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Prof. Dr. Rocio Macias
Experimental Hepatology and Drug Targeting, University of Salamanca, IBSAL, CIBERehd, Salamanca, Spain

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0 Biomarkers
0 Hepatology
0 chemoresistance
0 drug targeting
0 Biliary cancer

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Correspondence
Published: 17 May 2021 in Hepatology
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We thank Jansson & Sparrelid for their Letter to the Editor(1)regarding our publication(2). We stated that “based on our results, patients with liver metastases should not be offered therapeutic strategies suitable for early stages, in view of poor survival”. Jansson(1) argues that “the role of surgery in multiple intrahepatic cholangiocarcinoma (iCCA) should not be dismissed without further analysis”; similar to Zhang’s views(3).

ACS Style

Angela Lamarca; Alvaro Santos‐Laso; Kirsten Utpatel; Adelaida La Casta; Simone Stock; Alejandro Forner; Jorge Adeva; Trine Folseraas; Luca Fabris; Rocio Ir Macias; Marcin Krawczyk; Marek Krawczyk; Vincenzo Cardinale; Chiara Braconi; Domenico Alvaro; Matthias Evert; Jesus M. Banales; Juan W. Valle. REPLY:. Hepatology 2021, 1 .

AMA Style

Angela Lamarca, Alvaro Santos‐Laso, Kirsten Utpatel, Adelaida La Casta, Simone Stock, Alejandro Forner, Jorge Adeva, Trine Folseraas, Luca Fabris, Rocio Ir Macias, Marcin Krawczyk, Marek Krawczyk, Vincenzo Cardinale, Chiara Braconi, Domenico Alvaro, Matthias Evert, Jesus M. Banales, Juan W. Valle. REPLY:. Hepatology. 2021; ():1.

Chicago/Turabian Style

Angela Lamarca; Alvaro Santos‐Laso; Kirsten Utpatel; Adelaida La Casta; Simone Stock; Alejandro Forner; Jorge Adeva; Trine Folseraas; Luca Fabris; Rocio Ir Macias; Marcin Krawczyk; Marek Krawczyk; Vincenzo Cardinale; Chiara Braconi; Domenico Alvaro; Matthias Evert; Jesus M. Banales; Juan W. Valle. 2021. "REPLY:." Hepatology , no. : 1.

Review
Published: 13 May 2021 in Cancers
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Despite the crucial advances in understanding the biology of cholangiocarcinoma (CCA) achieved during the last decade, very little of this knowledge has been translated into clinical practice. Thus, CCA prognosis is among the most dismal of solid tumors. The reason is the frequent late diagnosis of this form of cancer, which makes surgical removal of the tumor impossible, together with the poor response to standard chemotherapy and targeted therapy with inhibitors of tyrosine kinase receptors. The discovery of genetic alterations with an impact on the malignant characteristics of CCA, such as proliferation, invasiveness, and the ability to generate metastases, has led to envisage to treat these patients with selective inhibitors of mutated proteins. Moreover, the hope of developing new tools to improve the dismal outcome of patients with advanced CCA also includes the use of small molecules and antibodies able to interact with proteins involved in the crosstalk between cancer and immune cells with the aim of enhancing the immune system’s attack against the tumor. The lack of effect of these new therapies in some patients with CCA is associated with the ability of tumor cells to continuously adapt to the pharmacological pressure by developing different mechanisms of resistance. However, the available information about these mechanisms for the new drugs and how they evolve is still limited.

ACS Style

Jose Marin; Paula Sanchon-Sanchez; Candela Cives-Losada; Sofía del Carmen; Jesús González-Santiago; Maria Monte; Rocio Macias. Novel Pharmacological Options in the Treatment of Cholangiocarcinoma: Mechanisms of Resistance. Cancers 2021, 13, 2358 .

AMA Style

Jose Marin, Paula Sanchon-Sanchez, Candela Cives-Losada, Sofía del Carmen, Jesús González-Santiago, Maria Monte, Rocio Macias. Novel Pharmacological Options in the Treatment of Cholangiocarcinoma: Mechanisms of Resistance. Cancers. 2021; 13 (10):2358.

Chicago/Turabian Style

Jose Marin; Paula Sanchon-Sanchez; Candela Cives-Losada; Sofía del Carmen; Jesús González-Santiago; Maria Monte; Rocio Macias. 2021. "Novel Pharmacological Options in the Treatment of Cholangiocarcinoma: Mechanisms of Resistance." Cancers 13, no. 10: 2358.

Editorial
Published: 02 May 2021 in Expert Opinion on Investigational Drugs
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ACS Style

Jose Jg Marin; Rocio Ir Macias. Understanding drug resistance mechanisms in cholangiocarcinoma: assisting the clinical development of investigational drugs. Expert Opinion on Investigational Drugs 2021, 1 -5.

AMA Style

Jose Jg Marin, Rocio Ir Macias. Understanding drug resistance mechanisms in cholangiocarcinoma: assisting the clinical development of investigational drugs. Expert Opinion on Investigational Drugs. 2021; ():1-5.

Chicago/Turabian Style

Jose Jg Marin; Rocio Ir Macias. 2021. "Understanding drug resistance mechanisms in cholangiocarcinoma: assisting the clinical development of investigational drugs." Expert Opinion on Investigational Drugs , no. : 1-5.

Correspondence
Published: 07 February 2021 in Hepatology
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We thank Zhang and colleagues for their Letter to the Editor (1) regarding our work (2). Our manuscript (“Liver Metastases of Intrahepatic Cholangiocarcinoma: Implications for an Updated Staging System”(2)), suggested changes to the American Joint Committee on Cancer (AJCC) staging classification for intrahepatic cholangiocarcinoma (iCCA), by classifying “liver metastases” as stage IV rather than stage II/III in the absence/presence of lymph node metastases, respectively, as per AJCC v.8 (3).

ACS Style

Angela Lamarca; Alvaro Santos‐Laso; Kirsten Utpatel; Adelaida La Casta; Simone Stock; Alejandro Forner; Jorge Adeva; Trine Folseraas; Luca Fabris; Rocio I. R. Macias; Marcin Krawczyk; Marek Krawczyk; Vincenzo Cardinale; Chiara Braconi; Domenico Alvaro; Matthias Evert; Jesus M. Banales; Juan W. Valle. REPLY:. Hepatology 2021, 74, 1129 -1131.

AMA Style

Angela Lamarca, Alvaro Santos‐Laso, Kirsten Utpatel, Adelaida La Casta, Simone Stock, Alejandro Forner, Jorge Adeva, Trine Folseraas, Luca Fabris, Rocio I. R. Macias, Marcin Krawczyk, Marek Krawczyk, Vincenzo Cardinale, Chiara Braconi, Domenico Alvaro, Matthias Evert, Jesus M. Banales, Juan W. Valle. REPLY:. Hepatology. 2021; 74 (2):1129-1131.

