Publications by authors named "Luis Aparicio"

33 Publications

Functional characterization of CD4+ T cell receptors crossreactive for SARS-CoV-2 and endemic coronaviruses.

J Clin Invest 2021 05;131(10)

Bloomberg~Kimmel Institute for Cancer Immunotherapy.

BACKGROUNDRecent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to crossrecognition by T cells specific for common cold coronaviruses (CCCs). True T cell crossreactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2.METHODSWe used the viral functional expansion of specific T cells (ViraFEST) platform to identify T cell responses crossreactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2-unexposed donors. Confirmation of SARS-CoV-2/CCC crossreactivity and assessments of functional avidity were performed using a TCR cloning and transfection system.RESULTSMemory CD4+ T cell clonotypes that crossrecognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Crossreactive T cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to monospecific CD4+ T cells, which was consistent with lower functional avidity of their TCRs for SARS-CoV-2 relative to CCC.CONCLUSIONSOur data confirm, for what we believe is the first time, the existence of unique memory CD4+ T cell clonotypes crossrecognizing SARS-CoV-2 and CCCs. The lower avidity of crossreactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that preexisting CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these crossreactive T cell responses affect clinical outcomes in COVID-19 patients.FUNDINGNIH funding (U54CA260492, P30CA006973, P41EB028239, R01AI153349, R01AI145435-A1, R21AI149760, and U19A1088791) was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, and the National Institute of Biomedical Imaging and Bioengineering. The Bloomberg~Kimmel Institute for Cancer Immunotherapy, The Johns Hopkins University Provost, and The Bill and Melinda Gates Foundation provided funding for this study.
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http://dx.doi.org/10.1172/JCI146922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121515PMC
May 2021

Patients with Minimal Hepatic Encephalopathy Show Altered Thermal Sensitivity and Autonomic Function.

J Clin Med 2021 Jan 11;10(2). Epub 2021 Jan 11.

INCLIVA, Health Research Institute, 46010 Valencia, Spain.

Cirrhotic patients may experience alterations in the peripheral nervous system and in somatosensory perception. Impairment of the somatosensory system could contribute to cognitive and motor alterations characteristic of minimal hepatic encephalopathy (MHE), which affects up to 40% of cirrhotic patients. We assessed the relationship between MHE and alterations in thermal, vibration, and/or heat pain sensitivity in 58 cirrhotic patients (38 without and 20 with MHE according to Psychometric Hepatic Encephalopathy Score) and 39 controls. All participants underwent attention and coordination tests, a nerve conduction study, autonomic function testing, and evaluation of sensory thresholds (vibration, cooling, and heat pain detection) by electromyography and quantitative sensory testing. The detection thresholds for cold and heat pain on the foot were higher in patients with, than those without MHE. This hyposensitivity was correlated with attention deficits. Reaction times in the foot were longer in patients with, than without MHE. Patients with normal sural nerve amplitude showed altered thermal sensitivity and autonomic function, with stronger alterations in patients with, than in those without MHE. MHE patients show a general decrease in cognitive and sensory abilities. Small fibers of the autonomic nervous system and thermal sensitivity are altered early on in MHE, before large sensory fibers. Quantitative sensory testing could be used as a marker of MHE.
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http://dx.doi.org/10.3390/jcm10020239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826803PMC
January 2021

A Random Matrix Theory Approach to Denoise Single-Cell Data.

Patterns (N Y) 2020 Jun 4;1(3):100035. Epub 2020 May 4.

Department of Systems Biology, Columbia University, New York NY 10032, USA.

Single-cell technologies provide the opportunity to identify new cellular states. However, a major obstacle to the identification of biological signals is noise in single-cell data. In addition, single-cell data are very sparse. We propose a new method based on random matrix theory to analyze and denoise single-cell sequencing data. The method uses the universal distributions predicted by random matrix theory for the eigenvalues and eigenvectors of random covariance/Wishart matrices to distinguish noise from signal. In addition, we explain how sparsity can cause spurious eigenvector localization, falsely identifying meaningful directions in the data. We show that roughly 95% of the information in single-cell data is compatible with the predictions of random matrix theory, about 3% is spurious signal induced by sparsity, and only the last 2% reflects true biological signal. We demonstrate the effectiveness of our approach by comparing with alternative techniques in a variety of examples with marked cell populations.
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http://dx.doi.org/10.1016/j.patter.2020.100035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660363PMC
June 2020

A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors.

Elife 2020 09 11;9. Epub 2020 Sep 11.

Department of Medicine, Columbia University Irving Medical Center, New York, United States.

Understanding the cellular constituents of the prostate is essential for identifying the cell of origin for prostate adenocarcinoma. Here, we describe a comprehensive single-cell atlas of the adult mouse prostate epithelium, which displays extensive heterogeneity. We observe distal lobe-specific luminal epithelial populations (LumA, LumD, LumL, and LumV), a proximally enriched luminal population (LumP) that is not lobe-specific, and a periurethral population (PrU) that shares both basal and luminal features. Functional analyses suggest that LumP and PrU cells have multipotent progenitor activity in organoid formation and tissue reconstitution assays. Furthermore, we show that mouse distal and proximal luminal cells are most similar to human acinar and ductal populations, that a PrU-like population is conserved between species, and that the mouse lateral prostate is most similar to the human peripheral zone. Our findings elucidate new prostate epithelial progenitors, and help resolve long-standing questions about anatomical relationships between the mouse and human prostate.
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http://dx.doi.org/10.7554/eLife.59465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529463PMC
September 2020

Association between ribs shape and pulmonary function in patients with Osteogenesis Imperfecta.

