Min Hu

Fibrosis usually results from dysregulated wound repair and is characterized by excessive scar tissue. It is a complex process with unclear mechanisms. Accumulating evidence indicates that epigenetic alterations, including histone acetylation, play a pivotal role in this process. Histone acetylation is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are enzymes that remove the acetyl groups from both histone and nonhistone proteins. Aberrant HDAC activities are observed in fibrotic diseases, including cardiac and pulmonary fibrosis. HDAC inhibitors (HDACIs) are molecules that block HDAC functions. HDACIs have been studied extensively in a variety of tumors. Currently, there are four HDACIs approved by the US Food and Drug Administration for cancer treatment yet none for fibrotic diseases. Emerging evidence from in vitro and in vivo preclinical studies has presented beneficial effects of HDACIs in preventing or reversing fibrogenesis. In this review, we summarize the latest findings of the roles of HDACs in the pathogenesis of cardiac and pulmonary fibrosis and highlight the potential applications of HDACIs in these two fibrotic diseases.

Liver fibrosis occurs in response to any etiology of chronic liver injury. Lack of appropriate clinical intervention will lead to liver cirrhosis or hepatocellular carcinoma (HCC), seriously affecting the quality of life of patients, but the current clinical treatments of liver fibrosis have not been developed yet. Recent studies have shown that hypoxia is a key factor promoting the progression of liver fibrosis. Hypoxia can cause liver fibrosis. Liver fibrosis can, in turn, profoundly further deepen the degree of hypoxia. Therefore, exploring the role of hypoxia in liver fibrosis will help to further understand the process of liver fibrosis, and provide the theoretical basis for its diagnosis and treatment, which is of great significance to avoid further deterioration of liver diseases and protect the life and health of patients. This review highlights the recent advances in cellular and molecular mechanisms of hypoxia in developments of liver fibrosis.

// Di Zheng 1, * , Min Hu 2, * , Yu Bai 2 , Xuehua Zhu 2 , Xuesong Lu 3 , Chunyan Wu 4 , Jiying Wang 1 , Li Liu 1 , Zheng Wang 3 , Jian Ni 1 , Zhenfan Yang 2 and Jianfang Xu 1 1 Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School, Shanghai, China 2 IMED Asia, AstraZeneca, Shanghai, China 3 Research and Development Information, AstraZeneca, Shanghai, China 4 Department of Pathology, Shanghai Pulmonary Hospital, Tongji University Medical School, Shanghai, China * These authors contributed equally to this work Correspondence to: Jianfang Xu, email: xujianfang63@aliyun.com Zhenfan Yang, email: Pamela.Yang@astrazeneca.com Keywords: EGFR, NSCLC, osimertinib, drug resistance, G796D Received: March 08, 2017      Accepted: May 04, 2017      Published: May 16, 2017 ABSTRACT Osimertinib is an effective third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved in multiple countries and regions for patients with EGFR T790M mutation-positive non-small cell lung cancer (NSCLC). Despite impressive initial tumor responses, development of drug resistance ultimately limits the benefit of this compound. Mechanisms of resistance to osimertinib are just beginning to emerge, such as EGFR C797S and L718Q mutations, BRAF V600E and PIK3CA E545K mutations, as well as ERBB2 and MET amplification. However, a comprehensive view is still missing. In this study, we presented the first case of Chinese NSCLC patient who developed resistance to osimertinib, and discovered de novo EGFR G796D mutation as a potential mechanism. Our findings provided insights into mechanisms of resistance to osimertinib and highlighted tumor heterogeneity and clonal evolution during the development of drug resistance.