Publications by authors named "Jesus Herranz"

38 Publications

Beam damage of single semiconductor nanowires during X-ray nanobeam diffraction experiments.

J Synchrotron Radiat 2020 Sep 12;27(Pt 5):1200-1208. Epub 2020 Aug 12.

Naturwissenschaftlich-Technische Fakultät der Universität Siegen, Siegen 57068, Germany.

Nanoprobe X-ray diffraction (nXRD) using focused synchrotron radiation is a powerful technique to study the structural properties of individual semiconductor nanowires. However, when performing the experiment under ambient conditions, the required high X-ray dose and prolonged exposure times can lead to radiation damage. To unveil the origin of radiation damage, a comparison is made of nXRD experiments carried out on individual semiconductor nanowires in their as-grown geometry both under ambient conditions and under He atmosphere at the microfocus station of the P08 beamline at the third-generation source PETRA III. Using an incident X-ray beam energy of 9 keV and photon flux of 10 s, the axial lattice parameter and tilt of individual GaAs/InGaAs/GaAs core-shell nanowires were monitored by continuously recording reciprocal-space maps of the 111 Bragg reflection at a fixed spatial position over several hours. In addition, the emission properties of the (In,Ga)As quantum well, the atomic composition of the exposed nanowires and the nanowire morphology were studied by cathodoluminescence spectroscopy, energy-dispersive X-ray spectroscopy and scanning electron microscopy, respectively, both prior to and after nXRD exposure. Nanowires exposed under ambient conditions show severe optical and morphological damage, which was reduced for nanowires exposed under He atmosphere. The observed damage can be largely attributed to an oxidation process from X-ray-induced ozone reactions in air. Due to the lower heat-transfer coefficient compared with GaAs, this oxide shell limits the heat transfer through the nanowire side facets, which is considered as the main channel of heat dissipation for nanowires in the as-grown geometry.
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http://dx.doi.org/10.1107/S1600577520009789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467348PMC
September 2020

Efficient adjustable light couplers of integrated III-V nanowire emitters on silicon waveguides based on ring resonators.

Opt Lett 2020 Sep;45(17):4702-4705

The development of integrated vertical III-V nanowire (NW) stimulated emitters in silicon photonics while achieving an efficient light coupling through vertical III-V NW lasers into horizontal optical silicon waveguides is demanding. This is mainly due to the directionality and contradiction of the simultaneously satisfied low threshold stimulated emission conditions of the vertical NWs and efficient light coupling from the NW emitters into the horizontal silicon waveguide. However, we propose a new, to the best of our knowledge, design by taking advantage of resonating features of ring structures and theoretically demonstrate that an interfacial ring resonator between GaAs NW emitters and the silicon waveguide achieves a coupling efficiency up to about 70% at a given wavelength. We also show that the interfacial resonator enables us to adjust the coupling efficiency from about 10% to over 70%. The adjustable coupling efficiency might also be a solution to compromise between the low threshold stimulated emission of NWs and efficient light coupling for realizing efficient silicon couplers based on integrated III-V NW lasers in silicon photonics. Besides the simple fabrication process compared to counterparts, we believe that the novel structure is promising for future optical on-chip data communication in silicon photonics, and the results are expandable to varying wavelengths and materials.
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http://dx.doi.org/10.1364/OL.398930DOI Listing
September 2020

Work function of GaAs(hkl) and its modification using PEI: mechanisms and substrate dependence.

Phys Chem Chem Phys 2019 Nov 1;21(44):24666-24673. Epub 2019 Nov 1.

Department of Physics, University of Warwick, Coventry, CV4 7AL, UK.

Spin-coating of poly(ethylenimine) (PEI) has been used to reduce the work function of GaAs (001), (110), (111)A and (111)B. The magnitude of the reduction immediately after coating varies significantly from 0.51 eV to 0.69 eV and depends on the surface crystal face, on the GaAs bulk doping and on the atomic termination of the GaAs. For all samples, the work function reduction shrinks in ambient air over the first 20 hours after spin coating, but reductions around 0.2-0.3 eV persist after 1 year of storage in air. Core-level photoemission of thin film PEI degradation in air is consistent with a two-stage reaction with CO and HO previously proposed in carbon capture studies. The total surface dipole from PEI coating is consistent with a combination of internal neutral amine dipole and an interface dipole whose magnitude depends on the surface termination. The contact potential difference measured by Kelvin probe force microscopy on a cleaved GaAs heterostructure is smaller on p-doped regions. This can be explained by surface doping due to the PEI, which increases the band bending on p-doped GaAs where Fermi level pinning is weak. Both surface doping and surface dipole should be accounted for when considering the effect of PEI coated on a semiconductor surface.
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http://dx.doi.org/10.1039/c9cp04490fDOI Listing
November 2019

Correlated Nanoscale Analysis of the Emission from Wurtzite versus Zincblende (In,Ga)As/GaAs Nanowire Core-Shell Quantum Wells.

Nano Lett 2019 Jul 5;19(7):4448-4457. Epub 2019 Jun 5.

Paul-Drude-Institut für Festkörperelektronik , Leibniz-Institut im Forschungsverbund Berlin e.V. , Hausvogteiplatz 5-7 , 10117 Berlin , Germany.

While the properties of wurtzite GaAs have been extensively studied during the past decade, little is known about the influence of the crystal polytype on ternary (In,Ga)As quantum well structures. We address this question with a unique combination of correlated, spatially resolved measurement techniques on core-shell nanowires that contain extended segments of both the zincblende and wurtzite polytypes. Cathodoluminescence hyperspectral imaging reveals a blue-shift of the quantum well emission energy by 75 ± 15 meV in the wurtzite polytype segment. Nanoprobe X-ray diffraction and atom probe tomography enable · calculations for the specific sample geometry to reveal two comparable contributions to this shift. First, there is a 30% drop in In mole fraction going from the zincblende to the wurtzite segment. Second, the quantum well is under compressive strain, which has a much stronger impact on the hole ground state in the wurtzite than in the zincblende segment. Our results highlight the role of the crystal structure in tuning the emission of (In,Ga)As quantum wells and pave the way to exploit the possibilities of three-dimensional band gap engineering in core-shell nanowire heterostructures. At the same time, we have demonstrated an advanced characterization toolkit for the investigation of semiconductor nanostructures.
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http://dx.doi.org/10.1021/acs.nanolett.9b01241DOI Listing
July 2019

Re-interpretation of PAM50 gene expression as quantitative tumor dimensions shows utility for clinical trials: application to prognosis and response to paclitaxel in breast cancer.