Chicago/Turabian Style

Angela Lamarca; Alvaro Santos‐Laso; Kirsten Utpatel; Adelaida La Casta; Simone Stock; Alejandro Forner; Jorge Adeva; Trine Folseraas; Luca Fabris; Rocio I. R. Macias; Marcin Krawczyk; Marek Krawczyk; Vincenzo Cardinale; Chiara Braconi; Domenico Alvaro; Matthias Evert; Jesus M. Banales; Juan W. Valle. 2021. "REPLY:." Hepatology 74, no. 2: 1129-1131.

Preprint content
Published: 18 January 2021
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Metabolic-associated fatty liver disease (MAFLD) is affecting more people globally. Indeed, MAFLD is associated with a spectrum of metabolic dysfunctions that can progress to hepatocellular carcinoma (MAFLD-HCC). This development can occur in a non-cirrhotic liver and thus, often lack clinical surveillance. Using comprehensive ultra-high-performance liquid chromatography mass-spectrometry, we investigated 1,295 metabolites in serum from 249 Caucasian liver patients. Here we show that MAFLD-HCC is characterized by a complete rearrangement of the serum lipidome which distinguishes MAFLD-HCC from other HCC patients. We used machine learning to build a diagnostic model for MAFLD to MAFLD-HCC. We quantified predictive metabolites and adjusted the model into the MAFLD-HCC Diagnostic Score, presenting superior diagnostic potential compared to current alpha-fetoprotein (AFP). The metabolic landscape shows a progressive depletion in unsaturated fatty acids and acylcarnitines during transformation. Therefore, serum metabolomics may provide valuable insight to monitor patients at risk, including morbidly obese, diabetics, and MAFLD patients.

ACS Style

Monika Lewinska; Alvaro Santos-Laso; Enara Arrretxe; Cristina Alonso; Raul Jimenez-Aguero; Emma Eizaguirre; María Pareja; Manuel Romero-Gomez; Marco Arrese; Malte Suppli; Filip Knop; Stine Oversoe; Gerda Villadsen; Thomas Decaens; Flair Carrilho; Claudia Oliveira; Bruno Sangro; Rocio Macias; Jesus Banales; Jesper Andersen. Serum lipidomics as diagnostic potential for metabolic-associated hepatocellular carcinoma. 2021, 1 .

AMA Style

Monika Lewinska, Alvaro Santos-Laso, Enara Arrretxe, Cristina Alonso, Raul Jimenez-Aguero, Emma Eizaguirre, María Pareja, Manuel Romero-Gomez, Marco Arrese, Malte Suppli, Filip Knop, Stine Oversoe, Gerda Villadsen, Thomas Decaens, Flair Carrilho, Claudia Oliveira, Bruno Sangro, Rocio Macias, Jesus Banales, Jesper Andersen. Serum lipidomics as diagnostic potential for metabolic-associated hepatocellular carcinoma. . 2021; ():1.

Chicago/Turabian Style

Monika Lewinska; Alvaro Santos-Laso; Enara Arrretxe; Cristina Alonso; Raul Jimenez-Aguero; Emma Eizaguirre; María Pareja; Manuel Romero-Gomez; Marco Arrese; Malte Suppli; Filip Knop; Stine Oversoe; Gerda Villadsen; Thomas Decaens; Flair Carrilho; Claudia Oliveira; Bruno Sangro; Rocio Macias; Jesus Banales; Jesper Andersen. 2021. "Serum lipidomics as diagnostic potential for metabolic-associated hepatocellular carcinoma." , no. : 1.

Original article
Published: 18 October 2020 in Hepatology
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Background Intrahepatic cholangiocarcinoma (iCCA) with liver metastases (LM) are perceived to have a poor prognosis but the American Joint Committee on Cancer (AJCC) classifies them as early stage in the absence of lymph nodes or extrahepatic spread. Methods Patients with iCCA from the European Network for the Study of Cholangiocarcinoma (ENS‐CCA) and Surveillance, Epidemiology, and End Results (SEER) registries with survival/staging (AJCCv.7) data were eligible. Modified staging was used (mAJCCv.7): Group‐A: stages‐I‐III (excluding T2bN0); Group‐B: stage‐IVa (excluding T2bN1M0); Group‐C: LM (T2bN0/1) and Group‐D: stage‐IVb (extra‐hepatic metastases). Survival analysis (Kaplan Meier and Cox Regression) was performed in an ENS‐CCA training cohort (TC) and findings internally [ENS‐CCA (iVC)] and externally [SEER] validated. The aim was to assess if LM (Group‐C) had a shorter survival compared to other early stages (Group‐A). A modified version of AJCCv.8 (mAJCCv.8) is proposed. Results Total of 574 and 4,171 patients from the ENS‐CCA and SEER registries were included. Following the new classification, 19.86% and 17.31% of patients from the ENS‐CCA and SEER registries were reclassified into the Group‐C, respectively. In the ENS‐CCA TC, multivariable Cox Regression was adjusted for obesity (p‐value 0.026) and performance status (p‐value <0.001); patients in Group‐C (HR 2.53 (95%CI 1.18‐5.42); p‐value 0.017) had a higher risk of death (vs Group‐A). Findings were validated in the ENS‐CCA iVC (HR 2.93 (95%CI 2.04‐4.19); p‐value <0.001) and in the SEER registry (HR of 1.88 (95%CI 1.68‐2.09); p‐value <0.001). Conclusions iCCA LM have a worse outcome than other early stages. As AJCCv.8 does not take this into consideration, a modification of AJCC v.8 (mAJCCv.8) including “liver metastases: multiple liver lesions, with or without vascular invasion” as a novel “M1a stage” is suggested.

ACS Style

Angela Lamarca; Alvaro Santos‐Laso; Kirsten Utpatel; Adelaida La Casta; Simone Stock; Alejandro Forner; Jorge Adeva; Trine Folseraas; Luca Fabris; Rocio I.R. Macias; Marcin Krawczyk; Marek Krawczyk; Vincenzo Cardinale; Chiara Braconi; Domenico Alvaro; Matthias Evert; Jesus M. Banales; Juan W. Valle; for the Group: on behalf of the European Network for the Study of Cholangiocarcinoma (ENS‐CCA). Liver Metastases of Intrahepatic Cholangiocarcinoma: Implications for an Updated Staging System. Hepatology 2020, 73, 2311 -2325.

AMA Style

Angela Lamarca, Alvaro Santos‐Laso, Kirsten Utpatel, Adelaida La Casta, Simone Stock, Alejandro Forner, Jorge Adeva, Trine Folseraas, Luca Fabris, Rocio I.R. Macias, Marcin Krawczyk, Marek Krawczyk, Vincenzo Cardinale, Chiara Braconi, Domenico Alvaro, Matthias Evert, Jesus M. Banales, Juan W. Valle, for the Group: on behalf of the European Network for the Study of Cholangiocarcinoma (ENS‐CCA). Liver Metastases of Intrahepatic Cholangiocarcinoma: Implications for an Updated Staging System. Hepatology. 2020; 73 (6):2311-2325.

