Purpose: Gemcitabine is an inhibitor of ribonucleotide reductase (RR) and DNA synthesis and is an effective agent in the treatment of pancreas cancer. The present study investigates whether the multitargeted antifolate pemetrexed would be synergistic with gemcitabine against MIA PaCa-2, PANC-1, and Capan-1 pancreatic cancer cell lines.Experimental Design: Cells were treated with gemcitabine and pemetrexed, and the type of drug interaction was assessed using the combination index. Cytotoxicity of gemcitabine was examined with inhibitors of (a) deoxycytidine kinase (dCK), which activates gemcitabine by phosphorylation, and (b) 5-nucleotidase (drug dephosphorylation) and cytidine deaminase (drug deamination), the main inactivating enzymes. The effects of gemcitabine and pemetrexed on cell cycle were analyzed by flow cytometry, and apoptosis was examined by fluorescence microscopy. Finally, quantitative, real-time PCR was used to study the pharmacogenetics of the drug combination.Results: Synergistic cytotoxicity and enhancement of apoptosis was demonstrated, mostly with the sequence pemetrexed3gemcitabine. Pemetrexed increased cells in S phase, the most sensitive to gemcitabine, and a positive correlation was found between the expression ratio of dCK:RR and gemcitabine sensitivity. Indeed, pemetrexed significantly enhanced dCK gene expression (؉227.9, ؉86.0, and ؉135.5% in MIA PaCa-2, PANC-1, and Capan-1 cells, respectively), and the crucial role of this enzyme was confirmed by impairment of gemcitabine cytotoxicity after dCK saturation with 2-deoxycytidine.Conclusions: These data demonstrate that the gemcitabine and pemetrexed combination displays scheduledependent synergistic cytotoxic activity, favorably modulates cell cycle, induces apoptosis, and enhances dCK expression in pancreatic cancer cells.

Standard-Nutzungsbedingungen:Die Dokumente auf EconStor dürfen zu eigenen wissenschaftlichen Zwecken und zum Privatgebrauch gespeichert und kopiert werden.Sie dürfen die Dokumente nicht für öffentliche oder kommerzielle Zwecke vervielfältigen, öffentlich ausstellen, öffentlich zugänglich machen, vertreiben oder anderweitig nutzen.Sofern die Verfasser die Dokumente unter Open-Content-Lizenzen (insbesondere CC-Lizenzen) zur Verfügung gestellt haben sollten, gelten abweichend von diesen Nutzungsbedingungen die in der dort genannten Lizenz gewährten Nutzungsrechte. www.econstor.eu The Institute for the Study of Labor (IZA) in Bonn is a local and virtual international research center and a place of communication between science, politics and business. IZA is an independent nonprofit organization supported by Deutsche Post Foundation. The center is associated with the University of Bonn and offers a stimulating research environment through its international network, workshops and conferences, data service, project support, research visits and doctoral program. IZA engages in (i) original and internationally competitive research in all fields of labor economics, (ii) development of policy concepts, and (iii) dissemination of research results and concepts to the interested public. Terms of use: Documents in D I S C U S S I O N P A P E R S E R I E SIZA Discussion Papers often represent preliminary work and are circulated to encourage discussion. Citation of such a paper should account for its provisional character. A revised version may be available directly from the author. Across the subjects of economics, sociology and demography, much has been written about the difficulties faced by immigrants. However, much less attention has been paid to the readjustment challenges migrants face on their return. In this paper, we examine whether and the extent to which a group of returned migrants experience higher degrees of social isolation and loneliness compared to compatriots who never lived abroad. The data used are from the first wave of the Irish Longitudinal Study on Ageing (TILDA). We find that social isolation is a significant feature of the lives of return migrants.

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Background: Patients with Mild Cognitive Impairment (MCI) and Vascular Cognitive Impairment (VCI) are at a high risk of progressing to dementia. Recent guidelines indicate the importance of promoting multidimensional and multi-domain interventions to prevent further decline. Due to its growing effectiveness, comparable to conventional face-to-face interventions, the use of technology is gaining relevance. Tele-rehabilitation systems have the potential to engage patients in multi-dimensional activity programs and to guarantee a low-cost continuum of care through remote control. A possible limitation of such programs is represented by the lack of familiarization with technology and computers in elderly people. The purpose of this study is to describe the feasibility, adherence, and appreciation of the GOAL Tele-R system, administered by a web-application through remote control in patients with MCI/VCI.Methods: Feasibility of the Tele-R system was evaluated by means of distribution of patients' attrition along the study phases, controlling for potential systematic bias in drop-out rates due to the technological device. Adherence was evaluated analyzing drop-out rates and indexes of carried out activities. Patients' appreciation was analyzed through ad hoc satisfaction questionnaire items.Results: Out of 86 approached patients, 25 (29%) were not enrolled, 30 (35%) dropped-out after randomization, and 31 (36%) completed the study (standard care group n = 12, the tele-R group n = 19). Compared to the tele-R group, rates of drop-outs resulted significantly higher for the standard care group (34 vs. 62%, respectively, p = 0.029). Taking into account baseline characteristics, females resulted in a statistically significant higher rate of drop-outs compared to males (66 vs. 27%, respectively, p = 0.003). Overall adherence to the proposed activities was 84% (85% for cognitive module and 83% for physical activity module). Concerning satisfaction, participants provided a good mean level of appreciation (3.7 ± 0.8, range 1–5), a positive feedback for usability, and a subjective perception of cognitive, emotional, and physical benefits due to the training.Conclusion: The GOAL Tele-R system seems a feasible technological rehabilitation program, reaching an acceptable level of adherence and appreciation in patients with an MCI/VCI condition.Clinical Trial Registration:www.ClinicalTrials.gov, ID: NCT03383549 (registration date: 26/dec/2017).

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