Isoliquiritigenin suppresses the progression of malignant melanoma via targeting H2A.Z.1-E2F1 pathway.

Cutaneous melanoma is one of the most prevalent tumors, and it is still a huge challenge in the current clinical treatment. Isoliquiritigenin (ISL), which is isolated from Glycyrrhiza uralensis Fisch., has been reported for its anti-tumor effect. However, the underlying mechanism and targets of ISL are still not be revealed clearly. In this study, differentiallyexpressedproteins were identified bylabel-free quantitative mass spectrometry. Two isoforms of the histone variant H2A.Z, including H2A.Z.1 and H2A.Z.2, were significantly down regulated after administration of ISL in melanoma. H2A.Z.1 was highly expressed in melanoma and correlated with poor prognosis of melanoma. The expression of H2A.Z was inhibited by ISL in a concentration-dependent manner. Overexpression of H2A.Z.1 in melanoma cell lines partly restored the repressed cell proliferation and cell cycle by ISL. Moreover, E2F1 was identified as one downstream target of H2A.Z.1, which was also highly expressed in melanoma and correlated with poor prognosis of melanoma. Furthermore, in vivo assays validated the inhibitory role of ISL in melanoma proliferation and the expression of H2A.Z.1 and E2F1.Aboveall,it is indicated that ISL inhibit melanoma proliferation via targeting H2A.Z.1-E2F1 pathway. These findings explain the anti-tumor mechanism of ISL and provide potential therapeutic targets for melanoma.

The binding profile of SARS-CoV-2 with human leukocyte antigen polymorphisms reveals critical alleles involved in immune evasion.

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), astonished the world and led to millions of deaths. Due to viral new mutations and immune evasion, SARS-CoV-2 ranked first in transmission and influence. The binding affinity of human leukocyte antigen (HLA) polymorphisms to SARS-CoV-2 might be related to immune escape, but the mechanisms remained unclear. In this study, we obtained the binding affinity of SARS-CoV-2 strains with different HLA proteins and identified 31 risk alleles. Subsequent structural predictions identified 10 active binding sites in these HLA proteins that may promote immune evasion. Particularly, we also found that the weak binding ability with HLA class I polymorphisms could contribute to the immune evasion of Omicron. These findings suggest important implications for preventing the immune evasion of SARS-CoV-2 and providing new insights for the vaccine design.

Comprehensive elaboration of circular RNA in multiple myeloma.

Circular RNAs (circRNAs), a novel category of endogenous non-coding RNAs, are usually well conserved across different species with a covalent closed-loop structure. Existing and emerging evidence confirms that circRNAs can function as regulators of alternative splicing, microRNA and RNA-binding protein sponges and translation, as well as gene transcription. In consideration of their multi-faceted functions, circRNAs are critically involved in hematological malignancies including multiple myeloma (MM). In particular, circRNAs have been found to play vital roles in tumor microenvironment and drug resistance, which may grant them potential roles as biomarkers for MM diagnosis and targeted therapy. In this review, we comprehensively elaborate the current state-of-the-art knowledge of circRNAs in MM, and then focus on their potential as biomarkers in diagnosis and therapy of MM.

Sequential Whole Exome Sequencing Reveals Somatic Mutations Associated with Platinum Response in NSCLC.

PURPOSE: Resistance is one of the main limitations of successful platinum treatment in non-small-cell lung cancer (NSCLC) patients. In this study, we aimed to identify somatic mutations associated with platinum response. PATIENTS AND METHODS: A total of 57 patients who received platinum-based chemotherapy only and 13 patients who received neoadjuvant chemotherapy (NAC) were enrolled. Somatic mutations were obtained from targeted and whole exome sequencing (WES). RESULTS: Somatic mutations in a total of 225 genes were observed. Nonsynonymous variants in EGFR, TTN, TP53 and KRAS, and copy number variations (SCNVs) in chromosome 8q24.3 and 22q11.21 were identified to be associated with platinum response. Based on these mutations, the mutational signature associated with the failure of DNA double-strand break and calcium signaling pathways were identified to be associated with platinum response. Besides, we observed a decrease in tumor mutational burden after chemotherapy. We also evaluated the mutation spectrum consistency between cell-free DNA (cfDNA) and tissue DNA. Somatic mutations detected in cfDNA were consistent with that in tDNA, which indicated that plasma might be used for somatic mutation detection. CONCLUSION: These results support that somatic mutations can affect platinum drug response and provide potential clinical biomarkers for NSCLC treatment.

The role of CSDE1 in translational reprogramming and human diseases.

CSDE1 (cold shock domain containing E1) plays a key role in translational reprogramming, which determines the fate of a number of RNAs during biological processes. Interestingly, the role of CSDE1 is bidirectional. It not only promotes and represses the translation of RNAs but also increases and decreases the abundance of RNAs. However, the mechanisms underlying this phenomenon are still unknown. In this review, we propose a "protein-RNA connector" model to explain this bidirectional role and depict its three versions: sequential connection, mutual connection and facilitating connection. As described in this molecular model, CSDE1 binds to RNAs and cooperates with other protein regulators. CSDE1 connects with different RNAs and their regulators for different purposes. The triple complex of CSDE1, a regulator and an RNA reprograms translation in different directions for each transcript. Meanwhile, a number of recent studies have found important roles for CSDE1 in human diseases. This model will help us to understand the role of CSDE1 in translational reprogramming and human diseases. Video Abstract.

Gene-gene and gene-environment interaction data for platinum-based chemotherapy in non-small cell lung cancer.

Gene-gene (GXG) and gene-environment (GXE) interactions play important roles in pharmacogenetics study. Simultaneously incorporating multiple single nucleotide polymorphisms (SNPs) and clinical factors is needed to explore the association of their interactions with drug response and toxicity phenotypes. We genotyped 504 SNPs in a total of 490 Chinese non-small cell lung cancer (NSCLC) patients, and the correlation of GXG and GXE interactions with platinum-based chemotherapeutic efficacy and safety were analyzed. In this data descriptor, we shared our data set which could help others to reuse them. All kinds of file types needed for GXG and GXE analysis were supplied. The process of genotyping and data analysis was also introduced step by step.

Clinical efficacy and safety of afatinib in the treatment of non-small-cell lung cancer in Chinese patients.

Compared with various malignant tumors, lung cancer has high incidence and the highest mortality worldwide. Non-small-cell lung cancer (NSCLC), the most common kind of lung cancer, is still a great threat to the world, including China. Surgery, platinum-based chemotherapy, and radiotherapy are still the primary treatments for NSCLC patients in the clinic, whereas immunotherapy and targeted therapy are gradually playing more important roles. A next-generation tyrosine kinase inhibitor (TKI), afatinib, was developed as a targeted reagent for epidermal growth factor receptor (EGFR). This targeted drug was effective in a series of trials. The US Food and Drug Administration then approved afatinib as a new first-line treatment for EGFR L858R and exon 19 deletion mutant patients in 2013. This review focused on current clinical studies of afatinib. Although this TKI was not widely available in China until recently, we aim to provide a reference for its future use in China.