J Adv Res 2020 Jan 22;21:177-185. Epub 2019 Oct 22.

Giaval Research Group, Department of Anatomy and Human Embryology, Faculty of Medicine, University of Valencia, Av. Blasco Ibanez, 15, 46010 Valencia, Spain.

The aim of the present study was to test the hypothesis that ribs shape changes in patients with OI are more relevant for respiratory function than thoracic spine shape. We used 3D geometric morphometrics to quantify rib cage morphology in OI patients and controls, and to investigate its relationship with forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), expressed as absolute value and as percentage of predicted value (% pred). Regression analyses on the full sample showed a significant relation between rib shape and FEV1, FVC and FVC % pred whereas thoracic spine shape was not related to any parameter. Subsequent regression analyses on OI patients confirmed significant relations between dynamic lung volumes and rib shape changes. Lower FVC and FEV1 values are identified in OI patients that present more horizontally aligned ribs, a greater antero-posterior depth due to extreme transverse curve at rib angles and a strong spine invagination, greater asymmetry, and a vertically short, thoraco-lumbar spine, which is relatively straight in at levels 1-8 and shows a marked kyphosis in the thoraco-lumbar transition. Our research seems to support that ribs shape is more relevant for ventilator mechanics in OI patients than the spine shape.
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http://dx.doi.org/10.1016/j.jare.2019.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015465PMC
January 2020

Selective improvement by rifaximin of changes in the immunophenotype in patients who improve minimal hepatic encephalopathy.

J Transl Med 2019 08 28;17(1):293. Epub 2019 Aug 28.

Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Valencia, Spain.

Background: Minimal hepatic encephalopathy (MHE) in cirrhotic patients is associated with specific changes in parameters of the immune system reflecting a more pro-inflammatory environment than in patients without MHE. The aims of this work were to assess the effects of rifaximin treatment of cirrhotic patients with MHE on: (1) MHE; (2) intermediate (CD14CD16) pro-inflammatory monocytes; (3) expression of early activation marker CD69 in T lymphocytes; (4) autoreactive CD4CD28 T lymphocytes; (5) differentiation of CD4 T lymphocytes to Th follicular and Th22; (6) serum IgG levels; and (7) levels of some pro-inflammatory cytokines.

Methods: These parameters were measured by immunophenotyping and cytokine profile analysis in 30 controls without liver disease, 30 cirrhotic patients without MHE and 22 patients with MHE. Patients with MHE were treated with rifaximin and the same parameters were measured at 3 and 6 months of treatment. We assessed if changes in these parameters are different in patients who improve MHE (responders) and those who remain in MHE (non-responders).

Results: Rifaximin improved MHE in 59% of patients with MHE. In these responder patients rifaximin normalized all alterations in the immune system measured while in non-responders it normalizes only IL-6, CCL20, and differentiation of T lymphocytes to Th22. Non-responder patients do not show increased expression of CD69 before treatment.

Conclusions: Rifaximin normalizes changes in the immune system in patients who improve MHE but not in non-responders. Some alterations before treatment are different in responders and non-responders. Understanding these differences may identify predictors of the response of MHE to rifaximin.
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http://dx.doi.org/10.1186/s12967-019-2046-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714107PMC
August 2019

Author Correction: Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.

Nat Med 2019 Jun;25(6):1022

Department of Systems Biology, Columbia University, New York, NY, USA.

In the version of this article originally published, the graph in Extended Data Fig. 2c was a duplication of Extended Data Fig. 2b. The correct version of Extended Data Fig. 2c is now available online.
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http://dx.doi.org/10.1038/s41591-019-0449-8DOI Listing
June 2019

The 2019 mathematical oncology roadmap.

Phys Biol 2019 06 19;16(4):041005. Epub 2019 Jun 19.

Department of Computational and Quantitative Medicine, Division of Mathematical Oncology, City of Hope National Medical Center, Duarte, CA 91010, United States of America. Author to whom any correspondence should be addressed.

Whether the nom de guerre is Mathematical Oncology, Computational or Systems Biology, Theoretical Biology, Evolutionary Oncology, Bioinformatics, or simply Basic Science, there is no denying that mathematics continues to play an increasingly prominent role in cancer research. Mathematical Oncology-defined here simply as the use of mathematics in cancer research-complements and overlaps with a number of other fields that rely on mathematics as a core methodology. As a result, Mathematical Oncology has a broad scope, ranging from theoretical studies to clinical trials designed with mathematical models. This Roadmap differentiates Mathematical Oncology from related fields and demonstrates specific areas of focus within this unique field of research. The dominant theme of this Roadmap is the personalization of medicine through mathematics, modelling, and simulation. This is achieved through the use of patient-specific clinical data to: develop individualized screening strategies to detect cancer earlier; make predictions of response to therapy; design adaptive, patient-specific treatment plans to overcome therapy resistance; and establish domain-specific standards to share model predictions and to make models and simulations reproducible. The cover art for this Roadmap was chosen as an apt metaphor for the beautiful, strange, and evolving relationship between mathematics and cancer.
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http://dx.doi.org/10.1088/1478-3975/ab1a09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6655440PMC
June 2019

Possible Clinical Implications of Geographic Differences in Prevalence of Double Transverse Foramen.

