Role of glycosphingolipid biosynthesis coregulators in malignant progression of thymoma.

As the most common malignancy from mediastinum, the metabolic reprogramming of thymoma is important in its development. Nevertheless, the connection between the metabolic map and thymoma development is yet to be discovered. Thymoma was categorized into three subcategories by unsupervised clustering of molecular markers for metabolic pathway presentation in the TCGA dataset. Different genes and functions enriched were demonstrated through the utilization of metabolic Gene Ontology (GO) analysis. To identify the main contributors in the development of thymic malignancy, we utilized Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The prognosis of thymoma was evaluated by screening the essential pathways and genes using GSVA scores and machine learning classifiers. Furthermore, we integrated the transcriptomics findings with spectrum metabolomics investigation, detected through LC-MS/MS, in order to establish the essential controller network of metabolic reprogramming during thymoma progression. The thymoma prognosis is related to glycosphingolipid biosynthesis-lacto and neolacto series pathway, of what high B3GNT5 indicate poor survival. The investigation revealed that glycosphingolipid charts have a significant impact on metabolic dysfunction and could potentially serve as crucial targets in the clinical advancement of metabolic therapy.

Expression of Programmed Cell Death 1 Ligand 2 in Patients With Thymoma and Thymomatous Myasthenia Gravis.

OBJECTIVES: This study aimed to examine the expression of programmed cell death 1 ligand 2 (PD-L2) in thymoma and thymomatous myasthenia gravis (MG). METHODS: The records of 70 patients with thymoma receiving surgical resection between January 2017 and December 2018 were retrospectively reviewed. Thymoma PD-L2 expression was evaluated by immunohistochemistry staining. Associations between PD-L2 expression and clinicopathologic features were examined. RESULTS: PD-L2 expression was positive in 41 patients (58.6%) and negative in 29 patients (41.4%). Of them, 33 had thymomatous MG. Patients with MG were more likely to be 50 years of age or younger (69.70% vs 35.14%); have more World Health Organization (WHO) type B thymomas (84.85% vs 64.86%); have tumors of smaller size (4.09 ± 2.33 cm vs 6.47 ± 2.42 cm); have positive PD-L2 expression (78.79% vs 40.54%); and have a higher percentage of PD-L2-positive cells, higher PD-L2 expression intensity, and score (all P < .05). Positive PD-L2 expression was associated with more type B thymomas, higher Masaoka-Koga stage, smaller tumor size, ectopic thymus, and MG (all P < .05). Factors significantly associated with MG were age under 50 years, tumor size less than 5 cm, and positive PD-L2 expression (all P < .05). CONCLUSIONS: Thymoma PD-L2 expression is significantly associated with thymomatous MG and WHO histologic types B2 and B3.

Neurological outcomes of extended thymectomy for thymomatous myasthenia gravis: Subxiphoid vs. trans-sternal approaches.