Chicago/Turabian Style

Angela Lamarca; Alvaro Santos‐Laso; Kirsten Utpatel; Adelaida La Casta; Simone Stock; Alejandro Forner; Jorge Adeva; Trine Folseraas; Luca Fabris; Rocio I.R. Macias; Marcin Krawczyk; Marek Krawczyk; Vincenzo Cardinale; Chiara Braconi; Domenico Alvaro; Matthias Evert; Jesus M. Banales; Juan W. Valle; for the Group: on behalf of the European Network for the Study of Cholangiocarcinoma (ENS‐CCA). 2020. "Liver Metastases of Intrahepatic Cholangiocarcinoma: Implications for an Updated Staging System." Hepatology 73, no. 6: 2311-2325.

Review
Published: 11 September 2020 in Cancers
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The unsatisfactory response of colorectal cancer (CRC) to pharmacological treatment contributes to the substantial global health burden caused by this disease. Over the last few decades, CRC has become the cause of more than 800,000 deaths per year. The reason is a combination of two factors: i) the late cancer detection, which is being partially solved by the implementation of mass screening of adults over age 50, permitting earlier diagnosis and treatment; ii) the inadequate response of advanced unresectable tumors (i.e., stages III and IV) to pharmacological therapy. The latter is due to the existence of complex mechanisms of chemoresistance (MOCs) that interact and synergize with each other, rendering CRC cells strongly refractory to the available pharmacological regimens based on conventional chemotherapy, such as pyrimidine analogs (5-fluorouracil, capecitabine, trifluridine, and tipiracil), oxaliplatin, and irinotecan, as well as drugs targeted toward tyrosine kinase receptors (regorafenib, aflibercept, bevacizumab, cetuximab, panitumumab, and ramucirumab), and, more recently, immune checkpoint inhibitors (nivolumab, ipilimumab, and pembrolizumab). In the present review, we have inventoried the genes involved in the lack of CRC response to pharmacological treatment, classifying them into seven groups (from MOC-1 to MOC-7) according to functional criteria to identify cancer cell weaknesses. This classification will be useful to pave the way for developing sensitizing tools consisting of i) new agents to be co-administered with the active drug; ii) pharmacological approaches, such as drug encapsulation (e.g., into labeled liposomes or exosomes); iii) gene therapy interventions aimed at restoring the impaired function of some proteins (e.g., uptake transporters and tumor suppressors) or abolishing that of others (such as export pumps and oncogenes).

ACS Style

Jose J.G. Marin; Rocio I.R. Macias; Maria J. Monte; Elisa Herraez; Ana Peleteiro-Vigil; Beatriz Sanchez De Blas; Oscar Briz Sanchez; Alvaro G. Temprano; Ricardo A. Espinosa-Escudero; Elisa Lozano; Oscar Briz; Marta R. Romero. Cellular Mechanisms Accounting for the Refractoriness of Colorectal Carcinoma to Pharmacological Treatment. Cancers 2020, 12, 2605 .

AMA Style

Jose J.G. Marin, Rocio I.R. Macias, Maria J. Monte, Elisa Herraez, Ana Peleteiro-Vigil, Beatriz Sanchez De Blas, Oscar Briz Sanchez, Alvaro G. Temprano, Ricardo A. Espinosa-Escudero, Elisa Lozano, Oscar Briz, Marta R. Romero. Cellular Mechanisms Accounting for the Refractoriness of Colorectal Carcinoma to Pharmacological Treatment. Cancers. 2020; 12 (9):2605.

Chicago/Turabian Style

Jose J.G. Marin; Rocio I.R. Macias; Maria J. Monte; Elisa Herraez; Ana Peleteiro-Vigil; Beatriz Sanchez De Blas; Oscar Briz Sanchez; Alvaro G. Temprano; Ricardo A. Espinosa-Escudero; Elisa Lozano; Oscar Briz; Marta R. Romero. 2020. "Cellular Mechanisms Accounting for the Refractoriness of Colorectal Carcinoma to Pharmacological Treatment." Cancers 12, no. 9: 2605.

Review
Published: 30 July 2020 in Cancers
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Gastric adenocarcinoma (GAC) is the most common histological type of gastric cancer, the fifth according to the frequency and the third among the deadliest cancers. GAC high mortality is due to a combination of factors, such as silent evolution, late clinical presentation, underlying genetic heterogeneity, and effective mechanisms of chemoresistance (MOCs) that make the available antitumor drugs scarcely useful. MOCs include reduced drug uptake (MOC-1a), enhanced drug efflux (MOC-1b), low proportion of active agents in tumor cells due to impaired pro-drug activation or active drug inactivation (MOC-2), changes in molecular targets sensitive to anticancer drugs (MOC-3), enhanced ability of cancer cells to repair drug-induced DNA damage (MOC-4), decreased function of pro-apoptotic factors versus up-regulation of anti-apoptotic genes (MOC-5), changes in tumor cell microenvironment altering the response to anticancer agents (MOC-6), and phenotypic transformations, including epithelial-mesenchymal transition (EMT) and the appearance of stemness characteristics (MOC-7). This review summarizes updated information regarding the molecular bases accounting for these mechanisms and their impact on the lack of clinical response to the pharmacological treatment currently used in GAC. This knowledge is required to identify novel biomarkers to predict treatment failure and druggable targets, and to develop sensitizing strategies to overcome drug refractoriness in GAC.

ACS Style

Jose J. G. Marin; Laura Perez-Silva; Rocio I. R. Macias; Maitane Asensio; Ana Peleteiro-Vigil; Anabel Sanchez-Martin; Candela Cives-Losada; Paula Sanchon-Sanchez; Beatriz Sanchez De Blas; Elisa Herraez; Oscar Briz; Elisa Lozano. Molecular Bases of Mechanisms Accounting for Drug Resistance in Gastric Adenocarcinoma. Cancers 2020, 12, 2116 .

AMA Style

Jose J. G. Marin, Laura Perez-Silva, Rocio I. R. Macias, Maitane Asensio, Ana Peleteiro-Vigil, Anabel Sanchez-Martin, Candela Cives-Losada, Paula Sanchon-Sanchez, Beatriz Sanchez De Blas, Elisa Herraez, Oscar Briz, Elisa Lozano. Molecular Bases of Mechanisms Accounting for Drug Resistance in Gastric Adenocarcinoma. Cancers. 2020; 12 (8):2116.

Chicago/Turabian Style

Jose J. G. Marin; Laura Perez-Silva; Rocio I. R. Macias; Maitane Asensio; Ana Peleteiro-Vigil; Anabel Sanchez-Martin; Candela Cives-Losada; Paula Sanchon-Sanchez; Beatriz Sanchez De Blas; Elisa Herraez; Oscar Briz; Elisa Lozano. 2020. "Molecular Bases of Mechanisms Accounting for Drug Resistance in Gastric Adenocarcinoma." Cancers 12, no. 8: 2116.

Consensus statement
Published: 30 June 2020 in Nature Reviews Gastroenterology & Hepatology
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Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.

