Institute Investigacion Sanitaria Gregorio Maranon IiSGM

Madrid, Spain

Institute Investigacion Sanitaria Gregorio Maranon IiSGM

Madrid, Spain
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Echavarria I.,Institute Investigacion Sanitaria Gregorio Maranon IiSGM | Lopez-Tarruella S.,Institute Investigacion Sanitaria Gregorio Maranon IiSGM | Marquez-Rodas I.,Institute Investigacion Sanitaria Gregorio Maranon IiSGM | Jerez Y.,Institute Investigacion Sanitaria Gregorio Maranon IiSGM | Martin M.,Complutense University of Madrid
Expert Review of Anticancer Therapy | Year: 2017

Introduction: Despite the advances in the treatment of HER2-positive breast cancer, resistance to actual chemotherapeutic regimens eventually occurs. Neratinib, an orally available pan-inhibitor of the ERBB family, represents an interesting new option for early-stage HER2-positive breast cancer. Areas covered: In this article, the development of neratinib, with a special focus on its potential value in the treatment of early-stage HER2-positive breast cancer, has been reviewed. For this purpose, a literature search was conducted, including preclinical studies, early-phase trials in advanced cancer with neratinib in monotherapy and in combination, and phase II and large phase III trials in the early setting. Management of neratinib-induced toxicity, future perspectives for the drug, and ongoing trials are also discussed in this review. Expert commentary: Neratinib is emerging as a promising oral drug for the treatment of HER2-positive breast cancer. Although FDA and EMA approval is derived from the extended adjuvant treatment, this setting may not be the ideal scenario to obtain the beneficial effects of neratinib. Confirmatory data in the neoadjuvant setting and subgroup analysis from the ExTENET trial might bring some light into the best setting for neratinib therapy. Data from confirmatory trials in the metastatic setting are also required. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Martinez-Bonet M.,CIBER ISCIII | Clemente M.I.,CIBER ISCIII | Clemente M.I.,Institute Investigacion Sanitaria Gregorio Maranon IiSGM | Alvarez S.,CIBER ISCIII | And 6 more authors.
Antiviral Research | Year: 2015

Although an effective combination of antiretroviral therapy (cART) controls HIV-1 viraemia in infected patients, viral latency established soon after infection hinders HIV-1 eradication. It has been shown that bryostatin-1 (BRY) inhibits HIV-infection in vitro and reactivates the latent virus through the protein kinase C-NF-κB pathway. We determined the in vitro potential effect of BRY in combination with currently used antiretroviral drugs. BRY alone or in combination with maraviroc (MVC)/Atripla (ATP) was tested for its capacity to reactivate latent virus and inhibit new infections. JLTRG-R5 cells and two latent HIV-1-infected cell lines, J89GFP and THP89GFP, were used as latency models. To quantify HIV infection, the reporter cell line TZM-bl was used. We found that BRY reactivates HIV-1 even in combination with MVC or ATP. Antiretroviral combinations with BRY do not interfere with BRY activity (i.e., the reactivation of latently infected cells) or with the antiviral activity of antiretroviral drugs. In addition, BRY-mediated down-modulation of surface CD4 and CXCR4 was not affected when it was used in combination with other antiretrovirals, and no hyperactivation or high-proliferation effects were observed in primary T cells. Moreover, the BRY treatment was able to reactivate HIV-1 in CD4+ T cells from HIV-1-infected patients under cART. Thus, we propose the use of BRY to purge the viral reservoir and recommend its combination with current antiretroviral treatments. © 2015 Elsevier B.V.

Serrano E.,Charles III University of Madrid | Blas J.G.,Charles III University of Madrid | Carretero J.,Charles III University of Madrid | Abella M.,Charles III University of Madrid | Abella M.,Institute Investigacion Sanitaria Gregorio Maranon IiSGM
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2017

The current disadvantages in computing platforms and the easy migration to the Cloud Computing paradigm have as consequence the migration of scientific applications to different task-based distributed computing frameworks. However, many of them have already been optimized for their execution on specific hardware accelerators like GPUs. In this work, we present an architecture design that aims to facilitate the execution of traditional HPC based applications into Big Data environments. We prove that the bigger memory capacity, the automatic task partitioning, and the higher computational power lead to a convergence to a highly distributed new execution model. Moreover, we present an study of the viability of our proposal through the use of GPUs inside the Apache Spark infrastructure. The architecture presented will be evaluated through a real medical imaging application. The evaluation results demonstrate that our approach obtains competitive execution times compared with the original application. © Springer International Publishing AG 2017.