Background: The subxiphoid approach has been widely used recently. However, there is little data focusing on neurological outcomes in patients with thymomatous myasthenia gravis (MG) who underwent subxiphoid thoracoscopic thymectomy. The purpose of this study was to compare the neurological outcomes of patients with thymomatous MG who underwent extended thymectomy with a subxiphoid or transthoracic approach 1 year postoperatively. Methods: The records of patients with Masaoka stage I and II thymomas who underwent extended thymectomy from January 2019 to December 2020 with tumor size less than 5 cm and thymomatous MG were retrospectively reviewed and evaluated. Neurological outcomes were measured by a quantitative myasthenia gravis score (QMGS), with a 2.3-point reduction in QMGS associated with improvement in clinical MG status. The clinical efficacy and variables affecting the outcomes were assessed using the Kaplan-Meier method and Cox proportional hazard regression analysis. Results: A total of 89 patients were included in the analysis, of which 44 had a subxiphoid approach and 45 had a trans-sternal approach. Mean QMGS decreased from 12 at initial diagnosis to 8.7 preoperatively and 5.6 at 12 months postoperatively in the subxiphoid group and from 12.1 to 8.9 to 6.0 in the transthoracic group. Thirteen patients (28.9%) who underwent the trans-sternal approach and 10 (22.7%) who underwent the subxiphoid approach did not have an improved clinical status compared with their preoperative status. The median time to clinical improvement was 3 months (95% CI, 2.15-3.85) for the subxiphoid approach and 6 months (95% CI, 5.54-6.46) for the trans-sternal approach. Univariate results showed that the subxiphoid approach was associated with a faster improvement in clinical status (HR = 1.701, 95% CI, 1.044-2.773, P < 0.05), and age ≦48 was associated with a faster improvement in clinical status (HR = 1.709, 95% CI, 1.044-2.799, P < 0.05). The multivariate model including age ≦48 (HR = 1.837, 95% CI, 1.093-3.086, P = 0.022) and the subxiphoid approach (HR = 1.892, 95% CI, 1.127-3.177, P = 0.016) was significantly associated with a faster improvement in clinical status. Conclusions: In patients with Masaoka stage I and II thymoma who underwent thymectomy, with tumor size less than 5 cm and thymomatous MG, age ≦48 years and the subxiphoid approach were associated with a rapid improvement in clinical status.

Efficiency of ectopic thymectomy by three surgical approaches in non-thymomatous myasthenia gravis.

BACKGROUND: To explore the efficiency of ectopic thymectomy by the three surgical approaches of trans-sternum, right unilateral thoracoscopy and thoracoscopic subxiphoid in patients with non-thymomatous myasthenia gravis. METHODS: 155 consecutive non-thymomatous myasthenia gravis patients who underwent extended thymectomy by 3 approaches including trans-sternum, right unilateral thoracoscopy and thoracoscopic subxiphoid in 1st affiliated hospital of Sun Yat-Sen University from January 2017 to October 2019 were reviewed. Differences of perioperative clinical characteristics in three surgical approaches were analyzed. RESULTS: Time to onset of myasthenia gravis (early or late) (p = 0.018), blood loss (p < 0.001), duration of operation (p = 0.031), duration and volume of thoracic drainage (p = 0.039 and p = 0.026), length of hospitalization (p = 0.039), the efficiency of ectopic thymectomy (p = 0.037), and the detection rate of ectopic thymus in the second quadrant (p = 0.018) were different among the three surgical approaches. In univariate logistic regression analysis, higher efficiency of ectopic thymectomy were associated with transsternal (OR 2.36, 95% CI 1.32-4.22, p = 0.011) and thoracoscopic subxiphoid approaches (OR 2.07, 95% CI 1.12-3.82, p = 0.033). In the multiple logistic regression analysis, the transsternal approach (OR 2.02, 95% CI 1.10-3.71, p = 0.024) was an independent protective factor for the efficiency of ectopic thymectomy. CONCLUSIONS: Both the right unilateral thoracoscopic and thoracoscopic subxiphoid approaches have advantages over the transsternal approach in short-term postoperative recovery. Transsternal approach is still the best choice for ectopic thymectomy while thoracoscopic subxiphoid approach show the potential as an alternative way.

Fisetin Alleviates Neointimal Hyperplasia via PPARγ/PON2 Antioxidative Pathway in SHR Rat Artery Injury Model.

