2,030 research outputs found
Assessment of the corneal collagen organization after chemical burn using second harmonic generation microscopy
The organization of the corneal stoma is modified due to different factors, including pathology, surgery or external damage. Here the changes in the organization of the corneal collagen fibers during natural healing after chemical burn are investigated using second harmonic generation (SHG) imaging. Moreover, the structure tensor (ST) was used as an objective tool for morphological analyses at different time points after burn (up to 6 months). Unlike control corneas that showed a regular distribution, the collagen pattern at 1 month of burn presented a non-organized arrangement. SHG signal levels noticeably decreased and individual fibers were hardly visible. Over time, the healing process led to a progressive re-organization of the fibers that could be quantified through the ST. At 6 months, the stroma distribution reached values similar to those of control eyes and a dominant direction of the fibers re-appeared. The present results show that SHG microscopy imaging combined with the ST method is able to objectively monitor the temporal regeneration of the corneal organization after chemical burn. Future implementations of this approach into clinically adapted devices would help to diagnose and quantify corneal changes, not only due to chemical damages, but also as a result of disease or surgical procedures
HIV infection and aging: enhanced Interferon- and Tumor Necrosis Factor-alpha production by the CD8(+) CD28(-) T subset
BACKGROUND: T cells from HIV(+) and aged individuals show parallels in terms of suppressed proliferative activity and interleukin-2 (I1-2) production and an increased number of CD8(+) CD28(-) T cells. In order to compare cytokine production from T cells from these two states, CD4(+) and CD8(+) T cells from HIV(+) aged, and normal young donors (controls) were monitored for cytokine production by flow cytometry, quantitative PCR and ELISA upon activation by PMA and anti-CD3. In addition, the CD8(+) T cell subsets CD28(+) and CD28(-) from the HIV(+) and the aged groups were evaluated for cytokine production by flow cytometry, and compared with those from young controls. RESULTS: Flow cytometric analysis indicated that CD8(+) T cells from both HIV(+) and aged donors showed an increase of approximately 2–3 fold over controls in percentage of cells producing inflammatory cytokines IFN-γ and TNF-α. Similar analysis also revealed that the production of interleukins-4,6 and 10, production was very low (1–2% of cells) and unchanged in these cells. Quantitative PCR also showed a substantial increase (4–5 fold) in IFN-γ and TNF-α mRNA from HIV(+) and aged CD8(+) T cells, as did ELISA for secreted IFN-γ and TNF-α (2.3–4 fold). Flow cytometric analysis showed that the CD8(+) CD28(-) T cell subset accounts for approximately 80–86% of the IFN-γ and TNF-α production from the CD8(+) subset in the aged and HIV(+) states. The CD4(+) T cell, while not significantly changed in the HIV(+) or aged states in terms of IFN-γ production, showed a small but significant increase in TNF-α production in both states. CONCLUSIONS: Our data appear compatible with physiologic conditions existing in HIV(+) and aged individuals, i.e. elevated serum levels and elevated CD8(+) T cell production of IFN-γ and TNF-α. Thus, the capacity for increased production of cytokines IFN-γ and TNF-α in the aged individual by the dominant CD8(+) CD28(-) subset may have a profound influence on the clinical state by aggravating inflammatory pathologies such as rheumatoid arthritis, and possibly Alzheimer's disease and Crohn's disease. In AIDS, these cytokines may contribute to wasting and cachexia. We theorize that the predominant phenotypic change to the cytotoxic CD8(+) CD28(-) T cell subsets in both the HIV(+) and the aged states may reflect a natural "endpoint" in CD8(+) T cell differentiation induced after a lifetime of immune activity (toward viruses, etc) in the aged, and after a massive accelerated response to HIV in the HIV-positive individual
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,
Ecosystem-bedrock interaction changes nutrient compartmentalization during early oxidative weathering
Ecosystem-bedrock interactions power the biogeochemical cycles of Earth's
shallow crust, supporting life, stimulating substrate transformation, and
spurring evolutionary innovation. While oxidative processes have dominated half
of terrestrial history, the relative contribution of the biosphere and its
chemical fingerprints on Earth's developing regolith are still poorly
constrained. Here, we report results from a two-year incipient weathering
experiment. We found that the mass release and compartmentalization of major
elements during weathering of granite, rhyolite, schist and basalt was
rock-specific and regulated by ecosystem components.