ACS Style

Jesus M. Banales; Jose J. G. Marin; Angela Lamarca; Pedro M. Rodrigues; Shahid A. Khan; Lewis R. Roberts; Vincenzo Cardinale; Guido Carpino; Jesper B. Andersen; Chiara Braconi; Diego F. Calvisi; Maria J. Perugorria; Luca Fabris; Luke Boulter; Rocio I. R. Macias; Eugenio Gaudio; Domenico Alvaro; Sergio A. Gradilone; Mario Strazzabosco; Marco Marzioni; Cédric Coulouarn; Laura Fouassier; Chiara Raggi; Pietro Invernizzi; Joachim C. Mertens; Anja Moncsek; Sumera Rizvi; Julie Heimbach; Bas Groot Koerkamp; Jordi Bruix; Alejandro Forner; John Bridgewater; Juan W. Valle; Gregory J. Gores. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nature Reviews Gastroenterology & Hepatology 2020, 17, 557 -588.

AMA Style

Jesus M. Banales, Jose J. G. Marin, Angela Lamarca, Pedro M. Rodrigues, Shahid A. Khan, Lewis R. Roberts, Vincenzo Cardinale, Guido Carpino, Jesper B. Andersen, Chiara Braconi, Diego F. Calvisi, Maria J. Perugorria, Luca Fabris, Luke Boulter, Rocio I. R. Macias, Eugenio Gaudio, Domenico Alvaro, Sergio A. Gradilone, Mario Strazzabosco, Marco Marzioni, Cédric Coulouarn, Laura Fouassier, Chiara Raggi, Pietro Invernizzi, Joachim C. Mertens, Anja Moncsek, Sumera Rizvi, Julie Heimbach, Bas Groot Koerkamp, Jordi Bruix, Alejandro Forner, John Bridgewater, Juan W. Valle, Gregory J. Gores. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nature Reviews Gastroenterology & Hepatology. 2020; 17 (9):557-588.

Chicago/Turabian Style

Jesus M. Banales; Jose J. G. Marin; Angela Lamarca; Pedro M. Rodrigues; Shahid A. Khan; Lewis R. Roberts; Vincenzo Cardinale; Guido Carpino; Jesper B. Andersen; Chiara Braconi; Diego F. Calvisi; Maria J. Perugorria; Luca Fabris; Luke Boulter; Rocio I. R. Macias; Eugenio Gaudio; Domenico Alvaro; Sergio A. Gradilone; Mario Strazzabosco; Marco Marzioni; Cédric Coulouarn; Laura Fouassier; Chiara Raggi; Pietro Invernizzi; Joachim C. Mertens; Anja Moncsek; Sumera Rizvi; Julie Heimbach; Bas Groot Koerkamp; Jordi Bruix; Alejandro Forner; John Bridgewater; Juan W. Valle; Gregory J. Gores. 2020. "Cholangiocarcinoma 2020: the next horizon in mechanisms and management." Nature Reviews Gastroenterology & Hepatology 17, no. 9: 557-588.

Review
Published: 23 June 2020 in Cancers
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The poor outcome of patients with non-surgically removable advanced hepatocellular carcinoma (HCC), the most frequent type of primary liver cancer, is mainly due to the high refractoriness of this aggressive tumor to classical chemotherapy. Novel pharmacological approaches based on the use of inhibitors of tyrosine kinases (TKIs), mainly sorafenib and regorafenib, have provided only a modest prolongation of the overall survival in these HCC patients. The present review is an update of the available information regarding our understanding of the molecular bases of mechanisms of chemoresistance (MOC) with a significant impact on the response of HCC to existing pharmacological tools, which include classical chemotherapeutic agents, TKIs and novel immune-sensitizing strategies. Many of the more than one hundred genes involved in seven MOC have been identified as potential biomarkers to predict the failure of treatment, as well as druggable targets to develop novel strategies aimed at increasing the sensitivity of HCC to pharmacological treatments.

ACS Style

Jose J.G. Marin; Rocio I.R. Macias; Maria J. Monte; Marta R. Romero; Maitane Asensio; Anabel Sanchez-Martin; Candela Cives-Losada; Alvaro G. Temprano; Ricardo Espinosa-Escudero; Maria Reviejo; Laura H. Bohorquez; Oscar Briz. Molecular Bases of Drug Resistance in Hepatocellular Carcinoma. Cancers 2020, 12, 1663 .

AMA Style

Jose J.G. Marin, Rocio I.R. Macias, Maria J. Monte, Marta R. Romero, Maitane Asensio, Anabel Sanchez-Martin, Candela Cives-Losada, Alvaro G. Temprano, Ricardo Espinosa-Escudero, Maria Reviejo, Laura H. Bohorquez, Oscar Briz. Molecular Bases of Drug Resistance in Hepatocellular Carcinoma. Cancers. 2020; 12 (6):1663.

Chicago/Turabian Style

Jose J.G. Marin; Rocio I.R. Macias; Maria J. Monte; Marta R. Romero; Maitane Asensio; Anabel Sanchez-Martin; Candela Cives-Losada; Alvaro G. Temprano; Ricardo Espinosa-Escudero; Maria Reviejo; Laura H. Bohorquez; Oscar Briz. 2020. "Molecular Bases of Drug Resistance in Hepatocellular Carcinoma." Cancers 12, no. 6: 1663.

Journal article
Published: 21 June 2020 in Cancers
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Cholangiocarcinoma (CCA) and pancreatic adenocarcinoma (PDAC) may lead to the development of extrahepatic obstructive cholestasis. However, biliary stenoses can also be caused by benign conditions, and the identification of their etiology still remains a clinical challenge. We performed metabolomic and proteomic analyses of bile from patients with benign (n = 36) and malignant conditions, CCA (n = 36) or PDAC (n = 57), undergoing endoscopic retrograde cholangiopancreatography with the aim of characterizing bile composition in biliopancreatic disease and identifying biomarkers for the differential diagnosis of biliary strictures. Comprehensive analyses of lipids, bile acids and small molecules were carried out using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (1H-NMR) in all patients. MS analysis of bile proteome was performed in five patients per group. We implemented artificial intelligence tools for the selection of biomarkers and algorithms with predictive capacity. Our machine-learning pipeline included the generation of synthetic data with properties of real data, the selection of potential biomarkers (metabolites or proteins) and their analysis with neural networks (NN). Selected biomarkers were then validated with real data. We identified panels of lipids (n = 10) and proteins (n = 5) that when analyzed with NN algorithms discriminated between patients with and without cancer with an unprecedented accuracy.

ACS Style

Jesús M. Urman; José M. Herranz; Iker Uriarte; María Rullán; Daniel Oyón; Belén González; Ignacio Fernandez-Urién; Juan Carrascosa; Federico Bolado; Lucía Zabalza; María Arechederra; Gloria Álvarez-Sola; Leticia Colyn; María U. Latasa; Leonor Puchades-Carrasco; Antonio Pineda-Lucena; María J. Iraburu; Marta Iruarrizaga-Lejarreta; Cristina Alonso; Bruno Sangro; Ana Purroy; Isabel Gil; Lorena Carmona; Francisco Javier Cubero; María L. Martínez-Chantar; Jesús M. Banales; Marta R. Romero; Rocio I.R. Macias; Maria J. Monte; Jose J. G. Marín; Juan J. Vila; Fernando J. Corrales; Carmen Berasain; Maite G. Fernández-Barrena; Matías A. Avila. Pilot Multi-Omic Analysis of Human Bile from Benign and Malignant Biliary Strictures: A Machine-Learning Approach. Cancers 2020, 12, 1644 .