Breast Cancer Res Treat 2019 May 23;175(1):129-139. Epub 2019 Jan 23.

Huntsman Cancer Institute, University of Utah, Salt Lake City, USA.

Background: We recently showed PAM50 gene expression data can be represented by five quantitative, orthogonal, multi-gene breast tumor traits. These novel tumor 'dimensions' were superior to categorical intrinsic subtypes for clustering in high-risk breast cancer pedigrees, indicating potential to represent underlying genetic susceptibilities and biological pathways. Here we explore the prognostic and predictive utility of these dimensions in a sub-study of GEICAM/9906, a Phase III randomized prospective clinical trial of paclitaxel in breast cancer.

Methods: Tumor dimensions, PC1-PC5, were calculated using pre-defined coefficients. Univariable and multivariable Cox proportional hazards (PH) models for disease-free survival (DFS) were used to identify associations between quantitative dimensions and prognosis or response to the addition of paclitaxel. Results were illustrated using Kaplan-Meier curves.

Results: Dimensions PC1 and PC5 were associated with DFS (Cox PH p = 6.7 [Formula: see text] 10 and p = 0.036), remaining significant after correction for standard clinical-pathological prognostic characteristics. Both dimensions were selected in the optimal multivariable model, together with nodal status and tumor size (Cox PH p = 1.4 [Formula: see text] 10). Interactions with treatment were identified for PC3 and PC4. Response to paclitaxel was restricted to tumors with low PC3 and PC4 (log-rank p = 0.0021). Women with tumors high for PC3 or PC4 showed no survival advantage.

Conclusions: Our proof-of-concept application of quantitative dimensions illustrated novel findings and clinical utility beyond standard clinical-pathological characteristics and categorical intrinsic subtypes for prognosis and predicting chemotherapy response. Consideration of expression data as quantitative tumor dimensions offers new potential to identify clinically important patient subsets in clinical trials and advance precision medicine.
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http://dx.doi.org/10.1007/s10549-018-05097-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491406PMC
May 2019

Predicting Response to Standard First-line Treatment in High-grade Serous Ovarian Carcinoma by Angiogenesis-related Genes.

Anticancer Res 2018 Sep;38(9):5393-5400

Molecular Pathology and Therapeutic Targets Group, La Paz University Hospital (IdiPAZ), Madrid, Spain

Background/aim: Predicting response to treatment in high-grade serous ovarian carcinoma (HGSOC) still remains a clinical challenge. The standard-of-care for first-line chemotherapy, based on a combination of carboplatin and paclitaxel, achieves a high response rate. However, the development of drug resistance is one of the major limitations to efficacy. Therefore, identification of biomarkers able to predict response to chemotherapy in patients with HGSOC is a critical step for prognosis and treatment of the disease. Several studies suggest that angiogenesis is an important process in the development of ovarian carcinoma and chemoresistance. The aim of this study was to identify a profile of angiogenesis-related genes as a biomarker for response to first-line chemotherapy in HGSOC.

Materials And Methods: Formalin-fixed paraffin-embedded samples from 39 patients with HGSOC who underwent surgical cytoreduction and received a first-line chemotherapy with carboplatin and paclitaxel were included in this study. Expression levels of 82 angiogenesis-related genes were measured by quantitative real-time polymerase chain reaction using TaqMan low-density arrays.

Results: Univariate analysis identified five genes [angiopoietin 1 (ANGPT1), aryl hydrocarbon receptor nuclear translocator (ARNT), CD34, epidermal growth factor (EGF) and matrix metallopeptidase 3 (MMP3)] as being statistically associated with response to treatment. Multivariable analysis by Lasso-penalized Cox regression generated a model with the combined expression of seven genes [angiotensinogen (AGT), CD34, EGF, erythropoietin receptor (EPOR), interleukin 8 (IL8), MMP3 and MMP7)]. The area under the receiver operating characteristics curve (0.679) and cross-validated Kaplan-Meier survival curves were used to estimate the accuracy of these predictors.

Conclusion: An angiogenesis-related gene expression profile useful for response prediction in HGSOC was identified, supporting the important role of angiogenesis in HGSOC.
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http://dx.doi.org/10.21873/anticanres.12869DOI Listing
September 2018

The role of glycosyltransferase enzyme GCNT3 in colon and ovarian cancer prognosis and chemoresistance.

Sci Rep 2018 05 31;8(1):8485. Epub 2018 May 31.

Molecular Oncology Group, IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain.

Glycosyltransferase enzyme GCNT3, has been proposed as a biomarker for prognosis in colorectal cancer (CRC). Our study goes in depth into the molecular basis of GCNT3 role in tumorigenesis and drug resistance, and it explores its potential role as biomarker in epithelial ovarian cancer (EOC). High levels of GCNT3 are associated with increased sensibility to 5-fluoracil in metastatic cells. Accordingly, GCNT3 re-expression leads to the gain of anti-carcinogenic cellular properties by reducing cell growth, invasion and by changing metabolic capacities. Integrated transcriptomic and proteomic analyses reveal that GCNT3 is linked to cellular cycle, mitosis and proliferation, response to drugs and metabolism pathways. The vascular epithelial growth factor A (VEGFA) arises as an attractive partner of GCNT3 functions in cell invasion and resistance. Finally, GCNT3 expression was analyzed in a cohort of 56 EOC patients followed by a meta-analysis of more than one thousand patients. This study reveals that GCNT3 might constitute a prognostic factor also in EOC, since its overexpression is associated with better clinical outcome and response to initial therapy. GCNT3 emerges as an essential glycosylation-related molecule in CRC and EOC progression, with potential interest as a predictive biomarker of response to chemotherapy.
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http://dx.doi.org/10.1038/s41598-018-26468-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5981315PMC
May 2018

The transcriptional and mutational landscapes of lipid metabolism-related genes in colon cancer.

