Some types of circular RNA (circRNA) are aberrantly expressed in human diseases including hepatocellular carcinoma (HCC). However, its regulation mechanism and diagnostic roles are largely unknown. Here, we identified that circRNA_104075 (circ_104075) was highly expressed in HCC tissues, cell lines and serum. Mechanistically, HNF4a bound to the −1409 to −1401 region of the circ_104075 promoter to stimulate the expression of circ_104075. Moreover, circ_104075 acted as a ceRNA to upregulate YAP expression by absorbing miR-582-3p. Interestingly, an N6-methyladenosine (m6A) motif was identified in the 353–357 region of YAP 3′UTR, and this m6A modification was essential for the interaction between miR-582-3p and YAP 3′UTR. Further, the diagnostic performance of circ_104075 was evaluated. The area under the receiver operating characteristic (AUC-ROC) for circ_104075 was 0.973 with a sensitivity of 96.0% and a specificity of 98.3%. Collectively, we determined that circ_104075 was highly expressed in HCC and elucidated its upstream and downstream regulatory mechanisms. circ_104075 additionally has the potential to serve as a new diagnostic biomarker in HCC. Targeting circ_104075 may provide new strategies in HCC diagnosis and therapy.

Highlights Mucinous epithelial ovarian cancer (mEOC) is a rare chemo-resistant subtype of ovarian cancer with distinct epidemiology, pathology and natural history.  mEOC can often masquerade as metastatic mucinous tumours from the gastrointestinal (GI) tract.  Molecularly, in contrast to high-grade serous ovarian cancer (HGSOC), mEOC are far less defined by p53 mutations and instead commonly harbour KRAS and HER 2 mutations.  The current gold standard of 1 st line platinum/taxane doublet chemotherapy, is more tailored towards HGSOC and generally ineffective for mEOC.  This review summarises the limited evidence for using GI style chemotherapeutic agents in treating mEOC and explores novel therapeutic possibilities such as targeting HER2, VEGF and Src. AbstractMucinous ovarian cancer represents approximately 3% of epithelial ovarian cancers (EOC).Despite this seemingly low prevalence, it remains a diagnostic and therapeutic conundrum that has resulted in numerous attempts to adopt novel strategies in managing this disease.Anecdotally, there has been a prevailing notion that established gold standard systemic regimens should be substituted for those utilised in cancers such as gastrointestinal (GI) malignancies; tumours that share more biological similarities than other EOC subtypes. This review summarises the plethora of small studies which have adopted this philosophy and influenced the design of the multinational GOG142 study, which was ultimately terminated due to poor accrual. To date, there is a paucity of evidence to support delivering 'GI style' chemotherapy for mucinous ovarian cancer over and above carboplatin-paclitaxel doublet therapy. Hence there is an urge to develop studies focused on targeted therapeutic agents driven by refined mutational analysis and conducted within the context of harmonised international collaborations.3

Background and AimWe investigated the prognostic importance of dickkopf-1(DKK1) and beta-catenin expression in triple negative breast cancers.MethodsThe expression of DKK1 and beta-catenin was evaluated in breast cell lines using RT-PCR and western blot. Immunohistochemistry was used to characterize the expression pattern of DKK1 and beta-catenin in 85 triple negative breast cancers and prognostic significance was assessed by Kaplan-Meier analysis and Cox proportional hazards regression modeling.ResultsThe expression of DKK1 was confirmed in hormone-resistant breast cell lines MDA-MB-231, MDA-MB-231-HM and MDA-MB-435. Expression of DKK1 in triple negative breast cancers correlated with cytoplasmic/nuclear beta-catenin (p = 0.000). Elevated expression of DKK1 and cytoplasmic/nuclear beta-catenin in triple negative cancers indicate poor outcome of patients. DKK1 was also a prognostic factor for patients with earlier stage or no lymph node metastasis.ConclusionDKK1 together with beta-catenin might be important prognostic factors in triple negative breast carcinoma. DKK1 might be a valuable biomarker in predicting the prognosis of patients with earlier stage or no lymph node metastasis. It is possible that through further understanding of the role of Wnt/beta-catenin pathway activation, beta-catenin would be a potential therapeutic target for the triple negative breast cancer.