Ferrando-Martinez S.,Institute Investigacion Sanitaria Gregorio Maranon IISGM | Ferrando-Martinez S.,University of Seville | Lorente R.,Institute Investigacion Sanitaria Gregorio Maranon IISGM | Gurbindo D.,Hospital General Universitario Gregorio Maranon | And 5 more authors.
Journal of Pediatrics | Year: 2014

Objective To perform an extensive analysis of the immune status of asymptomatic children with the 22q11.2 deletion syndrome, with special emphasis on the regulatory T cells (Treg) population. Study design Analysis of thymic function, frequency and absolute counts of immune subsets, and phenotype of Treg were performed in 10 asymptomatic children bearing the 22q11.2 deletion and compared with 12 age-matched, healthy children. Results Children with 22q11.2 deletion syndrome showed a curtailed thymic output, lower T-cell levels, and a homeostatic deregulation in the CD4 T-cell compartment, characterized by a greater proliferative history in the naïve CD4 T-cell subset. Treg numbers were markedly reduced in children with 22q11.2 deletion syndrome, and remaining Treg showed mostly an activated phenotype. Conclusions Reduced thymic output in children with 22q11.2 deletion syndrome could be related with an increased proliferation in the naïve CD4 T-cell compartment and the consequent Treg activation to ensure that T-cell expansion remains under control. Deregulated peripheral homeostasis and loss of suppressive capacity by Treg could compromise the integrity of T-cell immunity during adulthood and play a relevant role in the increased incidence of autoimmune diseases reported in patients with the 22q11.2 deletion syndrome. © 2014 Mosby Inc. All rights reserved.

Samaniego R.,Institute Investigacion Sanitaria Gregorio Maranon IiSGM | Estecha A.,Institute Investigacion Sanitaria Gregorio Maranon IiSGM | Relloso M.,Institute Investigacion Sanitaria Gregorio Maranon IiSGM | Longo N.,Institute Investigacion Sanitaria Gregorio Maranon IiSGM | And 5 more authors.
Journal of Investigative Dermatology | Year: 2013

To understand factors that regulate leukocyte entry and positioning within human melanoma tissues, we performed a multiparametric quantitative analysis of two separated regions: the intratumoral area and the peritumoral stroma. Using two mesenchymal markers, fibroblast activation protein (FAP) and CD90, we identified three subsets of mesenchymal cells (MCs): (i) intratumoral FAP + CD90 low/- MC, (ii) peritumoral FAP + CD90 + MC, and (iii) FAP - CD90 + perivascular MC. We characterized CD90 + MCs, which showed a stable CCL2-secretory phenotype when long-term expanded ex vivo, and heavily surrounded peritumoral Duffy antigen receptor for chemokine + (DARC) postcapillary venules, supporting a role for these vessels in peritumoral inflammatory leukocyte recruitment. Conversely, the intratumoral area was variably invaded by FAP + CD90 low/- MCs that colocalized with a distinct extracellular matrix (ECM) network. A positive correlation was observed between intratumoral stromal cell/ECM networks and leukocyte infiltration among tumor cells (TCs), as well as in a stroma-dependent xenograft tumor model. Adoptively transferred T lymphocytes preferentially infiltrated tumors composed of TC+MC, compared with TCs only. Altogether, our results suggest that a variety of MCs contribute to regulate different steps of leukocyte tumor infiltration, that is, CD90 + cells surrounding peritumoral vessels secrete CCL2 to recruit CCR2 + leukocytes at the tumor periphery, whereas intratumoral FAP + cells organize a stromal scaffold that contact guide further invasion among densely packed tumor cells. © 2013 The Society for Investigative Dermatology.