The phenotypic transformation of proliferation and migration in vascular smooth muscle cells (VSMCs) from media to intima is the basic pathology of neointimal hyperplasia after angioplasty in hypertensive patients. Angiotensin II (AngII) stimulates oxidative stress in VSMC, inducing VSMC proliferation and migration, which is a critical factor in both developments of hypertension and angioplasty-induced arterial restenosis. Fisetin, a plant flavonoid polyphenol, has been reported to be antioxidative and potent senolytic. It is unknown whether fisetin would inhibit neointimal hyperplasia. Therefore, we investigated the role of fisetin in neointimal formation in vitro and in vivo. The rat thoracic aortic smooth muscle cells (A10 cells) stimulated by AngII were used as the in vitro neointimal hyperplasia model, where AngII significantly induced the proliferation and migration in A10 cells. We found that fisetin could dose-dependently inhibit the effect of AngII via inducing the expression of an antioxidant, paraoxonase-2 (PON2), whose overexpression could inhibit the proliferation and migration of A10 cells and downexpression by siRNA had the opposite effect. Furthermore, we found the mechanism of fisetin's inducing PON2 expression involved PPARγ. Rosiglitazone, a PPARγ agonist, could increase PON2 expression in A10 cells, while the PPARγ inhibitor prevented the effect of fisetin on PON2. The in vivo neointimal hyperplasia model was established 2 weeks after the carotid artery balloon injury in SHR rats. Administration of fisetin (ip 3 mg/kg daily for 2 weeks) right after the injury significantly increased PON2 expression in the artery, inhibiting ROS production, and efficiently reduced carotid neointimal hyperplasia. These results indicate that fisetin increases the expression of antioxidant PON2 via activation of PPARγ, reducing oxidative stress, inhibiting VSMC proliferation and migration, and alleviates neointimal hyperplasia after intimal injury. PON2 may be a potential therapeutic target to reduce arterial remodeling after angioplasty in hypertensive patients.

Characteristics of genomic mutations and signaling pathway alterations in thymic epithelial tumors.

BACKGROUND: To elucidate the mechanisms of thymic epithelial tumor (TET) canceration by characterizing genomic mutations and signaling pathway alterations. METHODS: Primary tumor and blood samples were collected from 21 patients diagnosed with TETs (thymoma and thymic cancer), 15 of whom were screened by nucleic acid extraction and whole exon sequencing. Bioinformatics was used to comprehensively analyze the sequencing data for these samples, including gene mutation information and the difference of tumor mutation burden (TMB) between thymoma and thymic carcinoma groups. We performed signaling pathway and functional enrichment analysis using the WebGestalt 2017 toolkit. RESULTS: ZNF429 (36%) was the gene with the highest mutation frequency in thymic carcinoma. Mutations in BAP1 (14%), ABI1 (7%), BCL9L (7%), and CHEK2 (7%) were exclusively detected in thymic carcinoma, whereas ZNF721 mutations (14%) and PABPC1 (14%) were found exclusively in thymoma. The mean TMB values for thymic carcinoma and thymoma were 0.722 and 0.663 mutations per megabase (Mb), respectively, and these differences were not statistically significant. The ErbB signaling pathway was enriched in the thymoma and intersection groups, and pathways of central carbon metabolism in cancer, longevity regulating and MAPK signaling were only found in the thymoma group, while pathways in cancer (hsa05200) was found in the thymoma and thymic carcinoma groups. CONCLUSIONS: Multiple differences in somatic genes and pathways have been identified. Our findings provide insights into differences between thymoma and thymic carcinoma that could aid in designing personalized clinical therapeutic strategies.

Thymomatous myasthenia gravis: 10-year experience of a single center.

OBJECTIVES: To summarize the clinical features of thymomatous myasthenia gravis (T-MG), examine the association between MG and thymoma, and identify the related factors or predictors for long-term prognosis of T-MG. METHODS: A retrospective, observational study was conducted on 100 patients with T-MG and 96 patients with non-T-MG (NT-MG) between January 1, 2009 and December 31, 2019. The baseline characteristics were recorded for each patient. Logistic regression was used to measure the association between all clinical variables and T-MG prognosis. RESULTS: Between the T-MG and NT-MG groups, age at onset (45.66 ± 11.53 years vs 39.06 ± 14.39 years); age >40 years (72.0% vs. 40.6%); AChR-Ab positive rate (100.0% vs. 83.3%); Myasthenia Gravis Foundation of America (MGFA) classification at the worst condition (≥grade III, 61.0% vs. 33.0%); thyroid dysfunction (7.0% vs. 20.8%); and outcome (complete stable remission + pharmacologic remission + improvement, 74.0% vs. 93.7%) were statistically significant (P < .05). Presence of thymoma (OR = 0.196, 95%CI = 0.076-0.511, P = .001) was a risk factor for MG. Male sex, post-operative complications, higher grade of MGFA classification, and thymoma Masaoka-Koga pathological stage were risk predictors for long-term prognosis of T-MG (P < .1). Use of preoperative anticholinesterase drugs (OR = 5.504, 95%CI = 1.424-21.284, P = .013) was identified as an independent predictor for T-MG. CONCLUSION: T-MG is clinically different from NT-MG, and thymoma is considered a risk factor for MG. Preoperative anticholinesterase drug use is a protective factor for long-term prognosis of T-MG. A comprehensive understanding of the characteristics of T-MG will likely help improve its prognosis.