A tight interplay between physiological needs of different biota, mineral
dissolution rates, and substrate nutrient availability resulted in intricate
elemental distribution patterns. Biota accelerated CO2 mineralization over
abiotic controls as ecosystem complexity increased, and significantly modified
stoichiometry of mobilized elements. Microbial and fungal components inhibited
element leaching (23.4% and 7%), while plants increased leaching and biomass
retention by 63.4%. All biota left comparable biosignatures in the dissolved
weathering products. Nevertheless, the magnitude and allocation of weathered
fractions under abiotic and biotic treatments provide quantitative evidence for
the role of major biosphere components in the evolution of upper continental
crust, presenting critical information for large-scale biogeochemical models
and for the search for stable in situ biosignatures beyond Earth.Comment: 41 pages (MS, SI and Data), 16 figures (MS and SI), 6 tables (SI and
Data). Journal article manuscrip
Biofilm formation as a novel phenotypic feature of adherent-invasive Escherichia coli (AIEC)
<p>Abstract</p> <p>Background</p> <p>Crohn's disease (CD) is a high morbidity chronic inflammatory disorder of unknown aetiology. Adherent-invasive <it>Escherichia coli </it>(AIEC) has been recently implicated in the origin and perpetuation of CD. Because bacterial biofilms in the gut mucosa are suspected to play a role in CD and biofilm formation is a feature of certain pathogenic <it>E. coli </it>strains, we compared the biofilm formation capacity of 27 AIEC and 38 non-AIEC strains isolated from the intestinal mucosa. Biofilm formation capacity was then contrasted with the AIEC phenotype, the serotype, the phylotype, and the presence of virulence genes.</p> <p>Results</p> <p>Specific biofilm formation (SBF) indices were higher amongst AIEC than non-AIEC strains (P = 0.012). In addition, 65.4% of moderate to strong biofilms producers were AIEC, whereas 74.4% of weak biofilm producers were non-AIEC (P = 0.002). These data indicate that AIEC strains were more efficient biofilm producers than non-AIEC strains. Moreover, adhesion (P = 0.009) and invasion (P = 0.003) indices correlated positively with higher SBF indices. Additionally, motility (100%, P < 0.001), H1 type flagellin (53.8%, P < 0.001), serogroups O83 (19.2%, P = 0.008) and O22 (26.9%, P = 0.001), the presence of virulence genes such as <it>sfa/focDE </it>(38.5%, P = 0.003) and <it>ibeA </it>(26.9%, P = 0.017), and B2 phylotype (80.8%, P < 0.001) were frequent characteristics amongst biofilm producers.</p> <p>Conclusion</p> <p>The principal contribution of the present work is the finding that biofilm formation capacity is a novel, complementary pathogenic feature of the recently described AIEC pathovar. Characterization of AIEC specific genetic determinants, and the regulatory pathways, involved in biofilm formation will likely bring new insights into AIEC pathogenesis.</p
Cardiotrophin-1 defends the liver against ischemia-reperfusion injury and mediates the protective effect of ischemic preconditioning
Ischemia-reperfusion (I/R) liver injury occurs when blood flow is restored after prolonged ischemia. A short interruption of blood flow (ischemic preconditioning [IP]) induces tolerance to subsequent prolonged ischemia through ill-defined mechanisms. Cardiotrophin (CT)-1, a cytokine of the interleukin-6 family, exerts hepatoprotective effects and activates key survival pathways like JAK/STAT3. Here we show that administration of CT-1 to rats or mice protects against I/R liver injury and that CT-1-deficient mice are exceedingly sensitive to this type of damage. IP markedly reduced transaminase levels and abrogated caspase-3 and c-Jun-NH2-terminal kinase activation after I/R in normal mice but not in CT-1-null mice. Moreover, the protective effect afforded by IP was reduced by previous administration of neutralizing anti-CT-1 antibody. Prominent STAT3 phosphorylation in liver tissue was observed after IP plus I/R in normal mice but not in CT-1-null mice. Oxidative stress, a process involved in IP-induced hepatoprotection, was found to stimulate CT-1 release from isolated hepatocytes. Interestingly, brief ischemia followed by short reperfusion caused mild serum transaminase elevation and strong STAT3 activation in normal and IL-6-deficient mice, but failed to activate STAT3 and provoked marked hypertransaminasemia in CT-1-null animals. In conclusion, CT-1 is an essential endogenous defense of the liver against I/R and is a key mediator of the protective effect induced by IP
RAF1 kinase activity is dispensable for KRAS/p53 mutant lung tumor progression.
