Exportin-1 (XPO1) controls the nucleo-cytoplasmic trafficking of several key growth regulatory and tumor suppressor proteins. Nuclear export blockade through XPO1 inhibition is a target for therapeutic inhibition in many cancers. Studies have suggested XPO1 upregulation as an indicator of poor prognosis in gastric cancer. In the current study, we investigated the anti-tumor efficacy of selective inhibitors of nuclear export (SINE) compounds KPT-185, KTP-276 and clinical stage selinexor (KPT-330) in gastric cancer. XPO1 was found to be overexpressed in gastric cancer as compared to adjacent normal tissues and was correlated with poor survival outcomes. Among the 3 SINE compounds, in vitro targeting of XPO1 with selinexor resulted in greatest potency with significant anti-proliferative effects at nano molar concentrations. XPO1 inhibition by selinexor resulted in nuclear accumulation of p53, causing cell cycle arrest and apoptosis. Also, inhibition of XPO1 lead to the cytoplasmic retention of p21 and suppression of survivin. Orally administered selienxor caused significant inhibition of tumor growth in xenograft models of gastric cancer. Furthermore, combination of selinexor with irinotecan exhibited greater anti-tumor effect compared to individual treatment. Taken together, our study underscores the therapeutic utility of XPO1 targeting in gastric cancer and suggests the potential benefits of XPO1 inhibition in-combination with chemotherapy.

BackgroundPlatinum based therapy is commonly used in the treatment of advanced gastric cancer. However, resistance to chemotherapy is a major challenge that causes marked variation in individual response rate and survival rate. In this study, we aimed to identify the expression of GTSE1 and its correlation with cisplatin resistance in gastric cancer cells.MethodsMethylation profiling was carried out in tissue samples from gastric cancer patients before undergoing neoadjuvent therapy using docetaxel, cisplatin and 5FU (DCX) and in gastric cancer cell lines. The correlation between GTSE1 expression and methylation in gastric cancer cells was determined by RT-PCR and MSP respectively. GTSE1 expression was knocked-down using shRNA’s and its effects on cisplatin cytotoxicity and cell survival were detected by MTS, proliferation and clonogenic survival assays. Additionally, the effect of GTSE1 knock down in drug induced apoptosis was determined by western blotting and apoptosis assays.ResultsGTSE1 exhibited a differential methylation index in gastric cancer patients and in cell lines that correlated with DCX treatment response and cisplatin sensitivity, respectively. In-vitro, GTSE1 expression showed a direct correlation with hypomethylation. Interestingly, Cisplatin treatment induced a dose dependent up regulation as well as nuclear translocation of GTSE1 expression in gastric cancer cells. Knock down of GTSE1 enhanced cisplatin cytotoxity and led to a significant reduction in cell proliferation and clonogenic survival. Also, loss of GTSE1 expression caused a significant increase in P53 mediated apoptosis in cisplatin treated cells.ConclusionOur study identifies GTSE1 as a biomarker for cisplatin resistance in gastric cancer cells. This study also suggests the repressive role of GTSE1 in cisplatin induced apoptosis and signifies its potential utility as a therapeutic target for better clinical management of gastric cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1550-0) contains supplementary material, which is available to authorized users.

Pregnant women who were keen to undergo CMV testing demonstrated attitudes toward invasive testing and termination of pregnancy that were not significantly different from those of women who would refuse testing. Patient choice and expectations should be considered in the implementation of preventive measures against congenital CMV.

INTRODUCTIONInvasive prenatal diagnosis (IPD) has long been used to prenatally diagnose Down syndrome (DS), but it is associated with a small risk of miscarriage. Noninvasive prenatal testing (NIPT) is a highly sensitive screening test using cell-free DNA in maternal blood for detection of DS without the risk of miscarriage, but it confers a small risk of false-positive and false-negative results. The implementation of these procedures into clinical practice requires an understanding of stakeholder preferences.METHODS A total of 69 health professionals (HPs) and 301 women took part in a discrete choice experiment (DCE) in which preferences for four prenatal test attributes -accuracy, time of results, risk of miscarriage and amount of information provided -were assessed. Conditional logit regression was used to analyse the data. Data on demographics and ranked preferences for test attributes was collected, and a direct choice question regarding NIPT, IPD or neither test was posed to participants. RESULTSThe women showed a preference for test safety, whereas HPs prioritised test accuracy above all other attributes.When offered a direct choice of NIPT, IPD or neither test, women aged 35 years and older, those with previous miscarriage or who knew a child with DS were more likely to choose NIPT. Chinese women preferred NIPT, whereas Indian women preferred IPD.CONCLUSION Our data highlights the need for patient-specifi c counselling, taking into account previous experiences and cultural factors. Since women and HPs prioritise different test attributes, it is essential that HPs recognise these differences in order to provide non-biased counselling.