Data Vaults: a Database Welcome to Scientific File Repositories

Efficient management and exploration of high-volume scientific file repositories have become pivotal for advancement in science. We propose to demonstrate the Data Vault, an extension of the database system architecture that transparently opens scientific file repositories for efficient in-database processing and exploration. The Data Vault facilitates science data analysis using high-level declarative languages, such as the traditional SQL and the novel array-oriented SciQL. Data of interest are loaded from the attached repository in a just-in-time manner without need for up-front data ingestion. The demo is built around concrete implementations of the Data Vault for two scientific use cases: seismic time series and Earth observation images. The seismic Data Vault uses the queries submitted by the audience to illustrate the internals of Data Vault functioning by revealing the mechanisms of dynamic query plan generation and on-demand external data ingestion. The image Data Vault shows an application view from the perspective of data mining researchers

Novel compounds targeting the RNA-binding protein HuR : Structure-based design, synthesis and interaction studies

The key role of RNA-binding proteins (RBPs) in regulating post-transcriptional processes and their involvement in several pathologies (i.e., cancer and neurodegeneration) have highlighted their potential as therapeutic targets. In this scenario, Embryonic Lethal Abnormal Vision (ELAV) or Hu proteins and their complexes with target mRNAs have been gaining growing attention. Compounds able to modulate the complex stability could constitute an innovative pharmacological strategy for the treatment of numerous diseases. Nevertheless, medicinal-chemistry efforts aimed at developing such compounds are still at an early stage. As part of our ongoing research in this field, we hereby present the rational design and synthesis of structurally novel HuR ligands, potentially acting as HuR-RNA interferers. The following assessment of the structural features of their interaction with HuR, combining saturation-transfer difference NMR and in silico studies, provides a guide for further research on the development of new effective interfering compounds of the HuR-RNA complex

Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics

AbstractAdenovirus-mediated delivery of the immune-stimulatory cytokine Flt3L and the conditionally cytotoxic thymidine kinase (TK) induces tumor regression and long-term survival in preclinical glioma (glioblastoma multiforme [GBM]) models. Flt3L induces expansion and recruitment of plasmacytoid dendritic cells (pDCs) into the brain. Although pDCs can present antigen and produce powerful inflammatory cytokines, that is, interferon α (IFN-α), their role in tumor immunology remains debated. Thus, we studied the role of pDCs and IFN-α in Ad.TK/GCV+ Ad.Flt3L-mediated anti-GBM therapeutic efficacy. Our data indicate that the combined gene therapy induced recruitment of plasmacytoid DCs (pDCs) into the tumor mass; which were capable of in vivo phagocytosis, IFN-α release, and T-cell priming. Thus, we next used either pDCs or an Ad vector encoding IFN-α delivered within the tumor microenvironment. When rats were treated with Ad.TK/GCV in combination with pDCs or Ad-IFN-α, they exhibited 35% and 50% survival, respectively. However, whereas intracranial administration of Ad.TK/GCV + Ad.Flt3L exhibited a high safety profile, Ad-IFN-α led to severe local inflammation, with neurologic and systemic adverse effects. To elucidate whether the efficacy of the immunotherapy was dependent on IFN-α-secreting pDCs, we administered an Ad vector encoding B18R, an IFN-α antagonist, which abrogated the antitumoral effect of Ad.TK/GCV + Ad.Flt3L. Our data suggest that IFN-α release by activated pDCs plays a critical role in the antitumor effect mediated by Ad.TK/GCV + Ad.Flt3L. In summary, taken together, our results demonstrate that pDCs mediate anti-GBM therapeutic efficacy through the production of IFN-α, thus manipulation of pDCs constitutes an attractive new therapeutic target for the treatment of GBM

Release of HMGB1 in Response to Pro-Apoptotic Glioma Killing Strategies: Efficacy and Neurotoxicity

Purpose In preparation for a Phase I clinical trial utilizing a combined cytotoxic/immunotherapeutic strategy using adenoviruses expressing Flt3L (Ad-Flt3L) and thymidine kinase (Ad-TK) to treat glioblastoma (GBM), we tested the hypothesis that Ad-TK+GCV would be the optimal tumor killing agent in relation to efficacy and safety when compared to other pro-apoptotic approaches. Experimental Design and Results The efficacy and neurotoxicity of Ad-TK+GCV was compared with Ads encoding the pro-apoptotic cytokines (TNF-α, TRAIL, FasL), alone or in combination with Ad-Flt3L. In rats bearing small GBMs (day 4), only Ad-TK+GCV or Ad-FasL improved survival. In rats bearing large GBMs (day 9), the combination of Ad-Flt3L with Ad-FasL did not improve survival over FasL alone, while Ad-Flt3L combined with Ad-TK+GCV led to 70% long-term survival. Expression of FasL and TRAIL caused severe neuropathology, which was not encountered when we utilized Ad-TK+/−Ad-Flt3L. In vitro, all treatments elicited release HMGB1 from dying tumor cells. In vivo, the highest levels of circulating HMGB1 were observed after treatment with Ad-TK+GCV+Ad-Flt3L; HMGB1 was necessary for the therapeutic efficacy of AdTK+GCV+Ad-Flt3L, since its blockade with glycyrrhizin completely blocked tumor regression. We also demonstrated the killing efficacy of Ad-TK+GCV in human GBM cell lines and GBM primary cultures; which also elicited release of HMGB1. Conclusions Our results indicate that Ad-TK+GCV+Ad-Flt3L exhibits the highest efficacy and safety profile amongst the several pro-apoptotic approaches tested. The results reported further support the implementation of this combined approach in a Phase I clinical trial for GBM

