Clinical significance of miR-9-5p in NSCLC and its relationship with smoking.

Purpose: Dysregulated expression of microRNA (miRNAs) in lung cancer has been wildly reported. The clinicopathologic significance of miR-9-5p in non-small-cell lung cancer (NSCLC) patients and its effect on NSCLC progression were explored in this study. Patients and methods: A total of 76 NSCLC patients were included. miR-9-5p expression was evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Then, in vitro experiments including cell growth curve assays, colony formation assays, and transwell migration assays were performed. Further clinicopathological and prognostic values were explored using bioinformatics analysis of the TCGA database. Results: miR-9-5p expression was significantly increased in tumor tissues (both P < 0.0001). miR-9-5p expression was relatively higher in larger tumors (P = 0.0327) and in lung squamous carcinoma (LUSC) (P = 0. 0143). In addition, miR-9-5p was significantly upregulated in the normal lung tissues of cigarette smokers (P = 0.0099). In vitro, miR-9-5p was correlated with cell proliferation and migration. After that, bioinformatics analysis of the TCGA database indicated that miR-9-5p was correlated with tumor size (P = 0.0022), lymphatic metastasis (P = 0.0141), LUSC (P < 0.0001), and smoking history (P < 0.0001). Finally, a prognostic study indicated high miR-9-5p expression was correlated with poor prognosis in LUAD (P = 0.0121). Conclusion: Upregulation of miR-9-5p may have an oncogenic effect in NSCLC and may be related to smoking. The conclusion of this study may help find new prognostic and therapeutic targets for NSCLC and the exploration of the relationship between smoking and lung cancer.

HIF-1α/IL-8 axis in hypoxic macrophages promotes esophageal cancer progression by enhancing PD-L1 expression.

Esophageal cancer (EC) is a malignancy with poor prognosis and high mortality. Hypoxic microenvironment has also been proved to be an important feature of tumors. Herein, we mainly studied the influence of hypoxia-treated tumor-associated macrophages (TAMs) on EC malignant phenotype and related molecular mechanism. In this paper, we found that hypoxic macrophages contributed to EC cell proliferation, cell cycle progression, and metastasis. Besides, the hypoxia treatment expedited the transformation of macrophages into M2 polarization. The level of interleukin (IL)-8 was boosted in macrophages after hypoxia treatment. Moreover, hypoxia treatment heightened IL-8 secretion by macrophages via positively regulating hypoxia-inducible factor-1α (HIF-1α) expression. The IL-8 secreted by hypoxic macrophages facilitated EC cell proliferation, cell cycle progression, and metastasis by elevating ligand of programmed death 1 (PD-L1) expression. In the end, IL-8 also expedited EC tumorigenesis in vivo. In conclusion, HIF-1α/IL-8 axis in hypoxic macrophages could expedite EC advancement by upregulating PD-L1 level, which might deliver a novel thought for EC cure.

Dynamic changes in mental health status related to the COVID-19 pandemic among health care workers and inpatients in China.

Background: Exposure to coronavirus disease 2019 (COVID-19) can cause severe mental health problems, the dynamics of which remain unclear. This study evaluated the mental status of frontline health care workers (FHWs) and suspected infected patients (SIPs) during different periods of the COVID-19 outbreak. Materials and methods: Demographic and psychological data were collected through a cross-sectional survey of 409 participants in a hospital from 20 January to 7 August 2020. COVID-19 outbreaks were divided into three periods owing to the time, place, and scale, including the national outbreak period (a nationwide pandemic period from 20 January to 8 April 2020), sporadic period (a stable period from 9 April to 10 June), and local epidemic period (a local pandemic in Beijing from 11 June to 7 August 2020). Acute psychological disorders (APDs), including symptoms of anxiety and depression, were assessed using the Zung Self-Rating Anxiety/Depression Scale (SAS/SDS). Results: A total of 206 FHWs and 203 SIPs completed the electronic questionnaire. Overall, the prevalence rates of anxiety and depression among SIPs were 3.9 and 19.4%, respectively, while significantly higher prevalence rates (17.7 and 25.1%) were found among FHWs, P-value < 0.05. Psychological status among SIPs did not differ significantly across the three periods. The FHWs were more vulnerable, as their SAS and SDS scores and almost all the dimension scores were significantly higher during the local epidemic period than during the national outbreak and sporadic periods (all P-values < 0.001). The prevalence of anxiety (34.41%) and depression (41.94%) was significantly higher during the local epidemic period (P < 0.001). Logistic and linear mixed models showed that age, sex, and doctor-patient ratio especially, independently influenced most dimension scores of SAS and SDS among FHWs (P < 0.05). Conclusion: Compared to the COVID-19 epidemic at the national level, the local epidemic had a greater influence on FHWs' mental health. More attention should be given to the workload of FHWs.

