A novel frameshift mutation of the endoglin(ENG) gene causes hereditary hemorrhagic telangiectasia in a Chinese family.

PURPOSE: Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited disorder that involves epistaxis, mucocutaneous telangiectases, and visceral arteriovenous malformations (AVMs). This study aims to investigate the genetic causes in a Chinese family with HHT. METHODS: HHT was confirmed according to Curaçao's diagnostic criteria. Three patients diagnosed with HHT and healthy members were recruited. Whole-exome sequencing (WES) and sanger sequencing were performed to define the patient's genetically pathogenic factor. RESULTS: The proband presented with recurrent epistaxis, hepatopulmonary arteriovenous malformation, and adenocarcinoma. A novel frameshift mutation (c.1376_1377delAC, p.H459Lfs*41) of the ENG gene was revealed in affected individuals by WES. There was no report of this variant and predicted to be highly damaging by causing truncation of the ENG protein. CONCLUSION: We report a novel variant in the ENG gene in Chinese that extends the mutational and phenotypic spectra of the ENG gene, and also demonstrates the feasibility of WES in the application of genetic diagnosis of HHT.

Circ_0058124 Upregulates MAPK1 Expression to Promote Proliferation, Metastasis and Metabolic Abilities in Thyroid Cancer Through Sponging miR-940.

BACKGROUND: Thyroid cancer (TC) is an endocrine disease, and its progression is regulated by many factors, including circular RNAs (circRNAs). However, as a new circRNA, the role of circ_0058124 in TC is worth further exploration. METHODS: The expression levels of circ_0058124, microRNA-940 (miR-940) and mitogen-activated protein kinase 1 (MAPK1) were assessed by quantitative polymerase chain reaction (q-PCR). The circular characteristic of circ_0058124 was identified by oligo (dT)18 primers, Ribonuclease R (RNase R) and Actinomycin D (ActD), and its localization was determined by nuclear-cytoplasmic separation assay. Also, cell proliferation was detected by colony formation assay, and cell migration and invasion were assessed by transwell assay. Further, Seahorse XF Extracellular Flux Analyzer was used to measure the oxygen consumption rate (OCR) of cells. Besides, dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays were used to identify the mechanism of circ_0058124. Western blot (WB) analysis was used to test the MAPK1 protein level. In addition, mice xenograft models were constructed to test the effect of circ_0058124 on TC tumor growth in vivo. RESULTS: Circ_0058124 was highly expressed in TC and is a stable cyclic transcript, mainly located in the cytoplasm. Circ_0058124 knockdown suppressed proliferation, migration, invasion and metabolic abilities in TC cells. MiR-940 could be absorbed by circ_0058124, and the inhibition effect of its overexpression on TC progression could be reversed by overexpressed-circ_0058124. MAPK1 was a target of miR-940, and the suppression effect of its silencing on TC progression could be inverted by miR-940 inhibitor. Besides, MAPK1 expression was regulated by circ_0058124 and miR-940. Interference of circ_0058124 also reduced TC tumor growth in vivo. CONCLUSION: Circ_0058124 might play a carcinogenic role in TC progression by regulating the miR-940/MAPK1 axis, which might provide a new idea for the treatment of TC.

Upregulation of microRNA-141 suppresses epithelial-mesenchymal transition and lymph node metastasis in laryngeal cancer through HOXC6-dependent TGF-ß signaling pathway.