Perez A.,Hospital Universitario Virgen Of Las Nieves | Gonzalez-Manzano S.,University of Salamanca | Jimenez R.,University of Granada | Jimenez R.,Institute Investigacion Biosanitaria Of Granada | And 9 more authors.
Pharmacological Research | Year: 2014

Quercetin exerts vasodilator, antiplatelet and antiproliferative effects and reduces blood pressure, oxidative status and end-organ damage in hypertensive humans and animal models. We hypothesized that oral quercetin might induce vasodilator effects in humans and that they might be related to the deconjugation of quercetin-3-O-glucuronide (Q3GA). Design: double blind, randomized, placebo-controlled trial. Fifteen healthy volunteers (26 ± 5 years, 6 female) were given a capsule containing placebo, 200 or 400 mg of quercetin in random order in three consecutive weeks. At 2 h a dose-dependent increase in Q3GA was observed in plasma (∼0.4 and 1 μM for 200 and 400 mg, respectively) with minor levels of quercetin and isorhamnetin. No changes were observed in blood pressure. At 5 h quercetin induced and increase in brachial arterial diameter that correlated with the product of the levels of Q3GA by the plasma glucuronidase activity. There was an increase in urinary levels of glutathione but there was no increase in nitrites plus nitrates. Quercetin and isorhamnetin also relaxed human umbilical arteries in vitro while Q3GA was without effect. In conclusions, quercetin exerts acute vasodilator effects in vivo in normotensive, normocholesterolemic human subjects. These results are consistent with the effects being due to the deconjugation of the metabolite Q3GA. © 2014 Elsevier Ltd.

Serramia M.J.,Hospital General Universitario Gregorio Maranon | Serramia M.J.,Institute Investigacion Sanitaria Gregorio Maranon IISGM | Serramia M.J.,CIBER ISCIII | Alvarez S.,Hospital General Universitario Gregorio Maranon | And 14 more authors.
Journal of Controlled Release | Year: 2015

Nanotechnology offers a new platform for therapeutic delivery of antiretrovirals to the central nervous system (CNS). Nanoformulated antiretroviral drugs offer multifunctionality, that is, the ability to package multiple diagnostic and therapeutic agents in the same nanocompose, along with the added provisions of site-directed delivery, delivery across the blood-brain-barrier (BBB), and controlled release of therapeutics. We studied the viability of dendrimers and dendriplexes in human primary astrocytes, as well as their uptake by these astrocytes. Functional validation was performed by using specific siRNA against HIV-1 Nef to interfere to HIV-1 infectivity. A high efficiency in Nef silencing, reducing HIV-1 infectivity was observed in astrocytes treated with dendriplexes compared with control or siRandom treated astrocytes. More interestingly, we studied the biodistribution of the second generation of carbosilane dendrimer loaded with FITC (2G-(SNMe3I)11-FITC) in vivo, in BALB/c mice. Dendriplexes were inoculated into BALB/c mice by the retro-orbital venous plexus, and their localization was determined after 1 and 24 h post-injection. Dendriplexes were detected inside the brain by a sensitive imaging system of fluorescent imaging in vivo (IVIS Lumina), and by confocal microscopy analysis of sections of OCT-embedded tissues. The 2G-(SNMe3I)11-FITC dendrimer transported efficiently siRNA into the brain, crossing the BBB. Moreover, this dendrimer successfully delivered and transfected siRNA to HIV-infected human primary astrocytes and achieved gene silencing without causing cytotoxicity. These results highlight the potential of this nanoformulation in the treatment of neurological disorders. © 2014 Elsevier B.V. All rights reserved.

Montesinos P.,Charles III University of Madrid | Montesinos P.,Institute Investigacion Sanitaria Gregorio Maranon IiSGM | Abascal J.F.P.J.,Charles III University of Madrid | Abascal J.F.P.J.,Institute Investigacion Sanitaria Gregorio Maranon IiSGM | And 7 more authors.
Magnetic Resonance in Medicine | Year: 2014

Purpose Self-gated cine sequences are a common choice for cardiac MRI in preclinical applications. The aims of our work were to apply the compressed sensing technique to IntraGateFLASH cardiac MRI studies on rats and to find the maximum acceleration factor achievable with this technique. Theory and Methods Our reconstruction method extended the Split Bregman formulation to minimize the total variation in both space and time. In addition, we analyzed the influence of the undersampling pattern on the acceleration factor achievable. Results Our results show that acceleration factors of up to 15 are achievable with our technique when appropriate undersampling patterns are used. The introduction of a time-varying random sampling clearly improved the efficiency of the undersampling schemes. In terms of computational efficiency, the proposed reconstruction method has been shown to be competitive as compared with the fastest methods found in the literature. Conclusion We successfully applied our compressed sensing technique to self-gated cardiac cine acquisition in small animals, obtaining an acceleration factor of up to 15 with almost unnoticeable image degradation. Magn Reson Med 72:369-380, 2014. © 2013 Wiley Periodicals, Inc. Copyright © 2013 Wiley Periodicals, Inc.

