Circ_0087378 intensifies the malignant behavior of non-small cell lung cancer cells in vitro by facilitating DDR1 via sponging miR-199a-5p.

Background: Circular RNA hsa_circ_0087378 (circ_0087378) has been found to have different functions in different cancer types. However, its function in non-small cell lung cancer (NSCLC) remains unclear. This study revealed the effect of circ_0087378 on the malignant behavior of NSCLC cells in vitro to broaden the options for NSCLC treatment. Methods: This study detected the expression of circ_0087378 in NSCLC cells via real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The discoidin domain receptor 1 (DDR1) protein in NSCLC cells was investigated through western blot. The influence of circ_0087378 on the malignant behavior of NSCLC cells in vitro was investigated by cell counting kit-8 assay, colony formation assay, Transwell assay, and flow cytometry. Dual-luciferase reporter gene assay and RNA pull-down assay were performed to verify the binding between two genes. Results: Circ_0087378 was abundantly expressed in NSCLC cells. The loss of circ_0087378 repressed the proliferation, colony formation, migration, invasion, but enhanced the apoptosis in NSCLC cells in vitro. Circ_0087378 could repress microRNA-199a-5p (miR-199a-5p) by acting as a sponge. The loss of miR-199a-5p abrogated the inhibition of circ_0087378 loss on the malignant phenotype of NSCLC cells in vitro. DDR1 was directly repressed via miR-199a-5p. DDR1 counteracted the repressive role of miR-199a-5p on the malignant behavior of NSCLC cells in vitro. Conclusions: Circ_0087378 promotes the malignant behavior of NSCLC cells in vitro by facilitating DDR1 via sponging miR-199a-5p. It may be a promising target for treatment.

MYH9 is a novel cancer stem cell marker and prognostic indicator in esophageal cancer that promotes oncogenesis through the PI3K/AKT/mTOR axis.

MYH9 encodes the heavy chain of nonmuscle myosin IIA, a ubiquitously expressed cytoplasmic myosin that regulates the actin cytoskeleton, cell migration, cell polarization, and signal transduction in cancer cells. Here, we investigated the role of MYH9 in cancer stem cells (CSCs) associated with esophageal cancer (EC). The subcellular localization of MYH9 was investigated in SKGT-4 cells through immunofluorescent analysis. MYH9+ and MYH9- spheroid cells were derived from SKGT-4 cells by flow cytometry and compared for self-renewal capacity, tumorigenicity, CD133 positivity, cisplatin resistance, and phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) activity. MYH9 messenger RNA expression was assessed in 30 EC patients by quantitative reverse transcription-polymerase chain reaction. Kaplan-Meier curves were plotted to explore the influence of MYH9 on EC survival. MYH9 localized to the plasma membrane, cytoplasm, and nucleus of SKGT-4 cells. Spheroid cells displayed higher MYH9 expression and positivity compared to parental SKGT-4 cells. MYH9+ cells showed strong CSC characteristics, including in vivo tumorigenicity, migration, invasion, cisplatin resistance, and CD133+ positivity. MYH9 activated the PI3K/AKT/mTOR axis in CSCs and was upregulated in EC patients with poor survival. Collectively, these data show that MYH9 significantly promotes tumorigenesis by regulating PI3K/AKT/mTOR signaling in EC. MYH9 expression remarkably correlates with poor prognosis and represents a novel biomarker and drug target for the diagnosis and treatment of EC.

Single-port thoracoscopic resection of a posterior mediastinal Mullerian cyst in a woman.

Mullerian cysts are benign tumors that are very rare in the posterior mediastinum. It is necessary to distinguish Mullerian cysts from benign tumors or other types of cyst in the posterior mediastinum. A 42-year-old woman visited our hospital for a routine check-up, and a mediastinal mass was identified on chest computed tomography (CT). Contrast-enhanced chest magnetic resonance imaging (MRI) revealed a 4.0 × 2.6 × 2.8-cm mass, and a neurogenic tumor or esophageal cyst was suspected. Single-port thoracoscopic surgery was performed for cyst removal. Histopathological examination of the resected tissue revealed that the cyst wall was covered with a single layer of ciliated columnar epithelium. Immunohistochemical staining revealed positivity for paired box gene 8 (PAX8), Wilms tumor protein 1 (WT-1), estrogen receptor (ER), and progesterone receptor (PR). Therefore, a diagnosis of mediastinal Mullerian cyst was made. Mediastinal Mullerian cysts should be included in the differential diagnosis of posterior mediastinal cysts. Cystic lesions in the posterior mediastinum should be removed surgically and undergo immunohistochemical examination.