TrpA1 Regulates Thermal Nociception in Drosophila

Pain is a significant medical concern and represents a major unmet clinical need. The ability to perceive and react to tissue-damaging stimuli is essential in order to maintain bodily integrity in the face of environmental danger. To prevent damage the systems that detect noxious stimuli are therefore under strict evolutionary pressure. We developed a high-throughput behavioral method to identify genes contributing to thermal nociception in the fruit fly and have reported a large-scale screen that identified the Ca2+ channel straightjacket (stj) as a conserved regulator of thermal nociception. Here we present the minimal anatomical and neuronal requirements for Drosophila to avoid noxious heat in our novel behavioral paradigm. Bioinformatics analysis of our whole genome data set revealed 23 genes implicated in Ca2+ signaling that are required for noxious heat avoidance. One of these genes, the conserved thermoreceptor TrpA1, was confirmed as a bona fide “pain” gene in both adult and larval fly nociception paradigms. The nociceptive function of TrpA1 required expression within the Drosophila nervous system, specifically within nociceptive multi-dendritic (MD) sensory neurons. Therefore, our analysis identifies the channel TRPA1 as a conserved regulator of nociception

Human Flt3L Generates Dendritic Cells from Canine Peripheral Blood Precursors: Implications for a Dog Glioma Clinical Trial

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and carries a dismal prognosis. We have developed a conditional cytotoxic/immunotherapeutic approach using adenoviral vectors (Ads) encoding the immunostimulatory cytokine, human soluble fms-like tyrosine kinase 3 ligand (hsFlt3L) and the conditional cytotoxic molecule, i.e., Herpes Simplex Type 1- thymide kinase (TK). This therapy triggers an anti-tumor immune response that leads to tumor regression and anti-tumor immunological memory in intracranial rodent cancer models. We aim to test the efficacy of this immunotherapy in dogs bearing spontaneous GBM. In view of the controversy regarding the effect of human cytokines on dog immune cells, and considering that the efficacy of this treatment depends on hsFlt3L-stimulated dendritic cells (DCs), in the present work we tested the ability of Ad-encoded hsFlt3L to generate DCs from dog peripheral blood and compared its effects with canine IL-4 and GM-CSF.Our results demonstrate that hsFlT3L expressed form an Ad vector, generated DCs from peripheral blood cultures with very similar morphological and phenotypic characteristics to canine IL-4 and GM-CSF-cultured DCs. These include phagocytic activity and expression of CD11c, MHCII, CD80 and CD14. Maturation of DCs cultured under both conditions resulted in increased secretion of IL-6, TNF-alpha and IFN-gamma. Importantly, hsFlt3L-derived antigen presenting cells showed allostimulatory potential highlighting their ability to present antigen to T cells and elicit their proliferation.These results demonstrate that hsFlt3L induces the proliferation of canine DCs and support its use in upcoming clinical trials for canine GBM. Our data further support the translation of hsFlt3L to be used for dendritic cells' vaccination and gene therapeutic approaches from rodent models to canine patients and its future implementation in human clinical trials

Preclinical Models of Brain Metastasis

Research at the Brain Metastasis Group is supported by MINECO grants MINECO-Retos SAF2017-89643-R (M.V.), Bristol-Myers Squibb- Melanoma Research Alliance Young Investigator Award 2017 (498103) (M.V.), Beug Foundation’s Prize for Metastasis Research 2017 (M.V.), Fundación Ramón Areces (CIVP19S8163) (M.V.), Worldwide Cancer Research (19-0177) (M.V.), H2020-FETOPEN (828972)N

Compact frequency standard based on an intracavity sample of cold cesium atoms

We have demonstrated the possibility for a compact frequency standard based on a sample of cold cesium atoms. In a cylindrical microwave cavity, the atoms are cooled and interrogated during a free expansion and then detected. The operation of this experiment is different from conventional atomic fountains since all the steps are sequentially performed in the same position of space. In this paper we report the analysis of a Ramsey pattern observed to present a (47±5) Hz linewidth and a stability of (5±0.5)x10-13τ-1/2 for an integration time longer than 100 s. Some of the main limitations of the standard are analyzed. This present report demonstrates considerable improvement of our previous work [J. Opt. Soc. Am. B 25, 909 (2008)] where the atoms were in a free space and not inside a microwave cavity.FAPESPCNPqCAPESFAPESP-CNR

Enhancement of the activity of phenoxodiol by cisplatin in prostate cancer cells

Phenoxodiol is a novel isoflav-3-ene, currently undergoing clinical trials, that has a broad in vitro activity against a number of human cancer cell lines. Phenoxodiol alone inhibited DU145 and PC3 in a dose- and time-dependent manner with IC50 values of 8±1 and 38±9 μM, respectively. The combination of phenoxodiol and cisplatin was synergistic in DU145, and additive in PC3, as assessed by the Chou–Talalay method. Carboplatin was also synergistic in combination with phenoxodiol in DU145 cells. The activity of the phenoxodiol and cisplatin combination was confirmed in vivo using a DU145 xenograft model in nude mice. Pharmacokinetic data from these mice suggest that the mechanism of synergy may occur through a pharmacodynamic mechanism. An intracellular cisplatin accumulation assay showed a 35% (P<0.05) increase in the uptake of cisplatin when it was combined in a ratio of 1 μM: 5 μM phenoxodiol, resulting in a 300% (P<0.05) increase in DNA adducts. Taken together, our results suggest that phenoxodiol has interesting properties that make combination therapy with cisplatin or carboplatin appealing