Feasibility research of enhanced recovery after surgery implemented in esophageal cancer patients who underwent neoadjuvant chemotherapy.

BACKGROUND: Enhanced recovery after surgery (ERAS) is a perioperative management protocol to accelerate patient recovery. This study aimed to evaluate the feasibility of ERAS protocols implemented in patients who underwent neoadjuvant chemotherapy (NACT) before minimally invasive McKeown esophagectomy. METHODS: This retrospective study compared the short-term clinical outcomes in esophagectomy patients from June 2018 to June 2021. Subjects were divided into two categories: those who underwent NACT (NACT group) and the non-NACT group. RESULTS: There was no significant difference in total postoperative complication morbidity between the NACT and non-NACT groups (21.2% vs. 20.7%, P=0.936). In addition, the hospital length of stay post-surgery (7.90 vs. 7.71 days, P=0.424) was not significantly longer when compared to the non-NACT group. The time to chest tube removal (5.37 vs. 5.13 days, P=0.238) and first bowel movement (2.92 vs. 3.01 days, P=0.560) was also similar between the two groups. CONCLUSIONS: There was no significant difference in postoperative complications rate, postoperative hospital length of stay, and readmission rate between the two group. This study proved that ERAS protocols seemed to be safe and feasible for patients who received NACT before esophagectomy.

Enhanced Recovery After Surgery Improves Short-term Outcomes in Patients Undergoing Esophagectomy.

BACKGROUND: Enhanced recovery after surgery (ERAS) is a perioperative management protocol used to accelerate patient recovery. This study evaluated its benefits in patients with resectable esophageal cancer. METHODS: This retrospective study compared patients before (January 2013 to December 2016) and after (June 2018 to December 2020) ERAS protocol implementation in our hospital. A propensity score-matched analysis was used to compare short-term surgical outcomes between ERAS and non-ERAS groups. After propensity score matching each group included 243 patients. RESULTS: There were significant differences in hospital length of stay after surgery (7.40 vs 11.17 days, P < .001) and hospitalization cost (¥69380 vs ¥78075, P < .001) between the ERAS and non-ERAS groups. The time to chest tube removal (4.91 vs 7.16 days, P < .001) and first bowel movement (2.87 vs 3.97 days, P < .001) was significantly shorter in the ERAS group. However there was no significant difference in total postoperative complication morbidity (20.2% vs 25.1%, P = .193). The complication of postoperative atelectasis or pneumonia was significantly lower in the ERAS group (P = .003), but there was no significant difference in occurrence of at least grade III complications between the 2 groups (12.3% vs 11.5%, P = .889). CONCLUSIONS: We demonstrated that ERAS could reduce hospital stay, numerical pain scores, and hospitalization costs without increasing postoperative complication and readmission. Furthermore subgroup analyses revealed that ERAS was safe for older people (>70 years old).

Let-7b-3p inhibits tumor growth and metastasis by targeting the BRF2-mediated MAPK/ERK pathway in human lung adenocarcinoma.

BACKGROUND: Lung cancer is a malignant tumor with the highest morbidity and mortality rates worldwide, of which lung adenocarcinoma (LUAD) is the most common subtype. Overall, current treatments of LUAD are not satisfactory; therefore, novel targets need to be explored. Let-7b-3p is an important member of the let-7 family of microRNAs (miRNAs), and has not been studied separately in LUAD. This study aimed to investigate the role and molecular mechanism of let-7b-3p in LUAD. METHODS: Herein, let-7b-3p expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH) assays. MTT, colony formation assay, flow cytometry analysis, wound-healing, Transwell and in vivo experiments were conducted to assess let-7b-3p's function in LUAD. The downstream target TFIIB-related factor 2 (BRF2) was predicted using bioinformatics analyses and confirmed by dual-luciferase reporter assay and rescue experiments. Additionally, BRF2 was found to affect the MAPK/ERK pathway through transcriptome sequencing analysis and western blot (WB) assay. RESULTS: Let-7b-3p is downregulated in LUAD cells and tissue samples and low let-7b-3p expression is correlated with a poor prognosis in LUAD patients. Let-7b-3p suppresses the proliferation and metastasis of LUAD cells both in vivo and in vitro by directly targeting the BRF2-mediated MAPK/ERK pathway. CONCLUSIONS: Let-7b-3p inhibits the development of LUAD and is an ideal novel therapeutic target for the treatment of LUAD.

Circular RNA hsa-circ-000881 suppresses the progression of lung adenocarcinoma in vitro via a miR-665/PRICKLE2 axis.