World Neurosurg 2019 Jun 1;126:e570-e572. Epub 2019 Mar 1.

GIAVAL Research Group, Department of Anatomy and Human Embryology, University of Valencia, Faculty of Medicine, Valencia, Spain.

Background: The double transverse foramen (DBLTF) is a cervical spine anatomic variant. Current literature has presented prevalence values of DBLTF in Caucasian Mediterranean subjects that seem to be higher than those observed in other samples of subjects. Therefore we aimed to test if Caucasian Mediterranean subjects present a higher prevalence of the DBLTF than sub-Saharan African subjects.

Methods: We analyzed the presence of DBLTF in cervical spines of 100 skeletons from Caucasian Mediterranean subjects and 91 skeletons from sub-Saharan African subjects, resulting in a total of 1337 cervical vertebrae having been studied.

Results: No DBLTF was found in vertebrae C1, C2, and C3. The pattern of prevalence observed in all samples analyzed indicated the prevalence ranged from exhibiting the most to the least prevalence as C6 > C5 > C7 > C4. The sub-Saharan African subjects presented a significant reduced DBLTF prevalence of 2.2%, 14.3%, 19.8%, and 3.3% in C4 (P = 0.043), C5 (P = 0.004), C6 (P < 0.001), and C7 (P = 0.041), respectively, than that presented by Caucasian Mediterranean subjects (9.0%, 32.0%, 45.0%, 11.0% in C4, C5, C6, and C7, respectively).

Conclusions: Our study has revealed that this anatomic variation is more frequently found in Caucasian Mediterranean subjects than in sub-Saharan African subjects.
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http://dx.doi.org/10.1016/j.wneu.2019.02.096DOI Listing
June 2019

Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.

Nat Med 2019 03 11;25(3):462-469. Epub 2019 Feb 11.

Department of Systems Biology, Columbia University, New York, NY, USA.

Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.
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http://dx.doi.org/10.1038/s41591-019-0349-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810613PMC
March 2019

Clinical implications of epithelial cell plasticity in cancer progression.

Cancer Lett 2015 Sep 19;366(1):1-10. Epub 2015 Jun 19.

Grupo de Investigación Traslacional del Cáncer, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), As Xubias, 15006, A Coruña, Spain. Electronic address:

In the last few years, the role of epithelial cell plasticity in cancer biology research has gained increasing attention. This concept refers to the ability of the epithelial cells to dynamically switch between different phenotypic cellular states. This programme is particularly relevant during the epithelial-to-mesenchymal transition (EMT) in cancer progression. During colonization, epithelial cells first activate the EMT programme to disseminate from a primary tumour to reach a distant tissue site. During this process, cells are transported into the circulation and are able to escape the immune system of the host. Then, a reverse process called mesenchymal-to-epithelial transition (MET) occurs on cells that settle in the distant organs. Although epithelial cell plasticity has an important impact on tumour biology, the clinical relevance of this concept remains to be recapitulated. In this review, we will update the current state of epithelial cell plasticity in cancer progression and its clinical implications for the design of therapeutic strategies, the acquisition of multidrug resistance, and future perspectives for the management of cancer patients.
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http://dx.doi.org/10.1016/j.canlet.2015.06.007DOI Listing
September 2015

Congenital cervical vertebrae clefts in Klippel-Feil syndrome.

Spine J 2015 Jun 25;15(6):1490-1. Epub 2015 Feb 25.

Department of Anatomy and Human Embryology. Faculty of Medicine. University of Valencia. Avda. Blasco Ibanez 15, E46010. Valencia, Spain.

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http://dx.doi.org/10.1016/j.spinee.2015.02.028DOI Listing
June 2015

Enzalutamide: a new prostate cancer targeted therapy against the androgen receptor.

Cancer Treat Rev 2015 Mar 8;41(3):247-53. Epub 2015 Jan 8.

Medical Oncology Service, CHUA Coruña, Spain. Electronic address:

Enzalutamide (MDV3100), an androgen receptor-signalling inhibitor, represents the most recent compound added to the therapeutic armamentarium for the treatment of metastatic castration-resistant prostate cancer (mCRPC) who progressed to docetaxel. The anti-tumour activity and safety of enzalutamide has been demonstrated in a phase III clinical trial, showing a benefit in overall survival, which was the primary endpoint. There are no head-to-head studies comparing the different treatment options in this subset of patients. In this article, most relevant data published in the literature have been reviewed, with special attention to the therapeutic alternatives currently available for postdocexatel mCRPC patients, emphasising the mechanisms of action of the different drugs, efficacy and quality of life-related aspects.
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http://dx.doi.org/10.1016/j.ctrv.2014.12.006DOI Listing
March 2015

Congenital absence of the posterior right hemiarch.

