354 research outputs found

    Generation of Two Paclitaxel-Resistant High-Grade Serous Carcinoma Cell Lines With Increased Expression of P-Glycoprotein

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    Debulking surgery followed by chemotherapy are the standard of care for high-grade serous carcinoma. After an initial good response to treatment, the majority of patients relapse with a chemoresistant profile, leading to a poor overall survival. Chemotherapy regimens used in high-grade serous carcinomas are based in a combination of classical chemotherapeutic drugs, namely, Carboplatin and Paclitaxel. The mechanisms underlying drug resistance and new drug discovery are crucial to improve patients’ survival. To uncover the molecular mechanisms of chemoresistance and test drugs capable of overcoming this resistant profile, it is fundamental to use good cellular models capable of mimicking the chemoresistant disease. Herein, we established two high-grade serous carcinoma cell lines with intrinsic resistance to Carboplatin and induced Paclitaxel resistance (OVCAR8 PTX R C and OVCAR8 PTX R P) derived from the OVCAR8 cell line. These two chemoresistant cell line variants acquired an enhanced resistance to Paclitaxel-induced cell death by increasing the drug efflux capacity, and this resistance was stable in long-term culture and following freeze/thaw cycles. The mechanism underlying Paclitaxel resistance resides in a significant increase in P-glycoprotein expression and, when this drug efflux pump was blocked with Verapamil, cells re-acquired Paclitaxel sensitivity. We generated two high-grade serous carcinoma cell lines, with a double-chemoresistant (Carboplatin and Paclitaxel) phenotype that mimics the majority of tumor recurrences in ovarian cancer context. This robust tool is suitable for preliminary drug testing towards the development of therapeutic strategies to overcome chemoresistance.This work was developed at i3S/IPATIMUP, an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education, and partially supported by Funda̧cao para a Cîencia e a Tecnologia (FCT). This research was supported by European Regional Development Funds (ERDF) funds through the COMPETE 2020–Operational Program for Competitiveness and Internationalization (POCI), Portugal 2020, Funda̧cao para a Cîencia e a Tecnologia (FCT)/Minist́erio da Cîencia, Tecnologia e Inova̧cao (MCTES), under the project POCI 01-0145-FEDER-029503 (PTDC/MEC-ONC/29503/2017) and CESPU (Cooperativa de Ensino Superior Politécnico e Universitário) under the project ComeTarget_CESPU_2017 (to HB). MN acknowledges FCT/MCTES and UE for financial support through a PhD fellowship (2020.04720.BD) cosponsored by Fundo Social Europeu (FSE) through Programa Operacional Regional Norte (Norte 2020)

    Classic and spatial shift-share analysis of state-level employment change in Brazil

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    This paper combines classic and spatial shift-share decompositions of 1981 to 2006 employment change across the 27 states of Brazil. The classic shift-share method shows higher employment growth rates for underdeveloped regions that are due to an advantageous industry-mix and also due to additional job creation, commonly referred to as the competitive effect. Alternative decompositions proposed in the literature do not change this broad conclusion. Further examination employing exploratory spatial data analysis (ESDA) shows spatial correlation of both the industry-mix and the competitive effects. Considering that until the 1960s economic activities were more concentrated in southern regions of Brazil than they are nowadays, these results support beta convergence theories but also find evidence of agglomeration effects. Additionally, a very simple spatial decomposition is proposed that accounts for the spatially-weighted growth of surrounding states. Favourable growth in northern and centre-western states is basically associated with those states’ strengths in potential spatial spillover effect and in spatial competitive effect
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