Relationship of possible biomarkers with malignancy of thymic tumors: a meta-analysis.

BACKGROUND: Role of biomarkers for promotion of tumor proliferation (BPTPs) and for promotion of apoptosis (BPAs) in thymic malignant tumors is still unclear. The purpose of this study was to evaluate the relationship between BPTPs and/or BPAs and malignancy of thymic malignant tumors. METHODS: Studies on thymic malignant tumors and biomarkers were searched in PubMed, ISI Web of Knowledge, and Embase databases, and all statistical analyses were conducted using Review Manager. RESULTS: Twelve articles related to biomarkers and thymic malignant tumors were selected and analyzed. A relationship between BPAs and Masaoka stage was demonstrated for four markers, namely Bax, p73, Casp-9 and Bcl-2, included 138 stage I/II patients and 74 stage III/IV patients, and BPAs were significantly correlated with high Masaoka staging (P = 0.03). We further found a relationship between BPAs and degree of malignancy for four markers, namely Bax, p73, Casp-9 and Bcl-2, included 176 thymoma patients and 36 thymic carcinoma patients, and BPAs were significantly correlated with thymic carcinoma (P = 0.010). In addition, a relationship between BPTP and Masaoka staging was demonstrated for seven markers, namely Podoplanin, Glut-1, Muc-1, Egfr, Igf1r, c-Jun, and n-Ras, included 373 patients with stage I/II and 212 patients with stage III/IV, and BPTPs were significantly correlated with high Masaoka staging (P < 0.001). We also found a relationship between BPTPs and degree of malignancy for ten markers, namely Mesothelin, c-Kit (CD117), Egfr, Lat-1, Muc-1,Ema, Glut-1, Igf1r, c-Jun, and n-Ras, included 748 thymoma patients and 280 thymic carcinoma patients, and BPTPs were significantly correlated with thymic carcinoma (P < 0.001). CONCLUSION: These findings show that high levels of BPTPs or BPAs are more closely related to thymic carcinoma and Masaoka stage III/IV, suggesting that BPTPs and BPAs may play an important role in the occurrence and development of thymic malignant tumors.

Perioperative risk factors for occurrence of myasthenia gravis after thymectomy in patients with thymoma.

OBJECTIVES: The goal of this study was to identify the relationship between clinical characteristics and the occurrence of postoperative myasthenia gravis (PMG) in patients with thymomas and to further identify the relationship between PMG and prognosis. METHODS: Thymoma patients who had surgery at the First Affiliated Hospital of Sun Yat-sen University between July 2004 and July 2016 were reviewed and those who had no previous symptoms of myasthenia gravis were selected for further investigation. In total, 229 patients were included in the study; their clinical characteristics were gathered and analysed. RESULTS: Among the 229 patients, 19 (8.3%) had PMG. The time between the operation and the onset of myasthenia gravis was 134 days on average (range 2-730 days). Patients experiencing PMG showed a lower rate of complete thymoma resection (73.7% vs 91.4%; P = 0.014) and total thymectomy (63.2% vs 82.9%; P = 0.035) compared with those who did not. Univariable and multivariable logistic regression revealed that thymomectomy [odds ratio (OR) 2.81, 95% confidence interval (CI) 1.02-7.77; P = 0.047] and incomplete tumour resection (OR 3.79, 95% CI 1.20-11.98; P = 0.023) were associated with the occurrence of PMG. Multivariable Cox regression showed that the PMG was not related to overall survival (P = 0.087). CONCLUSIONS: This study revealed that incomplete tumour resection and thymomectomy were independent risk factors for PMG in thymoma patients with no previous history of myasthenia gravis.