Laryngeal cancer is one of the most malignant cancers among the head and neck malignant tumors. Abnormal expression of microRNAs (miRNAs) contributes to cancer development through regulating proliferation and apoptosis of cancer cells. In this study, we aim to explore the roles of microRNA-141 (miR-141), Homeobox C6 (HOXC6) and TGF-ß signaling pathway in epithelial-mesenchymal transition (EMT) and lymph node metastasis in laryngeal cancer. Initially, we identified differentially expressed genes in laryngeal cancer, among which HOXC6 was identified. Then the target miRNA of HOXC6 was predicted and verified. Next, expression of miR-141, HOXC6, TGF-ß1, Smad3, Vimentin and Snail in cancer tissues was detected. Then, AMC-HN-8 cells were transfected with miR-141 mimic, miR-141 inhibitor and HOXC6-siRNA to investigate specific role of miR-141, HOXC6 and TGF-ß signaling pathway in laryngeal cancer in vivo and in vitro. Our results showed that HOXC6 was a target gene of miR-141, which was downregulated in laryngeal cancer. Besides, overexpression of miR-141 could downregulate HOXC6 and inhibit the TGF-ß signaling pathway. Upregulation of miR-141 or silencing of HOXC6 can repress EMT, viability, migration and invasion abilities of laryngeal cancer cells. In addition, upregulation of miR-141 inhibited the tumor growth and lymph node metastasis in vivo. In summary, our findings demonstrated that upregulated miR-141 decreased HOXC6 expression, and inhibited the TGF-ß signaling pathway, EMT and lymph node metastasis in laryngeal cancer, which is of clinical significance in the treatment of laryngeal cancer.

Nasopharyngeal cancer combination chemoradiation therapy based on folic acid modified, gefitinib and yttrium 90 co-loaded, core-shell structured lipid-polymer hybrid nanoparticles.

Current treatment of advanced-stage nasopharyngeal carcinoma (NPC) is not satisfactory. Here, we developed a folic acid (FA) modified, gefitinib (GEF) and yttrium 90 (Y90) co-loaded, core-shell structured lipid-polymer hybrid nanoparticles (FA-GEF-Y90-LPNP). The size and zeta potential, drug release behavior, and uptake by tumor cells were investigated. The antitumor efficiency and toxicity of LPNP were evaluated in cancer cells and in tumor bearing mice. FA-GEF-Y90-LPNP with a mean size of 150 nm and zeta potential of -40 mV was able to enhance the accumulation in the NPC cells and exhibited the highest cytotoxicity. The AUC and T1/2 of FA-GEF-Y90-LPNP group was 217.62 ± 10.32 mg/L.h and 12.09 ± 0.43 h, respectively. FA-GEF-Y90-LPNP exhibited the best in vivo tumor inhibition ability, leading to a 221.2 ± 13.5 mm3 of tumor volume at day 21. FA-GEF-Y90-LPNP treatment resulted in almost no difference in the body weight. This may be the evidence that the systemic toxicity of FA-GEF-Y90-LPNP is low and may be used as safety system for the treatment of NPC.

Ailanthone Promotes Human Vestibular Schwannoma Cell Apoptosis and Autophagy by Downregulation of miR-21.

Ailanthone (AIL) is a quassinoid isolated from the traditional Chinese medicinal herb Ailanthus altissima. The antitumor activities of AIL have been reported in several cancers. The purpose of the present study was to explore the effect of AIL on vestibular schwannomas (VSs). Various concentrations of AIL (0-1 µM) were used to treat human primary VS cells, and then cell viability, proliferation, apoptosis, and autophagy were assessed. Expression of miR-21 in VS cells was altered by miRNA transfection. The functional actions of AIL on miR-21 dysregulated cells were also assessed. AIL significantly reduced the viability of VS cells, and the IC50 value was 0.48 ± 0.023 µM. In response to 0.6 µM AIL, BrdU+ cell rate and cyclin D1 expression were reduced, apoptotic cell rate was increased, caspase 3 and caspase 9 were cleaved, Beclin-1 and LC3-II were accumulated, and p62 was downregulated. miR-21 was lowly expressed in AIL-treated cells, and AIL-induced apoptosis and autophagy were attenuated by miR-21 overexpression. In addition, AIL downregulated Ras and Raf and deactivated MEK, ERK, mTOR, and p70S6K, while the downregulation and deactivation induced by AIL were reversed by miR-21 overexpression. To conclude, AIL inhibited VS cell proliferation and induced apoptosis and autophagy. The antitumor activities of AIL in VS cells were realized possibly via downregulation of miR-21 and blocking the Ras/Raf/MEK/ERK and mTOR pathways.

miR-146a C/G polymorphism increased the risk of head and neck cancer, but overall cancer risk: an analysis of 89 studies.