We thank Dr. Shiva Malek and her colleagues (Genentech Inc.) for sharing their results with us before publication. We also thank M. San Roman, R. Villar, M.C. Gonzalez, A. Lopez, N. Cabrera, P. Villanueva, J. Condo, O. Dominguez, and S. Ortega for excellent technical support. This work was supported by grants from the European Research Council (ERC-2015-AdG/695566, THERACAN); the Spanish Ministry of Science, Innovation, and Universities (RTC-2017-6576-1 and RTI2018094664-B-I00) and the Autonomous Community of Madrid (B2017/BMD-3884 iLUNG-CM) to M.B., as well as by a grant from the Spanish Ministry of Science, Innovation and Universities (RTI2018-094664-B-I00) to M.B. and M.M. M.B. is a recipient of an Endowed Chair from the AXA Research Fund. M.S., P.N., and F.F.-G. were supported by FPU fellowships from the Spanish Ministry of Education. L.E.-B. was a recipient of an FPI fellowship from the Spanish Ministry of Economy and Competitiveness. S.G.-A. is a recipient of a postdoctoral fellowship from the Asociacion Espanola Contra el Cancer (AECC).S
Egg consumption and dyslipidemia in a Mediterranean cohort
Introduction and objectives: Our aim was to prospectively evaluate the association between egg consumption and dyslipidemia in a Mediterranean cohort.
Methods: We followed-up 13,104 Spanish university graduates for a mean period of 8 years. Dietary habits at baseline were assessed using
a validated semi-quantitative 136-item food-frequency questionnaire. Self-reported blood concentrations of total cholesterol, high-density lipoproteins cholesterol (HDL-c) and triglycerides were evaluated according to categories of egg consumption after 6 and 8 years of follow-up. We
also assessed the association between baseline egg consumption and the incidence of hypercholesterolemia, low HDL-c concentrations and
hypertriglyceridemia during follow-up.
Results: We observed a significant inverse association for intermediate levels of egg consumption (2 to 4 eggs/week vs. less than 1 egg/week)
and hypertriglyceridemia with OR = 0.71 (95% confidence interval [CI]: 0.54 to 0.93, p < 0.05) in the multivariable-adjusted model. Using HDL-c
values after 8-year follow-up, we found an association between higher egg consumption and lower HDL-c levels (p for trend = 0.02) with an
adjusted difference of –4.01 mg/dl (-7.42 to -0.61) for > 4 vs. < 1 egg/week. Lower means of triglycerides were found in each of the three
upper categories of egg consumption compared to the lowest category (< 1 egg/week) with significant results for some of these categories both
after 6 and 8 year follow-up.
Conclusions: Our data do not support that higher egg consumption was associated with abnormal blood levels of total cholesterol or triglycerides;
an inverse association with HDL-c as a quantitative variable was found only in one of our analyses.Introducción y objetivos: evaluar prospectivamente la asociación entre el consumo de huevo y el riesgo de dislipidemia en una cohorte
mediterránea.
Métodos: se siguieron 13.104 graduados universitarios españoles durante un periodo medio de 8 años. La dieta se evaluó al inicio utilizando
un cuestionario semicuantitativo de frecuencia de consumo de alimentos repetidamente validado. Las concentraciones sanguíneas de colesterol
total, lipoproteínas de alta densidad (HDL-c) y triglicéridos autorreferidas fueron evaluadas según categorías de consumo de huevo tras 6 y 8
años de seguimiento. También se evaluó la asociación entre el consumo basal de huevo y la incidencia de hipercolesterolemia, concentraciones
bajas de HDL-c e hipertrigliceridemia durante el seguimiento.