Sisniega A.,Charles III University of Madrid | Sisniega A.,Institute Investigacion Sanitaria Gregorio Maranon IiSGM | Abella M.,Charles III University of Madrid | Abella M.,Institute Investigacion Sanitaria Gregorio Maranon IiSGM | And 5 more authors.
Physics in Medicine and Biology | Year: 2014

This work presents an approach to extend the dynamic range of x-ray flat panel detectors by combining two acquisitions of the same sample taken with two different x-ray photon flux levels and the same beam spectral configuration. In order to combine both datasets, the response of detector pixels was modelled in terms of mean and variance using a linear model. The model was extended to take into account the effect of pixel saturation. We estimated a joint probability density function (j-pdf) of the pixel values by assuming that each dataset follows an independent Gaussian distribution. This j-pdf was used for estimating the final pixel value of the high-dynamic-range dataset using a maximum likelihood method. The suitability of the pixel model for the representation of the detector signal was assessed using experimental data from a small-animal cone-beam micro-CT scanner equipped with a flat panel detector. The potential extension in dynamic range offered by our method was investigated for generic flat panel detectors using analytical expressions and simulations. The performance of the proposed dual-exposure approach in realistic imaging environments was compared with that of a regular single-exposure technique using experimental data from two different phantoms. Image quality was assessed in terms of signal-to-noise ratio, contrast, and analysis of profiles drawn on the images. The dynamic range, measured as the ratio between the exposure for saturation and the exposure equivalent to instrumentation noise, was increased from 76.9 to 166.7 when using our method. Dual-exposure results showed higher contrast-to-noise ratio and contrast resolution than the single-exposure acquisitions for the same x-ray dose. In addition, image artifacts were reduced in the combined dataset. This technique to extend the dynamic range of the detector without increasing the dose is particularly suited to image samples that contain both low and high attenuation regions. © 2014 Institute of Physics and Engineering in Medicine.

PubMed | Hospital General Universitario Gregorio Maranon, Hospital Clinico San Carlos, Institute Investigacion Sanitaria Gregorio Maranon IiSGM and Hospital Universitario Infanta Cristina
Type: | Journal: Breast cancer research and treatment | Year: 2017

In an era where neoadjuvant dual blockade is emerging as the standard of care for early and locally advanced HER2-positive breast cancer, we aimed to identify predictors of response to single-blockade chemotherapy.This retrospective analysis reviewed all the incident stage I-III HER2-positive breast cancer patients who received neoadjuvant docetaxel, carboplatin, and trastuzumab (TCH) in three institutions. pCR was defined as the absence of invasive tumor in breast and axillary nodes (ypT0/isypN0).From 2008 to 2015, 84 patients receiving neoadjuvant TCH were identified within our institutions. The mean age at diagnosis was 51.8years. 59.5% of the patients were hormone receptor (HR) positive, lymph node involvement occurred in 67.9%, and clinical distribution was 2.4, 65.5, and 32.1% for stage I, II, and III, respectively. pCR rate was 47.6%; there was a significantly lower response in HR-positive patients compared to HR-negative ones (34 vs 67.6%, p=0.005). pCR rate was associated with tumor size, whereas differences did not reach significance either for stage or for nodal status. Multivariate analysis found that only HR status was associated with response (p=0.003). At a median follow-up of 31.7months, disease-free survival, distant disease-free survival, and overall survival were 78.6, 85.7, and 94%, respectively. Breast-conserving surgery was performed in 44% of the patients. Overall, TCH was well tolerated, with low rates of grade 3-4 adverse events, and neither late toxicities nor cardiac dysfunctions were reported.Neoadjuvant TCH, an anthracycline-free single-blockade regimen, achieved a pCR of 47.6%. Further molecular analyses are required in order to identify stronger predictive markers of pCR and thus for an accurate selection of patients who do not benefit from dual blockade.

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