Oncotarget 2018 Jan 21;9(5):5919-5930. Epub 2017 Dec 21.

Molecular Oncology Group, IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain.

Metabolic alterations encountered in tumors are well recognized and considered as a hallmark of cancer. In addition to Warburg Effect, epidemiological and experimental studies support the crucial role of lipid metabolism in colorectal cancer (CRC). The overexpression of four lipid metabolism-related genes ( and genes) has been proposed as prognostic marker of stage II CRC (ColoLipidGene signature). In order to explore in depth the transcriptomic and genomic scenarios of , , and genes, we performed a transcriptomic meta-analysis in more than one thousand CRC individuals. Additionally we analyzed their genomic coding sequence in 95 patients, to find variants that could orchestrate CRC prognosis. We found that genetic variant rs3071, located on gene, defines a 9.77% of stage II CRC patients with high risk of death. Moreover, individuals with upregulation of and expression have an increased risk of CRC recurrence, independently of tumor stage. emerges as one of the main contributors to signature's prognostic effect. Indeed, both high expression and presence of tumoral genetic variants located in coding region, seem to be associated with CRC risk of death. In addition the non-synonymous polymorphism rs2230808, located on , is associated with gene expression. Patients carrying at least one copy of minor allele showed higher levels of expression than patients carrying homozygous major allele. This study broaden the prognostic value of and genes, independently of CRC tumor stage, leading to future precision medicine approaches and "omics"-guided therapies.
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http://dx.doi.org/10.18632/oncotarget.23592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814184PMC
January 2018

Targeting the lipid metabolic axis in colorectal cancer progression by therapeutic miRNAs: miR-19b-1 role.

J Lipid Res 2018 01 26;59(1):14-24. Epub 2017 Oct 26.

Molecular Oncology and Nutritional Genomics of Cancer Group, Instituto Madrileño de Estudios Avanzados (IMDEA) Food Institute, CEI UAM+CSIC, Madrid, Spain

An abnormal acyl-CoA synthetase/stearoyl-CoA desaturase (/) lipid network fuels colon cancer progression, endowing cells with invasive and migratory properties. Therapies against this metabolic network may be useful to improve clinical outcomes. Because micro-RNAs (miRNAs/miRs) are important epigenetic regulators, we investigated novel miRNAs targeting this pro-tumorigenic axis; hence to be used as therapeutic or prognostic miRNAs. Thirty-one putative common miRNAs were predicted to simultaneously target the three enzymes comprising the / network. Target validation by quantitative RT-PCR, Western blotting, and luciferase assays showed miR-544a, miR-142, and miR-19b-1 as major regulators of the metabolic axis, / Importantly, lower miR-19b-1 expression was associated with a decreased survival rate in colorectal cancer (CRC) patients, accordingly with / involvement in patient relapse. Finally, miR-19b-1 regulated the pro-tumorigenic axis, /, being able to inhibit invasion in colon cancer cells. Because its expression correlated with an increased survival rate in CRC patients, we propose miR-19b-1 as a potential noninvasive biomarker of disease-free survival and a promising therapeutic miRNA in CRC.
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http://dx.doi.org/10.1194/jlr.M076752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748493PMC
January 2018

MicroRNA-661 modulates redox and metabolic homeostasis in colon cancer.

Mol Oncol 2017 12 6;11(12):1768-1787. Epub 2017 Nov 6.

Precision Nutrition and Cancer Program, Molecular Oncology and Nutritional Genomics of Cancer Group, IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain.

Cancer cell survival and metastasis are dependent on metabolic reprogramming that is capable of increasing resistance to oxidative and energetic stress. Targeting these two processes can be crucial for cancer progression. Herein, we describe the role of microRNA-661 (miR661) as epigenetic regulator of colon cancer (CC) cell metabolism. MicroR661 induces a global increase in reactive oxygen species, specifically in mitochondrial superoxide anions, which appears to be mediated by decreased carbohydrate metabolism and pentose phosphate pathway, and by a higher dependency on mitochondrial respiration. MicroR661 overexpression in non-metastatic human CC cells induces an epithelial-to-mesenchymal transition phenotype, and a reduced tolerance to metabolic stress. This seems to be a general effect of miR661 in CC, since metastatic CC cell metabolism is also compromised upon miR661 overexpression. We propose hexose-6-phosphate dehydrogenase and pyruvate kinase M2 as two key players related to the observed metabolic reprogramming. Finally, the clinical relevance of miR661 expression levels in stage-II and III CC patients is discussed. In conclusion, we propose miR661 as a potential modulator of redox and metabolic homeostasis in CC.
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http://dx.doi.org/10.1002/1878-0261.12142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709620PMC
December 2017

Quantum Dot Self-Assembly Driven by a Surfactant-Induced Morphological Instability.

Phys Rev Lett 2017 Aug 24;119(8):086101. Epub 2017 Aug 24.

Paul-Drude-Institut für Festkörperelektronik, Hausvogteiplatz 5-7, 10117 Berlin, Germany.