BACKGROUND: Circular RNA (circRNA) has become a new focus in the field of tumor biology research in recent years. Many circRNAs have been showed to play an important role in the progression of lung adenocarcinoma (LUAD). In this work, we studied the oncological role of hsa-circ-000881 in LUAD and attempted to explore the related mechanism. METHODS: The relative expressions of hsa-circ-000881, miR-665, and PRICKLE2 were detected by RT-qPCR or western blot. Functional assays were conducted to analyze the role of hsa-circ-000881 in the proliferation, migration, and invasion of LUAD cells. A luciferase reporter assay was performed to verify whether hsa-circ-000881, miR-665, and PRICKLE2 interact with each other. RESULTS: Circ-000881 was remarkably downregulated in LUAD. Overexpression of circ-000881 attenuated cell growth, migration, and invasion, whereas its knockdown enhanced the malignancy of LUAD cells. The results of luciferase reporter assay and bioinformatics analysis confirmed that circ-000881 served as a sponge for miR-665, and PRICKLE2 was a direct target of miR-665.Overexpression of miR-665 or silencing of PRICKLE2 abolished circ-000881-mediated inhibition of malignant tumor behavior in LUAD cells. CONCLUSIONS: Circ-000881 has inhibitory effects on LUAD via a miR-665/PRICKLE2 axis, suggesting that circ-000881 may be an underlying therapeutic target for LUAD.

Expression of MiR-608 in Nonsmall Cell Lung Cancer and Molecular Mechanism of Apoptosis and Migration of A549 Cells.

OBJECTIVE: This Work is aimed at exploring the effect of microRNA (MiR)-608 on the function of nonsmall cell lung cancer (NSCLC) A549 cells and related mechanisms. METHODS: Blood samples of 106 NSCLC patients (experimental group) as well as 124 normal people (control group) were selected for relevant investigation. Polymerase chain reaction (PCR) as well as DNA sequencing was used to determine the genotyping of the MiR-608 rs4919510 polymorphism. MiR-608 expression in cells was detected by real-time PCR technology. Western blotting was used to detect changes in protein levels. NSCLC tissues as well as adjacent tissues were explored in 33 patients undergoing surgery. RESULTS: MiR-608 rs4919510 does not influence the incidence of NSCLC patients. In addition, MiR-608 expression was downregulated in the tumor tissue of NSCLC patients, while the transcription factor activating enhancer-binding protein 4 (TFAP4) expression was upregulated. MiR-608 promotes DOX- (Doxorubicin-) induced apoptosis by negatively regulating TFAP4 expression in NSCLC tissue. TFAP4 can significantly inhibit the migration of A549 cells. CONCLUSION: The findings in this investigation can contribute to the effective treatment of NSCLC patients. Also, the investigation can provide some theoretical support for the application of new targets for NSCLC treatment.

Discovery of furyl/thienyl ß-carboline derivatives as potent and selective PDE5 inhibitors with excellent vasorelaxant effect.

Based on our previous studies and predictive docking results, furans and thiophenes were introduced to the privileged tetrahydro-ß-carboline scaffold to generate more potent and selective PDE5 inhibitors. A total of 66 novel furyl/thienyl tetrahydro-ß-carboline derivatives were designed, synthesized and evaluated for PDE5 inhibition. Tetrahydro-ß-carboline-piperazinedione 19f and tetrahydro-ß-carboline-hydantoin 26b with optimized pendant 5-ethylfuran/5-ethylthiophene were identified as the most potent PDE5 inhibitors, and showed high selectivity towards PDE5 versus other PDE isozymes, especially PDE6 and PDE11. Further vasorelaxant activity assessments revealed that these PDE5 inhibitors also exhibited significant angiectasis on the norepinephrine-precontracted 3rd-order mesenteric arteries (110-150 µm) via NO-sGC-cGMP pathway, implying their further application for the treatment of vascular diseases.

ID1-induced p16/IL6 axis activation contributes to the resistant of hepatocellular carcinoma cells to sorafenib.

Sorafenib is the only approved drug for the treatment of advanced hepatocellular carcinoma (HCC). However, its efficacy is limited by the emergence of primary and/or acquired resistance. Senescence-associated secretory phenotype (SASP)-mediated chemo-resistance, which depends on the secreted bioactive molecules, has attracted increasing attention but never revealed in HCC. In this study, we investigated the effect of SASP-related p16/IL6 axis on sorafenib resistance in HCC. Initially, we noticed that HCC cells with a high level of p16/IL6 axis exhibited a low sensitivity to sorafenib. Further in vivo and in vitro studies demonstrated that such a primary resistance resulted from ID1-mediated activation of p16/IL6 axis. Overexpression of ID1 or IL6 blocking in sorafenib-resistant HCC cells could increase the cytotoxicity of sorafenib. Moreover, SASP-related p16/IL6 axis contributed to the formation of acquired resistance in cells received long-term exposure to sorafenib. In acquired sorafenib-resistant cells, ID1 low expression, p16/IL6 axis up-regulation, and AKT phosphorylation activation were observed. A reduced cytotoxicity of sorafenib was detected when sorafenib-sensitive cells incubated with conditioned media from the resistant cells, accompanied by the stimulation of AKT phosphorylation. The reversal of sorafenib resistance could be achieved through ID1 overexpression, IL6 blocking, and AKT pathway inhibition. Our study reveals that SASP-related p16/IL6 axis activation is responsible for sorafenib resistance, which will be a novel strategy to prevent the drug resistance.