Esophageal cancer with a double aortic arch: a case report and literature review.

BACKGROUND: Double aortic arch (DAA) is an extremely rare vascular malformation, even more so when coexisting with esophageal cancer. METHODS: We report a new case of DAA with esophageal cancer recently seen at our Thoracic Tumor Clinic and review cases of DAA coexisting with esophageal cancer reported in the literature of English language from 2010 to 2020. The purposes of our literature review were to explore how to best achieve radical esophagectomy while reducing postoperative complications. The clinical manifestations, diagnostic method, surgical approach, reconstruction route, and the extent of lymphadenectomy of esophageal cancer with DAA were analyzed in detail. RESULTS AND CONCLUSION: For such patients, 3D computed tomography is necessary for preoperative diagnosis. The surgical approach should consider factors such as the location of the tumor in the esophagus and whether the tumor is surrounded by DAA, as well as the position of the descending aorta and the requirements for the surgical field for lymphadenectomy. If esophageal reconstruction is required, the retrosternal route is preferred. We recommend that only patients with positive results of intraoperative frozen biopsy of recurrent laryngeal nerve lymph nodes should undergo three-field lymphadenectomy, which may be the best method to achieve radical esophagectomy for middle and lower esophageal cancers with DAA while minimizing postoperative complications.

Prognostic and Clinicopathologic Significance of Neutrophil-to-Lymphocyte Ratio in Esophageal Cancer: An Update Meta-Analysis.

Background: Esophageal cancer is one of the most common cancers with significant morbidity and mortality. It is important to predict the prognosis of patients. The purpose of this study was to comprehensively assess the prognostic and clinicopathologic significance of NLR in patients with esophageal cancer. Methods: A systematic literature search was performed using PubMed, Cochrane Library, Embase, Web of Science, MEDLINE, and CNKI. This meta-analysis was conducted in accordance with PRISMA guidelines. Hazard ratio (HR) with 95% confidence interval (CI) was used as the effect estimation to evaluate the prognostic role of NLR. Odds ratio (OR) was used to evaluate the relation between NLR and clinicopathologic characteristics. Results: A total of 8431 patients from 32 studies were included in this meta-analysis. The pooled results showed that elevated NLR might predict poor prognosis: The factors considered included overall survival (OS) (HR, 1.57; 95% CI, 1.40-1.75; P < .001), cancer-specific survival (CSS) (HR, 1.28; 95% CI, 1.09-1.49; P < .001), progression-free survival (PFS) (HR, 1.45; 95% CI, 1.29-1.72; P < .001), and disease-free survival (DFS) (HR,1.58; 95% CI, 1.27-1.97; P < .001). High NLR was also associated with tumor differentiation, tumor length, tumor invasion depth, lymph node metastasis, and clinical stage. No significant association was observed between NLR and metastasis stage (OR, 1.69; 95% CI, 0.98-2.98; P = .058). Conclusions: The results of this meta-analysis suggest that elevated NLR value might predict poor prognosis (OS, CSS, PFS, and DFS), according to abnormal clinicopathologic parameters.

C-terminal binding protein-2 is a prognostic marker for lung adenocarcinomas.

C-terminal binding protein-2 (CtBP2) a transcriptional corepressor, has been reported to involve in tumorigenesis and progression and predict a poor prognosis in several human cancers. However, few studies on CtBP2 in lung cancer tissues have been performed. In the present study, we first explored the CtBP2 gene expression profile from the the cancer genome atlas (TCGA) datasets, then western blot analysis and immunohistochemistry were performed to investigate and verified whether lung adenocarcinoma (LUAD) tissues exhibit deregulated CtBP2 expression. We evaluated the correlations between CtBP2 expression and the clinicopathological characteristics, and Kaplan-Meier survival analyses were performed to estimate the effect of CtBP2 expression on prognosis of LUAD patients. The results revealed that CtBP2 expression was significantly upregulated in LUAD tissues compared with normal lung tissues. Furthermore, increasing CtBP2 expression in LUAD was significantly associated with tumor differentiation (P = .028), tumor node metastasis (TNM) stage (P = .042). CtBP2 expression was significantly correlated with LUAD patients' survival (P = .028). In conclusion, the present study revealed that CtBP2 protein is a novel prognostic marker for LUAD. A further large-scale study is needed to confirm the present results.

[Association of MiR-155 expression with prognosis in resected 
stage III non-small cell lung cancer].

