Electric-Field Effects on the Internal Charge Reorganization Energies of Crystalline Organic Semiconductors.

The synergistic effects of molecular packing and external electric fields (EEFs, including axial and nonaxial fields) on the internal charge reorganization energies (λ) of typical p-type SMOS have been investigated. Combined quantum and molecular mechanics calculations show that, for all-ring-fused rigid molecules single-molecule approximation and neglect of EEFs are adequate for computing λ, while for nonrigid molecules with inter-ring carbon-carbon (IRCC) linkers, the above simplifications may cause a significant deviation from the actual λ. For nonrigid molecules, solid-state packing can prevent "bad" EEFs (Fz and Fyz) from enhancing λ (adverse to charge transfer), while it allows λ to be greatly reduced (in favor of charge transfer) if "good" EEFs (Fx, Fxy, Fxz and Fxyz) are imposed. Last, a simple strategy that can divide λ into each subring contribution for IRCC-linked molecules has been proposed.

SYT-SSX1 enhances the invasiveness and maintains stem-like cell properties in synovial sarcoma via induction of TGF-ß1/Smad signaling.

BACKGROUND: Synovial sarcoma (SS) is a type of soft tissue sarcoma (STS) of undetermined tissue origin, which is characterized by the recurrent pathognomonic chromosomal translocation t (X;18)(p11.2; q11.2). Studies have shown that SS is a malignant tumor originating from cancer stem cells or pluripotent mesenchymal stem cells and may be related to fusion genes. In addition, some studies have indicated that the induction of epithelial-mesenchymal transition (EMT) via the TGF-ß1/Smad signaling pathway leads to SS metastasis. METHODS: We analyzed the effects of SYT-SSX1 on the stemness of SS cells via TGF-ß1/Smad signaling in vitro. The SYT-SSX1 fusion gene high expression cell was constructed by lentiviral stable transfer technology. SYT-SSX1 and SW982 cells were cultured and tested for sphere-forming ability. The transwell migration assay and flow cytometry were used to assess the migration ability of the sphere cells as well as the expression of CSC-related markers. We treated SYT-SSX1 cells with rhTGF-ß1 (a recombinant agent of the TGF-ß1 signaling pathway) and SB431542 and observed morphological changes. A CCK-8 experiment and a western blot (WB) experiment were conducted to detect the expression of TGF-ß1 signaling pathway- and EMT-related proteins after treatment. The SYT-SSX1 cells were then cultured and their ability to form spheres was tested. Flow cytometry, WB, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of CSC surface markers on SYT-SSX1 sphere cells. RESULTS: It was found that SYT-SSX1 has stronger sphere-forming ability, migration ability, and higher expression of CSC-related molecules than SW982 cells. Through treating SYT-SSX1 and SW982 cells with rhTGF-ß1 and SB431542, we found that TGF-ß1 enhanced the proliferation of cells, induced EMT, and that TGF-ß1 enhanced the characteristics of tumor stem cells. CONCLUSIONS: Our results suggest that SYT-SSX1 enhances invasiveness and maintains stemness in SS cells via TGF-ß1/Smad signaling. These findings reveal an effective way to potentially improve the prognosis of patients with SS by eliminating the characteristics of cancer stem cells (CSCs) during treatment.

Identification of Potential Genomic Alterations and the circRNA-miRNA-mRNA Regulatory Network in Primary and Recurrent Synovial Sarcomas.

Introduction: Synovial sarcoma (SS) is one of the most invasive soft tissue sarcomas, prone to recurrence and metastasis, and the efficacy of surgical treatment and chemotherapy for SS remains poor. Therefore, the diagnosis and treatment of SS remain a significant challenge. This study aimed to analyze the mutated genes of primary SS (PSS) and recurrent SS (RSS), discover whether these sarcomas exhibit some potential mutated genes, and then predict associated microRNAs (miRNA) and circular RNAs (circRNA) by analyzing the mutated genes. We focused on the regulation mechanism of the circRNA-miRNA-mutated hub gene in PSS and RSS. Methods: We performed a comprehensive genomic analysis of four pairs of formalin-fixed paraffin-embedded samples of PSS and RSS, using Illumina human exon microarrays. The gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) function, and pathway enrichment of the mutated genes were analyzed, and the protein-protein interaction (PPI) network was forecast using String software 11.0. The hub genes were then obtained using the Molecular Complex Detection (MCODE) plug-in for Cytoscape 3.7.2 and were used to analyze overall survival (OS) using the Gene Expression Profiling Interactive Analysis (GEPIA) database. The corresponding miRNAs were obtained from the miRDB 5.0 and TargetScan 7.2 databases. The corresponding circRNAs of the hub genes were found through the miRNAs from these databases: Circbank, CircInteractome, and StarBase v2.0. Thereafter we set up a competing endogenous RNA (ceRNA) network with circRNA-miRNA and miRNA-messenger RNA (mRNA) pairs. Results: Using the chi-squared test, 391 mutated genes were screened using a significance level of p-values < 0.01 from the four pairs of PSS and RSS samples. A GO pathway analysis of 391 mutated genes demonstrated that differential expression mRNAs (DEmRNAs) might be bound up with the "positive regulation of neurogenesis," "cell growth," "axon part," "cell-substrate junction," or "protein phosphatase binding" of SS. The PPI network was constructed using 391 mutated genes, and 53 hub genes were identified (p < 0.05). Eight variant hub genes were discovered to be statistically significant using the OS analysis (p < 0.05). The circRNA-miRNA-mRNA (ceRNA) network was constructed, and it identified two circRNAs (hsa_circ_0070557 and hsa_circ_0070558), 10 miRNAs (hsa-let-7a-3p, hsa-let-7b-3p, hsa-let-7f-1-3p, hsa-let-7f-2-3p, hsa-mir-1244, hsa-mir-1197, hsa-mir-124-3p, hsa-mir-1249-5p, hsa-mir-1253, and hsa-mir-1271-5p) and five hub genes (CENPE, ENPP3, GPR18, MDC1, and PLOD2). Conclusion: This study screened novel biological markers and investigated the differentiated circRNA-miRNA-mutated hub gene axis, which may play a pivotal role in the nosogenesis of PSS and RSS. Some circRNAs may be deemed new diagnostic or therapeutic targets that could be conducive to the future clinical treatment of SS.