The association between single-nucleotide polymorphisms (SNPs) in the COX-2 gene and breast cancer risk is still ambiguous. We here try to derive a more precise estimation of the relationship by performing a meta-analysis based on currently available evidence from literature. More than 15 SNPs have been studied, and the most studied genetic variants were rs5275, rs5277, and rs20417. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association between each polymorphism and breast cancer risk under the codominant model, dominant model, and recessive model, respectively (nine studies with 6,968 cases and 9,126 controls for rs5275; three studies with 2,901 cases and 3,463 controls for rs20417; two studies with 5,551 cases and 6,208 controls for rs5277). No overall significant associations were observed in single-locus analysis between the three polymorphisms of COX-2 and breast cancer risk, though a borderline significant increased risk of breast cancer was detected with rs5277 in a recessive model (OR: 1.217, 95% CI: 0.958-1.547, P = 0.107). The results were not changed when studies were stratified by ethnicity. In conclusion, the present metaanalysis suggests that none of the most studied three SNPs (rs5275, rs20417, and rs5277) in the COX-2 gene is a conspicuous low-penetrant risk factor for developing breast cancer. There is a need for further large studies into the role of these polymorphisms (especially rs5277) and other potentially functional polymorphisms/haplotypes in the COX-2 gene as breast cancer risk modifiers.

Hearing loss is the most common sensory impairment, but limited studies focused on the association of socioeconomic status (SES) with hearing loss among adults of working age. This paper aimed to fill this gap among Chinese adults. We obtained data from Ear and Hearing Disorder Survey conducted in four provinces of China in 2014–2015. The survey was based on WHO Ear and Hearing Disorders Survey Protocol and 25,860 adults aged 25 to 59 years were selected in this study. Trained local examiners performed pure tone audiometry to screen people with hearing loss, and those who were screened positively for hearing loss were referred to audiologists to make final diagnosis. SES was measured by occupation, education and income. Results show after adjusting for SES measures and covariates, in urban areas, compared with white-collar workers, blue-collar workers and the unemployed were more likely to have hearing loss, with an odds ratio of 1.2 (95%CI: 1.0, 1.3) and 1.2 (95%CI: 1.0, 1.4), respectively. Compared with people with education of senior high school or above, those with junior high school, primary school and illiteracy had 1.6 (95%CI: 1.4, 1.8), 2.1(95%CI: 1.7, 2.5) and 2.6 (95%CI: 1.9, 3.7) times as likely to have hearing loss, respectively. In rural areas, the unemployed had 1.5 (95%CI: 1.0, 2.3) times the risk of hearing loss compared with white-collar workers, and illiterates had 1.6 (95%CI: 1.6, 2.1) times the risk of hearing loss compared with people with education of senior high school or above, after SES variables and covariates were taken into considerations. Income was not significantly associated with hearing loss in urban and rural areas. In conclusion, SES, in the form of occupation and education, was associated with hearing loss among working-aged population, and further studies are needed to explore the mechanism of such association.

The inhibitory effect of two chemokine decoy receptors (CDRs), DARC and D6, on breast cancer metastasis is mainly due to their ability to sequester pro-malignant chemokines. We hypothesized that genetic variants in the DARC and CCBP2 (encoding D6) genes may be associated with breast cancer progression. In the present study, we evaluated the genetic contributions of DARC and CCBP2 to metastatic potential, indicated by lymph node metastasis (LNM). Ten single-nucleotide polymorphisms (SNPs) (potentially functional SNPs and block-based tagging SNPs) in DARC and CCBP2 were genotyped in 785 breast cancer patients who had negative lymph nodes and 678 patients with positive lymph nodes. Two non-synonymous SNPs, rs12075 (G42D) in DARC and rs2228468 (S373Y) in CCBP2, were observed to be associated with LNM in univariate analysis and remained significant after adjustment for conventional clinical risk factors, with odds ratios (ORs) of 0.54 (95% confidence interval [CI], 0.37 to 0.79) and 0.78 (95% CI, 0.62 to 0.98), respectively. Additional functional experiments revealed that both of these significant SNPs could affect metastasis of breast cancer in xenograft models by differentially altering the chemokine sequestration ability of their corresponding proteins. Furthermore, heterozygous GD genotype of G42D on human erythrocytes had a significantly stronger chemokine sequestration ability than homozygous GG of G42D ex vivo. Our data suggest that the genetic variants in the CDR genes are probably associated with the varied metastatic potential of breast cancer. The underlying mechanism, though it needs to be further investigated, may be that CDR variants could affect the chemokine sequestration ability of CDR proteins.

