Background:Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive human malignancies with an overall 5-year survival rate of <5%. Despite significant advances in treatment of the disease during the past decade, the median survival rate (∼6 months) has hardly improved, warranting the need to identify novel targets for therapeutic approaches.Methods:Quantitative real time PCR, western blot analyses and immunohistochemical staining of tissue microarrays were used to analyse the expression of TTK gene in primary PDAC tissues and cell lines. To inhibit TTK kinase expression in a variety of pancreatic cancer cell lines, RNA interference was used. Functional roles of this kinase in the context of PDAC were studied using cell proliferation, viability and anchorage-independent growth assays. Western blotting, fluorescence-activated cell sorting analyses and fluorescence microscopy were used to gain mechanistic insight into the functional effects.Conclusions:We show that the dual specificity kinase TTK (also known as Mps1), is strongly overexpressed in human PDAC. Functionally, cell proliferation was significantly attenuated following TTK knockdown, whereas apoptosis and necrosis rates were significantly increased. In addition, anchorage-independent growth, a hallmark of malignant transformation and metastatic potential, was strongly impaired in the absence of TTK gene function. Interestingly, immortalised normal pancreatic hTERT-HPNE cells were not affected by loss of TTK function. Mechanistically, these effects in cancer cells were associated with increased formation of micronuclei, suggesting that loss of TTK function in pancreatic cancer cells results in chromosomal instability and mitotic catastrophe. Taken together, our data show that TTK function is critical for growth and proliferation of pancreatic cancer cells, thus establishing this kinase as an interesting new target for novel therapeutic approaches in combating this malignancy.

Pancreatic ductal adenocarcinoma (PDAC) carries the most dismal prognosis of all solid tumors and is generally strongly resistant to currently available chemo-and/or radiotherapy regimens, including targeted molecular therapies. Therefore, unraveling the molecular mechanisms underlying the aggressive behavior of pancreatic cancer is a necessary prerequisite for the development of novel therapeutic approaches. We previously identified the protein placenta-specific 8 (PLAC8, onzin) in a genome-wide search for target genes associated with pancreatic tumor progression and demonstrated that PLAC8 is strongly ectopically expressed in advanced preneoplastic lesions and invasive human PDAC. However, the molecular function of PLAC8 remained unclear, and accumulating evidence suggested its role is highly dependent on cellular and physiologic context. Here, we demonstrate that in contrast to other cellular systems, PLAC8 protein localizes to the inner face of the plasma membrane in pancreatic cancer cells, where it interacts with specific membranous structures in a temporally and spatially stable manner. Inhibition of PLAC8 expression strongly inhibited pancreatic cancer cell growth by attenuating cell-cycle progression, which was associated with transcriptional and/or posttranslational modification of the central cell-cycle regulators CDKN1A, retinoblastoma protein, and cyclin D1 (CCND1), but did not impact autophagy. Moreover, Plac8 deficiency significantly inhibited tumor formation in genetically engineered mouse models of pancreatic cancer. Together, our findings establish PLAC8 as a central mediator of tumor progression in PDAC and as a promising candidate gene for diagnostic and therapeutic targeting. Cancer Res; 76(1); 96-107. Ó2015 AACR.

BACKGROUND: Since 1999, the German Armed Forces (Bundeswehr) have been conducting 3-weeks preventive treatment programs aimed at psychological resource-strengthening in soldiers returning from deployment. METHODS: Five hundred participants of these programs received the Posttraumatic Stress Scale 10 (PTSS-10) before and after treatment and the rehabilitation assessment questionnaire of the German statutory pension insurance body. Sixty control group subjects received the PTSS-10 twice in an interval of 4-5 months without therapeutic interventions. RESULTS: Comparison of pre-and post-treatment PTSS-10 results in the covariance analysis showed an effect of the initial PTSS-10-stress-levels and rank category, not of the intervention. On average, the treatment program received 'very good' to 'excellent' overall ratings in the rehabilitation questionnaire. The acceptance of sports and movement therapy was significantly above average, whereas that of individual and group counselling was below. CONCLUSIONS: The results of this pilot study suggest a high acceptance of the post-deployment preventive program. Effectiveness in terms of psychometric improvement cannot be proven at this point.

<p>List of differentially expressed transcripts.</p>

<p>Summary of assays and effects from RPPA analyses.</p>