537 research outputs found

    Novel cryptophycin analogues and conjugates for tumor targeted therapy

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    Figueras Agustí E. Novel cryptophycin analogues and conjugates for tumor targeted therapy . Bielefeld: Universität Bielefeld; 2019.The cure of cancer represents an ultimate challenge for scientists from different fields. Cancer complexity and diversity hamper the discovery of a broadly applicable treatment, and consequently, cancer represents the second cause of premature death worldwide. Despite the continuous approval of new drugs, the cancer burden keeps increasing due to different factors and leaves a vast number of patients helpless. Conventional chemotherapy still represents the backbone of cancer medical care. However, these agents are not able to selectively accumulate at the disease site which limits their efficacy and cause severe side effects. In the last years, targeted therapy has appeared as an innovative approach to overcome the drawbacks shown by traditional chemotherapeutics. In this approach, a cytotoxic agent is directed to the tumor site through the covalent conjugation to homing devices (e.g. antibodies, small molecules). Cryptophycins are cyclic depsipeptides with natural origin that present high cytotoxicity against several cell lines. Although cryptophycins cannot be used as stand-alone agent due to their side effects, they hold great potential as cytotoxic agent for tumor targeted therapy. Therefore, the discovery of new cryptophycins that can be conjugated to homing devices and their vectorization could be translated in a significant therapeutic activity. In the first part (chapter 3), the discovery of new cryptophycin analogues that retain the high cytotoxicity of the parent compound and present a functional group that can be used for conjugation to a delivery vehicle was described. Moreover, the usage of molecular dynamics to predict the biological activity of new analogues was explored. The second part (chapters 4 and 5), describes the usage of cryptophycin-55 glycinate as payload in small molecule-drug conjugates (SMDCs). In chapter 4, the payload was conjugated to a ligand capable to target the carbonic anhydrase IX, a transmembrane enzyme that is widely overexpressed in tumors. The cytotoxic activity of the resulting conjugate was studied in vitro, and the therapeutic activity was investigated in mice. In chapter 5, the payload was further explored by coupling it to a cyclic peptide targeting the somatostatin receptor 2, a marker which is commonly overexpressed in neuroendocrine tumors. The cytotoxicity of the conjugates was evaluated in a cell-based assay. In this case, further investigations in their targeting properties and stability were performed. Finally, the antitumor activity of the lead compound was investigated in vivo

    Tumor-Targeting Peptides: The Functional Screen of Glioblastoma Homing Peptides to the Target Protein FABP3 (MDGI)

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    We recently identified the glioblastoma homing peptide CooP (CGLSGLGVA) using in vivo phage display screen. The mammary-derived growth inhibitor (MDGI/FABP3) was identified as its interacting partner. Here, we present an alanine scan of A-CooP to investigate the contribution of each amino acid residue to the binding to FABP3 by microscale thermophoresis (MST) and surface plasmon resonance (SPR). We also tested the binding affinity of the A-CooP-K, KA-CooP, and retro-inverso A-CooP analogues to the recombinant FABP3. According to the MST analysis, A-CooP showed micromolar (KD = 2.18 µM) affinity to FABP3. Alanine replacement of most of the amino acids did not affect peptide affinity to FABP3. The A-CooP-K variant showed superior binding affinity, while A-[Ala5]CooP and A-[Ala7]CooP, both replacing a glycine residue with alanine, showed negligible binding to FABP3. These results were corroborated in vitro and in vivo using glioblastoma models. Both A-CooP-K and A-CooP showed excellent binding in vitro and homing in vivo, while A-[Ala5]CooP and control peptides failed to bind the cells or home to the intracranial glioblastoma xenografts. These results provide insight into the FABP3–A-CooP interaction that may be important for future applications of drug conjugate design and development

    Novel unit B cryptophycin analogues as payloads for targeted therapy

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    Figueras Agustí E, Borbély AN, Ismail M, Frese M, Sewald N. Novel unit B cryptophycin analogues as payloads for targeted therapy. Beilstein Journal of Organic Chemistry. 2018;14:1281-1286.Cryptophycins are naturally occurring cytotoxins with great potential for chemotherapy. Since targeted therapy provides new perspectives for treatment of cancer, new potent analogues of cytotoxic agents containing functional groups for conjugation to homing devices are required. We describe the design, synthesis and biological evaluation of three new unit B cryptophycin analogues. The O-methyl group of the unit B D-tyrosine analogue was replaced by an O-(allyloxyethyl) moiety, an O-(hydroxyethyl) group, or an O-(((azidoethoxy) ethoxy) ethoyxethyl) substituent. While the former two maintain cytotoxicity in the subnanomolar range, the attachment of the triethylene glycol spacer with a terminal azide results in a complete loss of activity. Docking studies of the novel cryptophycin analogues to beta-tubulin provided a rationale for the observed cytotoxicities

    Impact of a system to assist in clinical decision-making in primary healthcare in Catalonia: prescription Self Audit

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    Clinical safety; Decision support system; Primary careSeguridad clínica; Sistema de soporte a la decisión; Atención primariaSeguretat clínica; Sistema de suport a la decisió; Atenció primàriaBackground In 2008, in the context of a complete computerisation of medical records, the Institut Català de la Salut (ICS, Catalan Health Institute) implemented a system in its electronic clinical workstation (ECW) to assist decision-making at the prescription level. This system is known as Self Audit, and it supports physicians in reviewing the medication of their patients. Self Audit provides lists of patients presenting medication-related problems (MRPs) that have potential for improvement, and provides therapeutic recommendations that are easy to apply from the system itself. The aim of this study was to analyse the main results derived from the use of Self Audit in primary care (PC) in Catalonia, and the effect of an incentive-based safety indicator on the results obtained. Methods A descriptive cross-sectional study was carried out to analyse variations in the MRPs detected by Self Audit during 2016, 2017, and 2018 in PC in Catalonia. The effect of a safety indicator on the results obtained was also studied. This safety indicator includes the most clinically relevant MRPs (i.e., therapeutic duplications, safety alerts from the Spanish Medicines Agency, and incidences of polymedication in patients over 65 years of age). Variation in the MRPs was measured using the differences between two evaluation points (initial and final). An MRP was considered resolved if the recommendation specified in the alert was followed. The prescriptions of 6411 PC doctors of the ICS who use the ECW and provide their services to 5.8 million Catalans through 288 PC teams were analysed. Results Analysis of the total safety-based MRPs detected by Self Audit gave overall resolutions from April to December of 9% (21,547) in 2016, 7% (15,924) in 2017, and 1% (2392) in 2018 out of the total number of MRPs recorded in April each year. Examination of the 3 types of MRPs with the highest clinical relevance that were linked to the safety indicator gave overall resolutions of 41% in 2016 (17,358), 20% in 2017 (7655), and 21% in 2018 (8135). Conclusions The ICS Self Audit tool assists in reducing the number of safety-based MRPs in a systematic manner, and yields superior results for the MRPs linked to a safety indicator included in the incentives of PC physicians.The primary care component of this study was funded by the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol). Scholarship to complete a PhD thesis in primary care

    Tumor-Targeting Peptides: The Functional Screen of Glioblastoma Homing Peptides to the Target Protein FABP3 (MDGI)

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    We recently identified the glioblastoma homing peptide CooP (CGLSGLGVA) using in vivo phage display screen. The mammary-derived growth inhibitor (MDGI/FABP3) was identified as its interacting partner. Here, we present an alanine scan of A-CooP to investigate the contribution of each amino acid residue to the binding to FABP3 by microscale thermophoresis (MST) and surface plasmon resonance (SPR). We also tested the binding affinity of the A-CooP-K, KA-CooP, and retro-inverso A-CooP analogues to the recombinant FABP3. According to the MST analysis, A-CooP showed micromolar (KD = 2.18 µM) affinity to FABP3. Alanine replacement of most of the amino acids did not affect peptide affinity to FABP3. The A-CooP-K variant showed superior binding affinity, while A-[Ala5]CooP and A-[Ala7]CooP, both replacing a glycine residue with alanine, showed negligible binding to FABP3. These results were corroborated in vitro and in vivo using glioblastoma models. Both A-CooP-K and A-CooP showed excellent binding in vitro and homing in vivo, while A-[Ala5]CooP and control peptides failed to bind the cells or home to the intracranial glioblastoma xenografts. These results provide insight into the FABP3–A-CooP interaction that may be important for future applications of drug conjugate design and development

    Impact of a system to assist in clinical decision-making in primary healthcare in Catalonia : prescription Self Audit

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    Altres ajuts: Institut Universitari d'InvestigaciĂł en AtenciĂł PrimĂ ria (IDIAP Jordi Gol). Scholarship to complete a PhD thesis in primary care.In 2008, in the context of a complete computerisation of medical records, the Institut CatalĂ  de la Salut (ICS, Catalan Health Institute) implemented a system in its electronic clinical workstation (ECW) to assist decision-making at the prescription level. This system is known as Self Audit, and it supports physicians in reviewing the medication of their patients. Self Audit provides lists of patients presenting medication-related problems (MRPs) that have potential for improvement, and provides therapeutic recommendations that are easy to apply from the system itself. The aim of this study was to analyse the main results derived from the use of Self Audit in primary care (PC) in Catalonia, and the effect of an incentive-based safety indicator on the results obtained. A descriptive cross-sectional study was carried out to analyse variations in the MRPs detected by Self Audit during 2016, 2017, and 2018 in PC in Catalonia. The effect of a safety indicator on the results obtained was also studied. This safety indicator includes the most clinically relevant MRPs (i.e., therapeutic duplications, safety alerts from the Spanish Medicines Agency, and incidences of polymedication in patients over 65 years of age). Variation in the MRPs was measured using the differences between two evaluation points (initial and final). An MRP was considered resolved if the recommendation specified in the alert was followed. The prescriptions of 6411 PC doctors of the ICS who use the ECW and provide their services to 5.8 million Catalans through 288 PC teams were analysed. Analysis of the total safety-based MRPs detected by Self Audit gave overall resolutions from April to December of 9% (21,547) in 2016, 7% (15,924) in 2017, and 1% (2392) in 2018 out of the total number of MRPs recorded in April each year. Examination of the 3 types of MRPs with the highest clinical relevance that were linked to the safety indicator gave overall resolutions of 41% in 2016 (17,358), 20% in 2017 (7655), and 21% in 2018 (8135). The ICS Self Audit tool assists in reducing the number of safety-based MRPs in a systematic manner, and yields superior results for the MRPs linked to a safety indicator included in the incentives of PC physicians

    An analysis of the currently available calibrations in Stromgren photometry by using open clusters

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    In recent years, several authors have revised the calibrations used to compute physical parameters (tex2html_wrap_inline498, tex2html_wrap_inline500, log g, [Fe/H]) from intrinsic colours in the tex2html_wrap_inline504 photometric system. For reddened stars, these intrinsic colours can be computed through the standard relations among colour indices for each of the regions defined by Strömgren (1966) on the HR diagram. We present a discussion of the coherence of these calibrations for main-sequence stars. Stars from open clusters are used to carry out this analysis. Assuming that individual reddening values and distances should be similar for all the members of a given open cluster, systematic differences among the calibrations used in each of the photometric regions might arise when comparing mean reddening values and distances for the members of each region. To classify the stars into Strömgren's regions we extended the algorithm presented by Figueras et al. (1991) to a wider range of spectral types and luminosity classes. The observational ZAMS are compared with the theoretical ZAMS from stellar evolutionary models, in the range tex2html_wrap_inline506 K. The discrepancies are also discussed

    Modelling the night sky brightness and light pollutionsources of Montsec protected area

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    We proceeded to the modelling of the night sky brightness of Montsec area (north-east of Spain), an astronomical protected area certified as a Starlight Reserve. We have used the hyperspectral version of ILLUMINA, an artificial sky brightness model. Ground based measurements for Montsec and other areas of Catalonia [15], [16], including both photometric and spectroscopic data, has been used to fit and evaluate the input parameters of the model. In this first modelling attempt, Lleida, the biggest city in the area, has been considered as the unique source of light pollution. In 2014 there was an update of the lighting infrastructure in Lleida. A detailed comparison of the sky brightness before and after the change is shown in order to measure the effects that different kind of lamps can produce. This information could be used to plan for future updates and improvements of the lighting systems in the area.Peer ReviewedPostprint (author's final draft

    A CubeSAT payload for in-situ monitoring of pentacene degradation due to atomic oxygen etching in LEO

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    This paper reports and discusses the design and ground tests of a CubeSat payload which allows to measure, in-situ and in real time, the degradation of a polymer of electronic interest due to atomic oxygen etching in LEO. It provides real-time information on how the degradation occurs, eliminating the need to work with samples recovered once the mission has finished. The polymer, TIPS-Pentacene, is deposited on the surface of a microelectromechanical (MEMS) cantilever, which works as a resonator embedded in a Pulsed Digital Oscillator circuit. The mass losses in the polymer due to atomic oxygen corrosion produce variations in the resonant frequency of the MEMS, which is continuously sensed by the circuit and transmitted to the ground. This way, polymer mass losses around 10-12 kg can be detected during the mission. The payload is a part of the 3Cat-1 mission, a nano-satellite aimed at carrying out several scientific experiments.Peer ReviewedPostprint (author's final draft

    Neonatal Neurobehavior and Diffusion MRI Changes in Brain Reorganization Due to Intrauterine Growth Restriction in a Rabbit Model

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    Background: Intrauterine growth restriction (IUGR) affects 5–10 % of all newborns and is associated with a high risk of abnormal neurodevelopment. The timing and patterns of brain reorganization underlying IUGR are poorly documented. We developed a rabbit model of IUGR allowing neonatal neurobehavioral assessment and high resolution brain diffusion magnetic resonance imaging (MRI). The aim of the study was to describe the pattern and functional correlates of fetal brain reorganization induced by IUGR. Methodology/Principal Findings: IUGR was induced in 10 New Zealand fetal rabbits by ligation of 40–50 % of uteroplacental vessels in one horn at 25 days of gestation. Ten contralateral horn fetuses were used as controls. Cesarean section was performed at 30 days (term 31 days). At postnatal day +1, neonates were assessed by validated neurobehavioral tests including evaluation of tone, spontaneous locomotion, reflex motor activity, motor responses to olfactory stimuli, and coordination of suck and swallow. Subsequently, brains were collected and fixed and MRI was performed using a high resolution acquisition scheme. Global and regional (manual delineation and voxel based analysis) diffusion tensor imaging parameters were analyzed. IUGR was associated with significantly poorer neurobehavioral performance in most domains. Voxel based analysis revealed fractional anisotropy (FA) differences in multiple brain regions of gray and white matter, including frontal, insular, occipital and temporal cortex, hippocampus, putamen, thalamus, claustrum, medial septa
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