siRNA of DNA polymerase iota inhibits the migration and invasion in the lung cancer cell A549.

DNA polymerase iota (polɩ) is a member of low-fidelity Y-family of DNA polymerases. Our previous studies have demonstrated that the overexpression of polι is associated with the poorer prognosis in lung cancer patients. Here, we designed the small interfering RNA (siRNA) targeting polɩ gene (POLI) to investigate the effect of polɩ on the proliferation, apoptosis, and invasion of the lung cancer cell line A549 in order to reveal the role of polι in lung cancer progression. Our results showed that siRNA of POLI had no significant effect on the proliferation and apoptosis of the lung cancer cell line A549. However, siRNA of POLI could inhibit the migration and invasion of the lung cancer cell line A549 by upregulating the E-cadherin expression and downregulating the expressions of N-cadherin, MMP2, and MMP9. Together, our findings indicate that polι plays a positive role in lung cancer progression via promoting the migration and invasion of lung cancer cells. Therefore, polι might be a potential target for the clinical treatment of lung cancer in the future.

Clinicopathological and prognostic significance of metastasis-associated protein 1 expression and its correlation with angiogenesis in lung invasive adenocarcinomas, based on the 2011 IASLC/ATS/ERS classification.

Based on previous findings regarding the angiogenic activities and prognostic roles of metastasis-associated protein 1 (MTA1) in early-stage non-small cell lung cancer, the clinicopathological and prognostic significance of MTA1 protein expression, and its correlation with angiogenesis in lung invasive adenocarcinoma, were further assessed in the present study, according to the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. High protein expression levels of MTA1 were commonly observed in patients with lung invasive adenocarcinoma, and were significantly correlated with tumor size (P=0.030), lymph node metastasis (P=0.021) and microvessel density (P=0.015). Survival analysis demonstrated that patients with high protein expression levels of MTA1 exhibited significantly shorter five-year disease-free and overall survival than those patients whose protein expression levels of MTA1 were low (24.5% vs. 48.7%, P=0.001, and 34.7% vs. 59.2%, P=0.005, respectively). In addition, Cox regression multivariate analysis demonstrated that high protein expression levels of MTA1 significantly correlated with unfavorable five-year disease-free survival (P=0.024). These findings indicate that MTA1 protein expression may possess clinical potential as an indicator of progressive phenotype. Therefore, MTA1 is a promising prognostic predictor to identify subgroups of patients with high risk of relapse, and a potentially novel therapeutic target for antiangiogenesis in patients with lung invasive adenocarcinoma.

Regulator of G-protein signaling 4: A novel tumor suppressor with prognostic significance in non-small cell lung cancer.

Regulator of G-protein signaling (RGS) family members are regulatory molecules which act as GTPase activating proteins (GAPs) for G alpha subunits of heterotrimeric G proteins. Emerging data indicated that RGS members were involved with tumorigenesis and metastasis. In the current study, we identified RGS4 as a novel tumor suppressor with prognostic significance in non-small cell lung cancer (NSCLC). To be specific, we found that RGS4 expression was higher in normal lung tissues than NSCLC specimens (P = 0.003). Further studies demonstrated that RGS4 was generally down-regulated in NSCLC specimens compared with the matched normal lung tissues, both at mRNA and protein levels. In addition, correlational analysis indicated that RGS4 expression levels negatively correlated with lymph node metastasis (P = 0.009) and TNM stage (P = 0.008). Survival analysis demonstrated that patients with lower RGS4 protein expression exhibited a much worse 5-year overall survival and 5-year disease-free survival than those with high expression. More importantly, we proved that over-expression of RGS4 in NSCLC cells decreased invasion and migration due to inhibition of MMP2/9 and reversal of EMT while down-regulation of RGS4 in normal lung cell lines promoted invasion and migration. At last, nude mice metastatic model proved that over-expression of RGS4 suppressed tumor metastasis in vivo. All of these results confirmed the critical role of RGS4 in NSCLC progression.