m6A modification regulates lung fibroblast-to-myofibroblast transition through modulating KCNH6 mRNA translation.

Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal lung disease characterized by progressive and non-reversible abnormal matrix deposition in lung parenchyma. Myofibroblasts originating mainly from resident fibroblasts via fibroblast-to-myofibroblast transition (FMT) are the dominant collagen-producing cells in pulmonary fibrosis. N6-methyladenosine (m6A) modification has been implicated in various biological processes. However, the role of m6A modification in pulmonary fibrosis remains elusive. In this study, we reveal that m6A modification is upregulated in a bleomycin (BLM)-induced pulmonary fibrosis mouse model, FMT-derived myofibroblasts, and IPF patient lung samples. Lowering m6A levels through silencing methyltransferase-like 3 (METTL3) inhibits the FMT process in vitro and in vivo. Mechanistically, KCNH6 is involved in the m6A-regulated FMT process. m6A modification regulates the expression of KCNH6 by modulating its translation in a YTH-domain family 1 (YTHDF1)-dependent manner. Together, our study highlights the critical role of m6A modification in pulmonary fibrosis. Manipulation of m6A modification through targeting METTL3 may become a promising strategy for the treatment of pulmonary fibrosis.

hERGCentral: a large database to store, retrieve, and analyze compound-human Ether-à-go-go related gene channel interactions to facilitate cardiotoxicity assessment in drug development.

The unintended and often promiscous inhibition of the cardiac human Ether-à-go-go related gene (hERG) potassium channel is a common cause for either delay or removal of therapeutic compounds from development and withdrawal of marketed drugs. The clinical manifestion is prolongation of the duration between QRS complex and T-wave measured by surface electrocardiogram (ECG)-hence Long QT Syndrome. There are several useful online resources documenting hERG inhibition by known drugs and bioactives. However, their utilities remain somewhat limited because they are biased toward well-studied compounds and their number of data points tends to be much smaller than many commercial compound libraries. The hERGCentral ( www.hergcentral.org ) is mainly based on experimental data obtained from a primary screen by electrophysiology against more than 300,000 structurally diverse compounds. The system is aimed to display and combine three resources: primary electrophysiological data, literature, as well as online reports and chemical library collections. Currently, hERGCentral has annotated datasets of more than 300,000 compounds including structures and chemophysiological properties of compounds, raw traces, and biophysical properties. The system enables a variety of query formats, including searches for hERG effects according to either chemical structure or properties, and alternatively according to the specific biophysical properties of current changes caused by a compound. Therefore, the hERGCentral, as a unique and evolving resource, will facilitate investigation of chemically induced hERG inhibition and therefore drug development.

Symptom and quality of life results of an international randomised phase III study of adjuvant vaccination with Bec2/BCG in responding patients with limited disease small-cell lung cancer.

AIMS: This study reports the symptom and HRQOL results in which standard treatment was compared to standard therapy plus Bec2, an anti-idiotypic antibody that mimics GD3, a ganglioside antigen. METHODS: Five hundred and fifteen LD SCLC patients were randomised to receive five vaccinations of Bec2 (2.5mg)/BCG vaccine arm (VA) or an observational arm (OA) administered over a 10-week period. Survival was the primary end-point; HRQOL was a secondary end-point, assessed using the EORTC QLQ-C30/LC 13. RESULTS: There was no improvement in survival or progression-free survival in the vaccination arm. At baseline patients in both arms demonstrated significantly impaired scores on the global QOL scale, when compared to a normative population. However, HRQOL and symptom scores between the two treatment arms were not statistically different at any time point. CONCLUSION: We found no benefits to patient HRQOL by additional vaccination with Bec2/BCG to LD SCLC for patients who have been undergoing standard therapy.