Systematic profiling and identification of the peptide-mediated interactions between human Yes-associated protein and its partners in esophageal cancer.

Human Yes-associated protein (YAP) is involved in the Hippo signaling pathway and serves as a coactivator to modulate gene expression, which contains a transactivation domain (TD) responsible for binding to the downstream TEA domain family (TEAD) of transcription factors and two WW1/2 domains that recognize the proline-rich motifs (PRMs) present in a variety of upstream protein partners through peptide-mediated interactions (PMIs). The downstream YAP TD-TEAD interactions are closely associated with gastric cancer, and a number of therapeutic agents have been developed to target the interactions. In contrast, the upstream YAP WW1/2-partner interactions are thought to be involved in esophageal cancer but still remain largely unexplored. Here, we attempted to elucidate the complicated PMIs between the YAP WW1/2 domains and various PRMs of YAP-interacting proteins. A total of 106 peptide segments carrying the class I WW-binding motif [P/L]Px[Y/P] were extracted from 22 partner candidates, which are potential recognition sites of YAP WW1/2 domains. Structural and energetic analyses of the intermolecular interactions between the domains and peptides created a systematic domain-peptide binding profile, from which a number of biologically functional PMIs were identified and then substantiated in vitro using fluorescence spectroscopy assays. It is revealed that: (a) The sequence requirement for the partner recognition site binding to YAP WW1/2 domains is a decapeptide segment that contains a core PRM motif as well as two three-residue extensions from each side of the motif; the core motif and extended sections are responsible for the binding stability and recognition specificity of domain-peptide interaction, respectively. (b) There is an exquisite difference in the recognition specificity of the two domains; the LPxP and PPxP appear to more prefer WW1 than WW2, whereas the WW2 can bind more effectively to LPxY and PPxY than WW1. (c) WW2 generally exhibits a higher affinity to the panel of recognition site candidates than WW1. In addition, a number of partner peptides were found as promising recognition sites of the two domains and/or to have a good selectivity between the two domains. For example, the DVL1 peptide was determined to have moderate affinity to WW2 and strong selectivity for WW2 over WW1. Hydrogen bonds play a central role in selectivity.

Neoadjuvant chemoradiotherapy with camrelizumab in patients with locally advanced esophageal squamous cell carcinoma.

Background: Neoadjuvant anti-programmed death receptor-1 (PD-1) blockade has been reported to improve the prognosis of locally advanced esophageal squamous cell carcinoma (ESCC). This study was aimed to evaluate the efficacy and safety of neoadjuvant camrelizumab plus chemoradiotherapy in locally advanced ESCC. Methods: We retrospectively enrolled ESCC patients who received camrelizumab plus chemoradiotherapy as neoadjuvant therapy before surgery from May 2019 to September 2021. Results: A total of 38 eligible patients were enrolled. The neoadjuvant treatment was well tolerated with no serious treatment-related adverse events. 36 (94.7%) patients achieved a R0 resection without hospital mortality or any other serious intraoperative complications. The objective response rate (ORR) was 63.2% and the disease control rate (DCR) was 100.0%. The major pathological response (MPR) was 50.0% and the complete pathological response (pCR) was 39.5%. With a median follow-up of 18.5 months, 6 (15.8%) patients had died. The overall survival (OS) and disease-free survival (DFS) at 12 months were 87.6% and 78.7%, respectively. Subgroup analysis demonstrated that patients who got MPR or pCR achieved improved survival, while PD-L1 expression did not reach statistically difference in predicting survival. Conclusions: Neoadjuvant camrelizumab plus chemoradiotherapy is safe and efficacious in treating patients with locally advanced ESCC.

Scaffold-based analysis of nonpeptide oncogenic FTase inhibitors using multiple similarity matching, binding affinity scoring and enzyme inhibition assay.

Oncogenic protein farnesyltransferase (FTase) is a key enzyme responsible for the lipid modification of a large and important number of proteins including Ras, which has been recognized as a druggable target of diverse cancers. Here, we report a systematic scaffold-based analysis to investigate the affinity, selectivity and cross-reactivity of nonpeptide inhibitors across ontology-enriched, disease-associated FTase mutants, by integrating multiple similarity matching, binding affinity scoring and enzyme inhibition assay. It is revealed that nonpeptide inhibitors are generally insensitive to FTase mutations; many of them cannot definitely select for wild-type target over mutant enzymes. Therefore, off-target is observed as a common phenomenon for the untargeted consequence of targeted therapies with FTase inhibition. This is not unexpected if considering that the enzyme active site is highly conserved in composition, configuration and function. The off-target, on the one hand, causes nonpeptide inhibitors with adverse drug reactions and, on the other hand, makes the inhibitors as promising candidates for the new use of old drugs. To practice the latter, a number of unexpected mutant-inhibitor interactions involved in cancer signaling pathways are uncovered in the created profile, from which several nonpeptide inhibitors are identified as insensitive to a drug-resistant mutation. Structural analysis suggests that the inhibitor ligands can bind to the mutant active site in a similar manner with wild-type target, although their nonbonded interactions appear to be impaired moderately upon the mutation.

microRNA-144 inhibits cell proliferation and invasion by directly targeting TIGAR in esophageal carcinoma.

microRNAs (miRNAs) have been identified to play vital roles in the development and progression of numerous different types of human malignancy, including esophageal squamous cell carcinoma (ESCC). In the present study, the biological function of microRNA-144 (miR-144) was investigated, as well as its underlying molecular mechanism in ESCC. The results revealed that miR-144 expression was significantly decreased, whereas the expression of TP53-inducible glycolysis and apoptosis regulator (TIGAR) was significantly increased in human ESCC tissues when compared with adjacent non-tumor tissues. An increase in TIGAR was significantly associated with tumor size and Tumor-Node-Metastasis staging in patients. Functional analysis revealed that the overexpression of miR-144 using lentivirus particles significantly inhibited cell proliferation and tumor colony formation, and induced cell apoptosis in EC9706 and EC109 cells. The autophagy activity was also enhanced by miR-144 activity. In addition, overexpression of miR-144 significantly inhibited tumor growth in vivo. In the present study, TIGAR was confirmed to be the downstream target of miR-144 in ESCC. siRNA-mediated downregulation of TIGAR inversely regulated the inhibition effect of miR-144 on ESCC cells. To conclude, the present study demonstrated that miR-144 inhibits proliferation and invasion in esophageal cancer by directly targeting TIGAR.

Gallstone ectopia in the lungs: case report and literature review.

Gallstone ectopia in the lungs is relatively rare, which accounts for its frequent misdiagnosis. This paper reports a case found in a suspicious lung cancer surgery. The patient received intrahepatic duct stone removal surgery and partial hepatectomy five months prior to the report. He started showing symptoms of cough and hemoptysis without any apparent cause one month before this report. Enhanced computed tomography showed a solid mass in the lower lobe of the right lung, which was considered as hamartoma or lung cancer. A wedge-shaped excision was then performed in the lower lobe of the right lung. After the surgery, postoperative findings and pathological examination results showed gallstone ectopia in the lung. This case reminds us that gallstones that overflow into the intraperitoneal section can enter the thoracic cavity through diaphragmatic weakness and travel to the lung, thus forming an inflammatory mass. The case also reminds us of the following points in clinical diagnosis: 1) remove gallstones to the greatest extent during cholelithiasis surgery to prevent the stones from migrating from the intraperitoneal area, which causes intraperitoneal and thoracic cavity complications; 2) conduct routine chest imaging examination after cholelithiasis surgery during the clinical follow-up period to facilitate early detection and timely treatment of intrathoracic complications; 3) inquire whether the patients suffering from a solid mass of the lower lobe of right lung, have cholelithiasis history to facilitate clinical diagnosis and avoid misdiagnosis, mistreatment, and treatment delay.