Two new alleles of the abscisic aldehyde oxidase 3 gene reveal its role in abscisic acid biosynthesis in seeds

9 páginas, 3 figuras, 3 tablas -- PAGS nros. 325-333The abscisic aldehyde oxidase 3 (AAO3) gene product of Arabidopsis catalyzes the final step in abscisic acid (ABA) biosynthesis. An aao3-1 mutant in a Landsberg erecta genetic background exhibited a wilty phenotype in rosette leaves, whereas seed dormancy was not affected (Seo et al., 2000a). Therefore, it was speculated that a different aldehyde oxidase would be the major contributor to ABA biosynthesis in seeds (Seo et al., 2000a). Through a screening based on germination under high-salt concentration, we isolated two mutants in a Columbia genetic background, initially named sre2-1 and sre2-2 (for salt resistant). Complementation tests with different ABA-deficient mutants indicated that sre2-1 and sre2-2 mutants were allelic to aao3-1, and therefore they were renamed as aao3-2 and aao3-3, respectively. Indeed, molecular characterization of the aao3-2 mutant revealed a T-DNA insertional mutation that abolished the transcription of AAO3 gene, while sequence analysis of AAO3 in aao3-3 mutant revealed a deletion of three nucleotides and several missense mutations. Physiological characterization of aao3-2 and aao3-3 mutants revealed a wilty phenotype and osmotolerance in germination assays. In contrast to aao3-1, both aao3-2 and aao3-3 mutants showed a reduced dormancy. Accordingly, ABA levels were reduced in dry seeds and rosette leaves of both aao3-2 and aao3-3. Taken together, these results indicate that AAO3 gene product plays a major role in seed ABA biosynthesisThis work was supported by the Ministerio de Ciencia y Tecnologia (grant no. BIO2002–03090) and FEDERPeer reviewe

Review of magnetic nanostructures grown by focused electron beam induced deposition (FEBID)

We review the current status of the use of focused electron beam induced deposition (FEBID) for the growth of magnetic nanostructures. This technique relies on the local dissociation of a precursor gas by means of an electron beam. The most promising results have been obtained using the Co₂(CO)₈ precursor, where the Co content in the grown nanodeposited material can be tailored up to more than 95%. Functional behaviour of these Co nanodeposits has been observed in applications such as arrays of magnetic dots for information storage and catalytic growth, magnetic tips for scanning probe microscopes, nano-Hall sensors for bead detection, nano-actuated magnetomechanical systems and nanowires for domain-wall manipulation. The review also covers interesting results observed in Fe-based and alloyed nanodeposits. Advantages and disadvantages of FEBID for the growth of magnetic nanostructures are discussed in the article as well as possible future directions in this field.Financial support by several projects is acknowledged: MAT2014-51982-C2-1-R, MAT2014-51982-C2-2-R and MAT2015-69725-REDT from MINECO (including FEDER funding), CELINA COST Action CM1301, Aragón Regional Government through project E26, FP7 Marie Curie Fellowship 3DMAGNANOW, EPSRC Early Career Fellowship EP/M008517/1 and Winton Fellowship