Circ_0001821 Affects Proliferation and the Cell Cycle in Esophageal Squamous Cell Carcinoma by Elevating BTRC-Mediated IKBA Ubiquitination.

Esophageal squamous cell carcinoma (ESCC) is a fatal human cancer featured with a tendency to metastasis and relapse. Increasing studies have emphasized the critical roles of circular RNAs (circRNA) in ESCC. This study targeted at a novel circRNA and uncovering its function and mechanisms in ESCC. Functional assays were implemented to evaluate proliferation and cell cycle of ESCC cells. Mechanistic analyses were conducted to explore the potential molecular mechanisms in ESCC cells. In vivo assay was also performed. Based on the collected data, circ_0001821 was highly expressed in ESCC cells. Circ_0001821 knockdown retarded ESCC cell proliferation and tumor growth, while promoting G2-M cell cycle arrest. With regard to its mechanism, RUNX3 promoted PVT1 transcription, further upregulating circ_0001821. Moreover, circ_0001821 sponged miR-423-5p to upregulate BTRC, thus promoting IKBA ubiquitination, and circ_0001821 decreased IKBA expression to activate NF-κB signaling pathway. Rescue assays demonstrated that circ_0001821 facilitated ESCC cell proliferation and cell cycle by downregulating IKBA. In summary, RUNX3-induced circ_0001821 switches on NF-κB signaling pathway via diminishing IKBA expression, functionally prompting ESCC cell proliferation and cell cycle. IMPLICATIONS: This study uncovered a novel molecular pathway in ESCC progression, which might provide potential biomarkers for ESCC diagnosis.

Early ligation of the pulmonary vein can reduce the dissemination of shed tumor cells during thoracoscopic lobectomy.

OBJECTIVE: The sequence of vessel ligation in lobectomy can significantly affect the hematogenous spread of circulating tumor cells (CTCs). Vein-first ligation substantially reduces CTC dissemination and achieves favorable survival compared with artery-first ligation. In this study, we further explored whether the timing of pulmonary vein (PV) ligation determined according to the early and late PV ligation technique is associated with CTC dissemination. METHODS: A total of 44 patients who underwent uniform 2-port video-assisted thoracoscopic surgery lobectomy were enrolled; the subjects were divided into the early ligation group (n = 18) and late ligation group (n = 26) according to whether PV ligation was prioritized during surgery. PV blood was obtained before PV ligation and after lobe resection. CTCs were detected using telomerase reverse transcriptase-based CTC detection and validated using FlowSight and fluorescence in situ hybridization. RESULTS: The median postoperative PV CTC (Post-PVCTC) count was 9 (interquartile range [IQR], 6-18), which was higher than the median preoperative PV CTC (Pre-PVCTC) count of 1 (IQR, 0-3; P < .001). Clinicopathologic correlation analysis showed that the Pre-PVCTC count correlated positively with TNM stage (P = .002) and lymph node metastasis (P = .002) and that the Post-PVCTC count correlated positively with tumor density (P = .043) and vessel/lymphatic invasion (P < .030). Interestingly, although no statistical difference in the median Pre-PVCTC count was observed, the median Post-PVCTC count in the early ligation group was 16 (IQR, 9.5-36.75), whereas that in the late ligation group it was 8 (IQR, 4.75-12.25), showing a significant difference (P = .004). CONCLUSIONS: We provide the first evidence to show that early PV ligation can prevent PVCTCs from spreading into the circulation, offering an innovative surgical concept for the principle sequence of pulmonary vessel management.

DDX10 promotes human lung carcinoma proliferation by U3 small nucleolar ribonucleoprotein IMP4.