In strained heteroepitaxy, two-dimensional layers can exhibit a critical thickness at which three-dimensional islands self-assemble, relieving misfit strain at the cost of an increased surface area. Here we show that such a morphological phase transition can be induced on demand using surfactants. We explore Bi as a surfactant in the growth of InAs on GaAs(110), and find that the presence of surface Bi induces Stranski-Krastanov growth of 3D islands, while growth without Bi always favors 2D layer formation. Exposing a static two monolayer thick InAs layer to Bi rapidly transforms the layer into 3D islands. Density functional theory calculations reveal that Bi as well as Sb reduce the energetic cost of 3D island formation by modifying surface energies. These 3D nanostructures behave as optically active quantum dots. This work illustrates how surfactants can enable quantum dot self-assembly where it otherwise would not occur.
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http://dx.doi.org/10.1103/PhysRevLett.119.086101DOI Listing
August 2017

Self-Assembly of InAs Nanostructures on the Sidewalls of GaAs Nanowires Directed by a Bi Surfactant.

Nano Lett 2017 07 29;17(7):4255-4260. Epub 2017 Jun 29.

Paul-Drude-Institut für Festkörperelektronik , Hausvogteiplatz 5-7, 10117 Berlin, Germany.

Surface energies play a dominant role in the self-assembly of three-dimensional (3D) nanostructures. In this Letter, we show that using surfactants to modify surface energies can provide a means to externally control nanostructure self-assembly, enabling the synthesis of novel hierarchical nanostructures. We explore Bi as a surfactant in the growth of InAs on the {11̅0} sidewall facets of GaAs nanowires. The presence of surface Bi induces the formation of InAs 3D islands by a process resembling the Stranski-Krastanov mechanism, which does not occur in the absence of Bi on these surfaces. The InAs 3D islands nucleate at the corners of the {11̅0} facets above a critical shell thickness and then elongate along ⟨110⟩ directions in the plane of the nanowire sidewalls. Exploiting this growth mechanism, we realize a series of novel hierarchical nanostructures, ranging from InAs quantum dots on single {11̅0} nanowire facets to zigzag-shaped nanorings completely encircling nanowire cores. Photoluminescence spectroscopy and cathodoluminescence spectral line scans reveal that small surfactant-induced InAs 3D islands behave as optically active quantum dots. This work illustrates how surfactants can provide an unprecedented level of external control over nanostructure self-assembly.
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http://dx.doi.org/10.1021/acs.nanolett.7b01185DOI Listing
July 2017

Multiple chemical sensitivity: Genotypic characterization, nutritional status and quality of life in 52 patients.

Med Clin (Barc) 2017 Aug 7;149(4):141-146. Epub 2017 Mar 7.

IMDEA-Food, Campus de Excelencia Internacional (CEI) UAM+CSIC, Madrid, España; Departamento de Producción y Caracterización de Nuevos Alimentos, Instituto de Investigación en Ciencias de la Alimentación (CIAL), Campus de Excelencia Internacional (CEI) UAM+CSIC, Madrid, España.

Background And Objectives: Multiple chemical sensitivity (MCS) is a chronic, multisystem syndrome of unknown etiology. The aim of the present study was to describe the nutritional status and quality of life of patients suffering from MCS, as well as to identify potential polymorphisms associated with this illness.

Patients And Methods: A cross-sectional, descriptive study was performed on patients with a diagnosis of MCS. Data on anthropometric and body composition variables, hand muscle strength and quality of life were collected. The selection of single nucleotide polymorphisms (SNPs) was based on genes previously associated with MCS and genes involved in inflammatory and oxidative stress pathways.

Results: A total of 52 patients (93.2% female), with a mean age of 50.9 (10.3) years were included in the study. Among them, based on their BMI, 48% had an inadequate nutritional status (17% were underweight and 32% were overweight or obese). Thirty percent of patients had a low muscle mass for their age, 84% had muscle strength below the tenth percentile, and 51.8% had a high fat mass percentage. Regarding quality of life, all median scores were lower than those of other illnesses assessed for every subscale assessed. Statistically significant differences between patient cases and controls were found with respect to rs1801133 (MTHFR), rs174546 (FADS1) and rs1801282 (PPARγ) polymorphisms.

Conclusion: A high percentage of patients had a poor nutritional status, low muscle strength and decreased muscle mass. These facts exacerbate the already-lower quality of life of these patients. Specific genetic polymorphisms associated with the syndrome or its pathogenesis were not identified.
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http://dx.doi.org/10.1016/j.medcli.2017.01.022DOI Listing
August 2017

3'UTR Polymorphism in ACSL1 Gene Correlates with Expression Levels and Poor Clinical Outcome in Colon Cancer Patients.

PLoS One 2016 19;11(12):e0168423. Epub 2016 Dec 19.

Molecular Oncology, IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain.

Strong evidence suggests that lipid metabolism (LM) has an essential role in tumor growth to support special energetic and structural requirements of tumor cells. Recently, overexpression of LM-related genes, apolipoproteins related to metabolic syndrome, and ACSL/SCD network involved in fatty acid activation have been proposed as prognostic markers of colon cancer (CC). Furthermore, activation of this latter lipid network has been recently demonstrated to confer invasive and stem cell properties to tumor cells promoting tumor aggressiveness and patient relapse. With the aim of elucidating whether any genetic variation within these genes could influence basal expression levels and consequent susceptibility to relapse, we genotype, in 284 CC patients, 57 polymorphisms located in the 7 genes of these lipid networks previously associated with worse clinical outcome of CC patients (ABCA1, ACSL1, AGPAT1, APOA2, APOC1, APOC2 and SCD), some of them related to CC aggressiveness. After adjusting with clinical confounding factors and multiple comparisons, an association between genotype and disease-free survival (DFS) was shown for rs8086 in 3'-UTR of ACSL1 gene (HR 3.08; 95% CI 1.69-5.63; adjusted p = 0.046). Furthermore, the risk T/T genotype had significantly higher ACSL1 gene expression levels than patients carrying C/T or C/C genotype (means = 5.34; 3.73; 2.37 respectively; p-value (ANOVA) = 0.019), suggesting a functional role of this variant. Thus, we have identified a "risk genotype" of ACSL1 gene that confers constitutive high levels of the enzyme, which is involved in the activation of fatty acids through conversion to acyl-CoA and has been recently related to increased invasiveness of tumor cells. These results suggest that rs8086 of ACSL1 could be a promising prognostic marker in CC patients, reinforcing the relevance of LM in the progression of CC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168423PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167383PMC
July 2017

Predictive value of angiogenesis-related gene profiling in patients with HER2-negative metastatic breast cancer treated with bevacizumab and weekly paclitaxel.