Prognostic role of upregulated P300 expression in human cancers: A clinical study of synovial sarcoma and a meta-analysis.

E1A binding protein p300 (P300) is a member of the histone acetyltransferase family of transcriptional co-activators, which are associated with various types of cancer. Numerous studies have evaluated the diagnostic value of P300, but their results are not consistent. Therefore, a clinical study and a meta-analysis were performed in the present study to investigate the prognostic value of P300 expression in human malignant neoplasms. Immunohistochemical (IHC) analysis was used to assess P300 expression in 43 paraffin-embedded primary synovial sarcoma (SS) samples. For the meta-analysis, eligible studies published until January 21, 2018 were identified by searching the PubMed, EMBASE and Web of Science databases. The IHC analysis indicated a high P300 expression rate in 33.3% (10/30) of biphasic SS (BSSs) and in 60% (6/10) of monophasic fibrous SS tissues. In BSS, the expression rate was significantly higher in the epithelial component (80.0%, 24/30) than that in the spindle-cell component (30.0%, 9/30; P<0.05). The meta-analysis indicated that high expression of P300 was associated with poor overall survival (OS) in digestive system malignant neoplasms (HR=1.54, 95% CI: 1.20-2.23), as well as with poor progression-free survival, recurrence-free survival and disease-free survival combined (HR=1.84, 95% CI: 1.36-2.47). Analysis of subgroups by ethnicity demonstrated that high expression of P300 was associated with poor OS in Asians (HR=1.72, 95% CI: 1.20-2.47) but favourable OS in Caucasians (HR=0.59, 95% CI: 0.47-0.73). Furthermore, high expression of P300 was associated with clinical stage [Relative Risk (RR)=1.30, 95% CI: 1.07-1.58], lymph node metastasis (RR=1.30, 95% CI: 1.03-1.64) and depth of invasion (RR=1.31, 95% CI: 1.07-1.60). P300 expression may therefore be a useful biomarker for predicting patient prognosis in various types of human cancer.

Significance of hydrogen sulfide in sepsis-induced myocardial injury in rats.

Sepsis-induced myocardial injury is a detrimental disorder for intensive care medicine due to its high rates of morbidity and mortality. Data suggest that nuclear factor (NF)-κB serves a critical role in the pathogenesis of myocardial injury. Hydrogen sulfide (H2S) serves an important role in the physiology and pathophysiology of regulatory mechanisms, particularly during an inflammatory reaction. However, the relationship between NF-κB and H2S in sepsis-induced myocardial injury is not well understood, and the underlying mechanisms remain unclear. In the present study, 60 male Sprague Dawley rats were randomly divided into the following six groups: A sham group, cecal ligation and puncture (CLP) group, sham + propargylglycine (PAG) group, CLP + PAG group, sham + sodium hydrosulfide (NaHS) group and CLP + NaHS group, with 10 rats in each group. The rats in all groups were sacrificed 12 h after surgery for sample collection. Compared with the sham group, it was observed that the concentrations of Creatine Kinase-MB (CK-MB) and cardiac troponin I (cTnI) in the serum, and pathological scores of myocardial tissue were significantly increased in the CLP, CLP + NaHS and CLP + PAG groups (P<0.05). The pathological scores and concentrations of CK-MB and cTnI were significantly higher in the CLP + PAG group (P<0.05) and significantly lower in the CLP + NaHS group (P<0.05) when compared with the CLP group. The expression of cystathionine-γ-lyase (CSE) mRNA and content of interleukin (IL)-10 were significantly higher in the CLP group compared with the CLP + PAG group (P<0.05), while the expression of myocardial NF-κB and content of tumor necrosis factor (TNF)-α in the CLP group were significantly lowered compared with the CLP + PAG group (P<0.05). The expression of NF-κB and content of TNF-α were significantly increased in the CLP group when compared with the CLP + NaHS group (P<0.05), while the content of myocardial IL-10 in the CLP group was significantly lower than in the CLP + NaHS group (P<0.05). In conclusion, H2S acted as an anti-inflammatory cytokine and biomarker in sepsis-induced myocardial injury. Furthermore, H2S may downregulate the NF-κB subunit p65 to mediate inflammatory responses. The present data suggest that myocardial injury in sepsis may be relieved through the regulation of H2S expression, and provide an experimental basis for the treatment of sepsis patients presenting with myocardial injury. In addition, myocardial injury in sepsis may be identified by monitoring changes in the expression of H2S.

