Reflections on drug resistance to KRASG12C inhibitors and gene silencing/editing tools for targeting mutant KRAS in cancer treatment.

KRAS is the most commonly mutated oncogene in human tumors, especially in lung, pancreatic, and colorectal cancers. Small-molecule inhibitors targeting mutant KRASG12C demonstrated promising anti-tumor effect in patients with non-small cell lung cancer harboring KRASG12C mutation, while the intrinsic and acquired drug resistance occurred frequently and might be inevitable. Unlike the protein-level inhibition approach, gene silencing/editing tools for DNA-level knockout and RNA-level knockdown of mutant KRAS may be advantageous since these approaches directly eliminate the production of mutant KRAS-encoded protein. An in-depth understanding of KRAS biology, drug resistance to KRASG12C inhibitors and gene silencing/editing methods applied for anti-KRAS therapy may give new insight into the therapeutic strategy for cancer treatment.

Community Physician-Guided Long-Term Domiciliary Oxygen Therapy Combined With Conventional Therapy in Stage IV COPD Patients.

PURPOSE: The aim of the study was to explore clinical effect of community physician-guided long-term domiciliary oxygen therapy (LTDOT) on patients with Stage IV chronic obstructive pulmonary disease (COPD). DESIGN: A retrospective study. METHODS: Fifty-four patients with Stage IV COPD were recruited and randomly divided into two groups (the LTDOT group and the control group). Patients in LTDOT group accepted additional oxygen therapy for more than 15 hours every day with continuous low flow (1-2 L/min) for 3 years. FINDINGS: PaO2 (O2 pressure), FEV1/FVC (forced vital capacity), and FEV1% (percentage of forced expiratory volume in 1 second) in the LTDOT group increased significantly after treatment. A significant decrease was observed on the BODE index in the LTDOT group (p < .05) but not in control group (p > .05). Frequencies and costs of hospitalization therapy and emergency medical services were markedly decreased after 3 years of LTDOT. CONCLUSION: Community physician-guided LTDOT can improve prognosis and reduce the costs for stage IV COPD patients. CLINICAL RELEVANCE: Rehabilitation nurses can be instrumental in helping patients with stage IV COPD learn principles of LTDOT.

Protein-protein interaction network analysis in chronic obstructive pulmonary disease.

BACKGROUND: The aim of this study was to investigate the gene expression profile of chronic obstructive pulmonary disease (COPD) patients and non-COPD patients. METHODS: Microarray raw data (GSE29133) was downloaded from Gene Expression Omnibus, including three COPD samples and three normal controls. Gene expression profiling was performed using Affymetrix human genome u133 plus 2.0 GeneChip. Differentially expressed genes were identified by Student's t test and genes with p < 0.05 were considered significantly changed. Up- and downregulated genes were submitted to the molecular signatures database (MSigDB) to search for a possible association with other previously published gene expression signatures. Furthermore, we constructed a COPD protein-protein interaction (PPI) network and used the connectivity map (cMap) to query for potential drugs for COPD. RESULTS: A total of 680 upregulated genes and 530 downregulated genes in COPD were identified. The MSigDB investigation found that upregulated genes were highly similar to gene signatures that respond to interferon and downregulated genes were similar to erythroid progenitor cells from fetal livers of E13.5 embryos with KLF1 knocked out. A PPI network consisting of 814 gene/proteins and 2,613 interactions was identified by Search Tool for the Retrieval of Interacting Genes. The cMap predicted helveticoside, disulfiram, and lanatoside C as the top three possible drugs that could perhaps treat COPD. CONCLUSION: Comprehensive analysis of the gene expression profile for COPD versus control reveals helveticoside, disulfiram, and lanatoside C as potential molecular targets in COPD. This evidence provides a new breakthrough in the medical treatment of patients with COPD.