Parasitic nematodes are a significant concern in human and veterinary medicine as well as agriculture. In this study, we prepared twenty-seven 5-phenyl-1H-indole derivatives bearing various substituents on the phenyl ring and assessed their efficacy against nematodes. Using Caenorhabditis elegans, we selected the most potent compounds and evaluated their toxicity on selected animal and plant-parasitic nematode species. Compounds featuring 4-chloro, 4-fluoro, and 4-trifluoromethoxy groups on the phenyl ring inhibited the motility of exsheathed L3 larvae of Hemonchus contortus while exhibiting limited cytotoxicity in mammalian cell cultures. These compounds showed similar effects against the plant-parasitic nematodes Heterodera schachtii and Ditylenchus destructor, albeit with reduced potency. We propose that the compounds might act as inhibitors of mitochondrial complex II as inferred from molecular modeling, decreased mitochondrial membrane potential, and reduced activity in C. elegans complex II mutants.
BackgroundLactylation, a novel post-translational modification of proteins, has been shown to promote tumor growth and inhibit the antitumor response of the tumor microenvironment (TME) in various ways. However, the complex mechanism of this modification in gastric cancer, particularly nonhistone lactylation and its interplay with tumor metabolism and immune escape, remains enigmatic.MethodsUsing single-cell RNA sequencing data and the AddModuleScore algorithm, we screened for lactylation-related genes at the single-cell level. We then integrated 10 machine learning algorithms and 101 combinations of these to construct a lactylation-related gene signature (LRS) model. The results were validated in the GEO dataset. Ultimately, we identified genes with prognostic predictive value, forming three gene feature profiles. We further analyzed the associations between lactylation-related gene risk scores and clinical features, mutation profiles, biological functions, immune cell infiltration, and immunotherapy response. For the core genes, we explored in-depth biological mechanisms through bioinformatics analysis and in vitro experiments.ResultsWe identified 119 lactylation-related genes at the single-cell level. Utilizing a computational framework with 101 combinations of machine learning algorithms, we successfully constructed a risk prediction model that includes three lactylation-associated genes. This model showed excellent performance in prognosis prediction and clinical translation. The study also found significant differences in clinical features, biological functions, immune cell infiltration, immune checkpoint expression, and immunotherapy response among patients in different risk groups.ConclusionsThe LRS model demonstrates significant potential for improving the management of gastric cancer patients and enhancing treatment outcomes, particularly in the areas of immunotherapy and immune escape. This discovery highlights the clinical importance of overall lactic acidification in gastric cancer and provides a foundation for mechanistic studies and targeted therapeutic strategies.
Colorectal cancer (CRC) is one of the most common and deadly cancers worldwide. Here we aim to identify and develop novel diagnostic biomarkers to detect early-stage CRC. Candidate biomarkers were identified from RNA-seq, validated using RT-qPCR essays and developed through the bioinformatics pipeline using multivariate binary logistic regression and receiver operating characteristic curve analysis. We identified a novel 2-gene signature within blood leukocytes which could robustly discriminate CRC from healthy controls (HC). Using an RT-qPCR assay based on the 2-gene signature, we detected CRC samples from HC samples with a sensitivity of 80% and a specificity of 81% in a training retrospective cohort of 314 samples and derived a logistic equation to calculate CRC risk probability termed as HIR-CRC. In an independent cohort of 178 samples, we validated 2-gene test and detected CRC from HC with a sensitivity of 82% and a specificity of 78%. Importantly, the 2-gene test can detect early-stage CRC and CRC which are tested negative for carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) with 76-88% sensitivity which is significantly higher than that of either CEA (31-56%) or CA19-9 (9-44%). The 2-gene signature described here can potentially fill an unmet clinical need for a robust screening assay to identify CRC patients at early stages when potentially curative treatment options are available. Yu Wang, Jinli Zhao, Heng Dong, Wei Wang, Yong Zeng, Jianxiang Chen. Application of Novel Immune Signatures for the Early Detection of Colorectal Cancer [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl):Abstract nr P12.
AbstractIn this chapter, we address the role of radiation as treatment modality in the context of oncological treatments given to patients. Physical aspects of the use of ionizing radiation (IR)—by either photons, neutrons, or charged (high linear energy transfer) particles—and their clinical application are summarized. Information is also provided regarding the radiobiological rationale of the use of conventional fractionation as well as alternative fractionation schedules using deviating total dose, fraction size, number of fractions, and the overall treatment time. Pro- and contra arguments of hypofractionation are discussed. In particular, the biological rationale and clinical application of Stereotactic Body Radiation Therapy (SBRT) are described. Furthermore, background information is given about FLASH radiotherapy (RT), which is an emerging new radiation method using ultra-high dose rate allowing the healthy, normal tissues and organs to be spared while maintaining the antitumor effect. Spatial fractionation of radiation in tumor therapy, another method that reduces damage to normal tissue is presented. Normal tissue doses could also be minimized by interstitial or intraluminal irradiation, i.e., brachytherapy, and herein an overview is given on the principles of brachytherapy and its clinical application. Furthermore, details are provided regarding the principles, clinical application, and limitations of boron neutron capture therapy (BNCT). Another important key issue in cancer therapy is the combination of RT with other treatment modalities, e.g., chemotherapy, targeted therapy, immunotherapy, hyperthermia, and hormonal therapy. Combination treatments are aimed to selectively enhance the effect of radiation in cancer cells or to trigger the immune system but also to minimize adverse effects on normal cells. The biological rationale of all these combination treatments as well as their application in clinical settings are outlined. To selectively reach high concentrations of radionuclides in tumor tissue, radioembolization is a highly interesting approach. Also, radioligand therapy which enables specific targeting of cancer cells, while causing minimal harm surrounding healthy tissues is presented. A brief overview is provided on how nanotechnology could contribute to the diagnosis and treatment of cancer. Last but not least, risk factors involved in acquiring secondary tumors after RT are discussed.