BACKGROUND AND OBJECTIVE: Despite undergoing curative resection, the 5-year survival rate for stage III non-small cell lung cancer (NSCLC) patients is less than 25%. There is a need for biomarkers for prediction of survival and guiding individual therapy. MiR-155 is one of most commonly upregulated miRNAs in malignancies, and regulates multiple pro-oncogenic pathways. We aimed to investigate the prognostic impact of miR-155 in resected stage III NSCLC patients. METHODS: Tumor formalin-fixed, paraffin-embedded (FFPE) from 162 resected stage III NSCLC patients were collected. Total RNA including miRNA was extracted, and qRT-PCR was used to determine the expression of miR-155. RESULTS: Spearman rank correlation test showed a positive correlation between miR-155 expression and nodal status (r=0.169, P=0.032). MiR-155 expression had a significant prognostic impact in the total cohort (P<0.001), in squamous cell carcinomas (P=0.002) and in adenocarcinomas (P=0.003). In N0-1 subgroup, miR-155 expression did not have a significant prognostic on overall survival in univariate analysis (P=0.319). In N2 subgroup, miR-155 had a negative prognostic effect on OS in univariate analysis (P<0.001). Cox regression analysis revealed that miR-155 expression was unfavorable prognostic factors of OS (RR=2.311, 95%CI: 1.479-3.611, P<0.001). CONCLUSIONS: High expression of miR-155 represents a valuable marker of poor clinical outcomes in patients with stage III NSCLC.

Mono-(2-ethylhexyl) phthalate induces injury in human umbilical vein endothelial cells.

Mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of di-(2-ethylhexyl) phthalate (DEHP), is a widespread environmental contaminant and has been proved to have potential adverse effects on the reproductive system, carcinogenicity, liver, kidney and developmental toxicities. However, the effect of MEHP on vascular system remains unclear. The main purpose of this study was to evaluate the cytotoxic effects of MEHP on human umbilical endothelial cells (HUVEC) and its possible molecular mechanism. HUVEC cells were treated with MEHP (0, 6.25, 12.5, 25,50 and 100 µM), and the cellular apoptosis and mitochondrial membrane potential as well as intracellular reactive oxygen species were determined. In present study, MEHP induced a dose-dependent cell injury in HUVEC cell via an apoptosis pathway as characterized by increased percentage of sub-G1, activation of caspase-3, -8 and -9, and increased ratio of Bax/bcl-2 mRNA and protein expression as well as cytochrome C releasing. In addition, there was obvious oxidative stress, represented by decreased glutathione level, increased malondialdehyde level and superoxide dismutase activity. N-Acetylcysteine, as an antioxidant that is a direct reactive oxygen species scavenger, could effectively block MEHP-induced reactive oxygen species generation, mitochondrial membrane potential loss and cell apoptosis. These data indicated that MEHP induced apoptosis in HUVEC cells through a reactive oxygen species-mediated mitochondria-dependent pathway.

Application of T-DNA activation tagging to identify glutamate receptor-like genes that enhance drought tolerance in plants.

KEY MESSAGE: A high-quality rice activation tagging population has been developed and screened for drought-tolerant lines using various water stress assays. One drought-tolerant line activated two rice glutamate receptor-like genes. Transgenic overexpression of the rice glutamate receptor-like genes conferred drought tolerance to rice and Arabidopsis. Rice (Oryza sativa) is a multi-billion dollar crop grown in more than one hundred countries, as well as a useful functional genetic tool for trait discovery. We have developed a population of more than 200,000 activation-tagged rice lines for use in forward genetic screens to identify genes that improve drought tolerance and other traits that improve yield and agronomic productivity. The population has an expected coverage of more than 90 % of rice genes. About 80 % of the lines have a single T-DNA insertion locus and this molecular feature simplifies gene identification. One of the lines identified in our screens, AH01486, exhibits improved drought tolerance. The AH01486 T-DNA locus is located in a region with two glutamate receptor-like genes. Constitutive overexpression of either glutamate receptor-like gene significantly enhances the drought tolerance of rice and Arabidopsis, thus revealing a novel function of this important gene family in plant biology.

Lead optimization of 2-(piperidin-3-yl)-1H-benzimidazoles: identification of 2-morpholin- and 2-thiomorpholin-2-yl-1H-benzimidazoles as selective and CNS penetrating H1-antihistamines for insomnia.

The structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pK(a) and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics.

Influence of pKa on the biotransformation of indene H1-antihistamines by CYP2D6.