Resultados: se observó una asociación entre los niveles intermedios de consumo de huevo (2-4 unidades/semana frente a < 1 unidad/semana)
y menor riesgo de hipertrigliceridemia con OR = 0,71 (intervalo de confianza del 95% [IC]: 0,54 a 0,93, p < 0,05) en el modelo más ajustado.
Tras 8 años de seguimiento, encontramos una asociación entre un mayor consumo de huevo y menores niveles de HDL-c (p tendencia lineal =
0,02) con una diferencia ajustada de -4,01 mg/dl (-7,42 a -0,61) para > 4 vs. < 1 unidad/semana. Se encontraron menores concentraciones
de triglicéridos en las tres categorías superiores de consumo de huevo en comparación con la inferior con resultados significativos para algunas
de estas categorías después de 6 y 8 años de seguimiento.
Conclusiones: un mayor consumo de huevo no se asoció con niveles anormales de colesterol total o triglicéridos; se encontró una asociación
inversa con HDL-c como variable cuantitativa solo en uno de nuestros análisis
Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas.
KRAS mutant lung adenocarcinomas remain intractable for targeted therapies. Genetic interrogation of KRAS downstream effectors, including the MAPK pathway and the interphase CDKs, identified CDK4 and RAF1 as the only targets whose genetic inactivation induces therapeutic responses without causing unacceptable toxicities. Concomitant CDK4 inactivation and RAF1 ablation prevented tumor progression and induced complete regression in 25% of KRAS/p53-driven advanced lung tumors, yet a significant percentage of those tumors that underwent partial regression retained a population of CDK4/RAF1-resistant cells. Characterization of these cells revealed two independent resistance mechanisms implicating hypermethylation of several tumor suppressors and increased PI3K activity. Importantly, these CDK4/RAF1-resistant cells can be pharmacologically controlled. These studies open the door to new therapeutic strategies to treat KRAS mutant lung cancer, including resistant tumors.We thank S. Ortega for the generation of the Cdk4FxKD mouse model; and M. San Roman, R. Villar, M. C. Gonzalez, A. Lopez, N. Cabrera, P. Villanueva, J. Condo, J. Klett, A. Cebria, A. Otero, O. Dominguez, G. Luengo, G. Garaulet, F. Mulero, and D. Megias for excellent technical support. This work was supported by European Research Council Grant ERC-2015-AdG/695566, THERACAN, Spanish Ministry of Science, Innovation, and Universities Grant RTC-2017-6576-1, and the Autonomous Community of Madrid Grant B2017/BMD-3884 iLUNG-CM (to M.B.); Spanish Ministry of Science, Innovation, and Universities Grant RTI2018-094664B-I00 (to M.B. and M.M.); and National Natural Science Foundation of China Grant 31771469 (to H.W.). M.B. is a recipient of an Endowed Chair from the AXA Research Fund. L.E.-B. is the recipient of an FPI fellowship from the Spanish Ministry of Economy and Competitiveness. F.F.-G., M.S., and P.N. were supported by an FPU fellowships from the Spanish Ministry of Education.S
Molecular features in a biphenotypic small cell sarcoma with neuroectodermal and muscle differentiation
We report a case of a 13-year-old girl with soft tissue sarcoma of the hand,
which showed muscle and neuroectodermal immunophenotypes. Molecular studies were
performed on RNA collected from fine-needle aspiration (FNA) cytology and
peripheral blood samples by nested reverse transcriptase-polymerase chain
reaction (RT-PCR) and Southern blot analysis. This biphenotypic tumor showed
simultaneous expression of EWS-FLI1 and PAX3-FKHR transcripts, specific of Ewing
family tumors and alveolar rhabdomyosarcoma, respectively. Although childhood
sarcomas with simultaneous muscle and neural differentiation have been described
to have EWS-FLI1 transcripts, there are no reports of tumors with both
transcripts. Cytological specimens are a good source of RNA for molecular
studie
- …