AMA Style

Jesús M. Urman, José M. Herranz, Iker Uriarte, María Rullán, Daniel Oyón, Belén González, Ignacio Fernandez-Urién, Juan Carrascosa, Federico Bolado, Lucía Zabalza, María Arechederra, Gloria Álvarez-Sola, Leticia Colyn, María U. Latasa, Leonor Puchades-Carrasco, Antonio Pineda-Lucena, María J. Iraburu, Marta Iruarrizaga-Lejarreta, Cristina Alonso, Bruno Sangro, Ana Purroy, Isabel Gil, Lorena Carmona, Francisco Javier Cubero, María L. Martínez-Chantar, Jesús M. Banales, Marta R. Romero, Rocio I.R. Macias, Maria J. Monte, Jose J. G. Marín, Juan J. Vila, Fernando J. Corrales, Carmen Berasain, Maite G. Fernández-Barrena, Matías A. Avila. Pilot Multi-Omic Analysis of Human Bile from Benign and Malignant Biliary Strictures: A Machine-Learning Approach. Cancers. 2020; 12 (6):1644.

Chicago/Turabian Style

Jesús M. Urman; José M. Herranz; Iker Uriarte; María Rullán; Daniel Oyón; Belén González; Ignacio Fernandez-Urién; Juan Carrascosa; Federico Bolado; Lucía Zabalza; María Arechederra; Gloria Álvarez-Sola; Leticia Colyn; María U. Latasa; Leonor Puchades-Carrasco; Antonio Pineda-Lucena; María J. Iraburu; Marta Iruarrizaga-Lejarreta; Cristina Alonso; Bruno Sangro; Ana Purroy; Isabel Gil; Lorena Carmona; Francisco Javier Cubero; María L. Martínez-Chantar; Jesús M. Banales; Marta R. Romero; Rocio I.R. Macias; Maria J. Monte; Jose J. G. Marín; Juan J. Vila; Fernando J. Corrales; Carmen Berasain; Maite G. Fernández-Barrena; Matías A. Avila. 2020. "Pilot Multi-Omic Analysis of Human Bile from Benign and Malignant Biliary Strictures: A Machine-Learning Approach." Cancers 12, no. 6: 1644.

Journal article
Published: 31 May 2020 in Cancers
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The diagnosis of adenocarcinomas located in the pancreas head, i.e., distal cholangiocarcinoma (dCCA) and pancreatic ductal adenocarcinoma (PDAC), constitutes a clinical challenge because they share many symptoms, are not easily distinguishable using imaging techniques and accurate biomarkers are not available. Searching for biomarkers with potential usefulness in the differential diagnosis of these tumors, we have determined serum metabolomic profiles in healthy controls and patients with dCCA, PDAC or benign pancreatic diseases (BPD). Ultra-high-performance liquid chromatography coupled to mass spectrometry (UHPLC-MS) analysis was performed in serum samples from dCCA (n = 34), PDAC (n = 38), BPD (n = 42) and control (n = 25) individuals, divided into discovery and validation cohorts. This approach permitted 484 metabolites to be determined, mainly lipids and amino acids. The analysis of the results led to the proposal of a logistic regression model able to discriminate patients with dCCA and PDAC (AUC value of 0.888) based on the combination of serum levels of nine metabolites (acylcarnitine AC(16:0), ceramide Cer(d18:1/24:0), phosphatidylcholines PC(20:0/0:0) and PC(O-16:0/20:3), lysophosphatidylcholines PC(20:0/0:0) and PC(0:0/20:0), lysophosphatidylethanolamine PE(P-18:2/0:0), and sphingomyelins SM(d18:2/22:0) and SM(d18:2/23:0)) and CA 19-9. In conclusion, we propose a novel specific panel of serum metabolites that can help in the differential diagnosis of dCCA and PDAC. Further validation of their clinical usefulness in prospective studies is required.

ACS Style

Rocio I. R. Macias; Luis Muñoz-Bellvís; Anabel Sánchez-Martín; Enara Arretxe; Ibon Martínez-Arranz; Ainhoa Lapitz; M. Laura Gutiérrez; Adelaida La La Casta; Cristina Alonso; Luis M. González; Matias A. Avila; Maria L. Martinez-Chantar; Rui E. Castro; Luis Bujanda; Jesus M. Banales; Jose J. G. Marin. A Novel Serum Metabolomic Profile for the Differential Diagnosis of Distal Cholangiocarcinoma and Pancreatic Ductal Adenocarcinoma. Cancers 2020, 12, 1433 .

AMA Style

Rocio I. R. Macias, Luis Muñoz-Bellvís, Anabel Sánchez-Martín, Enara Arretxe, Ibon Martínez-Arranz, Ainhoa Lapitz, M. Laura Gutiérrez, Adelaida La La Casta, Cristina Alonso, Luis M. González, Matias A. Avila, Maria L. Martinez-Chantar, Rui E. Castro, Luis Bujanda, Jesus M. Banales, Jose J. G. Marin. A Novel Serum Metabolomic Profile for the Differential Diagnosis of Distal Cholangiocarcinoma and Pancreatic Ductal Adenocarcinoma. Cancers. 2020; 12 (6):1433.

Chicago/Turabian Style

Rocio I. R. Macias; Luis Muñoz-Bellvís; Anabel Sánchez-Martín; Enara Arretxe; Ibon Martínez-Arranz; Ainhoa Lapitz; M. Laura Gutiérrez; Adelaida La La Casta; Cristina Alonso; Luis M. González; Matias A. Avila; Maria L. Martinez-Chantar; Rui E. Castro; Luis Bujanda; Jesus M. Banales; Jose J. G. Marin. 2020. "A Novel Serum Metabolomic Profile for the Differential Diagnosis of Distal Cholangiocarcinoma and Pancreatic Ductal Adenocarcinoma." Cancers 12, no. 6: 1433.