Drug delivery nanosystems for the localized treatment of glioblastoma multiforme

[EN] Glioblastoma multiforme is one of the most prevalent and malignant forms of central nervous system tumors. The treatment of glioblastoma remains a great challenge due to its location in the intracranial space and the presence of the blood-brain tumor barrier. There is an urgent need to develop novel therapy approaches for this tumor, to improve the clinical outcomes, and to reduce the rate of recurrence and adverse effects associated with present options. The formulation of therapeutic agents in nanostructures is one of the most promising approaches to treat glioblastoma due to the increased availability at the target site, and the possibility to co-deliver a range of drugs and diagnostic agents. Moreover, the local administration of nanostructures presents significant additional advantages, since it overcomes blood-brain barrier penetration issues to reach higher concentrations of therapeutic agents in the tumor area with minimal side effects. In this paper, we aim to review the attempts to develop nanostructures as local drug delivery systems able to deliver multiple agents for both therapeutic and diagnostic functions for the management of glioblastoma.This research was funded by an Ussher start-up funding award (School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin) and the European Union’s Horizon 2020 research and innovation program under Grant agreement No. 708036.Nam, L.; Coll Merino, MC.; Erthal, L.; De La Torre-Paredes, C.; Serrano, D.; Martínez-Máñez, R.; Santos-Martinez, M.... (2018). Drug delivery nanosystems for the localized treatment of glioblastoma multiforme. Materials. 11(5). https://doi.org/10.3390/ma11050779S115Goodenberger, M. L., & Jenkins, R. B. (2012). Genetics of adult glioma. Cancer Genetics, 205(12), 613-621. doi:10.1016/j.cancergen.2012.10.009Louis, D. N., Ohgaki, H., Wiestler, O. D., Cavenee, W. K., Burger, P. C., Jouvet, A., … Kleihues, P. (2007). The 2007 WHO Classification of Tumours of the Central Nervous System. Acta Neuropathologica, 114(2), 97-109. doi:10.1007/s00401-007-0243-4Gutkin, A., Cohen, Z. R., & Peer, D. (2016). Harnessing nanomedicine for therapeutic intervention in glioblastoma. Expert Opinion on Drug Delivery, 13(11), 1573-1582. doi:10.1080/17425247.2016.1200557Omuro, A. (2013). Glioblastoma and Other Malignant Gliomas. JAMA, 310(17), 1842. doi:10.1001/jama.2013.280319Wang, Y., & Jiang, T. (2013). Understanding high grade glioma: Molecular mechanism, therapy and comprehensive management. Cancer Letters, 331(2), 139-146. doi:10.1016/j.canlet.2012.12.024Gallego, O. (2015). Nonsurgical treatment of recurrent glioblastoma. Current Oncology, 22(4), 273. doi:10.3747/co.22.2436Carlsson, S. K., Brothers, S. P., & Wahlestedt, C. (2014). Emerging treatment strategies for glioblastoma multiforme. EMBO Molecular Medicine, 6(11), 1359-1370. doi:10.15252/emmm.201302627Yamasaki, F., Kurisu, K., Satoh, K., Arita, K., Sugiyama, K., Ohtaki, M., … Thohar, M. A. (2005). Apparent Diffusion Coefficient of Human Brain Tumors at MR Imaging. Radiology, 235(3), 985-991. doi:10.1148/radiol.2353031338Gupta, A., Young, R. J., Shah, A. D., Schweitzer, A. D., Graber, J. J., Shi, W., … Omuro, A. M. P. (2014). Pretreatment Dynamic Susceptibility Contrast MRI Perfusion in Glioblastoma: Prediction of EGFR Gene Amplification. Clinical Neuroradiology, 25(2), 143-150. doi:10.1007/s00062-014-0289-3Fakhoury, M. (2015). Drug delivery approaches for the treatment of glioblastoma multiforme. Artificial Cells, Nanomedicine, and Biotechnology, 44(6), 1365-1373. doi:10.3109/21691401.2015.1052467Štolc, S., Jakubíková, L., & Kukurová, I. (2011). Body distribution of 11C-methionine and 18FDG in rat measured by microPET. Interdisciplinary Toxicology, 4(1). doi:10.2478/v10102-011-0010-1Galldiks, N., Dunkl, V., Kracht, L. W., Vollmar, S., Jacobs, A. H., Fink, G. R., & Schroeter, M. (2012). Volumetry of [11C]-Methionine Positron Emission Tomographic Uptake as a Prognostic Marker before Treatment of Patients with Malignant Glioma. Molecular Imaging, 11(6), 7290.2012.00022. doi:10.2310/7290.2012.00022Louis, D. N., Perry, A., Reifenberger, G., von