Structure-activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H(1)-antihistamines. Reductions in pK(a) via incorporation of a ß-fluoro substituent or a heteroaryl moiety were shown to reduce contributions to metabolism through this pathway. Several compounds, including 8l, 8o, and 12f were identified with promising primary in vitro profiles and reduced biotransformation via CYP2D6.

Identification of a novel selective H1-antihistamine with optimized pharmacokinetic properties for clinical evaluation in the treatment of insomnia.

Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study.

Novel benzothiophene H1-antihistamines for the treatment of insomnia.

SAR of lead benzothiophene H(1)-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H(1)-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound.

Selectivity profiling of novel indene H(1)-antihistamines for the treatment of insomnia.

A series of indene analogs of the H(1)-antihistamine (-)-R-dimethindene was evaluated for selectivity in the search for potentially improved sedative-hypnotics. Variation of the 6-substitutent in the indene core in combination with a pendant electron rich heterocycle led to the identification of several potent H(1)-antihistamines with desirable selectivity over CYP enzymes, the M(1) muscarinic receptor and the hERG channel. These compounds were candidates for further ADME profiling and in vivo evaluation.

Characterization of novel selective H1-antihistamines for clinical evaluation in the treatment of insomnia.

Analogues of the known H(1)-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.

Brain-penetrating 2-aminobenzimidazole H(1)-antihistamines for the treatment of insomnia.

The benzimidazole core of the selective non-brain-penetrating H(1)-antihistamine mizolastine was used to identify a series of brain-penetrating H(1)-antihistamines for the potential treatment of insomnia. Using cassette PK studies, brain-penetrating H(1)-antihistamines were identified and in vivo efficacy was demonstrated in a rat EEG/EMG model. Further optimization focused on strategies to attenuate an identified hERG liability, leading to the discovery of 4i with a promising in vitro profile.

Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain.

Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.

[Diel rhythm of benthic macroinvertebrate's drift in streams in Hengshishui River watershed of Guangdong, China].

An investigation was conducted on the species composition and diel rhythm of benthic macroinvertebrate's drift in two adjacent 3rd order streams in the Hengshishui River watershed of Guangdong, China. One of the streams was seriously polluted by acid mine drainage (AMD) discharged from the Guangdong Dabaoshan Mine, with a very low pH (3.45) and high contents of heavy metals that exceeded the Chinese National Standards for surface water, and the another adjacent was a clean stream. The results showed that the individuals and species of benthic macroinvertebrates were much more in clean stream than in AMD-polluted stream. In the drift samples from clean stream, a total of 6871 macroinvertebrate individuals belonging to 52 taxa of 10 orders were collected, among which, 99.5% were aquatic insects. However, the total drift density was dominated by a few taxa, of which, the dominant drift taxa with relative abundance in excess of 5% included Pseudocloeon morum (28.5%), Cinygmina yixingensis (13.8%), Cheumatopsyche sp. (13.2%), Serratella albostriata (7.5%), Chironomidae (6.5%), and Psephenoides sp. (5.0%). The most abundant drifter both in species and in individuals was Ephemeroptera, constituting 65% of the entire caught (dominated by Baetidiae, which represented 63% of total mayfly individuals), followed by Trichoptera (18%). The macroinvertebrate's drift showed significant diel rhythm, i. e., the drift was strongly nocturnal, with the peaks at 21:00 and 2:00, and the average drift densities being (70.3 +/- 10.8) and (289.0 +/- 124.6) ( ind x 100 m(-3)), respectively. No diurnal drifter was observed. Most dominant drift taxa showed slightly differences in their drift peaks, but some dominant taxa, e. g., chironomids and Psephenoides sp., showed no clear diel rhythm of drift. Polypedilum sp., an acidophilic species of Chironomidae, was the only drift animal found in AMD-polluted stream, which had three distinct drift peaks, i. e., at 19:00, 0:00 and 4:00, with the highest drift density being only (6.7 +/- 5.2) (ind x 100 m(-3)). It was indicated that AMD not only reduced the numbers and species diversity of drift benthic macroinvertebrates, but also altered their drift patterns.

Design and synthesis of tricyclic imidazo[4,5-b]pyridin-2-ones as corticotropin-releasing factor-1 antagonists.

The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF(1)) antagonists are discussed herein. Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-induced adrenocorticotrophic hormone release. Pharmacokinetics studies in rats showed that 16g was orally bioavailable, had good brain penetration, and had a moderate half-life. In our effort to identify CRF(1) antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution.