Synthesis of 5-/8-Halogenated or Ethynylated Lipophilic Nucleobases as Potential Synthetic Intermediates for Supramolecular Chemistry

This is the peer reviewed version of the following article: European Journal of Organic Chemistry 2015.32 (2015): 7160-7175, which has been published in final form at http://dx.doi.org/10486/10.1002/ejoc.201501026A series of lipophilic nucleobases that are substituted at the 5- (pyrimidines) or 8- (purines) position with either a halogen atom or a terminal triple bond have been synthesized. The sequences and reactions studied in this work, which mainly comprise halogenation, alkylation, Sonogashira coupling, and trimethylsilylacetylene deprotection, have been carefully optimized, to reach the final compounds in the most straightforward and convenient way, with the highest possible purity and yield. These compounds include cytosine, isocytosine, and uracil derivatives as pyrimidine heterocycles, and guanine, isoguanine, and 2-aminoadenine derivatives as complementary purine bases. Variability was introduced at the N-1/N-9 positions of these pyrimidine/purine nucleobases, which were functionalized with alkyl or benzyl groups, as well as with protected amine or carboxylic acid substituents. The molecules prepared constitute a useful collection of synthetic intermediates for the field of chemical self-assembly. A series of lipophilic nucleobases substituted at the 5- (pyrimidines) or 8-position (purines) with either a halogen atom or a terminal triple bond have been synthesized. These molecules comprise a useful collection of synthetic intermediates for the field of chemical self-assemblyFunding from the European Research Council (ERC-StG 279548) and MINECO (CTQ2011-23659) is gratefully acknowledged. V.V.-G. is grateful for a F.P.I. fellowship from MINECO

Generation of Molecular Diversity from Amino Acids. A Source for the Discovery of New TRP Channel Modulators

Trabajo presentado en el IV RECI: New Horizons in Ion Channel Research, celebrado en Cuenca (España) del 12 al 13 de febrero de 2013.Ion channels are central and challenging targets in medicinal chemistry but, because of the scarce structural knowledge, rational approaches to ion channel modulators are still rare. Moreover, the multimodal activation of some channels, like TRPs, complicates still more the scenario for rational discovery programs. Due to these facts, most strategies directed to identify ion channel modulators rely on the screening of peptide and small-molecule libraries. In this context, we have been involved in the development of synthetic pathways for the generation of diverse, chiral, highly functionalized linear and heterocyclic scaffolds from amino acids, and in the production of discrete libraries from them. The screening of these libraries on different TRP channels has allowed the discovery of some innovative hits that have progressed to hit-to-lead optimization programs. This communication will deal with the synthesis, structural characterization, and biological evaluation of a collection of β,γ–diaminoester derivatives that display significant activity at TRPV1, TRPM8 and TRPA1 channels. Compound RGM04-7, a selective.Supported by MICINN grants: Consolider-Ingenio 2010 (CSD2008-00005 and CSD2006-00015), SAF2009-09323 and BFU2009-08346, and the Generalitat Valenciana (PROMETEO/2010/046)

Basal VEGF-A and ACE Plasma Levels of Metastatic Colorectal-Cancer Patients Have Prognostic Value for First-Line Treatment with Chemotherapy Plus Bevacizumab

The identification of factors that respond to anti-angiogenic therapy would represent a significant advance in the therapeutic management of metastatic-colorectal-cancer (mCRC) patients. We previously reported the relevance of VEGF-A and some components of the renin–angiotensin-aldosterone system (RAAS) in the response to anti-angiogenic therapy in cancer patients. Therefore, this prospective study aims to evaluate the prognostic value of basal plasma levels of VEGF-A and angiotensin-converting enzyme (ACE) in 73 mCRC patients who were to receive bevacizumab-based therapies as a first-line treatment. We found that high basal VEGF-A plasma levels were significantly associated with worse overall survival (OS) and progression-free survival (FPS). On the other hand, low ACE levels were significantly associated with poor OS. Importantly, a simple scoring system combining the basal plasma levels of VEGF-A and ACE efficiently stratified mCRC patients, according to OS, into high-risk or low-risk groups, prior to their treatment with bevacizumab. In conclusion, our study supports that VEGF-A and ACE may be potential biomarkers for selecting those mCRC patients who will most benefit from receiving chemotherapy plus bevacizumab treatment in first-line therapy. Additionally, our data reinforce the notion of a close association between the RAAS and the anti-angiogenic response in cancer

DIMENSIONES CONCEPTUALES DEL BIENESTAR DE PERSONAS CON PADECIMIENTOS CRÓNICOS

Se explora las dimensiones conceptuales del bienestar de personas con padecimientos crónicos de la ciudad de Guadalajara, México, a fin de generar propuestas de intervención educativa en salud en materia de enfermedades crónicas. Estudio transversal exploratorio realizado entre marzo y mayo de 2006 con 40 personas con Diabetes Mellitus e Hipertensión Arterial que participan en grupos de apoyo en Centros de Salud de la ciudad de Guadalajara, México, seleccionadas por muestreo propositivo. Se aplicaron entrevistas semiestructuradas mediante técnicas de listados libres y sorteo de montones. Se indagaron términos asociados al concepto de bienestar y grupos de dimensiones conceptuales. Se aplicó análisis de consenso mediante factorización de componentes principales y análisis dimensional, mediante conglomerados jerárquicos y escalas multidimensionales. El modelo de consenso mostró alta homogeneidad en las concepciones del bienestar (valor de 8.22). Las dimensiones comunes en las concepciones fueron: ser responsable, la felicidad (con las subdimensiones de tranquilidad, tener fe y tener salud), la disciplina (subdimensiones: desarrollo y mantenimiento así como prolongar la vida) y el vivir a gusto (valor de verosimilitud: stress<0.28). Las personas participantes mostraron en dichas dimensiones una visión holística del concepto de bienestar. Las dimensiones de responsabilidad y disciplina hacen referencia decisiones voluntarias de tipo más bien personal, donde la familia y el aspecto comunitario no son incluidos. La segunda dimensión es sobre elementos de tipo mental y social donde se incluyó a la felicidad y el vivir a gusto. Ello implica la práctica de acciones y cuidados de la salud mental, la vida espiritual y social. Se encontró además asociación del concepto de bienestar con el de salud mental.Palabras clave: bienestar, enfermedad crónica, concepciones culturaleswell-being, chronic illness, cultural conception

Inflammation, not hyperhomocysteinemia, is related to oxidative stress and hemostatic and endothelial dysfunction in uremia

Inflammation, not hyperhomocysteinemia, is related to oxidative stress and hemostatic and endothelial dysfunction in uremia.BackgroundSeveral cardiovascular risk factors are present in patients with chronic renal failure (CRF), among which are systemic inflammation and hyperhomocysteinemia. Increased oxidative stress, endothelial activation/dysfunction, and coagulation activation are considered integral components of the inflammatory response, but have also been proposed as mediators of plasma homocysteine (tHcy)-induced cell damage. Using correlation analysis, we assessed the relative contributions of inflammation and hyperhomocysteinemia in the abnormal oxidative stress, endothelial activation/dysfunction, and hemostasis activation in patients with CRF.MethodsThe relationships of inflammatory proteins and tHcy with plasma markers of these processes were studied in 64 patients with CRF (serum creatinine 526 ± 319 μmol/L) on conservative treatment, comparing the results with healthy controls (N = 15 to 40, depending on the measured variable) of similar sex and age.ResultsPatients had significant increases in inflammatory cytokines (TNF-α and IL-8) and acute-phase proteins (C-reactive protein, fibrinogen and α1-antitrypsin). tHcy was increased in 87.5% of patients (mean = 27.1 μmol/L, range 6.5 to 118). Patients had significant increases in (1) indices of oxidative stress: TBARS (thiobarbituric acid-reactive species), a marker of lipid peroxidation and AOPP (advanced oxidation protein products), a marker of protein oxidation; (2) endothelial cell markers such as von Willebrand factor (vWF:Ag), soluble ICAM-1 and soluble thrombomodulin (sTM); (3) markers of intravascular thrombin generation: thrombin-antithrombin complexes (TAT) and prothrombin fragment F1+2 (PF1+2); and (4) indices of activation of fibrinolysis: plasmin-antiplasmin complexes (PAP), fibrin degradation products (FnDP) and fibrinogen degradation products (FgDP). tHcy was significantly correlated with plasma creatinine (r = 0.29, P < 0.018) and with serum folate (r = -0.38, P < 0.002). However, no significant correlations were observed between tHcy and TBARS, AOPP, vWF:Ag, sICAM-1, sTM, TAT, F1+2, sTF, PAP, FnDP, and FgDP. Conversely, acute-phase proteins showed significant, positive correlations with most markers of oxidative stress, endothelial dysfunction and hemostatic activation.ConclusionsSystemic inflammation, which is closely associated with augmented oxidative stress, endothelial cell dysfunction and hemostatic activation, emerges as a major cardiovascular risk factor in CRF. tHcy is unrelated to these events. Thus, alternative mechanisms through which hyperhomocysteinemia could predispose to vascular lesion and thrombotic events in CRF needs to be investigated

Helical peptides from VEGF and Vammin hotspots for modulating the VEGF-VEGFR interaction

The design, synthesis, conformational studies and binding affinity for VEGF receptors of a collection of linear and cyclic peptide analogues of the N-terminal α-helix fragments 13-25 of VEGF and 1-13 of Vammin are described. Linear 13(14)-mer peptides were designed with the help of an AGADIR algorithm and prepared following peptide solid-phase synthetic protocols. Cyclic peptide derivatives were prepared on-resin from linear precursors with conveniently located Glu and Lys residues, by the formation of amide linkages. Conformational analysis, CD and NMR, showed that most synthesized peptides have a clear tendency to be structured as α-helices in solution. Some of the peptides were able to bind a VEGFR-1 receptor with moderate affinity. In addition to the described key residues (Phe17, Tyr21 and Tyr25), Val14 and Val20 seem to be relevant for affinity.Peer Reviewe

The Relationship between Information Utilization and Social Participation among Middle-aged and Older Adults

早大学位記番号:新8355早稲田大

The Combination of Neutrophil–Lymphocyte Ratio and Platelet–Lymphocyte Ratio with Liquid Biopsy Biomarkers Improves Prognosis Prediction in Metastatic Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a highly inflammatory microenvironment and liquid biopsy has emerged as a promising tool for the noninvasive analysis of this tumor. In this study, plasma was obtained from 58 metastatic PDAC patients, and neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), circulating cell-free DNA (cfDNA) concentration, and circulating RAS mutation were determined. We found that NLR was significantly associated with both overall survival (OS) and progression-free survival. Remarkably, NLR was an independent risk factor for poor OS. Moreover, NLR and PLR positively correlated, and combination of both inflammatory markers significantly improved the prognostic stratification of metastatic PDAC patients. NLR also showed a positive correlation with cfDNA levels and RAS mutant allelic fraction (MAF). Besides, we found that neutrophil activation contributed to cfDNA content in the plasma of metastatic PDAC patients. Finally, a multi-parameter prognosis model was designed by combining NLR, PLR, cfDNA levels, RAS mutation, RAS MAF, and CA19-9, which performs as a promising tool to predict the prognosis of metastatic PDAC patients. In conclusion, our study supports the idea that the use of systemic inflammatory markers along with circulating tumor-specific markers may constitute a valuable tool for the clinical management of metastatic PDAC patients

Circulating Cell-Free DNA-Based Liquid Biopsy Markers for the Non-Invasive Prognosis and Monitoring of Metastatic Pancreatic Cancer

Liquid biopsy may assist in the management of cancer patients, which can be particularly applicable in pancreatic ductal adenocarcinoma (PDAC). In this study, we investigated the utility of circulating cell-free DNA (cfDNA)-based markers as prognostic tools in metastatic PDAC. Plasma was obtained from 61 metastatic PDAC patients, and cfDNA levels and fragmentation were determined. BEAMing technique was used for quantitative determination of RAS mutation allele fraction (MAF) in cfDNA. We found that the prognosis was more accurately predicted by RAS mutation detection in plasma than in tissue. RAS mutation status in plasma was a strong independent prognostic factor for both overall survival (OS) and progression-free survival (PFS). Moreover, RAS MAF in cfDNA was also an independent risk factor for poor OS, and was strongly associated with primary tumours in the body/tail of the pancreas and liver metastases. Higher cfDNA levels and fragmentation were also associated with poorer OS and shorter PFS, body/tail tumors, and hepatic metastases, whereas cfDNA fragmentation positively correlated with RAS MAF. Remarkably, the combination of CA19-9 with MAF, cfDNA levels and fragmentation improved the prognostic stratification of patients. Furthermore, dynamics of RAS MAF better correlated with patients’ outcome than standard CA19-9 marker. In conclusion, our study supports the use of cfDNA-based liquid biopsy markers as clinical tools for the non-invasive prognosis and monitoring of metastatic PDAC patients

Research at the learning and vision mobile robotics group 2004-2005

Spanish Congress on Informatics (CEDI), 2005, Granada (España)This article presents the current trends on wheeled mobile robotics being pursued at the Learning and Vision Mobile Robotics Group (IRI). It includes an overview of recent results produced in our group in a wide range of areas, including robot localization, color invariance, segmentation, tracking, audio processing and object learning and recognition.This work was supported by projects: 'Supervised learning of industrial scenes by means of an active vision equipped mobile robot.' (J-00063), 'Integration of robust perception, learning, and navigation systems in mobile robotics' (J-0929).Peer Reviewe