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Martinez-Balibrea E.,Hospital Germans Trias I Pujol | Martinez-Balibrea E.,Health science Research Institute of the Germans Trias I Pujol Foundation IGTP | Martinez-Cardus A.,LHospitalet | Gines A.,Health science Research Institute of the Germans Trias I Pujol Foundation IGTP | And 11 more authors.
Molecular Cancer Therapeutics | Year: 2015

Oxaliplatin was the first platinum drug with proven activity against colorectal tumors, becoming a standard in the management of this malignancy. It is also considered for the treatment of pancreatic and gastric cancers. However, a major reason for treatment failure still is the existence of tumor intrinsic or acquired resistance. Consequently, it is important to understand the molecular mechanisms underlying the appearance of this phenomenon to find ways of circumventing it and to improve and optimize treatments. This review will be focused on recent discoveries about oxaliplatin tumor-related resistance mechanisms, including alterations in transport, detoxification, DNA damage response and repair, cell death (apoptotic and nonapoptotic), and epigenetic mechanisms. ©2015 AACR.

PubMed | Institute for Predictive and Personalized Medicine of Cancer IMPPC, Hospital CIMA Sanitas, Royal Infirmary and Health science Research Institute of the Germans Trias i Pujol Foundation IGTP
Type: | Journal: Scientific reports | Year: 2016

Resistance to oxaliplatin (OXA) is a complex process affecting the outcomes of metastatic colorectal cancer (CRC) patients treated with this drug. De-regulation of the NF-B signalling pathway has been proposed as an important mechanism involved in this phenomenon. Here, we show that NF-B was hyperactivated in in vitro models of OXA-acquired resistance but was attenuated by the addition of Curcumin, a non-toxic NF-B inhibitor. The concomitant combination of Curcumin+OXA was more effective and synergistic in cell lines with acquired resistance to OXA, leading to the reversion of their resistant phenotype, through the inhibition of the NF-B signalling cascade. Transcriptomic profiling revealed the up-regulation of three NF-B-regulated CXC-chemokines, CXCL8, CXCL1 and CXCL2, in the resistant cells that were more efficiently down-regulated after OXA+Curcumin treatment as compared to the sensitive cells. Moreover, CXCL8 and CXCL1 gene silencing made resistant cells more sensitive to OXA through the inhibition of the Akt/NF-B pathway. High expression of CXCL1 in FFPE samples from explant cultures of CRC patients-derived liver metastases was associated with response to OXA+Curcumin. In conclusion, we suggest that combination of OXA+Curcumin could be an effective treatment, for which CXCL1 could be used as a predictive marker, in CRC patients.

Lozano M.,Institute for Bioengineering of Catalonia IBEC | Lozano M.,Health science Research Institute of the Germans Trias i Pujol Foundation IGTP | Fiz J.A.,Institute for Bioengineering of Catalonia IBEC | Fiz J.A.,Pulmonology Service at Germans Trias i Pujol University Hospital | And 4 more authors.
Signal Processing | Year: 2016

The use of the Hilbert-Huang transform in the analysis of biomedical signals has increased during the past few years, but its use for respiratory sound (RS) analysis is still limited. The technique includes two steps: empirical mode decomposition (EMD) and instantaneous frequency (IF) estimation. Although the mode mixing (MM) problem of EMD has been widely discussed, this technique continues to be used in many RS analysis algorithms. In this study, we analyzed the MM effect in RS signals recorded from 30 asthmatic patients, and studied the performance of ensemble EMD (EEMD) and noise-assisted multivariate EMD (NA-MEMD) as means for preventing this effect. We propose quantitative parameters for measuring the size, reduction of MM, and residual noise level of each method. These parameters showed that EEMD is a good solution for MM, thus outperforming NA-MEMD. After testing different IF estimators, we propose Kay's method to calculate an EEMD-Kay-based Hilbert spectrum that offers high energy concentrations and high time and high frequency resolutions. We also propose an algorithm for the automatic characterization of continuous adventitious sounds (CAS). The tests performed showed that the proposed EEMD-Kay-based Hilbert spectrum makes it possible to determine CAS more precisely than other conventional time-frequency techniques. © 2015 Elsevier B.V. All rights reserved.

Manzano J.L.,University of Barcelona | Manzano J.L.,Health science Research Institute of the Germans Trias i Pujol Foundation IGTP | Layos L.,University of Barcelona | Buges C.,University of Barcelona | And 4 more authors.
Annals of Translational Medicine | Year: 2016

Patients with advanced melanoma have traditionally had very poor prognosis. However, since 2011 better understanding of the biology and epidemiology of this disease has revolutionized its treatment, with newer therapies becoming available. These newer therapies can be classified into immunotherapy and targeted therapy. The immunotherapy arsenal includes inhibitors of CTLA4, PD-1 and PDL-1, while targeted therapy focuses on BRAF and MEK. BRAF inhibitors (vemurafenib, dabrafenib) have shown benefit in terms of overall survival (OS) compared to chemotherapy, and their combination with MEK inhibitors has recently been shown to improve progression-free survival (PFS), compared with monotherapy with BRAF inhibitors. However, almost 20% of patients initially do not respond, due to intrinsic resistance to therapy and, of those who do, most eventually develop mechanisms of acquired resistance, including reactivation of the MAP kinase pathway, persistent activation of receptor tyrosine kinase (RTKS) receptor, activation of phosphatidyinositol-3OH kinase, overexpression of epidermal growth factor receptor (EGFR), and interactions with the tumor microenvironment. Herein we comment in detail on mechanisms of resistance to targeted therapy and discuss the strategies to overcome them. © Annals of Translational Medicine. All rights reserved.

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