Spine J 2015 Jan 28;15(1):207. Epub 2014 Sep 28.

Department of Anatomy and Human Embryology, University of Valencia, Faculty of Medicine, University of Valencia, Av. Blasco Ibanez, 15, E-46010, Valencia, Spain.

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http://dx.doi.org/10.1016/j.spinee.2014.09.009DOI Listing
January 2015

Difficulties in distinguishing between an atlas fracture and a congenital posterior atlas arch defect in postmortem analysis.

Forensic Sci Int 2014 Sep 26;242:e1-e5. Epub 2014 Jun 26.

CT and MRI Unit, ERESA, Department of Radiology, General University Hospital, Valencia, Spain.

We found one atlas from a sample of 148 skeletons (0.67%) that presented different anatomical variations which made it difficult to determine whether the vertebra had an atlas fracture, an unusual Type B posterior atlas arch defect, or a combination of both. We carried out a stereomicroscopy, radiographic, and computerized tomography scan study that revealed that the dry atlas we found presented a very uncommon congenital Type B posterior atlas arch defect, simulating a fracture. In short, the present paper has revealed that differentiating Type B posterior atlas arch defects from fractures in post-mortem dry vertebrae is more difficult than expected. Thus we believe that it can be easier than expected to mistake Type B posterior arch defects for fractures and vice versa in postmortem studies.
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http://dx.doi.org/10.1016/j.forsciint.2014.06.016DOI Listing
September 2014

Role of the microtubule-targeting drug vinflunine on cell-cell adhesions in bladder epithelial tumour cells.

BMC Cancer 2014 Jul 10;14:507. Epub 2014 Jul 10.

Translational Cancer Research Group, Instituto de Investigación Biomédica A Coruña (INIBIC), Complejo Hospitalario Universitario A Coruña (CHUAC), Sergas, As Xubias, 15006 A Coruña, España.

Background: Vinflunine (VFL) is a microtubule-targeting drug that suppresses microtubule dynamics, showing anti-metastatic properties both in vitro and in living cancer cells. An increasing body of evidence underlines the influence of the microtubules dynamics on the cadherin-dependent cell-cell adhesions. E-cadherin is a marker of epithelial-to-mesenchymal transition (EMT) and a tumour suppressor; its reduced levels in carcinoma are associated with poor prognosis. In this report, we investigate the role of VFL on cell-cell adhesions in bladder epithelial tumour cells.

Methods: Human bladder epithelial tumour cell lines HT1376, 5637, SW780, T24 and UMUC3 were used to analyse cadherin-dependent cell-cell adhesions under VFL treatment. VFL effect on growth inhibition was measured by using a MTT colorimetric cell viability assay. Western blot, immunofluorescence and transmission electron microscopy analyses were performed to assess the roles of VFL effect on cell-cell adhesions, epithelial-to-mesenchymal markers and apoptosis. The role of the proteasome in controlling cell-cell adhesion was studied using the proteasome inhibitor MG132.

Results: We show that VFL induces cell death in bladder cancer cells and activates epithelial differentiation of the remaining living cells, leading to an increase of E-cadherin-dependent cell-cell adhesion and a reduction of mesenchymal markers, such as N-cadherin or vimentin. Moreover, while E-cadherin is increased, the levels of Hakai, an E3 ubiquitin-ligase for E-cadherin, were significantly reduced in presence of VFL. In 5637, this reduction on Hakai expression was blocked by MG132 proteasome inhibitor, indicating that the proteasome pathway could be one of the molecular mechanisms involved in its degradation.

Conclusions: Our findings underscore a critical function for VFL in cell-cell adhesions of epithelial bladder tumour cells, suggesting a novel molecular mechanism by which VFL may impact upon EMT and metastasis.
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http://dx.doi.org/10.1186/1471-2407-14-507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107965PMC
July 2014

Phase II randomized study of figitumumab plus docetaxel and docetaxel alone with crossover for metastatic castration-resistant prostate cancer.

Clin Cancer Res 2014 04 17;20(7):1925-34. Epub 2014 Feb 17.

Authors' Affiliations: Royal Marsden NHS Foundation Trust and The Institute of Cancer Research UK, Sutton; Institut Català d'Oncologia, L'Hospitalet, Barcelona; University of Surrey, Surrey, United Kingdom; Yale University Cancer Center, New Haven; Centre Hospitalier de l'Universite de Montreal, Montreal; A Coruña University Hospital, A Coruña, Spain; Kantonsspital St. Gallen, St. Gallen, Switzerland; Fox Chase Cancer Center, Philadelphia, Pennsylvania; Pfizer Inc, Groton, Connecticut; and Lady Davis Institute for Medical Research, Jewish General Hospital and McGill University, Montreal, Quebec, Canada.

Purpose: Figitumumab is a human IgG2 monoclonal antibody targeting insulin-like growth factor 1 receptor (IGF-1R), with antitumor activity in prostate cancer. This phase II trial randomized chemotherapy-naïve men with progressing castration-resistant prostate cancer to receive figitumumab every 3 weeks with docetaxel/prednisone (Arm A) or docetaxel/prednisone alone (Arm B1). At progression on Arm B1, patients could cross over to the combination (Arm B2).