Oncotarget 2016 Apr;7(17):24217-27

Department of Medical Oncology, La Paz University Hospital, Madrid, Spain.

Bevacizumab plus weekly paclitaxel improves progression-free survival (PFS) in HER2-negative metastatic breast cancer (mBC), but its use has been questioned due to the absence of a predictive biomarker, lack of benefit in overall survival (OS) and increased toxicity. We examined the baseline tumor angiogenic-related gene expression of 60 patients with mBC with the aim of finding a signature that predicts benefit from this drug.Multivariate analysis by Lasso-penalized Cox regression generated two predictive models: one, named G-model, including 11 genes, and the other one, named GC-model, including 13 genes plus 5 clinical covariates. Both models identified patients with improved PFS (HR (Hazard Ratio) 2.57 and 4.04, respectively) and OS (HR 3.29 and 3.43, respectively). The G-model distinguished low and high risk patients in the first 6 months, whereas the GC-model maintained significance over time.
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http://dx.doi.org/10.18632/oncotarget.8128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029696PMC
April 2016

Polymorphism in the CLOCK gene may influence the effect of fat intake reduction on weight loss.

Nutrition 2016 Apr 6;32(4):453-60. Epub 2015 Nov 6.

Madrid Institute for Advanced Studies in Food, CEI UAM+CSIC, Madrid, Spain.

Objectives: The aim of this study was to assess the effect of a weight loss treatment on obesity- associated variables with respect to the CLOCK and FTO genotypes.

Methods: In all, 179 volunteers (78% female) participated in a 12-week calorie-restriction program; hypocaloric diets of between 5442 and 10048 kJ/d were individually prescribed to all participants. Dietetic, anthropometric, and biochemical data were collected at baseline and at the end of the intervention. When treatment was over, five single nucleotide polymorphisms (SNPs) were sought in CLOCK and FTO in all participants who provided consent. Bonferroni-corrected linear regression models were used to examine the influence of interactions of the type genotype × dietetic change on obesity-associated variables.

Results: Variation in the CLOCK and FTO genotypes had no significant influence on the change in obesity-associated variables. The interaction genotype × percentage intake of dietary fat had a significant influence on body mass index (BMI; adjusted P = 0.03). Participants carrying CLOCK rs3749474 (TT + CT) showed a positive association between the change in percentage intake of dietary fat and change in BMI (β = 0.044; 95% confidence interval [CI], 0.0119-0.0769; P = 0.008), whereas participants homozygous for the wild-type allele (CC) showed a negative, although nonsignificant association (β = -0.032; 95% CI, -0.0694 to 0.036; P = 0.077).

Conclusion: The possession of CLOCK rs3749474 may influence the effect of reducing the percentage intake of dietary fat on obesity-associated variables. Participants carrying this SNP might benefit more than others from weight loss treatment involving dietary fat restriction. The treatment of obesity might therefore be customized, depending on the alleles carried.
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http://dx.doi.org/10.1016/j.nut.2015.10.013DOI Listing
April 2016

A link between lipid metabolism and epithelial-mesenchymal transition provides a target for colon cancer therapy.

Oncotarget 2015 Nov;6(36):38719-36

Molecular Oncology and Nutritional Genomics of Cancer Group, IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain.

The alterations in carbohydrate metabolism that fuel tumor growth have been extensively studied. However, other metabolic pathways involved in malignant progression, demand further understanding. Here we describe a metabolic acyl-CoA synthetase/stearoyl-CoA desaturase ACSL/SCD network causing an epithelial-mesenchymal transition (EMT) program that promotes migration and invasion of colon cancer cells. The mesenchymal phenotype produced upon overexpression of these enzymes is reverted through reactivation of AMPK signaling. Furthermore, this network expression correlates with poorer clinical outcome of stage-II colon cancer patients. Finally, combined treatment with chemical inhibitors of ACSL/SCD selectively decreases cancer cell viability without reducing normal cells viability. Thus, ACSL/SCD network stimulates colon cancer progression through conferring increased energetic capacity and invasive and migratory properties to cancer cells, and might represent a new therapeutic opportunity for colon cancer treatment.
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http://dx.doi.org/10.18632/oncotarget.5340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770732PMC
November 2015

Role of re-growth interface preparation process for spectral line-width reduction of single InAs site-controlled quantum dots.

Nanotechnology 2015 May 21;26(19):195301. Epub 2015 Apr 21.

IMM-Instituto de Microelectrónica de Madrid (CNM-CSIC), Isaac Newton 8, PTM, E-28760 Tres Cantos, Madrid, Spain.

We present growth and optical characterization measurements of single InAs site-controlled quantum dots (SCQDs) grown by molecular beam epitaxy on GaAs (001) patterned substrates by atomic force microscopy oxidation lithography. InAs SCQDs directly grown on the patterned surface were used as a seed layer and strain template for the nucleation of optically active single InAs SCQDs. The preservation of the initial geometry of the engraved pattern motifs after the re-growth interface preparation process, the lack of buffer layer growth prior to InAs seed layer deposition and the development of suitable growth conditions provide us an improvement of the SCQDs' active layer optical properties while retaining a high ratio of single occupation (89%). In this work a fivefold reduction of the average optical line-width from 870 μeV to 156 μeV for InAs SCQDs located 15 nm from the re-growth interface is obtained by increasing the temperature of the initial thermal treatment step of the re-growth interface from 490 °C to 530 °C.
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http://dx.doi.org/10.1088/0957-4484/26/19/195301DOI Listing
May 2015

One-week administration of hydroxytyrosol to humans does not activate Phase II enzymes.