Several studies have evaluated the association of miR-146a C/G with head and neck cancer (HNC) susceptibility, and overall cancer risk, but with inconclusive outcomes. To drive a more precise estimation, we carried out this meta-analysis. The literature was searched from MEDLINE (mainly PubMed), Embase, the Cochrane Library, and Google Scholar databases to identify eligible studies. A total of 89 studies were included. The results showed that miR-146a C/G was significantly associated with increased HNC risk in dominant model (I2 =15.6%, Pheterogeneity=0.282, odds ratio (OR) =1.088, 95% confidence interval (CI) =1.002-1.182, P=0.044). However, no cancer risk was detected under all genetic models. By further stratified analysis, we found that rs4919510 mutation contributed to the risk of HNC amongst Asians under homozygote model (I2 =0, Pheterogeneity=0.541, OR =1.189, 95% CI =1.025-1.378, P=0.022), and dominant model (I2 =0, Pheterogeneity=0.959, OR =1.155, 95% CI =1.016-1.312, P=0.028). Simultaneously, in the stratified analysis by source of controls, a significantly increased cancer risk amongst population-based studies was found under homozygote model, dominant model, recessive model, and allele comparison model. However, no significant association was found in the stratified analysis by ethnicity and source of control. The results indicated that miR-146a C/G polymorphism may contribute to the increased HNC susceptibility and could be a promising target to forecast cancer risk for clinical practice. However, no significant association was found in subgroup analysis by ethnicity and source of control. To further confirm these results, well-designed large-scale case-control studies are needed in the future.

Role of SDF-1α/CXCR4 signaling pathway in clinicopathological features and prognosis of patients with nasopharyngeal carcinoma.

The present study aims to explore the role of stromal cell-derived factor-1α (SDF-1α)/stromal cell-derived factor receptor-4 (CXCR4) signaling pathway to the clinicopathological features and prognosis of patients with nasopharyngeal carcinoma (NPC). From January 2009 to December 2010, 102 patients with NPC and 80 patients with chronic nasopharyngitis were enrolled for the study. Immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting were employed to determine the expressions of SDF-1α and CXCR4 proteins in NPC tissues and chronic nasopharyngitis tissues. Chi-square test was conducted to analyze the associations of the expressions of SDF-1α and CXCR4 proteins with the clinicopathological features of NPC patients. Spearman rank correlation analysis was used to analyze the correlation between the SDF-1α protein expression and CXCR4 protein expression. The mRNA and protein expressions of SDF-1α and CXCR4 in NPC tissues were significantly higher than those in chronic nasopharyngitis tissues. The expressions of SDF-1α and CXCR4 proteins showed associations with T staging, N staging, tumor node metastasis (TNM) staging, skull base invasion, and cervical lymph node metastasis of NPC patients. Compared with NPC patients showing negative expressions of SDF-1α and CXCR4 proteins, those with positive expressions of SDF-1α and CXCR4 proteins had a significantly shorter survival time. SDF-1α protein, CXCR4 protein, EBV-IgG status, T staging, N staging, TNM staging, skull base invasion, and cervical lymph node metastasis were independent risk factors for the prognosis of NPC. The findings indicated that SDF-1α/CXCR4 signaling pathway might be associated with the clinicopathological features and prognosis of patients with NPC.

Oral bioavailability of curcumin: problems and advancements.

Curcumin is a natural compound of Curcuma longa L. and has shown many pharmacological activities such as anti-inflammatory, anti-oxidant in both preclinical and clinical studies. Moreover, curcumin has hepatoprotective, neuroprotective activities and protects against myocardial infarction. Particularly, curcumin has also demonstrated favorite anticancer efficacy. But limiting factors such as its extremely low oral bioavailability hampers its application as therapeutic agent. Therefore, many technologies have been developed and applied to overcome this limitation. This review described the main physicochemical properties of curcumin and summarized the recent studies in the design and development of oral delivery systems for curcumin to enhance the solubility and oral bioavailability, including liposomes, nanoparticles and polymeric micelles, phospholipid complexes, and microemulsions.

