Necrotizing enterocolitis (NEC), an acute intestinal inflammatory disease of premature infants, is one of the leading causes of death in neonates. Effective measures for clinical treatment are limited and there is a pressing need in searching for new therapeutic strategies. Jumonji domain-containing protein D3 (JMJD3), a histone H3 lysine 27 (H3K27) demethylase plays a proinflammatory role in sepsis and neuroinflammation. However, whether JMJD3 is involved in the pathogenesis of NEC has not been elucidated. Here we report that overexpressed JMJD3 was revealed in the intestine of NEC patients by bioinformatic analysis. Moreover, upregulated JMJD3 and suppressed H3K27me3 were detected in both NEC patients and neonatal mice subjected to experimental NEC. Importantly, administration of GSK-J4, a specific JMJD3 inhibitor, rescued neonatal mice from NEC-associated lethality by suppressing proinflammatory response with attenuated IL-6, TNF-α, and MCP-1 levels and ameliorating intestinal injury with reversed claudin-1, occludin, and E-cadherin expression. Remarkably, administration of GSK-J4 attenuated intestinal injury by inhibiting activation of intestinal necroptosis in NEC mice. Administration of GSK-J4 regulated intestinal inflammation via NF-κB and JAK2/STAT3 pathway. These results indicate that JMJD3 is involved in the development of NEC and inhibition of JMJD3 overexpression by mean of GSK-J4 could be a potential therapeutic approach in the prevention and treatment of NEC.

Induction of Trained Immunity Protects Neonatal Mice Against Microbial Sepsis by Boosting Both the Inflammatory Response and Antimicrobial Activity.

Background: Neonates are susceptible to a wide range of microbial infection and at a high risk to develop severe sepsis and septic shock. Emerged evidence has shown that induction of trained immunity triggers a much stronger inflammatory response in adult monocytes/macrophages, thereby conferring protection against microbial infection. Methods: This study was carried out to examine whether trained immunity is inducible and exerts its protection against microbial sepsis in neonates. Results: Induction of trained immunity by Bacillus Calmette-Guerin (BCG) plus bacterial lipoprotein (BLP) protected neonatal mice against cecal slurry peritonitis-induced polymicrobial sepsis, and this protection is associated with elevated circulating inflammatory cytokines, increased neutrophil recruitment, and accelerated bacterial clearance. In vitro stimulation of neonatal murine macrophages with BCG+BLP augmented both inflammatory response and antimicrobial activity. Notably, BCG+BLP stimulation resulted in epigenetic remodeling characterized by histone modifications with enhanced H3K4me3, H3K27Ac, and suppressed H3K9me3 at the promoters of the targeted inflammatory and antimicrobial genes. Critically, BCG+BLP stimulation led to a shift in cellular metabolism with increased glycolysis, which is the prerequisite for subsequent BCG+BLP-triggered epigenetic reprogramming and augmented inflammatory response and antimicrobial capacity. Conclusion: These results illustrate that BCG+BLP induces trained immunity in neonates, thereby protecting against microbial infection by boosting both inflammatory and antimicrobial responses.

Reduced Incidence of Necrotizing Enterocolitis due to the Anti-Inflammatory Effects of CXCL14 in Intestinal Tissue.

Bioinformatic analysis indicated that downregulated CXCL14 will occur in the intestinal tissue of patients with necrotizing enterocolitis (NEC). To reveal the relationship between CXCL14 and mucosal immune regulation, we designed and implemented the experiments to explore the potential function of CXCL14 in the pathogenesis of NEC. Firstly, this study confirmed that the expression of CXCL14 decreased in the intestinal tract of NEC children. Secondly, the experiments results showed that CXCL14 could ameliorate the inflammatory injury of intestinal tissue through the suppressive effect on the expression of TNF-α and INF-γ in vivo. Finally, we explained that activation of the TLR4 can reduce the expression level of CXCL14 in the intestinal tissue of mouse pups. Collectively, our study suggested that CXCL14 may negatively regulate the inflammatory response in intestinal tissue and play an essential role in NEC development and progression.

Comprehensive Analysis of Subtype-Specific Molecular Characteristics of Colon Cancer: Specific Genes, Driver Genes, Signaling Pathways, and Immunotherapy Responses.

