Tertiary lymphoid structural heterogeneity determines tumour immunity and prospects for clinical application.

Tertiary lymphoid structures (TLS) are clusters of immune cells that resemble and function similarly to secondary lymphoid organs (SLOs). While TLS is generally associated with an anti-tumour immune response in most cancer types, it has also been observed to act as a pro-tumour immune response. The heterogeneity of TLS function is largely determined by the composition of tumour-infiltrating lymphocytes (TILs) and the balance of cell subsets within the tumour-associated TLS (TA-TLS). TA-TLS of varying maturity, density, and location may have opposing effects on tumour immunity. Higher maturity and/or higher density TLS are often associated with favorable clinical outcomes and immunotherapeutic response, mainly due to crosstalk between different proportions of immune cell subpopulations in TA-TLS. Therefore, TLS can be used as a marker to predict the efficacy of immunotherapy in immune checkpoint blockade (ICB). Developing efficient imaging and induction methods to study TA-TLS is crucial for enhancing anti-tumour immunity. The integration of imaging techniques with biological materials, including nanoprobes and hydrogels, alongside artificial intelligence (AI), enables non-invasive in vivo visualization of TLS. In this review, we explore the dynamic interactions among T and B cell subpopulations of varying phenotypes that contribute to the structural and functional diversity of TLS, examining both existing and emerging techniques for TLS imaging and induction, focusing on cancer immunotherapies and biomaterials. We also highlight novel therapeutic approaches of TLS that are being explored with the aim of increasing ICB treatment efficacy and predicting prognosis.

Ferroptosis and EMT: key targets for combating cancer progression and therapy resistance.

Iron-dependent lipid peroxidation causes ferroptosis, a form of regulated cell death. Crucial steps in the formation of ferroptosis include the accumulation of ferrous ions (Fe2+) and lipid peroxidation, of which are controlled by glutathione peroxidase 4 (GPX4). Its crucial role in stopping the spread of cancer has been shown by numerous studies undertaken in the last ten years. Epithelial-mesenchymal transition (EMT) is the process by which epithelial cells acquire mesenchymal characteristics. EMT is connected to carcinogenesis, invasiveness, metastasis, and therapeutic resistance in cancer. It is controlled by a range of internal and external signals and changes the phenotype from epithelial to mesenchymal like. Studies have shown that mesenchymal cancer cells tend to be more ferroptotic than their epithelial counterparts. Drug-resistant cancer cells are more easily killed by inducers of ferroptosis when they undergo EMT. Therefore, understanding the interaction between ferroptosis and EMT will help identify novel cancer treatment targets. In-depth discussion is given to the regulation of ferroptosis, the potential application of EMT in the treatment of cancer, and the relationships between ferroptosis, EMT, and signaling pathways associated with tumors. Invasion, metastasis, and inflammation in cancer all include ferroptosis and EMT. The goal of this review is to provide suggestions for future research and practical guidance for applying ferroptosis and EMT in clinical practice.

Multifaceted role of redox pattern in the tumor immune microenvironment regarding autophagy and apoptosis.

The reversible oxidation-reduction homeostasis mechanism functions as a specific signal transduction system, eliciting related physiological responses. Disruptions to redox homeostasis can have negative consequences, including the potential for cancer development and progression, which are closely linked to a series of redox processes, such as adjustment of reactive oxygen species (ROS) levels and species, changes in antioxidant capacity, and differential effects of ROS on downstream cell fate and immune capacity. The tumor microenvironment (TME) exhibits a complex interplay between immunity and regulatory cell death, especially autophagy and apoptosis, which is crucially regulated by ROS. The present study aims to investigate the mechanism by which multi-source ROS affects apoptosis, autophagy, and the anti-tumor immune response in the TME and the mutual crosstalk between these three processes. Given the intricate role of ROS in controlling cell fate and immunity, we will further examine the relationship between traditional cancer therapy and ROS. It is worth noting that we will discuss some potential ROS-related treatment options for further future studies.

MPDZ is associated with immune infiltration and regulates migration and invasion by switching YAP1 phosphorylation in colorectal cancer.

BACKGROUND: Multiple PDZ Domain Crumbs Cell Polarity Complex Component (MPDZ) is involved in a few human cancers. However, the features and potential mechanisms of MPDZ in progression of colorectal cancer (CRC) remains unknown. METHODS: The prognostic role of MPDZ in CRC was determined by Kaplan-Meier and univariate regression analysis. Enrichment analysis was performed to characterize crucial pathways of MPDZ. Immune infiltration and immunotherapeutic outcome were further evaluated. CCK8, EDU, transwell, and wound healing assay were used to assess the influence of MPDZ on pernicious performance of CRC cells. CD8+ T cells and CRC cells were co-cultured to explore the effect of MPDZ on the tumor microenvironment. qRT-PCR, western blot, immunoprecipitation (IP), and methylated RNA immunoprecipitation (me-RIP) were implemented in seeking for the potential mechanisms of MPDZ in CRC. RESULTS: CRC patients with elevated MPDZ expression suffered from significantly worse prognosis. Enrichment analysis revealed that MPDZ involved in pathways related to metastasis and cell cycle in CRC. In addition, MPDZ expression were related to several immunoinhibitors and had the ability to predict immunotherapy response. Finally, in vitro assays demonstrated that MPDZ knockdown inhibited migration, invasion and immune evasion of CRC cells. Mechanistically, MPDZ knockdown enhanced YAP1 phosphorylation by increased LATS1 expression. Moreover, m6A-MPDZ mRNA may be recognized and degraded by m6A recognition protein YTHDF2. CONCLUSIONS: MPDZ was critical for CRC development and could be a promising candidate for the treatment of CRC patients.