Journal article
Published: 14 March 2020 in Cells
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: Cholangiocarcinoma (CCA) comprises a group of heterogeneous biliary cancers with dismal prognosis. The etiologies of most CCAs are unknown, but primary sclerosing cholangitis (PSC) is a risk factor. Non-invasive diagnosis of CCA is challenging and accurate biomarkers are lacking. We aimed to characterize the transcriptomic profile of serum and urine extracellular vesicles (EVs) from patients with CCA, PSC, ulcerative colitis (UC), and healthy individuals. Serum and urine EVs were isolated by serial ultracentrifugations and characterized by nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting. EVs transcriptome was determined by Illumina gene expression array [messenger RNAs (mRNA) and non-coding RNAs (ncRNAs)]. Differential RNA profiles were found in serum and urine EVs from patients with CCA compared to control groups (disease and healthy), showing high diagnostic capacity. The comparison of the mRNA profiles of serum or urine EVs from patients with CCA with the transcriptome of tumor tissues from two cohorts of patients, CCA cells in vitro, and CCA cells-derived EVs, identified 105 and 39 commonly-altered transcripts, respectively. Gene ontology analysis indicated that most commonly-altered mRNAs participate in carcinogenic steps. Overall, patients with CCA present specific RNA profiles in EVs mirroring the tumor, and constituting novel promising liquid biopsy biomarkers.

ACS Style

Ainhoa Lapitz; Ander Arbelaiz; Colm J. O’Rourke; Jose L. Lavin; Adelaida La Casta; Cesar Ibarra; Juan P. Jimeno; Alvaro Santos-Laso; Laura Izquierdo-Sanchez; Marcin Krawczyk; Maria J. Perugorria; Raul Jimenez-Aguero; Alberto Sanchez-Campos; Ioana Riaño; Esperanza Gónzalez; Frank Lammert; Marco Marzioni; Rocio I.R. Macias; Jose J. G. Marin; Tom H. Karlsen; Luis Bujanda; Juan M. Falcón-Pérez; Jesper B. Andersen; Ana M. Aransay; Pedro M. Rodrigues; Jesus M. Banales. Patients with Cholangiocarcinoma Present Specific RNA Profiles in Serum and Urine Extracellular Vesicles Mirroring the Tumor Expression: Novel Liquid Biopsy Biomarkers for Disease Diagnosis. Cells 2020, 9, 721 .

AMA Style

Ainhoa Lapitz, Ander Arbelaiz, Colm J. O’Rourke, Jose L. Lavin, Adelaida La Casta, Cesar Ibarra, Juan P. Jimeno, Alvaro Santos-Laso, Laura Izquierdo-Sanchez, Marcin Krawczyk, Maria J. Perugorria, Raul Jimenez-Aguero, Alberto Sanchez-Campos, Ioana Riaño, Esperanza Gónzalez, Frank Lammert, Marco Marzioni, Rocio I.R. Macias, Jose J. G. Marin, Tom H. Karlsen, Luis Bujanda, Juan M. Falcón-Pérez, Jesper B. Andersen, Ana M. Aransay, Pedro M. Rodrigues, Jesus M. Banales. Patients with Cholangiocarcinoma Present Specific RNA Profiles in Serum and Urine Extracellular Vesicles Mirroring the Tumor Expression: Novel Liquid Biopsy Biomarkers for Disease Diagnosis. Cells. 2020; 9 (3):721.

Chicago/Turabian Style

Ainhoa Lapitz; Ander Arbelaiz; Colm J. O’Rourke; Jose L. Lavin; Adelaida La Casta; Cesar Ibarra; Juan P. Jimeno; Alvaro Santos-Laso; Laura Izquierdo-Sanchez; Marcin Krawczyk; Maria J. Perugorria; Raul Jimenez-Aguero; Alberto Sanchez-Campos; Ioana Riaño; Esperanza Gónzalez; Frank Lammert; Marco Marzioni; Rocio I.R. Macias; Jose J. G. Marin; Tom H. Karlsen; Luis Bujanda; Juan M. Falcón-Pérez; Jesper B. Andersen; Ana M. Aransay; Pedro M. Rodrigues; Jesus M. Banales. 2020. "Patients with Cholangiocarcinoma Present Specific RNA Profiles in Serum and Urine Extracellular Vesicles Mirroring the Tumor Expression: Novel Liquid Biopsy Biomarkers for Disease Diagnosis." Cells 9, no. 3: 721.

Review
Published: 21 February 2020 in Cells
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The dismal prognosis of patients with advanced cholangiocarcinoma (CCA) is due, in part, to the extreme resistance of this type of liver cancer to available chemotherapeutic agents. Among the complex mechanisms accounting for CCA chemoresistance are those involving the impairment of drug uptake, which mainly occurs through transporters of the superfamily of solute carrier (SLC) proteins, and the active export of drugs from cancer cells, mainly through members of families B, C and G of ATP-binding cassette (ABC) proteins. Both mechanisms result in decreased amounts of active drugs able to reach their intracellular targets. Therefore, the “cancer transportome”, defined as the set of transporters expressed at a given moment in the tumor, is an essential element for defining the multidrug resistance (MDR) phenotype of cancer cells. For this reason, during the last two decades, plasma membrane transporters have been envisaged as targets for the development of strategies aimed at sensitizing cancer cells to chemotherapy, either by increasing the uptake or reducing the export of antitumor agents by modulating the expression/function of SLC and ABC proteins, respectively. Moreover, since some elements of the transportome are differentially expressed in CCA, their usefulness as biomarkers with diagnostic and prognostic purposes in CCA patients has been evaluated.

ACS Style

Jose J.G. Marin; Rocio I.R. Macias; Candela Cives-Losada; Ana Peleteiro-Vigil; Elisa Herraez; Elisa Lozano. Plasma Membrane Transporters as Biomarkers and Molecular Targets in Cholangiocarcinoma. Cells 2020, 9, 498 .

AMA Style

Jose J.G. Marin, Rocio I.R. Macias, Candela Cives-Losada, Ana Peleteiro-Vigil, Elisa Herraez, Elisa Lozano. Plasma Membrane Transporters as Biomarkers and Molecular Targets in Cholangiocarcinoma. Cells. 2020; 9 (2):498.

Chicago/Turabian Style

Jose J.G. Marin; Rocio I.R. Macias; Candela Cives-Losada; Ana Peleteiro-Vigil; Elisa Herraez; Elisa Lozano. 2020. "Plasma Membrane Transporters as Biomarkers and Molecular Targets in Cholangiocarcinoma." Cells 9, no. 2: 498.

Review
Published: 29 October 2019 in Cancers
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The lack of response to pharmacological treatment constitutes a substantial limitation in the handling of patients with primary liver cancers (PLCs). The existence of active mechanisms of chemoresistance (MOCs) in hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma hampers the usefulness of chemotherapy. A better understanding of MOCs is needed to develop strategies able to overcome drug refractoriness in PLCs. With this aim, several experimental models are commonly used. These include in vitro cell-free assays using subcellular systems; studies with primary cell cultures; cancer cell lines or heterologous expression systems; multicellular models, such as spheroids and organoids; and a variety of in vivo models in rodents, such as subcutaneous and orthotopic tumor xenografts or chemically or genetically induced liver carcinogenesis. Novel methods to perform programmed genomic edition and more efficient techniques to isolate circulating microvesicles offer new opportunities for establishing useful experimental tools for understanding the resistance to chemotherapy in PLCs. In the present review, using three criteria for information organization: (1) level of research; (2) type of MOC; and (3) type of PLC, we have summarized the advantages and limitations of the armamentarium available in the field of pharmacological investigation of PLC chemoresistance.