Colon cancer is a complex, heterogeneous disease. The Colorectal Cancer Subtyping Consortium reported a novel classification system for colon cancer in 2015 to better understand its heterogeneity. This molecular classification system divided colon cancer into four distinct consensus molecular subtypes (CMS 1, 2, 3, and 4). However, the characteristics of different colon cancer molecular subtypes have not been fully elucidated. This study comprehensively analyzed the molecular characteristics of varying colon cancer subtypes using multiple databases and algorithms, including The Cancer Genome Atlas (TCGA) database, DriverDBv3 database, CIBERSORT, and MCP-counter algorithms. We analyzed the alterations in the subtype-specific genes of different colon cancer subtypes, such as the RNA levels and DNA alterations, and showed that specific subtype-specific genes significantly affected prognosis. We also explored the changes in colon cancer driver genes and representative genes of 10 signaling pathways in different subtypes. We identified genes that were altered in specific subtypes. We further detected the infiltration of 22 immune cell types in four colon cancer subtypes and the infiltration level of primary immune cells among these subtypes. Additionally, we explored changes in immune checkpoint genes (ICGs) and immunotherapy responses among different colon cancer subtypes. This study may provide clues for the molecular mechanism of tumorigenesis and progression in colon cancer. It also offers potential biomarkers and targets for the clinical diagnosis and treatment of different colon cancer subtypes.

A novel and safe approach: middle cranial approach for laparoscopic right hemicolon cancer surgery with complete mesocolic excision.

BACKGROUND: Mastering right hemicolectomy techniques using laparoscopy in colorectal cancer surgery is very difficult. Although the long-term prognosis of laparoscopic right hemicolectomy (LRH) and complete mesocolic excision is unquestionable, different surgeons have their own opinions on routes of conducting LRH. OBJECTIVES: LRH surgery is very complex due to the upper abdominal anatomical structure and vascular variation. Therefore, it has been considered the most difficult of all colorectal cancer surgeries. Our innovative middle cranial approach (MCA) was developed to avoid unnecessary injuries and minimize the operative time, thereby reducing the patient's hospital stay and improving their short-term prognosis. METHODS: We compared 90 colon cancer patients who underwent the MCA between January 2016 and January 2017 with 82 patients who underwent the conventional central approach conducted by the same group of physicians (with Dr Cui as the surgeon) from 2011 to 2015. A short-term statistical analysis was performed. RESULTS: A total of 90 patients were included: 43 men and 47 women. Twenty-three patients underwent abdominal surgery (including stomach, rectum, and sigmoid colon surgery; appendectomy; and uterine attachment surgery). The median age of these patients was 62.6 (28-85) years; the median BMI was 22.9 (14.7-33.3) kg/m2; the mean bleeding volume was 53.9 (10-100) ml; the mean tumour diameter was 5.7 (0.8-9) cm, and the average number of lymph nodes detected was 19.2 (7-49). CONCLUSIONS: Our study showed that radical resection of right-sided colon cancer using the MCA was safe and feasible for the treatment of colorectal cancer patients.

[Decreased number and immune activity of splenic T lymphocytes in mice exposed to hypoxia at high altitude].

Objective: To explore the changes of splenic T lymphocyte subsets and functions in mice under high-altitude hypoxic conditions. Methods: After mice were exposed to an altitude of 400 m,2200 m and 4200 m for 30 days,ELISA was used to detect the concentrations of interleukin-4( IL-4) and interferon-γ( IFN-γ) in the cultured splenocyte supernatant; MTT assay was used to analyze the proliferation of splenic T lymphocytes; flow cytometry was performed to examine the alterations of splenic T lymphocyte subsets. Results: After exposed to hypoxia for 30 days,in comparison with the control group( 400 m),the spleen index of the mice increased significantly in both the 2200 m and 4200 m groups,and the spleen index of the 4200 m group was apparently higher than that of the 2200 m group; the concentration of IFN-γ in the splenocyte supernatant of the 4200 m and 2200 m groups significantly decreased,while the concentration of IL-4 had no obvious change. The proliferation of splenic T lymphocyte was reduced obviously in both the 2200 m and 4200 m groups,at the same time,the proliferation of T cells in the 4200 m group was markedly lower than that in the 2200 m group. The percentages of splenic CD3~+,CD4~+and CD8~+T lymphocytes decreased markedly in the 2200 m and 4200 m groups,among them,the number of CD4~+T cel s decreased significantly than CD8~+T cel s. In addition,CD3~+and CD4~+T lymphocyte percentages of the 4200 m group obviously decreased compared with the 2200 m group. Conclusion: In mice exposed to hypoxia at an altitude of 4200 m and 2200 m for 30 days,the number of T lymphocyte subsets and the proliferation ability of T cel s decrease,and the level of IFN-γ is decreased as well.