We conducted a study to investigate the role of excision repair cross-complimentary group 1 gene (ERCC1)-xeroderma pigmentosum complementation group F (XPF) gene polymorphisms in response to chemotherapy and clinical outcome of gastric patients. Three SNPs in ERCC1 (rs11615, rs3212986, and rs2298881) and two SNPs in XPF (rs2276465 and rs6498486) were extracted using Tiangen DNA kit (Tiangen Biotech, Beijing, China) according to the manufacturer's instructions. The median follow-up time was 36.4 months, and ranged from 2-60 months. During the follow-up period, 112 patients died from gastric cancer. Individuals carrying ERCC1 rs11615 AA and XPF rs6498486 CC genotypes were associated with poorer response to chemotherapy when compared with wild-type genotype, with the ORs (95 % CI) of 0.48 (0.25-0.94) and 0.38 (0.14-1.00). In the Cox proportional hazards model, individuals carrying ERCC1 rs11615 GA and AA genotype had 1.91 and 2.66 risk of death when compared with those carrying GG genotype. Patients carrying the XPF rs6498486 AC and CC genotype were associate with 2.17 and 4.91-fold risk of death when compared with wild-type genotype. In conclusion, we found that ERCC1 rs11615 and XPF rs2276465 may substantially contribute to the future design of individualized cancer treatment in gastric cancer patients.

(99m)Technetium-labeled diethylenetriamine pentaacetic acid-polyethylene glycol-folate (DTPA-PEG-folate) was synthesized and tested as a radiopharmaceutical agent, which targeted the lymphatic system with metastatic tumor. Folic acid was reacted with H2N-PEG-NH2 to yield H2N-PEG-folate. After purification by anion-exchange chromatography, the product was reacted with cyclic DTPA. By removal of unreacted DTPA by size-exclusion chromatography, DTPA-PEG-Folate was obtained. Fluorescein-5-isothiocyanate (FITC)-labeled DTPA-PEG-folate and DTPA-PEG-OCH3 were prepared via a dicyclohexylcarbodiimide-mediated coupling. In vitro competitive binding test showed that the uptake of [125I] folic acid was inhibited by DTPA-PEG-folate and the 50% inhibitory concentration was 4.37 pmol/L (R2 = 0.9922). The relative affinity of DTPA-PEG-FITC was 0.18 for human folate receptor comparing with folic acid. In cultured tumor cells, uptake of fluorescence-labeled DTPA-PEG-folate was found to increase significantly in folate-deficient medium compared with that of untargeted DTPA-PEG-OCH3 and FITC-ethylenediamine. The competition with free folic acid blocked the cell uptake of DTPA-PEG-folate. These results confirmed the DTPA-PEG-folate entered into KB cells through the folate receptor endocytosis pathway in vitro. The radiolabeled yield of [(99m)Tc] DTPA-PEG-folate was in excess of 98%, and specific activities of 7.4 kBq (0.2 microCi/microg) were achieved. After subcutaneous injection, [(99m)Tc] DTPA-PEG-folate exhibited an initial increase and successive decline of accumulation in popliteal nodes in normal Wistar rats. Expect for the kidney, uptake by other tissues was rather low. In a normal rabbit imagine study, the lymphatic vessels were readily visualized by single-photon-emission computed tomography following subcutaneous injection of [(99m)Tc] DTPA-PEG-folate. In conclusion, the [(99m)Tc] DTPA-PEG-folate conjugate may have a potential as a lymphatic tumor-targeted radiopharmaceutical.