ACS Style

Jose J. G. Marin; Elisa Herraez; Elisa Lozano; Rocio I. R. Macias; Oscar Briz. Models for Understanding Resistance to Chemotherapy in Liver Cancer. Cancers 2019, 11, 1677 .

AMA Style

Jose J. G. Marin, Elisa Herraez, Elisa Lozano, Rocio I. R. Macias, Oscar Briz. Models for Understanding Resistance to Chemotherapy in Liver Cancer. Cancers. 2019; 11 (11):1677.

Chicago/Turabian Style

Jose J. G. Marin; Elisa Herraez; Elisa Lozano; Rocio I. R. Macias; Oscar Briz. 2019. "Models for Understanding Resistance to Chemotherapy in Liver Cancer." Cancers 11, no. 11: 1677.

Journal article
Published: 24 October 2019 in Biochemical Pharmacology
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Owing to intrinsic and acquired chemoresistance, the response of gastric adenocarcinoma (GAC) to chemotherapy is very poor. Here we have investigated the role of transportome in reducing the intracellular content of anticancer drugs and conferring multidrug resistance (MDR) phenotype. Tumors specimens and paired adjacent tissue were analyzed to determine the MDR signature by TaqMan Low-Density Arrays and single-gene qPCR. Strategies of sensitization were evaluated in vitro using the GAC-derived cell line AGS and in vivo using a subcutaneous xenograft model in immunodeficient nude mice. Several transporters involved in drug uptake and export, which are present in healthy stomach, were highly expressed in GAC. In contrast, the cancer-type OATP1B3 was almost exclusively expressed in tumor tissue. The transportome profile varied depending on tumor anatomical location, differentiation, and stage. Immunofluorescence analysis revealed high MRP1 and MRP4 expression at the plasma membrane of tumor cells as well as AGS cells in culture, in which MRP inhibition resulted in selective sensitization to cytotoxic MRP substrates, such as sorafenib, docetaxel, etoposide, and doxorubicin. In mice with subcutaneous tumors formed by AGS cells, sorafenib alone failed to prevent tumor growth. In contrast, this drug induced a marked inhibitory effect when it was co-administered with diclofenac. In conclusion, MRP1 and MRP4 play an important role in the lack of response of GAC to drugs that are transported by these export pumps. Moreover, agents, such as sorafenib, considered at present useless to treat GAC, may become active antitumor drugs when co-administered with non-toxic MRP inhibitors, such as diclofenac.

ACS Style

Ruba Al-Abdulla; Laura Perez-Silva; Elisa Lozano; Rocio I.R. Macias; Elisa Herraez; Mar Abad; Nerea Segues; Luis Bujanda; Oscar Briz; María Del María del Mar. Sensitizing gastric adenocarcinoma to chemotherapy by pharmacological manipulation of drug transporters. Biochemical Pharmacology 2019, 171, 113682 .

AMA Style

Ruba Al-Abdulla, Laura Perez-Silva, Elisa Lozano, Rocio I.R. Macias, Elisa Herraez, Mar Abad, Nerea Segues, Luis Bujanda, Oscar Briz, María Del María del Mar. Sensitizing gastric adenocarcinoma to chemotherapy by pharmacological manipulation of drug transporters. Biochemical Pharmacology. 2019; 171 ():113682.

Chicago/Turabian Style

Ruba Al-Abdulla; Laura Perez-Silva; Elisa Lozano; Rocio I.R. Macias; Elisa Herraez; Mar Abad; Nerea Segues; Luis Bujanda; Oscar Briz; María Del María del Mar. 2019. "Sensitizing gastric adenocarcinoma to chemotherapy by pharmacological manipulation of drug transporters." Biochemical Pharmacology 171, no. : 113682.

Journal article
Published: 02 August 2019 in Antioxidants
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The phenolic composition of hydroethanolic extracts of Mentha aquatica L., Lavandula dentata L. and Leonurus cardiaca L., obtained from plants grown under organic cultivation, was determined and their hepatoprotective effects were investigated in vitro. L. cardiaca extract was rich in phenylethenoid glycosides, especially lavandolifolioside (254 ± 36 μg/mg), whereas rosmarinic acid and eriodictyol-O-rutinoside were the major phenolic compounds of L. dentata and M. aquatica extracts, accounting for 68 ± 7 μg/mg and 145 ± 22 μg/mg, respectively. These differential phenolic components presumably account for their dissimilar antioxidant properties. While L. cardiaca extract showed moderate biological effects, M. aquatica extract displayed high antioxidant activity in chemical models, and that of L. dentata was effective in counteracting potassium dichromate-induced ROS generation in human hepatocarcinoma cells. Moreover, M. aquatica extract (50 μg/mL) and its mixture (50%/50%) with L. dentata extract displayed an effective cytoprotective effect.

ACS Style

Olívia R. Pereira; Rocio I. R. Macias; Maria R. M. Domingues; Jose J. G. Marin; Susana M. Cardoso. Hepatoprotection of Mentha aquatica L., Lavandula dentata L. and Leonurus cardiaca L. Antioxidants 2019, 8, 267 .

AMA Style

Olívia R. Pereira, Rocio I. R. Macias, Maria R. M. Domingues, Jose J. G. Marin, Susana M. Cardoso. Hepatoprotection of Mentha aquatica L., Lavandula dentata L. and Leonurus cardiaca L. Antioxidants. 2019; 8 (8):267.

Chicago/Turabian Style

Olívia R. Pereira; Rocio I. R. Macias; Maria R. M. Domingues; Jose J. G. Marin; Susana M. Cardoso. 2019. "Hepatoprotection of Mentha aquatica L., Lavandula dentata L. and Leonurus cardiaca L." Antioxidants 8, no. 8: 267.

Original article
Published: 10 April 2019 in Hepatology
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Although the multi‐tyrosine kinase inhibitor sorafenib is useful in the treatment of several cancers, cholangiocarcinoma (CCA) is refractory to this drug. Among other mechanisms of chemoresistance, impaired uptake through human organic cation transporter type 1 (hOCT1) (gene SLC22A1) has been suggested. Here we have investigated the events accounting for this phenotypic characteristic and have evaluated the interest of selective gene therapy strategies to overcome this limitation. Gene expression and DNA methylation of SLC22A1 were analyzed using intrahepatic (iCCA) and extrahepatic (eCCA) biopsies (Copenhagen and Salamanca cohorts; n = 132) and The Cancer Genome Atlas (TCGA)‐CHOL (n = 36). Decreased hOCT1 mRNA correlated with hypermethylation status of the SLC22A1 promoter. Treatment of CCA cells with decitabine (demethylating agent) or butyrate (histone deacetylase inhibitor) restored hOCT1 expression and increased sorafenib uptake. MicroRNAs able to induce hOCT1 mRNA decay were analyzed in paired samples of TCGA‐CHOL (n = 9) and Copenhagen (n = 57) cohorts. Consistent up‐regulation in tumor tissue was found for miR‐141 and miR‐330. High proportion of aberrant hOCT1 mRNA splicing in CCA was also seen. Lentiviral‐mediated transduction of eCCA (EGI‐1 and TFK‐1) and iCCA (HuCCT1) cells with hOCT1 enhanced sorafenib uptake and cytotoxic effects. In chemically induced CCA in rats, reduced rOct1 expression was accompanied by impaired sorafenib uptake. In xenograft models of eCCA cells implanted in mouse liver, poor response to sorafenib was observed. However, tumor growth was markedly reduced by cotreatment with sorafenib and adenoviral vectors encoding hOCT1 under the control of the BIRC5 promoter, a gene highly up‐regulated in CCA. Conclusion: The reason for impaired hOCT1‐mediated sorafenib uptake by CCA is multifactorial. Gene therapy capable of selectively inducing hOCT1 in tumor cells can be considered a potentially useful chemosensitization strategy to improve the response of CCA to sorafenib.