BACKGROUND: Lung cancer is a common tumor and a leading cause of death worldwide. DEAD/H box RNA helicases (DDX) include several family members which regulate mRNA translation in cancer cells. In this study, we demonstrated that DEAD/H box RNA helicase 10 (DDX10) was significantly upregulated in lung cancer tissues compared with adjacent nontumor tissues. METHODS: DDX10 expression was knocked down with shRNA in order to investigate the impact on A549 lung cancer cell growth and related molecular mechanisms in vitro and in vivo. DDX10 expression in lung cancer was assessed using online databases and patient samples. RESULTS: DDX10 knockdown significantly inhibited the proliferation of lung cancer cells in vitro and in vivo. Furthermore, the bioinformatic tool indicated the putative downstream protein U3 small nucleolar ribonucleoprotein 4 (IMP4). Our data showed a positive correlation between IMP4 and DDX10. We found that IMP4 overexpression could reverse the effect of DDX10 knockdown on the proliferation and apoptosis of A549 cells. CONCLUSIONS: The findings of this study suggest that DDX10/IMP4 might be a novel target for lung cancer diagnosis and treatment.

Combination of CT and telomerase+ circulating tumor cells improves diagnosis of small pulmonary nodules.

BACKGROUNDEarly diagnosis and treatment are key to the long-term survival of lung cancer patients. Although CT has significantly contributed to the early diagnosis of lung cancer, there are still consequences of excessive or delayed treatment. By improving the sensitivity and specificity of circulating tumor cell (CTC) detection, a solution was proposed for differentiating benign from malignant pulmonary nodules.METHODSIn this study, we used telomerase reverse transcriptase-based (TERT-based) CTC detection (TBCD) to distinguish benign from malignant pulmonary nodules < 2 cm and compared this method with the pathological diagnosis as the gold standard. FlowSight and FISH were used to confirm the CTCs detected by TBCD.RESULTSOur results suggest that CTCs based on TBCD can be used as independent biomarkers to distinguish benign from malignant nodules and are significantly superior to serum tumor markers. When the detection threshold was 1, the detection sensitivity and specificity of CTC diagnosis were 0.854 and 0.839, respectively. For pulmonary nodules ≤ 1 cm and 1-2 cm, the sensitivity and specificity of CTCs were both higher than 77%. Additionally, the diagnostic ability of CTC-assisted CT was compared by CT detection. The results show that CT combined with CTCs could significantly improve the differentiation ability of benign and malignant nodules in lung nodules < 2 cm and that the sensitivity and specificity could reach 0.899 and 0.839, respectively.CONCLUSIONTBCD can effectively diagnose pulmonary nodules and be used as an effective auxiliary diagnostic scheme for CT diagnosis.FUNDINGNational Key Research and Development Project grant nos. 2019YFC1315700 and 2017YFC1308702, CAMS Initiative for Innovative Medicine grant no. 2017-I2M-1-005, and National Natural Science Foundation of China grant no. 81472013.

Copy number variation in plasma as a tool for lung cancer prediction using Extreme Gradient Boosting (XGBoost) classifier.

BACKGROUND: The main cause of cancer death is lung cancer (LC) which usually presents at an advanced stage, but its early detection would increase the benefits of treatment. Blood is particularly favored in clinical research given the possibility of using it for relatively noninvasive analyses. Copy number variation (CNV) is a common genetic change in tumor genomes, and many studies have indicated that CNV-derived cell-free DNA (cfDNA) from plasma could be feasible as a biomarker for cancer diagnosis. METHODS: In this study, we determined the possibility of using chromosomal arm-level CNV from cfDNA as a biomarker for lung cancer diagnosis in a small cohort of 40 patients and 41 healthy controls. Arm-level CNV distributions were analyzed based on z score, and the machine-learning algorithm Extreme Gradient Boosting (XGBoost) was applied for cancer prediction. RESULTS: The results showed that amplifications tended to emerge on chromosomes 3q, 8q, 12p, and 7q. Deletions were frequently detected on chromosomes 22q, 3p, 5q, 16q, 10q, and 15q. Upon applying a trained XGBoost classifier, specificity and sensitivity of 100% were finally achieved in the test group (12 patients and 13 healthy controls). In addition, five-fold cross-validation proved the stability of the model. Finally, our results suggested that the integration of four arm-level CNVs and the concentration of cfDNA into the trained XGBoost classifier provides a potential method for detecting lung cancer. CONCLUSION: Our results suggested that the integration of four arm-level CNVs and the concentration from of cfDNA integrated withinto the trained XGBoost classifier could become provides a potentially method for detecting lung cancer detection. KEY POINTS: Significant findings of the study: Healthy individuals have different arm-level CNV profiles from cancer patients. Amplifications tend to emerge on chromosome 3q, 8q, 12p, 7q and deletions tend to emerge on chromosome 22q, 3p, 5q, 16q, 10q, 15q. WHAT THIS STUDY ADDS: CfDNA concentration, arm 10q, 3q, 8q, 3p, and 22q are key features for prediction. Trained XGBoost classifier is a potential method for lung cancer detection.