Pharmacol Res 2015 May-Jun;95-96:132-7. Epub 2015 Mar 30.

Laboratory of Functional Foods, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM+CSIC, Madrid, Spain; Department of Molecular Medicine, University of Padova, Italy. Electronic address:

The notion that (poly)phenols act as direct free radical scavengers is being challenged by mere chemical and biochemical considerations such as bioavailability and intracellular concentrations. An alternative hypothesis that is gaining considerable traction is that (poly)phenols are processed by the body as xenobiotics via the Keap1/Nrf2/ARE signaling axis, leading to the induction of Phase II enzymes. However, there are no solid human data to confirm this interesting supposition. In this study, we tested the activities of hydroxytyrosol (HT) on Phase II enzymes' expression in a double-blind, randomized, placebo-controlled study. We tested two HT doses, i.e. 5 and 25mg/d, vs. placebo following a Latin square design. We report that HT is well tolerated but does not significantly modify Phase II enzyme expression in peripheral blood mononuclear cells. Moreover, we were unable to record significant effects on a variety of surrogate markers of cardiovascular disease such as lipid profile and inflammation and oxidation markers. Available evidence indicates that the "hormesis hypothesis" that (poly)phenols activate Phase II enzymes requires solid human confirmation that might be provided by future trials. This study is registered at ClinicalTrials.gov (identifier: NCT02273622).
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http://dx.doi.org/10.1016/j.phrs.2015.03.018DOI Listing
March 2016

ColoLipidGene: signature of lipid metabolism-related genes to predict prognosis in stage-II colon cancer patients.

Oncotarget 2015 Mar;6(9):7348-63

Molecular Oncology, IMDEA-Food Institute, CEI UAM+CSIC, Madrid (Spain).

Lipid metabolism plays an essential role in carcinogenesis due to the requirements of tumoral cells to sustain increased structural, energetic and biosynthetic precursor demands for cell proliferation. We investigated the association between expression of lipid metabolism-related genes and clinical outcome in intermediate-stage colon cancer patients with the aim of identifying a metabolic profile associated with greater malignancy and increased risk of relapse. Expression profile of 70 lipid metabolism-related genes was determined in 77 patients with stage II colon cancer. Cox regression analyses using c-index methodology was applied to identify a metabolic-related signature associated to prognosis. The metabolic signature was further confirmed in two independent validation sets of 120 patients and additionally, in a group of 264 patients from a public database. The combined analysis of these 4 genes, ABCA1, ACSL1, AGPAT1 and SCD, constitutes a metabolic-signature (ColoLipidGene) able to accurately stratify stage II colon cancer patients with 5-fold higher risk of relapse with strong statistical power in the four independent groups of patients. The identification of a group of 4 genes that predict survival in intermediate-stage colon cancer patients allows delineation of a high-risk group that may benefit from adjuvant therapy, and avoids the toxic and unnecessary chemotherapy in patients classified as low-risk group.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466690PMC
http://dx.doi.org/10.18632/oncotarget.3130DOI Listing
March 2015

Clinical relevance of the differential expression of the glycosyltransferase gene GCNT3 in colon cancer.

Eur J Cancer 2015 Jan 11;51(1):1-8. Epub 2014 Nov 11.

IMDEA-Food Institute, CEI UAM+CSIC, Madrid 28049, Spain. Electronic address:

Altered glycosylation is considered a universal cancer hallmark. Mucin-type core 2 1,6-N-acetylglucosaminyltransferase enzyme (C2GnT-M), encoded by the GCNT3 gene, has been reported to be altered in tumours and to possess tumour suppressor properties. In this work, we aimed to determine the possible role of GCNT3 gene expression as prognostic marker in colon cancer. We investigated the differential expression of GCNT3 gene among tumour samples from stage II colon cancer patients by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Univariate and Multivariate Cox regression analyses were used to determine the correlation between GCNT3 expression and disease-free survival. The risk of relapse in GCNT3 low-expressing cancer patients was significantly higher than that in GCNT3 high-expressing patients in both training (Hazard Ratio (HR) 4.26, p=0.002) and validation (HR 3.06, p=0.024) series of patients, and this association was independent of clinical factors. Additionally, qRT-PCR was used to explore the modulation of GCNT3 expression by different antitumour drugs. Three chemotherapeutic agents with different mechanism of action (5-fluorouracil, bortezomib and paclitaxel) significantly induced GCNT3 expression in several cancer cells, being observed the correlation between antitumour action and GCNT3 modulation, whereas this gene was not modulated in cells that do not respond to treatment. Overall, these results indicate that low GCNT3 expression is a promising prognostic biomarker for colon cancer that could be used to identify early-stage colon cancer patients at high risk of relapse. Additionally, our results suggest that this enzyme might also constitute a biomarker to monitor tumour response to chemotherapy in cancer patients.
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http://dx.doi.org/10.1016/j.ejca.2014.10.021DOI Listing
January 2015

Genes associated with metabolic syndrome predict disease-free survival in stage II colorectal cancer patients. A novel link between metabolic dysregulation and colorectal cancer.

Mol Oncol 2014 Dec 10;8(8):1469-81. Epub 2014 Jun 10.

IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain. Electronic address:

Studies have recently suggested that metabolic syndrome and its components increase the risk of colorectal cancer. Both diseases are increasing in most countries, and the genetic association between them has not been fully elucidated. The objective of this study was to assess the association between genetic risk factors of metabolic syndrome or related conditions (obesity, hyperlipidaemia, diabetes mellitus type 2) and clinical outcome in stage II colorectal cancer patients. Expression levels of several genes related to metabolic syndrome and associated alterations were analysed by real-time qPCR in two equivalent but independent sets of stage II colorectal cancer patients. Using logistic regression models and cross-validation analysis with all tumour samples, we developed a metabolic syndrome-related gene expression profile to predict clinical outcome in stage II colorectal cancer patients. The results showed that a gene expression profile constituted by genes previously related to metabolic syndrome was significantly associated with clinical outcome of stage II colorectal cancer patients. This metabolic profile was able to identify patients with a low risk and high risk of relapse. Its predictive value was validated using an independent set of stage II colorectal cancer patients. The identification of a set of genes related to metabolic syndrome that predict survival in intermediate-stage colorectal cancer patients allows delineation of a high-risk group that may benefit from adjuvant therapy and avoid the toxic and unnecessary chemotherapy in patients classified as low risk. Our results also confirm the linkage between metabolic disorder and colorectal cancer and suggest the potential for cancer prevention and/or treatment by targeting these genes.
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http://dx.doi.org/10.1016/j.molonc.2014.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528602PMC
December 2014

A genetic variant of PPARA modulates cardiovascular risk biomarkers after milk consumption.

Nutrition 2014 Oct 12;30(10):1144-50. Epub 2014 Mar 12.

IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain; Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA.

Objective: The association of dairy food consumption with the risk for developing cardiovascular disease (CVD) has been investigated in many studies, but results often have been contradictory. The aim of the present study was to determine whether genetic polymorphisms are associated with interindividual variation in the response of CVD risk biomarker values after milk consumption.

Methods: Fourteen single nucleotide polymorphisms (SNPs) in nine genes related to lipid metabolism were examined in 161 volunteers randomly allocated to consume either 500 mL/d of skimmed (S) or semi-skimmed (SS) milk for 1 year in addition to their usual diets. Total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) and low-density lipoprotein/HDL-C ratios were used as biomarkers of CVD risk. Three-way repeated-measures analysis of variance was used to examine the effect of time, treatment (S or SS), and genotype on these biomarkers.

Results: A TT genotype for the proliferator-activated receptor alpha polymorphism (PPARA rs135549 SNP) was significantly associated with a reduction in the TC/HDL and LDL/HDL ratios after 12 mo of S milk intake (mean reduction -0.29, 95% confidence interval [CI], -0.63 to 0.05; P = 0.0015 and -0.31, 95% CI, -0.58 to -0.03; P = 0.0005, respectively). However, no differences were observed after consuming either S or SS milk in the C allele carriers.

Conclusions: Saturated fatty acid consumption has long been linked to an increased risk for CVD; indeed, the consumption of saturated fat-free products is recommended as a means of reducing this risk. However, the present results suggest that many individuals might not benefit from such general recommendations. Genetic analysis of PPARA rs135549 might help identify those individuals who are more likely to benefit from reducing the saturated fatty acid content of their diet.
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http://dx.doi.org/10.1016/j.nut.2014.02.012DOI Listing
October 2014

Genetic variation in the TP53 pathway and bladder cancer risk. a comprehensive analysis.

PLoS One 2014 12;9(5):e89952. Epub 2014 May 12.

Spanish National Cancer Research Center (CNIO), Madrid, Spain.

Introduction: Germline variants in TP63 have been consistently associated with several tumors, including bladder cancer, indicating the importance of TP53 pathway in cancer genetic susceptibility. However, variants in other related genes, including TP53 rs1042522 (Arg72Pro), still present controversial results. We carried out an in depth assessment of associations between common germline variants in the TP53 pathway and bladder cancer risk.

Material And Methods: We investigated 184 tagSNPs from 18 genes in 1,058 cases and 1,138 controls from the Spanish Bladder Cancer/EPICURO Study. Cases were newly-diagnosed bladder cancer patients during 1998-2001. Hospital controls were age-gender, and area matched to cases. SNPs were genotyped in blood DNA using Illumina Golden Gate and TaqMan assays. Cases were subphenotyped according to stage/grade and tumor p53 expression. We applied classical tests to assess individual SNP associations and the Least Absolute Shrinkage and Selection Operator (LASSO)-penalized logistic regression analysis to assess multiple SNPs simultaneously.

Results: Based on classical analyses, SNPs in BAK1 (1), IGF1R (5), P53AIP1 (1), PMAIP1 (2), SERINPB5 (3), TP63 (3), and TP73 (1) showed significant associations at p-value≤0.05. However, no evidence of association, either with overall risk or with specific disease subtypes, was observed after correction for multiple testing (p-value≥0.8). LASSO selected the SNP rs6567355 in SERPINB5 with 83% of reproducibility. This SNP provided an OR = 1.21, 95%CI 1.05-1.38, p-value = 0.006, and a corrected p-value = 0.5 when controlling for over-estimation.

Discussion: We found no strong evidence that common variants in the TP53 pathway are associated with bladder cancer susceptibility. Our study suggests that it is unlikely that TP53 Arg72Pro is implicated in the UCB in white Europeans. SERPINB5 and TP63 variation deserve further exploration in extended studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0089952PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018346PMC
January 2015

Whole genome prediction of bladder cancer risk with the Bayesian LASSO.

Genet Epidemiol 2014 Jul 5;38(5):467-76. Epub 2014 May 5.

Spanish National Cancer Research Center (CNIO), Madrid, Spain.

To build a predictive model for urothelial carcinoma of the bladder (UCB) risk combining both genomic and nongenomic data, 1,127 cases and 1,090 controls from the Spanish Bladder Cancer/EPICURO study were genotyped using the HumanHap 1M SNP array. After quality control filters, genotypes from 475,290 variants were available. Nongenomic information comprised age, gender, region, and smoking status. Three Bayesian threshold models were implemented including: (1) only genomic information, (2) only nongenomic data, and (3) both sources of information. The three models were applied to the whole population, to only nonsmokers, to male smokers, and to extreme phenotypes to potentiate the UCB genetic component. The area under the ROC curve allowed evaluating the predictive ability of each model in a 10-fold cross-validation scenario. Smoking status showed the highest predictive ability of UCB risk (AUCtest = 0.62). On the other hand, the AUC of all genetic variants was poorer (0.53). When the extreme phenotype approach was applied, the predictive ability of the genomic model improved 15%. This study represents a first attempt to build a predictive model for UCB risk combining both genomic and nongenomic data and applying state-of-the-art statistical approaches. However, the lack of genetic relatedness among individuals, the complexity of UCB etiology, as well as a relatively small statistical power, may explain the low predictive ability for UCB risk. The study confirms the difficulty of predicting complex diseases using genetic data, and suggests the limited translational potential of findings from this type of data into public health interventions.
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http://dx.doi.org/10.1002/gepi.21809DOI Listing
July 2014

High quality factor GaAs-based photonic crystal microcavities by epitaxial re-growth.