Experimental Design: Prostate-specific antigen (PSA) response was the primary endpoint; response assessment on the two arms was noncomparative and tested separately; H0 = 0.45 versus HA = 0.60 (α = 0.05; β = 0.09) for Arm A; H0 = 0.05 versus HA = 0.20 (α = 0.05, β = 0.10) for Arm B2. A comparison of progression-free survival (PFS) on Arms A and B1 was planned.

Results: A total of 204 patients were randomized and 199 treated (Arm A: 97; Arm B1: 102); 37 patients crossed over to Arm B2 (median number of cycles started: Arm A = 8; B1 = 8; B2 = 4). PSA responses occurred in 52% and 60% of Arms A and B1, respectively; the primary PSA response objective in Arm A was not met. Median PFS was 4.9 and 7.9 months, respectively (HR = 1.44; 95% confidence interval, 1.06-1.96). PSA response rate was 28% in Arm B2. The figitumumab combination appeared more toxic, with more treatment-related grade 3/4 adverse events (75% vs. 56%), particularly hyperglycemia, diarrhea, and asthenia, as well as treatment-related serious adverse events (41% vs. 15%), and all-causality grade 5 adverse events (18% vs. 8%).

Conclusion: IGF-1R targeting may merit further evaluation in this disease in selected populations, but combination with docetaxel is not recommended.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-1869DOI Listing
April 2014

Posttranscriptional regulation by RNA-binding proteins during epithelial-to-mesenchymal transition.

Cell Mol Life Sci 2013 Dec 29;70(23):4463-77. Epub 2013 May 29.

Servizo de Oncología Médica, Complejo Hospitalario Universitario A Coruña (CHUAC), SERGAS, A Coruña, Spain.

Epithelial-to-mesenchymal transition (EMT), one of the crucial steps for carcinoma cells to acquire invasive capacity, results from the disruption of cell-cell contacts and the acquisition of a motile mesenchymal phenotype. Although the transcriptional events controlling EMT have been extensively studied, in recent years, several posttranscriptional mechanisms have emerged as critical in the regulation of EMT during tumor progression. In this review, we highlight the regulation of posttranscriptional events in EMT by RNA-binding proteins (RBPs). RBPs are responsible for controlling pre-mRNA splicing, capping, and polyadenylation, as well as mRNA export, turnover, localization, and translation. We discuss the most relevant aspects of RBPs controlling the metabolism of EMT-related mRNAs, and describe the implication of novel posttranscriptional mechanisms regulating EMT in response to different signaling pathways. Novel insight into posttranscriptional regulation of EMT by RBPs is uncovering new therapeutic targets in cancer invasion and metastasis.
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http://dx.doi.org/10.1007/s00018-013-1379-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827902PMC
December 2013

miR-203 regulates cell proliferation through its influence on Hakai expression.

PLoS One 2012 20;7(12):e52568. Epub 2012 Dec 20.

Translational Cancer Research Group, Instituto de Investigación Biomédica A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña (CHUAC)-SERGAS, A Coruña, Spain.

Gene expression is potently regulated through the action of microRNAs (miRNAs). Here, we present evidence of a miRNA regulating Hakai protein. Hakai was discovered as an E3 ubiquitin-ligase that mediates the posttranslational downregulation of E-cadherin, a major component of adherens junctions in epithelial cells and a potent tumour suppressor. Recent data have provided evidence that Hakai affects cell proliferation in an E-cadherin-independent manner, thus revealing a role for Hakai in the early stages of tumour progression. Furthermore, Hakai is highly up-regulated in human colon adenocarcinomas compared to normal tissues. However, the molecular mechanisms that regulate Hakai abundance are unknown. We identified two putative sites of miR-203 interaction on the Hakai mRNA, in its 3'-untranslated region (UTR). In several human carcinoma cell lines tested, overexpression of a miR-203 precursor (Pre-miR-203) reduced Hakai abundance, while inhibiting miR-203 by using an antisense RNA (Anti-miR-203) elevated Hakai levels. The repressive influence of miR-203 on the Hakai 3'-UTR was confirmed using heterologous reporter constructs. In keeping with Hakai's proliferative influence, Anti-miR-203 significantly increased cell number and BrdU incorporation, while Pre-miR-203 reduced these parameters. Importantly, the growth-promoting effects of anti-miR-203 required the presence of Hakai, because downregulation of Hakai by siRNA suppressed its proliferative action. Finally, in situ hybridization showed that miR-203 expression is attenuated in colon tumour tissues compared to normal colon tissues, suggesting that miR-203 could be a potential new prognostic marker and therapeutic target to explore in colon cancer. In conclusion, our findings reveal, for the first time, a post-transcriptional regulator of Hakai expression. Furthermore, by lowering Hakai abundance, miR-203 also reduces Hakai-regulated-cell division.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0052568PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527564PMC
June 2013

Crossing paths in Human Renal Cell Carcinoma (hRCC).

Int J Mol Sci 2012 Oct 5;13(10):12710-33. Epub 2012 Oct 5.