Enhanced Therapeutic Efficacy of a Novel Oncolytic Herpes Simplex Virus Type 2 Encoding an Antibody Against Programmed Cell Death 1.

The efficacy of immune checkpoint blockade therapy against immunologically "cold" tumors can be enhanced by applying the checkpoint inhibitors in combination with oncolytic viruses. Alternatively, the oncolytic virus construct has been modified to express factors that boost oncolytic virus function. We engineered a novel oncolytic herpes simplex virus 2 (HSV2) encoding an anti-human programmed cell death 1 (PD-1) monoclonal antibody (oHSV2-aPD1). This virus resulted in the detectable expression of a functional monoclonal antibody against human PD-1 by infecting eukaryotic cells. Therapeutic efficacy of oHSV2-aPD1 proved superior to unmodified oncolytic HSV2 treatment or PD-1 blockade alone and as effective as their combination in the poorly immunogenic melanoma models. Additionally, local oHSV2-aPD1 treatment induced a durable antitumor response and activated many immune effector cells and molecules both in the tumor microenvironment and in the systemic immune system. This provides support for combinatorial strategies involving local administration of an oncolytic HSV2 expressing a PD-1 inhibitor.

Circulating tumor cells in the pulmonary vein increase significantly after lobectomy: A prospective observational study.

BACKGROUND: It has been reported that there are more circulating tumor cells (CTCs) in the pulmonary vein (PV) than in the peripheral blood; however, it is unclear whether the CTC count changes in the PV after resection of a lung lobe. METHODS: Thirty-three lung cancer patients were recruited for the study, including 17 who underwent lobectomy via video-assisted thoracoscopic surgery and 16 via open thoracotomy. Sixty-six blood specimens were sampled from the PV before the PV was interrupted and after lobectomy. The CTCs were quantified using the oHSV1-hTERT-GFP method. RESULTS: Before PV interruption, the CTC (pre-CTC) detection rate was 79.0% (26/33), the mean number of CTCs was 3.36 (median 2, range: 0-18), and there was no significant relationship between the pre-CTC count and clinical factors, such as histologic findings and pathological T stage (P > 0.05). After lobectomy, the CTC (post-CTC) detection rate was 100% (33/33), the average number of CTCs was 14.88 (median 11, range: 1-69), and the post-CTC count was significantly higher in patients in whom the PV was interrupted prior to the pulmonary artery (PA) than in patients in whom the PA was interrupted before the PV (P = 0.016). Overall, the CTC count was significantly higher following surgery (P < 0.001). CONCLUSION: Post-CTC counts were significantly higher than pre-CTC counts, suggesting that surgical manipulation may potentially dislodge tumor cells into the PV. Interrupting the PV prior to the PA during lobectomy may prevent partial CTC entry into the circulation.

Primary lung squamous cell carcinoma with gastric metastasis: A case report.

Approximately 50% of patients with primary lung cancer have distant metastasis at the time of their first visit, but gastric metastasis is a rare occurrence. Herein, we report a case of progressive dysphagia as the first symptom and the final diagnosis of primary lung squamous cell carcinoma metastasis. A 61-year-old man was diagnosed with a solitary left lower lobe tumor and a solitary carcinoma of gastric cardia suspected to be metastatic or malignant stromal tumors. After surgical resection, the final diagnoses were primary differentiated squamous cell lung cancer, metastatic squamous cell carcinoma of the stomach, and secondary lymph node metastasis. Gastrointestinal metastasis should be suspected in lung cancer patients with gastrointestinal symptoms. Gastric cancer metastasis from lung cancer is most likely the result of the aspiration of cancer cells containing sputum into the stomach.

[Research Progresses of Circulating Tumor Cells in Diagnosis and Treatment of 
Early Lung Cancer].