Deimling, A., Figarella-Branger, D., Cavenee, W. K., … Ellison, D. W. (2016). The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathologica, 131(6), 803-820. doi:10.1007/s00401-016-1545-1Martínez-Garcia, M., Álvarez-Linera, J., Carrato, C., Ley, L., Luque, R., Maldonado, X., … Gil-Gil, M. (2017). SEOM clinical guidelines for diagnosis and treatment of glioblastoma (2017). Clinical and Translational Oncology, 20(1), 22-28. doi:10.1007/s12094-017-1763-6WILSON, C. B. (1964). Glioblastoma Multiforme. Archives of Neurology, 11(5), 562. doi:10.1001/archneur.1964.00460230112012Juratli, T. A., Schackert, G., & Krex, D. (2013). Current status of local therapy in malignant gliomas — A clinical review of three selected approaches. Pharmacology & Therapeutics, 139(3), 341-358. doi:10.1016/j.pharmthera.2013.05.003Westphal, M., Hilt, D. C., Bortey, E., Delavault, P., Olivares, R., Warnke, P. C., … Ram, Z. (2003). A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro-Oncology, 5(2), 79-88. doi:10.1093/neuonc/5.2.79Chamberlain, M., Rhun, E., & Taillibert, S. (2015). The future of high-grade glioma: Where we are and where are we going. Surgical Neurology International, 6(2), 9. doi:10.4103/2152-7806.151331Stupp, R., Mason, W. P., van den Bent, M. J., Weller, M., Fisher, B., Taphoorn, M. J. B., … Mirimanoff, R. O. (2005). Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. New England Journal of Medicine, 352(10), 987-996. doi:10.1056/nejmoa043330Lee, C. Y. (2017). Strategies of temozolomide in future glioblastoma treatment. OncoTargets and Therapy, Volume 10, 265-270. doi:10.2147/ott.s120662Mun, E. J., Babiker, H. M., Weinberg, U., Kirson, E. D., & Von Hoff, D. D. (2017). Tumor-Treating Fields: A Fourth Modality in Cancer Treatment. Clinical Cancer Research, 24(2), 266-275. doi:10.1158/1078-0432.ccr-17-1117Stupp, R., Taillibert, S., Kanner, A., Kesari, S., Toms, S. A., Barnett, G. H., … Ram, Z. (2015). Tumor treating fields (TTFields): A novel treatment modality added to standard chemo- and radiotherapy in newly diagnosed glioblastoma—First report of the full dataset of the EF14 randomized phase III trial. Journal of Clinical Oncology, 33(15_suppl), 2000-2000. doi:10.1200/jco.2015.33.15_suppl.2000Bernard-Arnoux, F., Lamure, M., Ducray, F., Aulagner, G., Honnorat, J., & Armoiry, X. (2016). The cost-effectiveness of tumor-treating fields therapy in patients with newly diagnosed glioblastoma. Neuro-Oncology, 18(8), 1129-1136. doi:10.1093/neuonc/now102Stupp, R., Hegi, M. E., Mason, W. P., van den Bent, M. J., Taphoorn, M. J., Janzer, R. C., … Mirimanoff, R.-O. (2009). Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. The Lancet Oncology, 10(5), 459-466. doi:10.1016/s1470-2045(09)70025-7Preusser, M., de Ribaupierre, S., Wöhrer, A., Erridge, S. C., Hegi, M., Weller, M., & Stupp, R. (2011). Current concepts and management of glioblastoma. Annals of Neurology, 70(1), 9-21. doi:10.1002/ana.22425FDA Grants Genentech’s Avastin Full Approval for Most Aggressive Form of Brain Cancerhttps://www.gene.com/media/press-releases/14695/2017-12-05/fda-grants-genentechs-avastin-full-approWick, W., Stupp, R., Gorlia, T., Bendszus, M., Sahm, F., Bromberg, J. E., … Van Den Bent, M. J. (2016). Phase II part of EORTC study 26101: The sequence of bevacizumab and lomustine in patients with first recurrence of a glioblastoma. Journal of Clinical Oncology, 34(15_suppl), 2019-2019. doi:10.1200/jco.2016.34.15_suppl.2019Liu, W.-Y., Wang, Z.-B., Zhang, L.-C., Wei, X., & Li, L. (2012). Tight Junction in Blood-Brain Barrier: An Overview of Structure, Regulation, and Regulator Substances. CNS Neuroscience & Therapeutics, 18(8), 609-615. doi:10.1111/j.1755-5949.2012.00340.xRonaldson, P. T., & Davis, T. P. (2011). Targeting blood–brain barrier changes during inflammatory pain: an opportunity for optimizing CNS drug delivery. Therapeutic Delivery, 2(8), 1015-1041. doi:10.4155/tde.11.67S. Hersh, D., S. Wadajkar, A., B. Roberts, N., G. Perez, J., P. Connolly, N., Frenkel, V., … J. Kim, A. (2016). Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier. Current Pharmaceutical Design, 22(9), 1177-1193. doi:10.2174/1381612822666151221150733Patel, M. M., Goyal, B. R., Bhadada, S. V., Bhatt, J. S., & Amin, A. F. (2009). Getting into the Brain. CNS Drugs, 23(1), 35-58. doi:10.2165/0023210-200923010-00003Clark, D. E. (2003). In silico prediction of blood–brain barrier permeation. Drug Discovery Today, 8(20), 927-933. doi:10.1016/s1359-6446(03)02827-7Gleeson, M. P. (2008). Generation of a Set of Simple, Interpretable ADMET Rules of Thumb. Journal of Medicinal Chemistry, 51(4), 817-834. doi:10.1021/jm701122qHervé, F., Ghinea, N., & Scherrmann, J.-M. (2008). CNS Delivery Via Adsorptive Transcytosis. The AAPS Journal, 10(3), 455-472. doi:10.1208/s12248-008-9055-2Van Tellingen, O., Yetkin-Arik, B., de Gooijer, M. C., Wesseling, P., Wurdinger, T., & de Vries, H. E. (2015). Overcoming the blood–brain tumor barrier for effective glioblastoma treatment. Drug Resistance Updates, 19, 1-12. doi:10.1016/j.drup.2015.02.002Ostermann, S. (2004). Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Temozolomide in Malignant Glioma Patients. Clinical Cancer Research, 10(11), 3728-3736. doi:10.1158/1078-0432.ccr-03-0807Laquintana, V., Trapani, A., Denora, N., Wang, F., Gallo, J. M., & Trapani, G. (2009). New strategies to deliver anticancer drugs to brain tumors. Expert Opinion on Drug Delivery, 6(10), 1017-1032. doi:10.1517/17425240903167942Zhan, C., Gu, B., Xie, C., Li, J., Liu, Y., & Lu, W. (2010). Cyclic RGD conjugated poly(ethylene glycol)-co-poly(lactic acid) micelle enhances paclitaxel anti-glioblastoma effect. Journal of Controlled Release, 143(1), 136-142. doi:10.1016/j.jconrel.2009.12.020Kondo, Y., Kondo, S., Tanaka, Y., Haqqi, T., Barna, B. P., & Cowell, J. K. (1998). Inhibition of telomerase increases the susceptibility of human malignant glioblastoma cells to cisplatin-induced apoptosis. Oncogene, 16(17), 2243-2248. doi:10.1038/sj.onc.1201754Wang, P. P., Frazier, J., & Brem, H. (2002). Local drug delivery to the brain. Advanced Drug Delivery Reviews, 54(7), 987-1013. doi:10.1016/s0169-409x(02)00054-6De Souza, R., Zahedi, P., Allen, C. J., & Piquette-Miller, M. (2010). Polymeric drug delivery systems for localized cancer chemotherapy. Drug Delivery, 17(6), 365-375. doi:10.3109/10717541003762854Wolinsky, J. B., Colson, Y. L., & Grinstaff, M. W. (2012). Local drug delivery strategies for cancer treatment: Gels, nanoparticles, polymeric films, rods, and wafers. Journal of Controlled Release, 159(1), 14-26. doi:10.1016/j.jconrel.2011.11.031Chakroun, R. W., Zhang, P., Lin, R., Schiapparelli, P., Quinones-Hinojosa, A., & Cui, H. (2017). Nanotherapeutic systems for local treatment of brain tumors. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 10(1), e1479. doi:10.1002/wnan.1479Mathios, D., Kim, J. E., Mangraviti, A., Phallen, J., Park, C.-K., Jackson, C. M., … Lim, M. (2016). Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM. Science Translational Medicine, 8(370), 370ra180-370ra180. doi:10.1126/scitranslmed.aag2942Chaichana, K. L., Pinheiro, L., & Brem, H. (2015). Delivery of local therapeutics to the brain: working toward advancing treatment for malignant gliomas. Therapeutic Delivery, 6(3), 353-369. doi:10.4155/tde.14.114Patchell, R. A., Regine, W. F., Ashton, P., Tibbs, P. A., Wilson, D., Shappley, D., & Young, B. (2002). Journal of Neuro-Oncology, 60(1), 37-42. doi:10.1023/a:1020291229317Hassenbusch, S. J., Nardone, E. M., Levin, V. A., Leeds, N., & Pietronigro, D. (2003). Stereotactic Injection of DTI-015 into Recurrent Malignant Gliomas: Phase I/II Trial. Neoplasia, 5(1), 9-16. doi:10.1016/s1476-5586(03)80012-xBoiardi, A., Eoli, M., Salmaggi, A., Zappacosta, B., Fariselli, L., Milanesi, I., … Silvani, A. (2001). Journal of Neuro-Oncology, 54(1), 39-47. doi:10.1023/a:1012510513780Lidar, Z., Mardor, Y., Jonas, T., Pfeffer, R., Faibel, M., Nass, D., … Ram, Z. (2004). Convection-enhanced delivery of paclitaxel for the treatment of recurrent malignant glioma: a Phase I/II clinical study. Journal of Neurosurgery, 100(3), 472-479. doi:10.3171/jns.2004.100.3.0472Bruce, J. N., Fine, R. L., Canoll, P., Yun, J., Kennedy, B. C., Rosenfeld, S. S., … DeLaPaz, R. L. (2011). Regression of Recurrent Malignant Gliomas With Convection-Enhanced Delivery of Topotecan. Neurosurgery, 69(6), 1272-1280. doi:10.1227/neu.0b013e3182233e24Carpentier, A., Metellus, P., Ursu, R., Zohar, S., Lafitte, F., Barrie, M., … Carpentier, A. F. (2010). Intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma: a phase II study. Neuro-Oncology, 12(4), 401-408. doi:10.1093/neuonc/nop047Bogdahn, U., Hau, P., Stockhammer, G., Venkataramana, N. K., Mahapatra, A. K., … Suri, A. (2010). Targeted therapy for high-grade glioma with the TGF- 2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro-Oncology, 13(1), 132-142. doi:10.1093/neuonc/noq142Iwamoto, F. M., Lamborn, K. R., Robins, H. I., Mehta, M. P., Chang, S. M., Butowski, N. A., … Fine, H. A. (2010). Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02). Neuro-Oncology, 12(8), 855-861. doi:10.1093/neuonc/noq025Brem, S., Tyler, B., Li, K., Pradilla, G., Legnani, F., Caplan, J., & Brem, H. (2007). Local delivery of temozolomide by biodegradable polymers is superior to oral administration in a rodent glioma model. Cancer Chemotherapy and Pharmacology, 60(5), 643-650. doi:10.1007/s00280-006-0407-2Recinos, V. R., Tyler, B. M., Bekelis, K., Sunshine, S. B., Vellimana, A., Li, K. W., & Brem, H. (2010). Combination of Intracranial Temozolomide With Intracranial Carmustine Improves Survival When Compared With Either Treatment Alone in a Rodent Glioma Model. Neurosurgery, 66(3), 530-537. doi:10.1227/01.neu.0000365263.14725.39Storm, P. B., Moriarity, J. L., Tyler, B., Burger, P. C., Brem, H., & Weingart, J. (2002). Journal of Neuro-Oncology, 56(3), 209-217. doi:10.1023/a:1015003232713Scott, A. W., Tyler, B. M., Masi, B. C., Upadhyay, U. M., Patta, Y. R., Grossman, R., … Cima, M. J. (2011). Intracranial microcapsule drug delivery device for the treatment of an experimental gliosarcoma model. Biomaterials, 32(10), 2532-2539. doi:10.1016/j.biomaterials.2010.12.020Kim, G. Y., Tyler, B. M., Tupper, M. M., Karp, J. M., Langer, R. S., Brem, H., & Cima, M. J. (2007). Resorbable polymer microchips releasing BCNU inhibit tumor growth in the rat 9L flank model. Journal of Controlled Release, 123(2), 172-178. doi:10.1016/j.jconrel.2007.08.003Masi, B. C., Tyler, B. M., Bow, H., Wicks, R. T., Xue, Y., Brem, H., … Cima, M. J. (2012). Intracranial MEMS based temozolomide delivery in a 9L rat gliosarcoma model. Biomaterials, 33(23), 5768-5775. doi:10.1016/j.biomaterials.2012.04.048Li, X., Tsibouklis, J., Weng, T., Zhang, B., Yin, G., Feng, G., … Mikhalovsky, S. V. (2016). Nano carriers for drug transport across the blood–brain barrier. Journal of Drug Targeting, 25(1), 17-28. doi:10.1080/1061186x.2016.1184272Mangraviti, A., Gullotti, D., Tyler, B., & Brem, H. (2016). Nanobiotechnology-based delivery strategies: New frontiers in brain tumor targeted therapies. Journal of Controlled Release, 240, 443-453. doi:10.1016/j.jconrel.2016.03.031Torchilin, V. P. (2009). Passive and Active Drug Targeting: Drug Delivery to Tumors as an Example. Handbook of Experimental Pharmacology, 3-53. doi:10.1007/978-3-642-00477-3_1Rippe, B., Rosengren, B.-I., Carlsson, O., & Venturoli, D. (2002). Transendothelial Transport: The Vesicle Controversy. Journal of Vascular Research, 39(5), 375-390. doi:10.1159/000064521Hobbs, S. K., Monsky, W. L., Yuan, F., Roberts, W. G., Griffith, L., Torchilin, V. P., & Jain, R. K. (1998). Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment. Proceedings of the National Academy of Sciences, 95(8), 4607-4612. doi:10.1073/pnas.95.8.4607Lammers, T., Kiessling, F., Hennink, W. E., & Storm, G. (2012). Drug targeting to tumors: Principles, pitfalls and (pre-) clinical progress. Journal of Controlled Release, 161(2), 175-187. doi:10.1016/j.jconrel.2011.09.063Danhier, F. (2016). To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine? Journal of Controlled Release, 244, 108-121. doi:10.1016/j.jconrel.2016.11.015Petros, R. A., & DeSimone, J. M. (2010). Strategies in the design of nanoparticles for therapeutic applications. Nature Reviews Drug Discovery, 9(8), 615-627. doi:10.1038/nrd2591Chouly, C., Pouliquen, D., Lucet, I., Jeune, J. J., & Jallet, P. (1996). Development of superparamagnetic nanoparticles for MRI: effect of particle size, charge and surface nature on biodistribution. Journal of Microencapsulation, 13(3), 245-255. doi:10.3109/02652049609026013OWENSIII, D., & PEPPAS, N. (2006). Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. International Journal of Pharmaceutics, 307(1), 93-102. doi:10.1016/j.ijpharm.2005.10.010Salvador-Morales, C., Zhang, L., Langer, R., & Farokhzad, O. C. (2009). Immunocompatibility properties of lipid–polymer hybrid nanoparticles with heterogeneous surface functional groups. Biomaterials, 30(12), 2231-2240. doi:10.1016/j.biomaterials.2009.01.005Zhan, C., & Lu, W. (2012). The Blood-Brain/Tumor Barriers: Challenges and Chances for Malignant Gliomas Targeted Drug Delivery. Current Pharmaceutical Biotechnology, 13(12), 2380-2387. doi:10.2174/138920112803341798Steiniger, S. C. J., Kreuter, J., Khalansky, A. S., Skidan, I. N., Bobruskin, A. I., Smirnova, Z. S., … Gelperina, S. E. (2004). Chemotherapy of glioblastoma in rats using doxorubicin-loaded nanoparticles. International Journal of Cancer, 109(5), 759-767. doi:10.1002/ijc.20048Wohlfart, S., Khalansky, A. S., Bernreuther, C., Michaelis, M., Cinatl, J., Glatzel, M., & Kreuter, J. (2011). Treatment of glioblastoma with poly(isohexyl cyanoacrylate) nanoparticles. International Journal of Pharmaceutics, 415(1-2), 244-251. doi:10.1016/j.ijpharm.2011.05.046Zanotto-Filho, A., Coradini, K., Braganhol, E., Schröder, R., de Oliveira, C. M., Simões-Pires, A., … Moreira, J. C. F. (2013). Curcumin-loaded lipid-core nanocapsules as a strategy to improve pharmacological efficacy of curcumin in glioma treatment. European Journal of Pharmaceutics and Biopharmaceutics, 83(2), 156-167. doi:10.1016/j.ejpb.2012.10.019Gao, H. (2016). Perspectives on Dual Targeting Delivery Systems for Brain Tumors. Journal of Neuroimmune Pharmacology, 12(1), 6-16. doi:10.1007/s11481-016-9687-4Pinto, M. P., Arce, M., Yameen, B., & Vilos, C. (2017). Targeted brain delivery nanoparticles for malignant gliomas. Nanomedicine, 12(1), 59-72. doi:10.2217/nnm-2016-0307Fang, C., Wang, K., Stephen, Z. R., Mu, Q., Kievit, F. M., Chiu, D. T., … Zhang, M. (2015). Temozolomide Nanoparticles for Targeted Glioblastoma Therapy. ACS Applied Materials & Interfaces, 7(12), 6674-6682. doi:10.1021/am5092165Ke, W., Shao, K., Huang, R., Han, L., Liu, Y., Li, J., … Jiang, C. (2009). Gene delivery targeted to the brain using an Angiopep-conjugated polyethyleneglycol-modified polyamidoamine dendrimer. Biomaterials, 30(36), 6976-6985. doi:10.1016/j.biomaterials.2009.08.049Xin, H., Jiang, X., Gu, J., Sha, X., Chen, L., Law, K., … Fang, X. (2011). Angiopep-conjugated poly(ethylene glycol)-co-poly(ε-caprolactone) nanoparticles as dual-targeting drug delivery system for brain glioma. Biomaterials, 32(18), 4293-4305. doi:10.1016/j.biomaterials.2011.02.044Zhang, B., Wang, H., Liao, Z., Wang, Y., Hu, Y., Yang, J., … Jiang, X. (2014). EGFP–EGF1-conjugated nanoparticles for targeting both neovascular and glioma cells in therapy of brain glioma. Biomaterials, 35(13), 4133-4145. doi:10.1016/j.biomaterials.2014.01.071Zhang, P., Hu, L., Yin, Q., Feng, L., & Li, Y. (2012). Transferrin-Modified c[RGDfK]-Paclitaxel Loaded Hybrid Micelle for Sequential Blood-Brain Barrier Penetration and Glioma Targeting Therapy. Molecular Pharmaceutics, 9(6), 1590-1598. doi:10.1021/mp200600tMa, D. (2014). Enhancing endosomal escape for nanoparticle mediated siRNA delivery. Nanoscale, 6(12), 6415. doi:10.1039/c4nr00018hShim, M. S., & Kwon, Y. J. (2012). Stimuli-responsive polymers and nanomaterials for gene delivery and imaging applications. Advanced Drug Delivery Reviews, 64(11), 1046-1059. doi:10.1016/j.addr.2012.01.018Zarebkohan, A., Najafi, F., Moghimi, H. R., Hemmati, M., Deevband, M. R., & Kazemi, B. (2015). Synthesis and characterization of a PAMAM dendrimer nanocarrier functionalized by SRL peptide for targeted gene delivery to the brain. European Journal of Pharmaceutical Sciences, 78, 19-30. doi:10.1016/j.ejps.2015.06.024Hynynen, K., McDannold, N., Vykhodtseva, N., & Jolesz, F. A. (2001). Noninvasive MR Imaging–guided Focal Opening of the Blood-Brain Barrier in Rabbits. Radiology, 220(3), 640-646. doi:10.1148/radiol.2202001804Nance, E., Timbie, K., Miller, G. W., Song, J., Louttit, C., Klibanov, A. L., … Price, R. J. (2014). Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood − brain barrier using MRI-guided focused ultrasound. Journal of Controlled Release, 189, 123-132. doi:10.1016/j.jconrel.2014.06.031Mead,