Biomedical Research Institute (INIBIC), CHU A Coruña, Xubias de Abaixo s/n, PC 15006, A Coruña, Spain.

Historically, cell-signaling pathways have been studied as the compilation of isolated elements into a unique cascade that transmits extracellular stimuli to the tumor cell nucleus. Today, growing evidence supports the fact that intracellular drivers of tumor progression do not flow in a single linear pathway, but disseminate into multiple intracellular pathways. An improved understanding of the complexity of cancer depends on the elucidation of the underlying regulatory networks at the cellular and intercellular levels and in their temporal dimension. The high complexity of the intracellular cascades causes the complete inhibition of the growth of one tumor cell to be very unlikely, except in cases in which the so-called “oncogene addiction” is known to be a clear trigger for tumor catastrophe, such as in the case of gastrointestinal stromal tumors or chronic myeloid leukemia. In other words, the separation and isolation of the driver from the passengers is required to improve accuracy in cancer treatment. This review will summarize the signaling pathway crossroads that govern renal cell carcinoma proliferation and the emerging understanding of how these pathways facilitate tumor escape. We outline the available evidence supporting the putative links between different signaling pathways and how they may influence tumor proliferation, differentiation, apoptosis, angiogenesis, metabolism and invasiveness. The conclusion is that tumor cells may generate their own crossroads/crosstalk among signaling pathways, thereby reducing their dependence on stimulation of their physiologic pathways.
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http://dx.doi.org/10.3390/ijms131012710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3497295PMC
October 2012

Biological influence of Hakai in cancer: a 10-year review.

Cancer Metastasis Rev 2012 Jun;31(1-2):375-86

Servizo de Oncología Médica, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain.

In order to metastasize, cancer cells must first detach from the primary tumor, migrate, invade through tissues, and attach to a second site. Hakai was discovered as an E3 ubiquitin-ligase that mediates the posttranslational downregulation of E-cadherin, a major component of adherens junctions in epithelial cells that is characterized as a potent tumor suppressor and is modulated during various processes including epithelial-mesenchymal transition. Recent data have provided evidences for novel biological functional role of Hakai during tumor progression and other diseases. Here, we will review the knowledge that has been accumulated since Hakai discovery 10 years ago and its implication in human cancer disease. We will highlight the different signaling pathways leading to the influence on Hakai and suggest its potential usefulness as therapeutic target for cancer.
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http://dx.doi.org/10.1007/s10555-012-9348-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350634PMC
June 2012

Sunitinib: the first to arrive at first-line metastatic renal cell carcinoma.

Adv Ther 2012 Mar 7;29(3):202-17. Epub 2012 Feb 7.

Oncology Department, Hospital Universitario Lucus Augusti, Lugo, Spain.

Tyrosine kinase inhibitors (TKIs) are beneficial for the treatment of renal cell carcinoma (RCC), gastrointestinal stromal tumors (GIST), pancreatic neuroendocrine tumors (pNETs), and other tumors. The antitumor activity of sunitinib has been based on time-related parameters such as progression-free survival (PFS) and overall survival (OS). Advances in knowledge of the molecular mechanisms and oncogenic processes associated with RCC have enabled the availability of rational targets for pharmacotherapy. Although each small molecule is modeled to block the activity of selected kinase signaling enzymes, it is increasingly evident that many have nontargeted effects (on other kinases) that may cause unexpected complications. The recommended dose for sunitinib in patients with advanced RCC is a 50 mg oral daily dose, with or without food, on a 4/2 week schedule (4 weeks "on" vs. 2 weeks "off") until progression. An alternative continuous 37.5 mg/day dosing schedule has also been evaluated and appears to be well tolerated, allowing the maintenance of the dose density of sunitinib with a similar outcome. The continuous administration schedule provides a constant exposure to the drug, and may prevent potential tumor regrowth and angiogenesis recovery. Most side effects are reversible and should not result in sunitinib discontinuation. In this article, the body of evidence behind the use of sunitinib in metastatic RCC (mRCC) compared to other targeted agents that have recently come into the field is summarized, and the need for correct management of an adverse event profile in order to better optimize available treatment options is underlined.
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http://dx.doi.org/10.1007/s12325-011-0099-9DOI Listing
March 2012

Hakai reduces cell-substratum adhesion and increases epithelial cell invasion.

BMC Cancer 2011 Nov 3;11:474. Epub 2011 Nov 3.

Translational Cancer Research Group, Instituto de Investigación Biomédica A Coruña (INIBIC), Complejo Hospitalario Universitario A Coruña (CHUAC), SERGAS, A Coruña, Spain.

Background: The dynamic regulation of cell-cell adhesions is crucial for developmental processes, including tissue formation, differentiation and motility. Adherens junctions are important components of the junctional complex between cells and are necessary for maintaining cell homeostasis and normal tissue architecture. E-cadherin is the prototype and best-characterized protein member of adherens junctions in mammalian epithelial cells. Regarded as a tumour suppressor, E-cadherin loss is associated with poor prognosis in carcinoma. The E3 ubiquitin-ligase Hakai was the first reported posttranslational regulator of the E-cadherin complex. Hakai specifically targetted E-cadherin for internalization and degradation and thereby lowered epithelial cell-cell contact. Hakai was also implicated in controlling proliferation, and promoted cancer-related gene expression by increasing the binding of RNA-binding protein PSF to RNAs encoding oncogenic proteins. We sought to investigate the possible implication of Hakai in cell-substratum adhesions and invasion in epithelial cells.