Expression of fibronectin in esophageal squamous cell carcinoma and its role in migration.

BACKGROUND: Fibronectin (FN) is a high-molecular-weight glycoprotein component of the extracellular matrix involved in cell adhesion, migration, metastasis, proliferation and differentiation, as well as embryogenesis, wound healing, and blood coagulation. Considerable recent research has established that tumor expression of FN is closely associated with tumor formation and development as well as disease prognosis. However, the mechanisms underlying this relationship have remained unclear. The aim of this study was to investigate FN protein expression in esophageal squamous cell carcinoma (ESCC) and determine its potential prognostic relevance, while also elucidating the source and function of FN. METHODS: We conducted immunohistochemical analyses of protein expression in primary tumors of ESCC patients and analyzed their association with standard prognostic parameters and clinical outcomes. Expression of FN in two ESCC cell lines (Eca-109 and TE-1) was also examined by RT-PCR, immunofluorescence, and ELISA. ESCC cells were cultured in a microenvironment containing a high FN content, and changes in their morphology and migration ability were assessed by microscopy, wound-healing assays, and Transwell assays. RESULTS: FN expression in ESCC specimens was mainly detected in the tumor stroma, with very little FN detected in tumor cells. Stromal FN content in ESCC specimens was associated with lymphatic metastasis (P = 0.032) and prognosis. In this latter context, patients with high tumor stromal expression of FN showed worse overall survival (P = 0.002) and progression-free survival (P < 0.001) than those with low expression of FN. Interestingly, FN expression and secretion in ESCC cell lines (Eca-109 and TE-1) was found to be low, but these cells adopted a more migratory phenotype when cultured in vitro in a microenvironment containing high levels of FN. CONCLUSIONS: High FN expression in the stroma of ESCC tumors is closely associated with poor prognosis of patients. High stromal FN content facilitates tumor cell metastasis by promoting morphological changes and improving the motility and migratory ability of ESCC cells.

The potential role of postbronchoscopic fever on the postoperative outcomes in patients with non-small cell lung cancer.

BACKGROUND: Postbronchoscopic fever is a common adverse reaction in operable non-small cell lung cancer (NSCLC) patients. To explore the potential role of postbronchoscopic fever on the postoperative outcomes in patients with NSCLC. METHODS: Patients diagnosed with NSCLC were enrolled in this study. Patients were divided into two groups: fever group (postbronchoscopic fever) and normal group (without postbronchoscopic fever). RESULTS: Seventy-five cases were enrolled. Twelve cases (16%) developed postbronchoscopic fever. The fever group was found to have longer postoperative fever time (1.9 vs. 0.8 days, P<0.05), more postoperative antibiotic use (3.4 vs. 2.5 days, P<0.05) and longer drainage (7.2 vs. 4.7 days, P<0.05). WBC counts of the fever group were higher than those of the no-fever group on the first (14.5 vs. 11.4×109/L, P<0.05) and third (11.0 vs. 9.2, P<0.05) postoperative day. Outcomes were different especially in the older subgroup (>60 years). CONCLUSIONS: Postbronchoscopic fever may be a predictor of longer postoperative fever, longer drainage and more antibiotic use in patients with NSCLC postoperatively.

Clinical outcome and predictive factors of postoperative myasthenic crisis in 173 thymomatous myasthenia gravis patients.

