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BACKGROUND: Protein kinase membrane associated tyrosine/threonine 1 (PKMYT1) regulates cell cycle and is a part of DNA damage repair (DDR)-related signaling. Recent studies have identified a role for PKMYT1 in tumor immunity and DDR. Thus, we initiated this study aiming to characterize the molecular and immunological portrait of PKMYT1 in cancer. METHODS: Transcriptomic data extrapolated from Genotype-Tissue Expression (GTEx), The Cancer Genome Atlas (TCGA), and Cancer Cell Line Encyclopedia (CCLE) datasets were used to determine the mRNA expression levels of PKMYT1. PKMYT1 mRNA expression status was correlated with patients’ prognosis as well as immune neoantigens, and immune checkpoints in 34 different tumors. The Tumor Immune Estimation Resource (TIMER) dataset was used to analyze immune infiltrating scores. RESULTS: PKMYT1 mRNA is differentially expressed in common tumors and high expression levels of PKMYT1 mRNA is associated with poor prognosis except for malignant thymoma (THYM). In addition, PKMYT1 mRNA expression was correlated with tumor-infiltrating immune cells particularly in lung squamous cell carcinoma, esophageal carcinoma, THYM, and lung adenocarcinoma. An upregulation of immune checkpoints and neoantigens was observed in tumors with a high PKMYT1 mRNA expression. Data from gene set enrichment analysis (GSEA) revealed that PKMYT1 is involved in tumor immunogenicity, metabolism, and cell cycle progression. CONCLUSIONS: PKMYT1 is differentially expressed in various cancers and exerts an important effect on tumor immunity and progression. The PKMYT1 gene holds the potential as a new potential biomarker. Therefore, further studies are clearly needed to elaborate our findings.

BACKGROUND: Senescence marker protein 30 (SMP30), which plays a pivotal role as a suppressor protein in cell proliferation, among other regulatory actions, is a marker of aging that shows decreased expression during senescence. Decreased SMP30 has been identified in several human cancers, but its expression and role in human non-small cell lung cancer (NSCLC) remain unclear. METHODS: Using tumor tissue and matched adjacent normal tissue from 341 patients with resected NSCLC, we assessed SMP30 expression using immunohistochemical methods. The relationship between SMP30 expression and clinicopathologic characteristics was investigated by Kaplan-Meier survival analysis and multivariate analysis. Cell viability assay, colony formation assay, EdU incorporation assay and in vivo tumor xenograft models were also performed to investigate NSCLC cell proliferation using A549 and H1299 cell lines. Recombinant lentivirus-meditated in vivo gene overexpression and Western blot were performed to clarify the underlying molecular mechanism of SMP30 inhibiting NSCLC proliferation. RESULTS: SMP30 expression was frequently downregulated in NSCLC tissue, as compared with adjacent non-tumor tissue. Kaplan-Meier survival analyses revealed NSCLC patients with low SMP30 expression had a significantly worse overall survival (OS), with median OS of 18 vs. 67 months in high SMP30 expression group. SMP30 overexpression significantly inhibited A549 and H1299 cell proliferation both in vitro and in tumor xenografts and downregulated the expression of c-Myc and CyclinD1 protein. Moreover, Western blot analyses confirmed that SMP30 overexpression significantly inhibited the histone deacetylase 4 (HDAC4) level in NSCLC cells, and HDAC4 overexpression reversed SMP30-mediated NSCLC repression both in vitro and in vivo. CONCLUSIONS: SMP30 inhibited NSCLC proliferation by reducing HDAC4 expression, and SMP30 and HDAC4 may serve as new prognostic biomarkers and future therapeutic targets for NSCLC.

