Proposal of a Novel Setup for Linac Monitoring Using a Specifically Designed Plastic Scintillator and a Spectrophotometer

In this work we report the design, implementation and results of an alternative monitoring system for a linear accelerator (LINAC) used in medical therapy. The system proposed consist in aslab of scintillator plastic with awavelength shifter fiberoptically coupled to collect the light generated,and a Spectrophotometer Ocean Optics USB4000 as analyzer. The control was made with two computers, one into the therapy room and another, using a VNC (Virtual Network Computer) and Ethernet wire, outside of the room in order to avoid radiation exposure. The LINAC dose range covered was 1, 2, 3, 4, 5, 10, 20, 30 and 40 Monitor Units (MU) with 6 and 18 MeV energy photons. The spectrum obtained was compared with the measures of the LINAC ionization camera used to calibrate it. The results obtained allowus to propose this device as an alternative method to monitor the LINAC performance

ProOpDB: Prokaryotic Operon DataBase

The Prokaryotic Operon DataBase (ProOpDB, http://operons.ibt.unam.mx/OperonPredictor) constitutes one of the most precise and complete repositories of operon predictions now available. Using our novel and highly accurate operon identification algorithm, we have predicted the operon structures of more than 1200 prokaryotic genomes. ProOpDB offers diverse alternatives by which a set of operon predictions can be retrieved including: (i) organism name, (ii) metabolic pathways, as defined by the KEGG database, (iii) gene orthology, as defined by the COG database, (iv) conserved protein domains, as defined by the Pfam database, (v) reference gene and (vi) reference operon, among others. In order to limit the operon output to non-redundant organisms, ProOpDB offers an efficient method to select the most representative organisms based on a precompiled phylogenetic distances matrix. In addition, the ProOpDB operon predictions are used directly as the input data of our Gene Context Tool to visualize their genomic context and retrieve the sequence of their corresponding 5′ regulatory regions, as well as the nucleotide or amino acid sequences of their genes

Compositional Variations in Apatite and Petrogenetic Significance: Examples from Peraluminous Granites and Related Pegmatites and Hydrothermal Veins from the Central Iberian Zone (Spain and Portugal)

Apatite can be used as an archive of processes occurring during the evolution of granitic magmas and as a pegmatite exploration tool. With this aim, a detailed compositional study of apatite was performed on different Variscan granites, pegmatites and quartz veins from the Central Iberian Zone. Manganese in granitic apatite increases with increasing evolution degree. Such Mn increase would not be related to changes in the fO(2) during evolution but rather to a higher proportion of Mn in residual melts, joined to an increase in SiO2 content and peraluminosity. In the case of pegmatitic apatite, the fO(2) and the polymerization degree of the melts seem not to have influenced the Mn and Fe contents but the higher availability of these transition elements and/or the lack of minerals competing for them. The subrounded Fe-Mn phosphate nodules, where apatite often occurs in P-rich pegmatites and P-rich quartz dykes, probably crystallized from a P-rich melt exsolved from the pegmatitic melt and where Fe, Mn and Cl would partition. The low Mn and Fe contents in the apatite from the quartz veins may be attributed either to the low availability of these elements in the late hydrothermal fluids derived from the granitic and pegmatitic melts, or to a high fO(2). The Rare Earth Elements, Sr and Y are the main trace elements of the studied apatites. The REE contents of apatite decrease with the evolution of their hosting rocks. The REE patterns show in general strong tetrad effects that are probably not related to the fluids' activity in the system. On the contrary, the fluids likely drive the non-CHARAC behavior of apatite from the most evolved granitic and pegmatitic units. Low fO(2) conditions seem to be related to strong Eu anomalies observed for most of the apatites associated with different granitic units, barren and P-rich pegmatites. The positive Eu anomalies in some apatites from leucogranites and Li-rich pegmatites could reflect their early character, prior to the crystallization of feldspars. The increase in the Sr content in apatite from Li-rich pegmatites and B-P +/- F-rich leucogranites could be related to problems in accommodating this element in the albite structure, favoring its incorporation into apatite. The triangular plots sigma REE-Sr-Y and U-Th-Pb of apatites, as well as the Eu anomaly versus the TE1,3 diagram, seem to be potentially good as petrogenetic indicators, mainly for pegmatites and, to a lesser extent, for granites from the CIZ

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,

Clinical implications of changing thyroglobulin and antithyroglobulin antibodies analytical methods in the follow-up of patients with differentiated thyroid carcinoma

Background and aims: Patients’ response to treatment in differentiated thyroid cancer (DTC) is classified according to serum thyroglobulin concentrations (Tg), usually using the American Thyroid Association guidelines and considering potential interfering anti-thyroglobulin antibodies (Ab-Tg). We aim to evaluate the clinical implications of changing Tg and Ab-Tg quantification method. Material and methods: Tg and Ab-Tg were quantified in 82 serum samples (60 from DTC patients) by Elecsys and Access immunoassays. Results: Elecsys immunoassay rendered higher values of Tg than Access: mean bias 5.03 ng/mL (95%CI:- 14.14–24.21). In DTC patients, there was an almost perfect agreement for response classification (kappa index = 0.833). Discrepancies appeared in patients with undetermined response, with a more tendency to subclassification with Access. Ab-Tg showed a poor correlation (r = 0.5394). When Elecsys cut-off was reduced to 43 IU/ mL, agreement for positive/negative classification improved from a kappa index of 0.607 to 0.650. Prospective study with personalized follow-up showed that only 6.3% of Tg results required an analytical confirmation, being confirmed 93% of them. Conclusions: Despite the biases observed, clinical impact of an analytical change is minimal in patients’ management. However, cautious and personalized follow-up period after the change is still mandatory, especially in patients with Tg levels between 0.2 and 1 ng/mL

Synthesis and anti-HIV-1 activities of new pyrimido[5,4-b]indoles

A set of new pyrimido[5,4-b]indole derivatives that are structurally related to some non-nucleside HIV-1 reverse transcriptase inhibitors were synthesized and biologically evaluated for their activity as inhibitors of wild and mutant HIV-1 RT types in an 'in vitro' recombinant HIV-1 RT screening assay, as well as anti-infectives in HLT4lacZ-1IIIB cells. Preliminary structure-activity relationships suggest that activity is promoted by simultaneous substitution in positions 2 and 4, especially when chains of alkyldiamine type are present, and by electron-releasing substituents (methoxy) in positions 7 and 8. The inactivity or the very low activity of title derivatives does not suggest interest in AIDS therapy