Pyroptosis-Derived Long Noncoding RNA Profiles Reveal a Novel Signature for Evaluating the Prognosis of Patients With Lung Adenocarcinoma.

PURPOSE: Long noncoding RNAs (lncRNAs) were recently implicated in modifying pyroptosis. Nonetheless, pyroptosis-related lncRNAs and their possible clinical relevance persist largely uninvestigated in lung adenocarcinoma (LUAD). MATERIALS AND METHODS: A sum of 921 samples were collected from three independent data sets. We obtained pyroptosis-related genes from both the Molecular Signatures Database and relevant literature sources and used four machine learning techniques, comprising stepwise Cox, ridge regression, least absolute shrinkage and selection operator, and random forest. Multiple bioinformatics approaches were used to further investigate the underlying mechanisms. RESULTS: In total, 39 differentially expressed pyroptosis genes were identified by comparing normal and tumor samples. Correlation analysis revealed 933 pyroptosis-related lncRNAs. Furthermore, univariate Cox regression determined 11 lncRNAs that exhibited stable associations with prognosis in the three cohorts, which were used to construct the pyroptosis-derived lncRNA signature. After analyzing the optimal results from four machine learning algorithms, we ultimately selected random forest to develop the pyroptosis-derived lncRNA signature. This signature was proven to be an independent prognostic factor and exhibited robust performance in three cohorts. CONCLUSION: We provided novel insight and established a pyroptosis-derived lncRNA signature for patients with LUAD, exhibiting strong predictive capabilities in both the training and validation sets.

Systematic analysis of transcriptome signature for improving outcomes in lung adenocarcinoma.

PURPOSE: The updated guidelines highlight gene expression-based multigene panel as a critical tool to assess overall survival (OS) and improve treatment for lung adenocarcinoma (LUAD) patients. Nevertheless, genome-wide expression signatures are still limited in real clinical utility because of insufficient data utilization, a lack of critical validation, and inapposite machine learning algorithms. METHODS: 2330 primary LUAD samples were enrolled from 11 independent cohorts. Seventy-six algorithm combinations based on ten machine learning algorithms were applied. A total of 108 published gene expression signatures were collected. Multiple pharmacogenomics databases and resources were utilized to identify precision therapeutic drugs. RESULTS: We comprehensively developed a robust machine learning-derived genome-wide expression signature (RGS) according to stably OS-associated RNAs (OSRs). RGS was an independent risk element and remained robust and reproducible power by comparing it with general clinical parameters, molecular characteristics, and 108 published signatures. RGS-based stratification possessed different biological behaviors, molecular mechanisms, and immune microenvironment patterns. Integrating multiple databases and previous studies, we identified that alisertib was sensitive to the high-risk group, and RITA was sensitive to the low-risk group. CONCLUSION: Our study offers an appealing platform to screen dismal prognosis LUAD patients to improve clinical outcomes by optimizing precision therapy.

Associations Between Life's Essential 8 and Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) is closely associated with cardiovascular disease. We aimed to examine the association of Life's Essential 8 (LE8), the recently updated measurement of cardiovascular health, with the prevalence of CKD among US adults. METHODS AND RESULTS: This population-based cross-sectional study used data from the National Health and Nutrition Examination Survey from 2007 to 2018 and included adults aged ≥20 years. Multivariable logistic and restricted cubic spline models were used to assess the associations between LE8 and CKD. Among 24 960 participants, 4437 were determined to have CKD (weighted percentage, 14.11%). After the adjustment of potential confounders, higher LE8 scores were associated with reduced odds of CKD (odds ratio for each 10-point increase, 0.79 [95% CI, 0.76-0.83]), and a nonlinear dose-response relationship was observed. Similar patterns were also identified in the associations of health behavior and health factor scores with CKD. Meanwhile, higher scores for blood glucose (odds ratio, for each 10-point increase, 0.88 [95% CI, 0.87-0.90]) and blood pressure (odds ratio, for each 10-point increase, 0.92 [95% CI, 0.91-0.94]) in the LE8 component are significantly associated with a lower prevalence of CKD. The inversed association of LE8 score and CKD was significantly stronger among middle-aged, male, and coupled participants. CONCLUSIONS: LE8 was negatively associated with the prevalence of CKD in a nonlinear fashion. Promoting adherence to optimal cardiovascular health levels may be beneficial to reduce the burden of CKD.