Clinical value of serum Epstein-Barr virus DNA assay in the diagnosis of nasopharyngeal carcinoma.

Serum Epstein-Barr virus DNA has been approved for diagnosing nasopharyngeal carcinoma (NPC). The goal of this meta-analysis was to evaluate the clinical value of the serum Epstein-Barr virus DNA in the diagnosis of NPC. The PubMed, Embase, Web of Knowledge, Chinese Wanfang Med Online, and National Knowledge Infrastructure (CNKI) databases were searched to identify suitable studies. The pooled sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), and diagnostic odds ratio (DOR) of the serum Epstein-Barr virus DNA for the diagnosis of NPC were calculated. Summary receiver operating characteristic curves were used to summarize overall test performances. Meta-Disc 1.4 and Stata 12.0 softwares were used to analyze the data. A total of 2,520 patients from ten trials were subjected to meta-analysis. The summary estimates of the serum Epstein-Barr virus DNA for NPC diagnosis were as follows: sensitivity 0.69 (95 % confidence interval (CI) 0.65-0.72), specificity 0.84 (95 % CI = 0.82-0.86), LR + 4.81 (95 % CI = 2.94-7.88), LR - 0.25 (95 % CI = 0.13-0.48), DOR 24.65 (95 % CI = 12.64-48.07), and area under the summary receiver operator characteristic (SROC) curve (AUC) was 0.8979. Our study demonstrates that the serum Epstein-Barr virus DNA could be a useful tumor marker for NPC diagnosis.

Serum Zta antibody of Epstein-Barr virus exerts potential function in the diagnosis of nasopharyngeal cancer.

The diagnosis of nasopharyngeal cancer (NPC) remains a clinical challenge. Many studies have assessed the diagnostic potential of Zta antibody of the Epstein-Barr virus (EBV) in NPC patients but with controversial results. This study aims to summarize the overall diagnostic performance of EBV Zta antibody in NPC. Based on a comprehensive search of the Pubmed and Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Wanfang Databases and China Citation Databases, we identified outcome data from all articles estimating diagnostic accuracy of EBV Zta antibody for NPC. A summary estimation for sensitivity, specificity, and other diagnostic indexes were pooled using a bivariate model. The overall measure of accuracy was calculated using summary receiver operating characteristic curve and the area under curve (AUC) was calculated. According to our inclusion criteria, 17 studies with 11,822 subjects (1,645 NPC cases, 10,177 controls) were included. The summary estimates were: sensitivity 0.87 (95 % confidence interval [CI] = 0.86-0.89), specificity 0.94 (95 % CI = 0.93-0.94), positive likelihood ratio 8.05 (95 % CI = 5.59-11.59), negative likelihood ratio 0.16 (95 % CI = 0.12-0.21), diagnostic odds ratio 52.93 (95 % CI = 29.95-93.56), the AUC and Q* index were 0.9352 and 0.8714, respectively. In conclusion, serum EBV Zta had a better diagnostic performance for NPC. Further studies should be performed to confirm our findings.

[Determination of Si, Al and other in biological samples by ICP-AES with fusion with LiBO2 after dry ashing].

An alkaline sample digestion procedure using fusion with lithium metaborate (LiBO2) after dry ashing was developed. Silicon, aluminium and other, a total of 10 elements in different kinds of biological samples, were measured by ICP-AES. The detection limit of this method was 0.15 microg x mL(-1) for Si and 0.03 microg x mL(-1) for Al. The accuracy and precision of the method were demonstrated by analyzing certified reference materials poplar leaves (GBW07604). The precision was less than 3% and the accuracy was -0.03% for Si and -3% for Al. This method was applied to the certification of a series of ten biological reference materials. The results were satisfied.