Background Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and is characterized by high morbidity and mortality. However, the detailed molecular mechanisms underlying malignant progression of ESCC remain unclear. Methods 140 patients with esophageal squamous cell carcinoma who underwent surgery were enrolled in this study. Clinicopathologic characteristics and Kaplan–Meier survival analysis were performed to investigate DNMT3A expression and HDAC9 expression. Cell functional experiments were implemented both in vivo and in vitro to investigate the effects on ESCC cell proliferation and metastasis. Recombinant lentivirus–meditated gene overexpression or knockdown showed that HDAC9 participated in DNMT3A-mediated ESCC progression in vivo and in vitro, and this was further confirmed by HDAC inhibitor (SAHA) and immunohistochemical. Results We first demonstrated that DNMT3A expression was significantly higher in ESCC tissues than in corresponding adjacent non-cancerous tissues, and high DNMT3A expression was associated with poor prognosis. Then we confirmed that DNMT3A promoted proliferation and metastasis of ESCC cells in vivo and in vitro, suggesting that DNMT3A may be a promising therapeutic target for preventing esophageal cancer. Additionally, we found that DNMT3A up-regulated HDAC9, and HDAC9 overexpression significantly reversed the inhibitory effect caused by DNMT3A gene knockdown. In addition, we further confirmed the involvement of HDAC9 in DNMT3A-mediated carcinogenesis using HDAC inhibitor (SAHA). At last, we also validated HDAC9 expression was significantly higher in ESCC tissues than in corresponding adjacent non-tumour tissues, and high HDAC9 expression was positively associated with poor prognosis. Interestingly, Spearman correlation analysis confirmed a significant positive correlation between DNMT3A and HDAC9 expression. and ESCC patients with simultaneous DNMT3A and HDAC9 expression have the worst prognosis. Conclusions These results suggest that HDAC9 is involved in DNMT3A-mediated progression of ESCC, and targeting DNMT3A and HDAC9 may be a potential ESCC therapeutic strategy.

Melatonin is a hormone synthesized in the pineal gland and has widespread physiological and pharmacological functions. Moreover, it can activate protective receptor-dependent processes. These processes can prevent tissue carcinogenesis and inhibit malignant tumor progression and metastasis. Therefore, we investigated the regulatory effects of melatonin on dysregulated circular RNAs in human lung adenocarcinoma (LUAD) cells. In this study, we treated LUAD cells with melatonin and measured the expression of hsa_circ_0017109, miR-135b-3p, and TOX3 by quantitative reverse transcription polymerase chain reaction. Colony formation and cell counting kit-8 assays were used to determine cell proliferation. The wound-healing assay and Transwell experiment were carried out to evaluate the migration potential and invasive capacity of LUAD cells. Also, cell apoptosis was detected using a cell apoptosis kit, and protein production was identified by Western blot. It was suggested that melatonin could inhibit LUAD progression in vivo and in vitro, and the role of TOX3 in this process was explored. Additionally, hsa_circ_0017109 was found to sponge miR-135b-3p, a downstream factor of circ_0017109, which was demonstrated to target TOX3 in LUAD cells and could promote the Hippo pathway and epithelial-mesenchymal transition pathway. To summarize, we demonstrated that melatonin decreases the expression of circ_0017109 and suppresses the non-small-cell lung cancer cell migration, invasion, and proliferation through decreasing TOX3 expression via direct activation of miR-135b-3p.

BACKGROUND: Centromere protein U (CENP-U) is a component of the kinetochore and can regulate the cell cycle as a receptor of polo-like kinase 1 (PLK1). Recent studies have partially identified the role of CENP-U in tumor progression, but the underlying mechanisms of CENP-U in tumor immunity remain obscure. METHODS: We performed pan-cancer analysis to evaluate the role of CENP-U in immunity and proliferation with data from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE) datasets, and Genotype-Tissue Expression (GTEx) project. Results of CENP-U expression and related clinicopathological data were obtained to show the expression levels, prognosis, tumor progression, immune neoantigens, and immune checkpoints of CENP-U in 33 tumors. The Tumor Immune Estimation Resource (TIMER) dataset was used to analyze immune infiltration scores. RESULTS: Results of the pan-cancer analysis demonstrated that CENP-U is differentially expressed in normal tissues and common tumor tissues. Moreover, differentially expressed CENP-U was also identified between matched normal and tumor tissues, and the high expression level of CENP-U was associated with poor prognosis for 33 kinds of tumor except for that of thymoma (THYM) and lymphoid neoplasm diffuse large B-cell lymphoma (DLBC). Furthermore, the correlation between CENP-U expression and immune checkpoints and immune neoantigens was determined. In addition, CENP-U expression was correlated with tumor-infiltrating immune cells especially in THYM but not in lung squamous cell carcinoma (LUSC), esophageal carcinoma (ESCA), or lung adenocarcinoma (LUAD). Finally, gene set enrichment analysis (GSEA) indicated that CENP-U is critically involved in tumor proliferation, immunity, and metabolism. CONCLUSIONS: CENP-U, a mitosis-related kinase, was found to be differentially expressed across different cancer types and to play an important role in tumor progression and immunity. CENP-U holds the potential to be a prognostic marker, whose targeting may provide therapeutic benefit.

Background: Multimodal therapies, such as perioperative chemotherapy and neoadjuvant chemoradiotherapy together with surgical advances, have improved the outcomes of patients with resectableesophageal cancer (EC).However, the 5-year survival of these patients remains below 50%. The advent of immunotherapy has resulted in novel approaches to advanced or metastatic disease, but the role of immunotherapy in the neoadjuvant settings has not yet to be established. In this single-arm study, the efficacy and safetyofneoadjuvant pembrolizumab plus chemotherapy were evaluatedin patients with resectableesophageal squamous cell carcinoma (ESCC).Methods: This study was conducted at 2 hospitals(in Xi'an and Tianjin)and included patients with ESCC of clinical stage II–IVAwho underwent surgery within 4 to 6 weeks after completing treatment withpembrolizumab(200mg) combined with a conventional chemotherapy regimen (3 cycles). The efficacy and safety of this combination treatment were evaluated as primary endpointsof the study. This study was retrospectively registered (Registration number: ChiCTR2100048917).Results:A total of 22 patients (including 18 men) were enrolled, of whom 17 patients progressed to surgery,4 patients refused surgery due to tumor regression and symptomatic relief, and 1 patient had progressive disease. As determinedby the Response Evaluation Criteria in Solid Tumors(RECIST,version 1.1), 7 patients (31.8%) had a partial response and 4 (18.2%) patients hada complete response, which translated to an objective response rate of 50%. The symptom remission rate was 90.9% according to the Stooler classification. Five patients (22.7%) experienced serious treatment-related adverse events of grade 3–4 (including anorexia, vomiting, fatigue, alopecia and hypoadrenalism). Postoperative pathology revealed a major pathological response in 14 cases (82.3%) and a complete pathological response in 8 cases (47.1%). Programmed death-ligand 1expression in pretreatment specimens was not significantly associated with the percentage of residual viable tumor (RVT)(r=-0.55, p=0.08). Changes in counts of CD68+ macrophage between pre- and post-treatment specimens wereweakly correlated with RVT(r=0.71; p=0.07), while a positive correlation was observed between postoperative Foxp3+T cells/CD4+Tcellsratios and RVT(r=0.84, p=0.03).Conclusion: The combination of neoadjuvantimmunotherapy and chemotherapy for ESCC is associated with a high pathological response and immunologic effects in the tumor microenvironment. It has acceptable toxicity and great efficacy, suggesting a strong rationale for its further evaluation in randomized clinical trials.Trial registration: ChiCTR, ChiCTR2100048917. Registered 19 July 2021 - Retrospectively registered, https://www.chictr.org.cn/edit.aspx?pid=130073&htm=4

Neoadjuvant immunotherapy for patients with locally advanced esophageal cancer (EC) has developed rapidly in recent years. The efficacy and safety outcomes may change the recommended neoadjuvant therapeutic regimens for patients with EC.Systematic screening for articles focusing on the efficacy and safety of neoadjuvant immunotherapy in locally advanced and surgically resectable EC was performed using PubMed, Embase, Web of Science and international tumor congresses. Meta-analysis of non-comparative binary outcomes was carried out to combine the main results. The pooled results were compared with the traditional neoadjuvant chemotherapy (nCT) and chemoradiotherapy (nCRT) using direct comparative analysis. The results were expressed as the risk ratio (RR).A total of 20 articles with 621 patients were included in the present study. The pooled pathological complete response and major pathological response rates were 33.8% (95% CI: 29.6%-37.9%) and 53.5% (95% CI: 47.9%-59%), respectively, in the neoadjuvant immunotherapy combined with chemotherapy (nICT) group and 39.8% (95% CI: 27%-53.9%) and 88.8% (95% CI: 64.8%-97.2%) in the neoadjuvant immunotherapy combined with chemoradiotherapy (nICRT) group, respectively. In addition, the pooled grade 3-4 treatment-related adverse events (TRAEs) rate was 19.4% (95% CI: 11.5%-31.5%) in the nICT group. The results of direct comparison showed that compared with nCRT and nICRT, nICT could improve safety while achieving comparable efficacy. The results of subgroup analysis, sensitivity analysis and publication bias evaluation indicated that the above findings were stable and reliable.The current meta-analysis revealed that neoadjuvant immunotherapy in patients with locally advanced EC was safe and effective and nICT could be used as the recommended neoadjuvant therapeutic option for patients with EC. However, additional studies are urgently needed to reveal the long-term outcomes of neoadjuvant immunotherapy.

A method has been developed for analyzing the elastodynamic response ofhigh-speed flexible linkage mechanisms with piezoelectric sensors andactuators. The finite element analysis model is obtained by using amixed variational approach with Hamilton's principle. An efficientsolution method is developed on the basis of complex mode theory. Afour-bar linkage mechanism with all flexible links is employed as anexample to demonstrate the capability of the proposed method. Theinvestigation provides a theoretical basis for complex mode activevibration control of high-speed flexible mechanism systems.