The role of clonal communication and heterogeneity in breast cancer

Background: Cancer is a rapidly evolving, multifactorial disease that accumulates numerous genetic and epigenetic alterations. This results in molecular and phenotypic heterogeneity within the tumor, the complexity of which is further amplified through specific interactions between cancer cells. We aimed to dissect the molecular mechanisms underlying the cooperation between different clones. Methods: We produced clonal cell lines derived from the MDA-MB-231 breast cancer cell line, using the UbC-StarTrack system, which allowed tracking of multiple clones by color: GFP C3, mKO E10 and Sapphire D7. Characterization of these clones was performed by growth rate, cell metabolic activity, wound healing, invasion assays and genetic and epigenetic arrays. Tumorigenicity was tested by orthotopic and intravenous injections. Clonal cooperation was evaluated by medium complementation, co-culture and co-injection assays. Results: Characterization of these clones in vitro revealed clear genetic and epigenetic differences that affected growth rate, cell metabolic activity, morphology and cytokine expression among cell lines. In vivo, all clonal cell lines were able to form tumors; however, injection of an equal mix of the different clones led to tumors with very few mKO E10 cells. Additionally, the mKO E10 clonal cell line showed a significant inability to form lung metastases. These results confirm that even in stable cell lines heterogeneity is present. In vitro, the complementation of growth medium with medium or exosomes from parental or clonal cell lines increased the growth rate of the other clones. Complementation assays, co-growth and co-injection of mKO E10 and GFP C3 clonal cell lines increased the efficiency of invasion and migration. Conclusions: These findings support a model where interplay between clones confers aggressiveness, and which may allow identification of the factors involved in cellular communication that could play a role in clonal cooperation and thus represent new targets for preventing tumor progression

Smart ICTs for the enhancement of traffic logistics in the Port of Seville

Las ponencias del congreso pueden descargarse desde: http://www.pianc.org.ar/_stage/papers_in.phpThis paper focuses in the optimization of intermodal transport by the development of a freight geolocation and telecontrol platform for intermodal transport. This system, Cooperative Unitized Tracking System (CUTS), is being developed under the project TECNOPORT2025, which is an initiative of the Port Authority of Seville (PAS), co-funded by the European Commission by means of the ERDF (European Region Development Funds), under the Pre-commercial Public Procurement model aiming the “Port of Future”

Smart Navigation System for the Port of Seville

Las ponencias del congreso pueden descargarse desde: http://www.pianc.org.ar/_stage/papers_in.phpThis paper focuses in the development of an information platform for rivers and integrated navigation aid system in waterways. The proposed system will not only offer vessel traffic services (VTS) and other RIS basic services but also those advanced and customized services of interest for the Port of Seville. This system, eRIO, is being developed under the project TECNOPORT2025 which is initiative of the Port Authority of Seville, co-funded by the European Commission by means of the European Region Development Funds, under the Pre-commercial Public Procurement model aiming the “Port of Future”

Impact of oestrus synchronization devices on ewes vaginal microbiota and artificial insemination outcome

Introduction: The low pregnancy rate by artificial insemination in sheep represents a fundamental challenge for breeding programs. In this species, oestrus synchronization is carried out by manipulating hormonal regimens through the insertion of progestogen intravaginal devices. This reproductive strategy may alter the vaginal microbiota affecting the artificial insemination outcome. Methods: In this study, we analyzed the vaginal microbiome of 94 vaginal swabs collected from 47 ewes with alternative treatments applied to the progesterone-releasing intravaginal devices (probiotic, maltodextrin, antibiotic and control), in two sample periods (before placing and after removing the devices). To our knowledge, this is the first study using nanopore-based metagenome sequencing for vaginal microbiome characterization in livestock. Results: Our results revealed a significant lower abundance of the genera Oenococcus (Firmicutes) and Neisseria (Proteobacteria) in pregnant compared to non-pregnant ewes. We also detected a significant lower abundance of Campylobacter in the group of samples treated with the probiotic. Discussion: Although the use of probiotics represents a promising practice to improve insemination results, the election of the suitable species and concentration requires further investigation. In addition, the use of progestogen in the synchronization devices seemed to increase the alpha-diversity and decrease the abundance of harmful microorganisms belonging to Gammaproteobacteria and Fusobacteriia classes, suggesting a beneficial effect of their use.This work was funded by INIA-GENOVIS (grant CON19-043-MGA), Ministerio de Economía y Competitividad, Spain (grant RTI-2018-096487-R-C33), and also has received financial support from Fondos FEDER.artificial inseminationfertilitynanoporeovinereproductionvaginal microbiotametagenomemicrobiomePublishe