As one of the important liquid biopsies, circulating tumor cells (CTCs) shows more and more clinical values in the treatment of lung cancer such as diagnostic screening, treatment evaluation, postoperative monitoring, and prognosis predicting etc. A large number of small pulmonary nodules patients are detected when screening the high risk population of lung cancer. However, small lung nodules are not equal to lung cancer, and 90%-95% of them are benign lesion, therefore, to accurately and correctly differentiate whether it is benign or malignant when patients firstly detected and treat a small pulmonary nodule is become a new opportunity and challenge for clinician. With the improvement of CTCs detection technology, whether it will play an important role in early differential diagnosis of lung cancer. And whether it will have clinical significance to early lung cancer surgery operations. These require further researches and explorations so as to achieve clinical transformation in the future.

Expression of cyclooxygenase-2, vascular endothelial growth factor, and epidermal growth factor receptor in Chinese patients with esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a frequently occurring cancer with poor prognosis despite combined therapeutic strategies. The aim of the current study was to elucidate a further finding on the clinicopathologic significance of immunohistochemical expression of cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), and epidermal growth factor receptor (EGFR) in Chinese patients with ESCC. METHODS: Formalin-fixed paraffin-embedded surgically resected tumor samples were obtained from 140 randomly selected Chinese patients with ESCC. Sections were immunohistochemically stained for COX-2, VEGF, and EGFR. The correlations between clinicopathological features and the high expression of COX-2, VEGF, and EGFR were analyzed using the Statistical Package for the Social Sciences 19.0 software (IBM Inc., Chicago, IL, USA). RESULTS: In the present study, high expression of COX-2, EGFR, and VEGF was found in 64.3%, 62.1%, and 65.0%, respectively. Results showed that COX-2 overexpression was significantly correlated with degree of differentiation (P = 0.000), and lymph node metastasis (negative/positive, P = 0.002). EGFR and VEGF overexpression was significantly correlated with a differentiated degree, T stage, N stage, and tumor, node, metastases stage. CONCLUSION: High expression of COX-2, EGFR, and VEGF is an unfavorable prognostic factor in ESCC, and could be used as a poor prognosis indicator for the ESCC patients. Targeting therapy to these three targets should be considered to the combined treatment in ESCC.

[Variations in Serum CEA and CYFRA21-1 Levels Before and After Surgery Facilitate Prognosis of Non-small Cell Lung Cancer Patients].

BACKGROUND AND OBJECTIVE: Serum carcinoembryonic antigen (CEA) and the soluble fragment of cytokeratin 19 (CYFRA21-1) are important tumor markers (TMs) in the preoperative examination of patients with non-small cell lung cancer (NSCLC). However, the prognostic role of these markers in NSCLC patients remains controversial. The aim of the study was to investigate the clinical significance of serum CEA variances and CYFRA21-1 levels for the prognosis of NSCLC patients following surgery. METHODS: This retrospective study investigated the clinical records and follow-up sessions of 175 patients with NSCLC who accepted surgery and adjuvant chemotherapy. Patients were subdivided into groups based on serum CEA and CYFRA21-1 levels. Survival analysis was conducted using Kaplan-Meier method for each group. The prognostic factor was evaluated using Cox proportional hazards model. RESULTS: The overall survival (OS) of patients with high preoperative CEA or CYFRA21-1 levels was lower than that of patients with normal preoperative CEA or CYFRA21-1 levels. The OS displayed a significant difference (P=0.001) between groups with high and normal preoperative CYFRA21-1. Compared with groups exhibiting normal preoperative and postoperative levels of CEA or CYFRA21-1, the OS was shorter for groups with high preoperative and postoperative levels of CEA or CYFRA21-1. The difference of the paired groups was significant (P<0.05). Compared with the groups with normal preoperative and postoperative levels of CEA and CYFRA21-1, the OS was lower for the groups with high preoperative and postoperative levels of CEA and CYFRA21-1, which indicated a significant difference (P<0.001). The CEACYFRA211 (HHHH), CEACYFRA211 (NNHH), CYFRA21-1 (HH), CEA (HH), and male gender were identified as independent prognostic factors (P<0.05). CONCLUSIONS: This study suggested that the prognosis of NSCLC patients was not significantly satisfactory if preoperative and postoperative level of serum CEA or CYFRA21-1 was higher than standard value, especially if the preoperative and postoperative levels of CYFRA21-1 and CEA were higher than the standard values. The measurement of preoperative and postoperative levels of CYFRA21-1 and CEA proved helpful for the prognosis of patients with NSCLC.
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