PURPOSE: Thymectomy is the first-line therapy for thymomatous myasthenia gravis patients. The aim of this study is to explore the clinical outcome and predictors of postoperative myasthenic crisis (POMC) in these patients. METHOD: Clinical data of 173 thymomatous myasthenia gravis patients undergoing thymectomy from January 2000 to March 2013 were, retrospectively reviewed. Variables potentially affecting the occurrence of POMC were evaluated using binary logistic regression analysis. The difference in survival was determined by the log-rank test. RESULT: Fifty-one patients experienced POMC. Univariate analysis revealed that events significantly associated with increased risk of POMC include symptom duration before operation >2.75months, preoperative bulbar symptoms, incomplete resection, operation time ≥122.5 min and advanced stages (stage III or IV). Multivariate logistic regression analysis showed that preoperative bulbar symptoms (OR = 3.207 [1.413-7.278]; P = 0.005) and incomplete resection (OR = 4.182 [1.332-13.135]; P = 0.014) were independent risk factors for POMC. Twenty-eight patients (16.9%) died during the follow-up. The log-rank test revealed survival for patients with POMC was significantly worse than that for patients without POMC (P = 0.042). CONCLUSION: The important risk factors for developing POMC in thymomatous myasthenia gravis patients include the preoperative bulbar symptoms and incomplete resection of thymoma. Moreover, the patients with POMC had a worse prognosis compared with patients without POMC. Our study highlights the need of appropriate preoperative management of thymomatous myasthenia gravis patients to prevent the occurrence of POMC.

Exogenous H2S promotes cancer progression by activating JAK2/STAT3 signaling pathway in esophageal EC109 cells.

Hydrogen sulfide (H2S) plays an important role in diverse physiological and pathophysiological processes in cancer cells both in vitro and in vivo. We have previously shown that exogenous H2S exerts its biological effects on hepatoma, glioma, and esophageal cancer cells through the activation of NF-κB, p38-MAPK/ERK1/2-COX-2, and HSP90 pathways. However, the role of H2S and the underlying mechanism in esophageal squamous cell carcinoma remain unclear. Here we investigated whether exogenous H2S contributes to the biological behavior of esophageal squamous cancer cell line EC109, through the activation of JAK2/STAT3 signaling pathway. EC109 cells were treated with NaHS (a donor of H2S) and AG490 (a specific inhibitor of JAK2/STAT3 signaling pathway). The expression levels of p-JAK2, p-STAT3, caspase-3/9/12, Bax, Bcl-2, MMP-2/9, and VEGFR were measured by western blot analysis. Cell viability was detected by CCK-8 and quantified by direct counting of cells under a microscope. Cell migration was analyzed by the scratch-wound assay, while the level of VEGF was measured by ELISA. Cells treated with NaHS for 24 h showed significant upregulation of p-JAK2, and p-STAT3 expression, as well as increased cell viability when compared to the control cells. The expression levels of caspase-3/9/12 and Bax decreased, while those of Bcl-2, MMP-2/9, VEGFR, and VEGF increased. NaHS induced the migration of EC109 cells. However, co-treatment with NaHS and AG490 significantly inhibited these effects. Thus, JAK2/STAT3 signaling pathway may contribute to H2S-induced cell proliferation, anti-apoptosis, migration, and angiogenesis in EC109 cells.

Ectopic right parietal pleural thymic carcinoma: a rare case and review of the literature.

Ectopic thymic carcinoma is extremely rare. We present a case of a 73-year-old male patient with ectopic right parietal pleural thymic carcinoma and performed a literature review. Computed tomography (CT) of the chest demonstrated a sharp-edged soft tissue mass with intense enhancement measuring 47 mm × 29 mm with a broader base adjacent to the right axillary chest wall at the level of the 5th rib. There was no hilar or mediastinal lymphadenopathy or evidence of a mediastinal tumor or pleural nodules. A totally extra-pleural tumor resection and partial right lung resection was performed. Histological examination demonstrated infiltrative growth typical of carcinoma cells with a nest-like distribution locally invading the surface of the lung tissue. Immunohistochemical examination confirmed the diagnosis of thymic squamous carcinoma positive for CD5. Mediastinal radical radiotherapy (60 Gy) was performed postoperatively. The patient was followed for 17 months without any evidence of recurrence or metastasis.

Midkine is a serum and urinary biomarker for the detection and prognosis of non-small cell lung cancer.