Methods: Parental MDCK cells and MDCK cells stably overexpressing Hakai were used to analyse cell-substratum adhesion and invasion capabilities. Western blot and immunofluoresecence analyses were performed to assess the roles of Paxillin, FAK and Vinculin in cell-substratum adhesion. The role of the proteasome in controlling cell-substratum adhesion was studied using two proteasome inhibitors, lactacystin and MG132. To study the molecular mechanisms controlling Paxillin expression, MDCK cells expressing E-cadherin shRNA in a tetracycline-inducible manner was employed.

Results: Here, we present evidence that implicate Hakai in reducing cell-substratum adhesion and increasing epithelial cell invasion, two hallmark features of cancer progression and metastasis. Paxillin, an important protein component of the cell-matrix adhesion, was completely absent from focal adhesions and focal contacts in Hakai-overexpressing MDCK cells. The expression of Paxillin was found to be regulated by a proteasome-independent mechanism, possibly due to the decreased abundance of E-cadherin.

Conclusions: Taken together, these results suggest that Hakai may be involved in two hallmark aspects of tumour progression, the lowering cell-substratum adhesion and the enhancement of cell invasion.
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http://dx.doi.org/10.1186/1471-2407-11-474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229560PMC
November 2011

Sunitinib-induced asthenia: from molecular basis to clinical relief.

Cancer Biol Ther 2011 Nov;12(9):765-71

Clinical Oncology Department, A Coruña University Hospital, A Coruña, Spain.

Asthenia-fatigue syndrome (AFS) is defined as a persistent, subjective sense of tiredness related to cancer or its treatment and greatly impacts quality of life among cancer patients. All tyrosine kinase inhibitors, but especially sunitinib, may induce AFS. The reason for sunitinib-induced AFS is not yet well understood. Adverse events caused by sunitinib associated with AFS may include anemia, hypothyroidism, nausea and vomiting. However, AFS is also reported when active treatment with sunitinib is ongoing, and no other relevant adverse event can justify it. The molecular mechanisms by which sunitinib triggers AFS remain elusive. Sunitinib displays multiple off-target tyrosine-kinase interactions and competitively inhibits multiple proteins through the blockade of their ATP-binding sites. The broad spectrum of kinases inhibited may play a key role not only in terms of activity but also in terms of toxicity induced by sunitinib. This study considered different clinical observations and current metabolic and pharmacological knowledge, leading to hypotheses regarding which molecular mechanisms may be involved in sunitinib-induced AFS in cancer patients. Deeper knowledge of the molecular mode of action of sunitinib may lead to improved optimization of its clinical use.
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http://dx.doi.org/10.4161/cbt.12.9.18138DOI Listing
November 2011

Vinflunine: a new vision that may translate into antiangiogenic and antimetastatic activity.

Anticancer Drugs 2012 Jan;23(1):1-11

Medical Oncology Service, CHU A Coruña, Spain.

Microtubules and tubulin are major dynamic and structural cellular components that play a key role in several cell functions, including division, signalling and intracellular trafficking. Normal epithelial cells have a highly structured, rigid cytoskeletal network that is compatible with cell motility. Thus, tubulin and microtubules are compelling cellular targets for chemotherapy. In fact, among anticancer agents, those that target microtubules constitute one of the most effective classes of chemotherapeutics in cancer. The list of compounds that target either tubulin or microtubules is extensive and consists of chemically unique compounds that bind to the tubulin dimers and destabilize microtubules (Vinca alkaloids) and those that bind to the microtubule polymer and stabilize microtubules (taxanes). Tumour-induced angiogenesis, the formation of new capillaries from existing blood vessels, and epithelial-mesenchymal transition are two steps that are critical for both tumour growth and metastatic spread. Three possible mechanisms of action are described with vinflunine, the new-generation Vinca alkaloid to arrive in clinical practice are as follows: it acts against tubulin and microtubules, disrupts newly formed blood vessels and seems to be able to reduce the metastatic process as shown in preclinical studies. These findings support the hypothesis that vinflunine, by blocking microtubule functions that contribute to cell shape, polarization, migration and other processes, might be responsible not only for tumour-cytostatic but also for specific antiangiogenic or antiepithelial-mesenchymal transition effects.
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http://dx.doi.org/10.1097/CAD.0b013e32834d237bDOI Listing
January 2012

A novel procedure for protein extraction from formalin-fixed paraffin-embedded tissues.

Proteomics 2011 Jun 18;11(12):2555-9. Epub 2011 May 18.

Translational Cancer Research Group, Proteo-Red-ISCIII, Instituto de Investigación Biomédica A Coruña, Coruña, Spain.