Opt Express 2013 Dec;21(25):31615-22

We investigate L7 photonic crystal microcavities (PCMs) fabricated by epitaxial re-growth of GaAs pre-patterned substrates, containing InAs quantum dots. The resulting PCMs show hexagonal shaped nano-holes due to the development of preferential crystallographic facets during the re-growth step. Through a careful control of the fabrication processes, we demonstrate that the photonic modes are preserved throughout the process. The quality factor (Q) of the photonic modes in the re-grown PCMs strongly depends on the relative orientation between photonic lattice and crystallographic directions. The optical modes of the re-grown PCMs preserve the linear polarization and, for the most favorable orientation, a 36% of the Q measured in PCMs fabricated by the conventional procedure is observed, exhibiting values up to ~6000. The results aim to the future integration of site-controlled QDs with high-Q PCMs for quantum photonics and quantum integrated circuits.
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http://dx.doi.org/10.1364/OE.21.031615DOI Listing
December 2013

A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46,450 cases and 42,461 controls from the breast cancer association consortium.

Hum Mol Genet 2014 Apr 15;23(7):1934-46. Epub 2013 Nov 15.

Human Cancer Genetics Programme and.

Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70,917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46,450 breast cancer cases and 42,461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10(-4)) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10(-8). Results from the second analytic approach were consistent with those from the first (P > 10(-10)). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.
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http://dx.doi.org/10.1093/hmg/ddt581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943524PMC
April 2014

Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy.

Nat Genet 2013 Dec 13;45(12):1464-9. Epub 2013 Oct 13.

Epithelial Carcinogenesis Group, Molecular Pathology Programme, CNIO (Spanish National Cancer Research Centre), Madrid, Spain.

Urothelial bladder cancer (UBC) is heterogeneous at the clinical, pathological and genetic levels. Tumor invasiveness (T) and grade (G) are the main factors associated with outcome and determine patient management. A discovery exome sequencing screen (n = 17), followed by a prevalence screen (n = 60), identified new genes mutated in this tumor coding for proteins involved in chromatin modification (MLL2, ASXL2 and BPTF), cell division (STAG2, SMC1A and SMC1B) and DNA repair (ATM, ERCC2 and FANCA). STAG2, a subunit of cohesin, was significantly and commonly mutated or lost in UBC, mainly in tumors of low stage or grade, and its loss was associated with improved outcome. Loss of expression was often observed in chromosomally stable tumors, and STAG2 knockdown in bladder cancer cells did not increase aneuploidy. STAG2 reintroduction in non-expressing cells led to reduced colony formation. Our findings indicate that STAG2 is a new UBC tumor suppressor acting through mechanisms that are different from its role in preventing aneuploidy.
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http://dx.doi.org/10.1038/ng.2799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840052PMC
December 2013

[Basic principles for the development of biomarkers in oncology].

Arch Esp Urol 2013 Jun;66(5):423-31

Grupo de Epidemiología Genética y Molecular, Centro Nacional de Investigaciones Oncológicas, Madrid, España.

The accelerated expansion of the knowledge of genetic and molecular basics of cancer, together with the recent development of molecular biology techniques, have had a significant impact in the field of oncology, among other medical disciplines. So, over the last few years, we are crossing from an empiricism-based model to an evidence-based model in which drugs are adapted depending of the molecular alterations which result crucial for tumor development (both for carcinogenesis and acquisition of an aggressive phenotype leading to tumor invasion and resistance to therapy). The molecular alterations /variations offer the possibility of being detected and used as biomarkers in clinical practice. Biomarkers may have multiple applications in the field of oncology, from determining the risk to suffer the disease to prediction of response to therapy, including diagnosis, prognosis and disease monitoring, with the final aim of performing a more personalized medicine and achieving greater efficacy for the therapies selected, diminishing each therapy's own adverse events. Considering the importance biomarkers may get to have in clinical decision making, it is basic that their development is performed under straight evaluation and validation rules. In this article we review the various types of biomarkers and the basic methodological principles for their development, validation and subsequent clinical application.
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June 2013

Pulmonary rehabilitation after total laryngectomy: a randomized cross-over clinical trial comparing two different heat and moisture exchangers (HMEs).

Eur Arch Otorhinolaryngol 2013 Sep 18;270(9):2479-84. Epub 2013 Apr 18.

Complexo Hospitalario Universitario A Coruña, Lugar Xubias De Arriba 84, 15006 La Coruña, Spain.

Post-laryngectomy heat and moisture exchanger (HME) use is known to have a beneficial effect on tracheal climate, pulmonary symptoms and related aspects. This study aims to investigate differences in clinical effects between the first and second generation Provox HMEs. The second generation (Provox XtraHME) has better humidification properties than the first generation (Provox HME), and has been shown to further improve tracheal climate. Forty-five laryngectomized patients, who were already using an HME, participated in a prospective, randomized cross-over clinical study in which each HME was used for 6 weeks. Results showed that for most parameters studied, the second generation HME performed equally well or better than the first generation HME. The improvement in tracheal climate translated into patients reporting significantly less tracheal dryness with the second generation than with the first generation (p = 0.039). Using an HME with better humidification properties is related to a reduction in tracheal dryness in our study population.
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http://dx.doi.org/10.1007/s00405-013-2493-1DOI Listing
September 2013