Profibrotic role of inducible heat shock protein 90α isoform in systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune disease that affects skin and multiple internal organs. TGF-β, a central trigger of cutaneous fibrosis, activates fibroblasts with the involvement of the stress-inducible chaperone heat shock protein 90 isoform α (Hsp90α). Available evidence supports overexpression and secretion of Hsp90α as a feature in profibrotic pathological conditions. The aim of this work is to investigate the expression and function of Hsp90α in experimental models of skin fibrosis such as human fibroblasts, C57BL/6 mice, and in human SSc. For this purpose, we generated a new experimental model based on doxorubicin administration with improved characteristics with respect to the bleomycin model. We visualized disease progression in vivo by fluorescence imaging. In this work, we obtained Hsp90α mRNA overexpression in human skin fibroblasts, in bleomycin- and doxorubicin-induced mouse fibrotic skin, and in lungs of bleomycin- and doxorubicin-treated mice. Hsp90α-deficient mice showed significantly decreased skin thickness compared with wild-type mice in both animal models. In SSc patients, serum Hsp90α levels were increased in patients with lung involvement and in patients with the diffuse form of SSc (dSSc) compared with patients with the limited form of SSc. The serum Hsp90α levels of patients dSSc were correlated with the Rodnan score and the forced vital capacity variable. These results provide new supportive evidence of the contribution of the Hsp90α isoform in the development of skin fibrosis. In SSc, these results indicated that higher serum levels were associated with dSSc and lung fibrosis.This work was supported by Spanish Ministerio de Economía, Industria y Competitividad, Gobierno de España Grant RTI2018-095214-B-I00, as well as by the Instituto de Formación e Investigación Marqués de Valdecilla IDIVAL (InnVal 17/22; InnVal 20/34), 2020UCI22-PUB-0003 Gobierno de Cantabria (to A.V.V.), SAF2016-75195-R (to J.M.), SAF2017-82905-R (to R.M.), and (NextVal 18/14) to A.P

Propéptido natriurético cerebral como marcador de evolución digestiva en el recién nacido prematuro

Introducción: Antecedentes y objetivo: el ductus arterioso persistente hemodinámicamente significativo (DAP-HS) se asocia a mayor riesgo de enterocolitis necrotizante (ECN) y peor tolerancia enteral en los recién nacidos prematuros (RNPT). Se ha demostrado asociación entre el propéptido natriurético cerebral (proBNP) y el DAP-HS. Nuestro objetivo fue analizar la relación entre los niveles de proBNP y la tolerancia enteral, el riesgo de ECN y la ganancia ponderal en el RNPT. Material y métodos: estudio retrospectivo observacional, que incluyó a RNPT menores de 32 semanas de gestación y/o 1.500 g, con estudio ecocardiográfico y determinación de niveles de proBNP a las 48-72 horas de vida. Resultados: de 117 pacientes incluidos, el 65, 8% tuvo un DAPHS y el 9, 4% presentó ECN confirmada. El DAP-HS se asoció a mayor duración de la nutrición parenteral (p < 0, 001), a ECN confirmada (p = 0, 006) y a peor ganancia ponderal durante el ingreso (p < 0, 001). Los valores de proBNP se relacionaron con la ECN (no ECN 12.189, 5 pg/ml, rango 654-247.986; ECN 41.445 pg/ml, rango 15.275-166.172; p < 0, 001), sin encontrar asociación con el resto de variables de evolución digestiva. En el análisis multivariante de regresión logística, las variables relacionadas de forma independiente con el desarrollo de ECN fueron la edad gestacional y el proBNP superior a 22.400 pg/ml (OR 13, 386; IC 95% 1, 541-116, 262; p = 0, 019). Conclusiones: el proBNP podría ser un marcador precoz de patología digestiva grave en el RNPT. Los niveles elevados podrían relacionarse con mayor riesgo de ECN en los neonatos más inmaduros. Introduction: Background and objective: hemodynamically significant patent ductus arteriosus (HS-PDA) is associated with an increased risk of necrotizing enterocolitis (NEC) and worse enteral tolerance in preterm newborns (PN). An association has been demonstrated between brain natriuretic propeptide (proBNP) and HS-PDA. Our objective was to analyze the relationship between proBNP levels and enteral tolerance, NEC risk and weight gain in PN. Material and methods: a retrospective study was performed in neonates born before 32 weeks' gestation or with birth weight below 1500 grams, in whom proBNP determination and echocardiography were performed at 48 to 72 h of life. Results: 117 patients were included. 65.8% had a HS-PDA and 9.4% had an outcome of NEC. HS-PDA was associated with longer duration of parenteral nutrition (p < 0.001), a confirmed NEC (p = 0.006) and worse weight gain during admission (p < 0.001). ProBNP levels were associated to NEC (no NEC 12189.5 pg / mL, range 654-247986; NEC 41445 pg/mL, range 15275-166172, p < 0.001). No association was found with the rest of gastrointestinal outcomes. Multivariate logistic regression analysis showed a significant association of NEC with gestational age and proBNP above 22, 400 pg/mL (OR 13, 386, 95% CI 1, 541-116, 262, p = 0.019). Conclusions: proBNP could be an early marker of severe digestive pathology in PN. Increased proBNP levels could be associated with a significant increased risk of NEC in very immature newborns