ACS Style

Elisa Lozano; Rocio I.R. Macias; Maria J Monte; Maitane Asensio; Sofia Del Carmen; Laura Sanchez‐Vicente; Marta Alonso-Peña; Ruba Al‐Abdulla; Patricia Munoz‐Garrido; Letizia Satriano; Colm J. O'Rourke; Jesus Banales; Matias Avila; Maria Luz Martinez Chantar; Jesper B. Andersen; Oscar Briz; Jose J.G. Marin. Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy. Hepatology 2019, 70, 1246 -1261.

AMA Style

Elisa Lozano, Rocio I.R. Macias, Maria J Monte, Maitane Asensio, Sofia Del Carmen, Laura Sanchez‐Vicente, Marta Alonso-Peña, Ruba Al‐Abdulla, Patricia Munoz‐Garrido, Letizia Satriano, Colm J. O'Rourke, Jesus Banales, Matias Avila, Maria Luz Martinez Chantar, Jesper B. Andersen, Oscar Briz, Jose J.G. Marin. Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy. Hepatology. 2019; 70 (4):1246-1261.

Chicago/Turabian Style

Elisa Lozano; Rocio I.R. Macias; Maria J Monte; Maitane Asensio; Sofia Del Carmen; Laura Sanchez‐Vicente; Marta Alonso-Peña; Ruba Al‐Abdulla; Patricia Munoz‐Garrido; Letizia Satriano; Colm J. O'Rourke; Jesus Banales; Matias Avila; Maria Luz Martinez Chantar; Jesper B. Andersen; Oscar Briz; Jose J.G. Marin. 2019. "Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy." Hepatology 70, no. 4: 1246-1261.

Review
Published: 22 March 2019 in Cancers
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The most frequent liver tumor in children is hepatoblastoma (HB), which derives from embryonic parenchymal liver cells or hepatoblasts. Hepatocellular carcinoma (HCC), which rarely affects young people, causes one fourth of deaths due to cancer in adults. In contrast, HB usually has better prognosis, but this is still poor in 20% of cases. Although more responsive to chemotherapy than HCC, the failure of pharmacological treatment used before and/or after surgical resection is an important limitation in the management of patients with HB. To advance in the implementation of personalized medicine it is important to select the best combination among available anti-HB drugs, such as platinum derivatives, anthracyclines, etoposide, tyrosine-kinase inhibitors, Vinca alkaloids, 5-fluorouracil, monoclonal antibodies, irinotecan and nitrogen mustards. This requires predicting the sensitivity to these drugs of each tumor at each time because, it should be kept in mind, that cancer chemoresistance is a dynamic process of Darwinian nature. For this goal it is necessary to improve our understanding of the mechanisms of chemoresistance involved in the refractoriness of HB against the pharmacological challenge and how they evolve during treatment. In this review we have summarized the current knowledge on the multifactorial and complex factors responsible for the lack of response of HB to chemotherapy.

ACS Style

Jose J. G. Marin; Candela Cives-Losada; Maitane Asensio; Elisa Lozano; Oscar Briz; Rocio I. R. Macias. Mechanisms of Anticancer Drug Resistance in Hepatoblastoma. Cancers 2019, 11, 407 .

AMA Style

Jose J. G. Marin, Candela Cives-Losada, Maitane Asensio, Elisa Lozano, Oscar Briz, Rocio I. R. Macias. Mechanisms of Anticancer Drug Resistance in Hepatoblastoma. Cancers. 2019; 11 (3):407.

Chicago/Turabian Style

Jose J. G. Marin; Candela Cives-Losada; Maitane Asensio; Elisa Lozano; Oscar Briz; Rocio I. R. Macias. 2019. "Mechanisms of Anticancer Drug Resistance in Hepatoblastoma." Cancers 11, no. 3: 407.

Reviews
Published: 06 March 2019 in Liver International
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The high mortality rate of cholangiocarcinoma (CCA) is due, in part, to the lack of non‐invasive approaches able to accurately detect this silent tumour at early stages, when therapeutic options can be potentially curative or may at least increase the overall survival of patients. The fact that the majority of CCA tumours are not linked to any known aetiological factor highly compromises the monitoring of patients at risk for tumour development and also their early diagnosis. Combination of clinical/biochemical features, imaging techniques and analysis of non‐specific tumour biomarkers in serum are commonly used to help in the diagnosis of CCA, but tumour biopsy is usually required to confirm the diagnosis. Moreover, no prognostic biomarkers are currently used in the clinical setting, deserving more innovative research, and international validation and consensus. Important efforts have been made in the last years to identify new accurate non‐invasive biomarkers, by using innovative techniques and high‐throughput omics technologies. This review summarises and discusses the advances in the investigation of novel diagnostic and prognostic biomarkers in CCA and envisions the future directions in this field of research. This article is protected by copyright. All rights reserved.

ACS Style

Rocio I. R. Macias; Miroslaw Kornek; Pedro M. Rodrigues; Nuno Paiva; Rui E. Castro; Sabine Urban; Stephen Pereira; Massimiliano Cadamuro; Christian Rupp; Sven H. Loosen; Tom Luedde; Jesus Banales. Diagnostic and prognostic biomarkers in cholangiocarcinoma. Liver International 2019, 39, 108 -122.

AMA Style

Rocio I. R. Macias, Miroslaw Kornek, Pedro M. Rodrigues, Nuno Paiva, Rui E. Castro, Sabine Urban, Stephen Pereira, Massimiliano Cadamuro, Christian Rupp, Sven H. Loosen, Tom Luedde, Jesus Banales. Diagnostic and prognostic biomarkers in cholangiocarcinoma. Liver International. 2019; 39 (S1):108-122.

Chicago/Turabian Style

Rocio I. R. Macias; Miroslaw Kornek; Pedro M. Rodrigues; Nuno Paiva; Rui E. Castro; Sabine Urban; Stephen Pereira; Massimiliano Cadamuro; Christian Rupp; Sven H. Loosen; Tom Luedde; Jesus Banales. 2019. "Diagnostic and prognostic biomarkers in cholangiocarcinoma." Liver International 39, no. S1: 108-122.