Most of the archived pathological specimens in hospitals are kept as formalin-fixed paraffin-embedded tissues (FFPE) for long-term preservation. Up to now, these samples are only used for immunohistochemistry in a clinical routine as it is difficult to recover intact protein from these FFPE tissues. Here, we report a novel, short time-consuming and cost-effective method to extract full-length, non-degraded proteins from FFPE tissues. This procedure is combined with an effective and non-toxic deparaffinisation process and an extraction method based on antigen-retrieval, high concentration of SDS and high temperature. We have obtained enough intact protein to be detected by Western blotting analysis. This technique will allow utilising these stored FFPE tissues in several applications for protein analysis helping to advance the translational studies in cancer and other diseases.
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http://dx.doi.org/10.1002/pmic.201000809DOI Listing
June 2011

Glucose transporter expression and the potential role of fructose in renal cell carcinoma: A correlation with pathological parameters.

Mol Med Rep 2010 Jul-Aug;3(4):575-80

A Coruña University Hospital, 15006 A Coruña, Spain.

All mammalian cells contain one or more members of the facilitative glucose transporter (GLUT) gene family. Glucose transporter membrane proteins (GLUT) regulate the movement of glucose between the extracellular and intracellular compartments, maintaining a constant supply of glucose available for metabolism. Tumor cells are highly energy-dependent, therefore GLUT overexpression is often observed. In fact, overexpression of GLUT1 has been correlated with hypoxia markers in several tumor types, including renal cell carcinoma (RCC). We retrospectively analyzed 80 paraffin-embedded RCC samples. The pattern of GLUT1-5 expression in RCC specimens was evaluated using tissue-array technology and correlated with histological tumor characteristics. Pathological parameters included tumor location, renal pelvis, vein and lymph vessel invasion, capsule breakage, histological subtype, Furhman grade, hilar invasion and tumor stage at diagnosis. The expression of five facilitative glucose transporters, GLUT1 (erythrocyte type), GLUT2 (liver type), GLUT3 (brain type), GLUT4 (muscle/fat type) and GLUT5 (small intestinal type), was semi-quantitatively analyzed. In non-parametric, Mann-Whitney U and Kruskal-Wallis tests, a significant positive correlation was consistently found between moderately differentiated RCC tissues and the expression of GLUT5 (p=0.024). Patients who had pelvic invasion and capsule breakage at diagnosis also showed increased GLUT5 expression levels (p=0.039 and p=0.019, respectively). Moreover, GLUT5 showed statistical significance in those samples identified as being of clear cell histological type (p=0.001). A high expression of GLUT5 in human RCC was observed. GLUT5 appears to be correlated with grade II differentiation, locoregional invasion and aggressiveness, and may play a role in RCC development.
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http://dx.doi.org/10.3892/mmr_00000300DOI Listing
October 2012

Potential role of sugar transporters in cancer and their relationship with anticancer therapy.

Int J Endocrinol 2010 18;2010. Epub 2010 Jul 18.

Biomedical Research Institute, A Coruña University Hospital, As Xubias 84, 15006 A Coruña, Spain.

Sugars, primarily glucose and fructose, are the main energy source of cells. Because of their hydrophilic nature, cells use a number of transporter proteins to introduce sugars through their plasma membrane. Cancer cells are well known to display an enhanced sugar uptake and consumption. In fact, sugar transporters are deregulated in cancer cells so they incorporate higher amounts of sugar than normal cells. In this paper, we compile the most significant data available about biochemical and biological properties of sugar transporters in normal tissues and we review the available information about sugar carrier expression in different types of cancer. Moreover, we describe the possible pharmacological interactions between drugs currently used in anticancer therapy and the expression or function of facilitative sugar transporters. Finally, we also go into the insights about the future design of drugs targeted against sugar utilization in cancer cells.
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http://dx.doi.org/10.1155/2010/205357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913528PMC
July 2011

Evaluation of COX-2, EGFR, and p53 as biomarkers of non-dysplastic oral leukoplakias.

Exp Mol Pathol 2010 Oct 1;89(2):197-203. Epub 2010 Jul 1.

Medicine Department, University of La Coruña, La Coruña, Spain.

Objective: Identify candidate SEBs (surrogate endpoint biomarkers) for premalignant trends in head and neck mucosa.

Study Design: Study, by qPCR (quantitative real-time polymerase chain reaction), the expression of COX-2, EGFR and p53 in 24 biopsies of non-dysplastic oral leukoplakia and contra-lateral normal-appearing mucosa.

Results: COX-2 was up-regulated in leukoplakia (79.2%); whereas EGFR and p53 were up-regulated (p>0.05) in oral contra-lateral normal-appearing mucosa (60% and 46% respectively). Also, p53 expression was correlated with tobacco smoke habits and Spearman's rank correlation coefficient showed a positive linear correlation between p53 and EGFR mRNA expression levels.

Conclusions: COX-2 would serve as SEB of oral leukoplakia. The results suggest that p53 appears to be one of the molecular targets of tobacco-related carcinogens in leukoplakia and that the co-expression of p53 and EGFR may play a role in this kind of oral pre-cancerous lesion. More detailed studies of EGFR and p53 should be continued in the future.
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http://dx.doi.org/10.1016/j.yexmp.2010.06.004DOI Listing
October 2010