Midkine, a heparin-binding growth factor, has been identified as a promising cancer biomarker. In non-small cell lung cancer (NSCLC), the serum and urine midkine levels have not been intensively investigated. The aim of the present study was to investigate the diagnostic and prognostic potential of serum and urine midkine levels in patients with NSCLC. The serum midkine levels were measured in 153 patients with NSCLC, 23 patients with benign pulmonary disease and 95 healthy controls using ELISA. Urine midkine levels were examined in 20 controls and 45 patients with NSCLC. Midkine expression in tumor tissues from 72 patients with NSCLC who underwent definitive surgical resection without any pre-operative treatments was examined by immunohistochemistry. Serum levels were significantly higher in patients with NSCLC than in healthy controls (657.36±496.58 pg/ml vs. 194.49±122.57 pg/ml, P<0.001). As shown in the ROC curve analysis, the sensitivity and specificity of the cut-off serum midkine concentration of 400 pg/ml for predicting the presence of NSCLC were 71.2% and 88.1%, respectively. Positive correlations between the serum midkine levels and immunohistochemistry staining scores (r=0.315, P=0.007) and between the serum midkine levels and urine midkine levels (r=0.636, P<0.001) were observed using Spearman's bivariate correlations. The serum midkine concentration was identified as an independent prognostic factor by multivariate analysis, and its overexpression yielded a relative risk of death of 2.072 (0.01.

Synthesis of acyl oleanolic acid-uracil conjugates and their anti-tumor activity.

BACKGROUND: Oleanolic acid, which can be isolated from many foods and medicinal plants, has been reported to possess diverse biological activities. It has been found that the acylation of the hydroxyl groups of the A-ring in the triterpene skeleton of oleanolic acid could be favorable for biological activities. The pyrimidinyl group has been constructed in many new compounds in various anti-tumor studies. RESULTS: Five acyl oleanolic acid-uracil conjugates were synthesized. Most of the IC50 values of these conjugates were lower than 10.0 µM, and some of them were even under 0.1 µM. Cytotoxicity selectivity detection revealed that conjugate 4c exhibited low cytotoxicity towards the normal human liver cell line HL-7702. Further studies revealed that 4c clearly possessed apoptosis inducing effects, could arrest the Hep-G2 cell line in the G1 phase, induce late-stage apoptosis, and activate effector caspase-3/9 to trigger apoptosis. CONCLUSIONS: Conjugates of five different acyl OA derivatives with uracil were synthesized and identified as possessing high selectivity toward tumor cell lines. These conjugates could induce apoptosis in Hep-G2 cells by triggering caspase-3/9 activity.Graphical abstractFive acyl oleanolic aicd-uracil conjugates were synthesized. These conjugates exhibited selective cytotoxicity toward tumor cells achieved via inducing apoptosis by activation of caspase-3/9.

Exogenous hydrogen sulfide exerts proliferation, anti-apoptosis, angiopoiesis and migration effects via activating HSP90 pathway in EC109 cells.

Hydrogen sulfide (H2S) participates in diverse physiological and pathophysiologic processes of cancer both in vitro and in vivo. We have previously reported the proliferation/anti-apoptosis/angiogenesis/migration effects of exogenous H2S on liver cancer and glioma via amplifying the activation of NF-κB and p38 MAPK/ERK1/2-COX-2 pathway. However, the effects of H2S on EC109 esophageal cells remain unclear. The present study demonstrated the effects of exogenous H2S on cancer cell growth via activating HSP90 pathways in EC109 esophageal cells. EC109 esophageal cells were treated with 400 µmol/l NaHS (a donor of H2S) for 24 h. The expression levels of HSP90, bcl-2, caspase-3, bax and MMP-2 were detected by western blot assay. Cell viability was detected by Cell Counting Kit-8 (CCK-8). The migration rate was analyzed using a Transwell migration assay and ImageJ software. NaHS promoted cell proliferation, as evidenced by an increase in cell viability. In addition, NaHS treatment reduced apoptosis, as indicated by the increased bcl-2 expression and decreased cleaved caspase-3 and bax expression. Importantly, exposure of NaHS increased the expression of MMP-2, the migration rate and expression of VEGF. Notably, co-treatment of EC109 cells with NaHS and GA (an inhibitor of HSP90 pathway) largely suppressed the aforementioned NaHS-induced effects. The findings of the present study provided novel evidence that HSP90 pathway was involved in NaHS-induced cancer cell proliferation, anti-apoptosis, angiopoiesis and migration in EC109 esophageal cells.