Transforming growth factor-ß1 signaling promotes epithelial-mesenchymal transition-like phenomena, cell motility, and cell invasion in synovial sarcoma cells.

The epithelial-to-mesenchymal transition (EMT) and the reverse process (the mesenchymal-to-epithelial transition [MET]) have been shown to be associated with tumor cell invasion and metastasis in different carcinomas. The EMT and MET have recently been shown to play a key role in the pathogenic processes of sarcomas, which are completely different from those of carcinomas. However, the definitive roles of the EMT in the tumorigenesis of synovial sarcomas remain unknown. Here, we explored whether transforming growth factor (TGF)-ß signaling, an important oncogenic event in synovial sarcoma, modulates tumor cell characteristics related to the EMT, such as cell adhesion, migration, invasion, and proliferation. Interestingly, we found that TGF-ß1 induced tumor cell activation, resulting in a tendency to aggregate and biphasic-like features. TGF-ß1 also caused downregulation of E-cadherin and subsequent upregulation of N-cadherin, Snail, and Slug, which are responsible for EMT-like phenomena and increased cell motility and invasion. To further investigate the roles of TGF-ß1 in the EMT, we established a SW982 cell line with stable TGF-ß1 inhibition viaSB431542.These cells exhibited significantly decreased motility, migration, and proliferation (P = 0.001). Taken together, our data demonstrated that alterations in the TGF-ß1/Smad signaling pathway could regulate the expression of EMT-related factors and the EMT process, resulting in changes in tumor cell invasion, migration, and proliferation in synovial sarcoma cells. These results may provide a important insights into therapeutic interventions and contribute to the present understanding of tumor progression in patients.

Down-regulated E-cadherin expression is associated with poor five-year overall survival in bone and soft tissue sarcoma: results of a meta-analysis.

PURPOSE: To conduct a meta-analysis to evaluate the prognostic role of E-cadherin expression in bone and soft tissue sarcomas. METHODS: The PubMed, EMBASE, and Web of Science databases were searched using terms related to E-cadherin, sarcoma, and prognosis for all articles published in English before March 2014. Pooled effect was calculated from the available data to evaluate the association between negative E-cadherin expression and 5-year overall survival and tumor clinicopathological features in sarcoma patients. Pooled odds ratios (OR) and risk ratios (RR) with 95% confidence intervals (CI) were calculated using a fixed-effects model. RESULT: Eight studies met the selection criteria and reported on 812 subjects. A total of 496 subjects showed positive E-cadherin expression (59.9%). Negative E-cadherin expression in bone and soft tissue sarcomas was correlated with lower 5-year overall survival (OR = 3.831; 95% CI: 2.246-6.534), and was associated with higher clinical stage (RR = 1.446; 95% CI: 1.030-2.028) and with male sex (RR = 0.678; 95% CI: 0.493-0.933). CONCLUSION: In the E-cadherin negative group, 5-year overall survival was significantly worse than in the E-cadherin positive group. However, further studies are required to confirm these results.

The correlation between morphology and the expression of TGF-ß signaling pathway proteins and epithelial-mesenchymal transition-related proteins in synovial sarcomas.

Synovial sarcoma (SS) is a malignant tumor of soft tissue and is noted for late local recurrence and metastasis. Aberrant epithelial-mesenchymal transition (EMT) has been implicated in the pathogenesis of diverse human malignancies. Immunohistochemical techniques were used to assess EMT-related proteins (E-cadherin, N-cadherin, ß-catenin, Snail, and Slug) and the TGF-ß1 pathway (TGF-ß1 and Smad2/3) proteins expression in different histological subtypes and epithelial mesenchymal compositions of SS. The expression of cell-surface (E-cadherin) and cytoskeletal proteins (ß-catenin) were higher significantly in biphasic SSs (BSSs) (70.4%, 51.9%) than MFSSs (both for 10%). Among monophasic fibrous SSs (MFSSs) samples, E-cadherin protein expression was negatively correlated with expression Snail, Slug, TGF-ß1, and Smad2/3. The expression levels of Snail and Smad2/3 were correlated with the pTNM stage (I-II vs. III-IV; P=0.047, P=0.021) and TGF-ß1 exhibited a tendency toward a positive correlation with pTNM stage (I-II vs. III-IV; P=0.052), but did not correlate with the histological grade (p>0.05). Interestingly, our data showed that expression of E-cadherin protein correlated with greater survival in SS patients. Overexpression of Snail, and TGF-ß1 is associated with suppressed expression of E-cadherin in MFSSs, which supports the hypothesis that the MFSS subtype may have developed via neoplastic EMT.