Despite the discovery of oncogenes in human tumor DNA 40 years ago, the development of effective targeted therapies directed against has lagged behind those more successful advancements in the field of therapeutic tyrosine kinase inhibitors targeting other oncogenes such as , , and . The discoveries that (1) malignant oncogenes differ from their wild-type counterparts by only a single amino acid change and (2) covalent inhibition of the cysteine residue at codon 12 of in its inactive GDP-bound state resulted in effective inhibition of oncogenic RAS signaling and have catalyzed a dramatic shift in mindset toward -driven cancers. Although the development of allele-selective KRAS inhibitors has changed a treatment paradigm, the clinical activity of these agents is more modest than tyrosine kinase inhibitors targeting other oncogene-driven cancers. Heterogeneous resistance mechanisms generally result in the restoration of RAS/mitogen-activated protein kinase pathway signaling. Many approaches are being evaluated to overcome this resistance, with many combinatorial clinical trials ongoing. Furthermore, because and are more prevalent than , there remains an unmet need for additional therapeutic strategies for these patients. Thus, our current translational standing could be described as "the end of the beginning," with additional discovery and research innovation needed to address the enormous disease burden imposed by -mutant cancers. Here, we describe the development of KRAS inhibitors, the challenges of resistance to these inhibitors, strategies to mitigate that resistance, and new approaches being taken to address other -mutant cancers.
Key Laboratory of Plant Nutrition and the Agro-Environment in Northwest China, Ministry of Agriculture and Rural Affairs, College of Natural Resources and Environment, Northwest A & F University, Yangling, Shaanxi 712100, China.
Microplastics (MPs) have been confirmed as a hotspot for antibiotic resistance genes (ARGs) in wastewater. However, the impact of MPs on the transfer of ARGs in wastewater treatment remains unclear. This study investigated the roles and mechanisms of conventional (polystyrene, PS) and biodegradable (polylactic acid, PLA) MPs in the conjugative transfer of ARGs during ultraviolet disinfection.
Background: Esophageal cancer, particularly esophageal squamous cell carcinoma (ESCC), is a leading cause of cancer-related death and has a poor prognosis. Despite the advancements in multidisciplinary therapies, resistance to conventional treatments warrants the development of novel therapeutic strategies. Ferroptosis, a form of cell death dependent on intracellular iron, has emerged as a potential mechanism for targeting cancer cells resistant to apoptosis.
As many proteins prioritize functionality over constancy of structure, a proteome is the shortest stave in the Liebig's barrel of cell sustainability. In this regard, both prokaryotes and eukaryotes possess abundant machinery supporting the quality of the proteome in healthy and stressful conditions. This machinery, namely chaperones, assists in folding, refolding, and the utilization of client proteins.
Bacterial blight in pomegranate, caused by pv. (Xcp), is one of the most devastating diseases, leading to substantial economic losses in pomegranate production. Methods for blight management in pomegranate production are scarce and not well established.
Introduction: There are complex interactions between host and gut microbes during weaning, many of the mechanisms are not yet fully understood. Previous research mainly focuses on commercial pigs, whereas limited information has been known about the host and gut microbe interactions in miniature pigs.
Methods: To address the issue in Bama miniature piglets that were weaned 30 days after birth, we collected samples on days 25 and 36 for metabolomics, transcriptomics, and microgenomics analysis.