Preoperative serum fibrinogen is an independent prognostic factor in operable esophageal cancer.

In order to fully elucidate the association between serum fibrinogen and prognosis of esophageal cancer, we examined serum fibrinogen concentrations in 1512 patients who underwent esophagectomy by the Clauss method. The impact of fibrinogen on overall survival and disease-free survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models. Hyperfibrinogenemia was significantly associated with older age, male gender, smoking, alcohol consumption, weight loss, advanced pathological T stage and lymph node metastasis. Patients with hyperfibrinogenemia exhibited poor OS (HR=1.20, 95%CI: 1.04-1.38, P=0.012) and DFS (HR=1.18, 95%CI: 1.03-1.35, P=0.019). Subgroup analysis further exhibited an significant association between hyperfibrinogenemia and poor OS (P<0.001), DFS (P<0.001) in esophageal squamous cell carcinoma (P<0.001) and early pathological stage (I-II) (P=0.001). Collectively, this study indicates that preoperative serum fibrinogen is an independent prognostic factor for survival in esophageal cancer.

Conjugation of Uridine with Oleanolic Acid Derivatives as Potential Antitumor Agents.

According to fused two bioactive moieties together by bonds covalently and available as a new single hybrid entity known as pharmacophore hybridization, a total of 10 targeted uridine-oleanolic acid hybrids were synthesized. Most of these hybrids showed excellent proliferation inhibition against tested Hep-G2, A549, BGC-823, MCF-7, and PC-3 tumor cell lines (IC50 < 8 µm), even with some IC50 values under 0.1 µm. The detection of cytotoxicity selectivity revealed that hybrids 5 and 18 exhibited low cytotoxicity toward normal human liver cell HL-7702. Further studies revealed that selected hybrid 5 could induce apoptosis in Hep-G2 cells through the investigation of acridine orange/ethidium bromide, Hoechst 33258 fluorescence stainings, and annexin V/propidium iodide assay. It was also found that hybrid 5 could induce mitochondrial membrane potential disruption, arrest Hep-G2 cell line at G1 phase, and activate effector caspase-3/9 to trigger cell apoptosis.

Preoperative Anxiety in Patients With Myasthenia Gravis and Risk for Myasthenic Crisis After Extended Transsternal Thymectomy: A CONSORT Study.

A thymectomy can ameliorate the symptoms of myasthenia gravis (MG) and prevent the progression of ocular MG (OMG) to generalized MG (GMG). However, postoperative myasthenic crisis (POMC) is a serious post-thymectomy complication. Preoperative anxiety (POA) is common but typically neglected in MG patients. The association of POA with POMC has not yet been examined.From June 2007 to December 2013, 541 cases of MG were admitted to the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China). All cases underwent extended transsternal thymectomy (ETT). The clinical and pathological characteristics of these patients, including POA and POMC, were analyzed.A total of 179 patients experienced POA and 67 patients experienced POMC. Patients with POA were more likely to have POMC, a thymoma, and an ectopic thymus. Univariate analysis showed that POMC correlated with POA, presence of an ectopic thymus, dose of pyridostigmine bromide (PYR), presence of a thymoma, MGFA stage, preoperative myasthenic crisis, and postoperative pneumonia. Multivariate logistic regression analysis showed that the independent risk factors for POMC were POA, preoperative myasthenic crisis, higher dose of PYR, and postoperative pneumonia.Our results suggest that clinicians should consider the risk factors for POMC-especially preoperative anxiety-before performing a thymectomy in patients with MG.