Changzhi Medical College

Human epidermal growth factor receptor 2 (HER2) is a critical biomarker and therapeutic target in gastric/gastroesophageal junction (G/GEJ) cancers, despite the initial success of HER2-targeted therapies, such as trastuzumab, resistance to these drugs has emerged as a major impediment to effective long-term treatment. This review examines the mechanisms of drug resistance in HER2-positive G/GEJ cancer, the primary mechanisms of resistance explored include alterations in the HER2 receptor itself, such as mutations and changes in expression levels, as well as downstream signaling pathways, and interactions with the tumor microenvironment (TME). Furthermore, the review discusses the Novel therapeutic approaches, including the use of antibody-drug conjugates (ADCs) and combination therapies are assessed for their potential to enhance outcomes. By integrating recent research findings and clinical trials, this review aims to provide oncologists and researchers with insights into developing more effective treatments for patients with drug-resistant HER2-positive G/GEJ cancer.

Heat shock has been known to induce hyperplasia in esophageal epithelial cells. It is widely considered as a crucial risk factor in the initiation and development of esophageal squamous cell carcinoma (ESCC), yet our understanding of the underlying mechanisms remains limited. The m6A modification of mRNA plays a role in mediating several cellular processes and is critical during cell stress. Our study revealed that inhibiting of m6A 'writer' components of ESCC cells exhibit higher death rates and slower recovery after heat shock. After normalization using mRNA expression profiles, 91.08 % of significantly changed m6A modifications aligned with corresponding mRNA abundance changes, with no evidence of over-modification, while the increase in m6A modification of 8.92 % of heat-shock associated genes far exceeded the increase in mRNA (hyper - m6A modification), and A/U rich motifs were commonly observed in the 3'UTR of these gene. Inside the nucleus, the binding of HSP70s in m6A writer complex promote the hyper - m6A modification in specific mRNAs after heat shock. The stronger nuclear localization of HSP70 in ESCC tissues correlates with a poor prognosis for the patients. In conclusion, our research revealed that the nuclear HSP70 protein could bind to the METTL3/14 writer complex and regulate mRNA's m6A modification. Our results provide a new perspective for research into how HSP70 protein regulates mRNA stability and suggests a new direction for the comprehensive prevention and treatment of ESCC.

Cognitive impairment is a common side effect of docetaxel (DTX)-based chemotherapy. The novel neuroprotective agent edaravone dexborneol (ED) was found to alleviate the adverse phenotype caused by DTX. However, the underlying mechanism remains unexplored. By analyzing mRNA-sequencing data, we noticed that the expression of S100 calcium-binding protein A11 (S100A11), a protector of the nervous system, was decreased in DTX-treated rats with cognitive damage, but ED administration reversed the trend. Therefore, we speculated that S100A11 might be involved in the protective effects of ED on DTX-induced cognitive impairment. Sprague-Dawley rats were intraperitoneally injected with DTX to induce cognitive impairment, followed by intraperitoneal injection of ED after DTX induction. The results showed that ED treatment mitigated cognitive impairment caused by DTX. Next, adenoviruses carrying sequences encoding S100A11 were given to rats receiving DTX treatment. S100A11 overexpression alleviated cognitive dysfunction of DTX-treated rats, as evidenced by the decreased escape latency and swimming distance, and the increased number of platform crossings. Mechanically, S100A11 overexpression inhibited neuronal apoptosis by inactivating the MAPK signaling pathway. Further rescue experiments showed that S100A11 knockdown reversed the defensive role of ED in DTX-induced neuronal damage. In conclusion, ED ameliorates cognitive dysfunction caused by DTX by upregulating the S100A11 expression and subsequently inactivating the MAPK signaling pathway.