LTßR-RelB signaling in intestinal epithelial cells protects from chemotherapy-induced mucosal damage.

The intricate immune mechanisms governing mucosal healing following intestinal damage induced by cytotoxic drugs remain poorly understood. The goal of this study was to investigate the role of lymphotoxin beta receptor (LTßR) signaling in chemotherapy-induced intestinal damage. LTßR deficient mice exhibited heightened body weight loss, exacerbated intestinal pathology, increased proinflammatory cytokine expression, reduced IL-22 expression, and proliferation of intestinal epithelial cells following methotrexate (MTX) treatment. Furthermore, LTßR-/-IL-22-/- mice succumbed to MTX treatment, suggesting that LTßR- and IL-22- dependent pathways jointly promote mucosal repair. Although both LTßR ligands LIGHT and LTß were upregulated in the intestine early after MTX treatment, LIGHT-/- mice, but not LTß-/- mice, displayed exacerbated disease. Further, we revealed the critical role of T cells in mucosal repair as T cell-deficient mice failed to upregulate intestinal LIGHT expression and exhibited increased body weight loss and intestinal pathology. Analysis of mice with conditional inactivation of LTßR revealed that LTßR signaling in intestinal epithelial cells, but not in Lgr5+ intestinal stem cells, macrophages or dendritic cells was critical for mucosal repair. Furthermore, inactivation of the non-canonical NF-kB pathway member RelB in intestinal epithelial cells promoted MTX-induced disease. Based on these results, we propose a model wherein LIGHT produced by T cells activates LTßR-RelB signaling in intestinal epithelial cells to facilitate mucosal repair following chemotherapy treatment.

Factors associated with peroral endoscopic myotomy for achalasia outcomes: systematic review and meta-analysis.

BACKGROUND: Peroral endoscopic myotomy (POEM) is an emerging effective treatment for achalasia. However, a significant proportion of patients do not respond well to the treatment. After over a decade of clinical practice, potential risk factors associated with POEM failure have been identified. This meta-analysis aimed to summarize the evidence of risk factors for POEM failure. METHODS: A systematic literature search was conducted on PubMed, Embase, Web of Science, and Cochrane Library from inception to June 10th, 2022. We included English studies that reported POEM outcomes in achalasia patients and identified risk factors for POEM failure. Relevant information was extracted and analyzed using fixed- or randomized-effect models to pool the effect size. RESULTS: A total of 27 studies comprising 9371 patients with achalasia were included in this review. The pooled failure rate was 8% (90% CI 7%-10%). We identified sigmoid esophagus (OR 1.90, 95% CI 1.45-2.47), type I achalasia (OR 1.30, 95% CI 1.04-1.63), and type III achalasia (OR 1.26, 95% CI 0.89-1.78) were associated with a worse clinical response. Conversely, type II achalasia was associated with a better response (OR 0.59, 95% CI 0.47-0.75). Prior treatment with Heller myotomy (OR 5.75, 95% CI 3.97-8.34) and prior balloon dilation (OR 1.18, 95% CI 1.07-1.29) were also associated with a higher risk of clinical failure. CONCLUSION: Our meta-analysis results demonstrated that sigmoid esophagus, manometric achalasia subtype, and prior treatment were associated with POEM failure. This information could be used to guide treatment decisions and improve the success rate of POEM in achalasia patients.

A pyroptosis-related gene signature for prognosis and immune microenvironment of pancreatic cancer.

Pancreatic cancer is one of the most lethal tumors owing to its unspecific symptoms during the early stage and multiple treatment resistances. Pyroptosis, a newly discovered gasdermin-mediated cell death, facilitates anti- or pro-tumor effects in a variety of cancers, whereas the impact of pyroptosis in pancreatic cancer remains unclear. Therefore, we downloaded RNA expression and clinic data from the TCGA-PAAD cohort and were surprised to find that most pyroptosis-related genes (PRGs) are not only overexpressed in tumor tissue but also strongly associated with overall survival. For their remarkable prognostic value, cox regression analysis and lasso regression were used to establish a five-gene signature. All patients were divided into low- and high-risk groups based on the media value of the risk score, and we discovered that low-risk patients had better outcomes in both the testing and validation cohorts using time receiver operating characteristic (ROC), nomograms, survival, and decision analysis. More importantly, a higher somatic mutation burden and less immune cell infiltration were found in the high-risk group. Following that, we predicted tumor response to chemotherapy and immunotherapy in both low- and high-risk groups, which suggests patients with low risk were more likely to respond to both immunotherapy and chemotherapy. To summarize, our study established an effective model that can help clinicians better predict patients' drug responses and outcomes, and we also present basic evidence for future pyroptosis related studies in pancreatic cancer.

Redefining the Role of Lymphotoxin Beta Receptor in the Maintenance of Lymphoid Organs and Immune Cell Homeostasis in Adulthood.

Lymphotoxin beta receptor (LTßR) is a promising therapeutic target in autoimmune and infectious diseases as well as cancer. Mice with genetic inactivation of LTßR display multiple defects in development and organization of lymphoid organs, mucosal immune responses, IgA production and an autoimmune phenotype. As these defects are imprinted in embryogenesis and neonate stages, the impact of LTßR signaling in adulthood remains unclear. Here, to overcome developmental defects, we generated mice with inducible ubiquitous genetic inactivation of LTßR in adult mice (iLTßRΔ/Δ mice) and redefined the role of LTßR signaling in organization of lymphoid organs, immune response to mucosal bacterial pathogen, IgA production and autoimmunity. In spleen, postnatal LTßR signaling is required for development of B cell follicles, follicular dendritic cells (FDCs), recruitment of neutrophils and maintenance of the marginal zone. Lymph nodes of iLTßRΔ/Δ mice were reduced in size, lacked FDCs, and had disorganized subcapsular sinus macrophages. Peyer`s patches were smaller in size and numbers, and displayed reduced FDCs. The number of isolated lymphoid follicles in small intestine and colon were also reduced. In contrast to LTßR-/- mice, iLTßRΔ/Δ mice displayed normal thymus structure and did not develop signs of systemic inflammation and autoimmunity. Further, our results suggest that LTßR signaling in adulthood is required for homeostasis of neutrophils, NK, and iNKT cells, but is dispensable for the maintenance of polyclonal IgA production. However, iLTßRΔ/Δ mice exhibited an increased sensitivity to C. rodentium infection and failed to develop pathogen-specific IgA responses. Collectively, our study uncovers new insights of LTßR signaling in adulthood for the maintenance of lymphoid organs, neutrophils, NK and iNKT cells, and IgA production in response to mucosal bacterial pathogen.