35 research outputs found
Vegetation und Vegetationsdynamik auf dem Zugspitzplatt (Bayerische Alpen) Natur- und Kulturlandschaft im hochalpinen Raum als Produkt natürlicher, anthropogener und zoogener Einflüsse
Enhanced Drug Photosafety by Interchromophoric Interaction Due to Intramolecular Charge Separation
[EN] Imatinib is a synthetic tyrosinase inhibitor that is employed for the treatment of some kinds of human cancer. This drug has a low phototoxicity towards DNA, but its pyridylpyrimidine (1) fragment by itself exhibits significant phototoxicitiy. The intrinsic mechanism that leads to the enhanced photosafety of Imatinib is not yet known. Here, the properties of the excited state and interchromophoric interactions of Imatinib have been explored by using ultrafast laser flash photolysis and agarose electrophoresis studies. An intramolecular charge separation was directly observed for the irradiated Imatinib, which accounts for the relaxation of its excited state. An anionic form of pyridylpyrimidine (1) was deduced from the results of time-resolved resonance Raman spectra and by quenching experimental studies on compound 1 and diaminotoluene. In contrast, compound 1 efficiently transformed into triplet excited states with a long lifetime, which explained the phototoxicity associated with this fragment. This work provides insight into how to design drugs with lower phototoxicitiy or improved photostability by using interchromophoric interactions.This work was supported by Natural Science Foundation of China (21773151) and Shantou University Initial Funding (NTF16010). The Support from the Hong Kong Research Grants Council grants GRF 17307916, AoE/P-03/08, SEG HKU/07, The University of Hong Kong Development Fund 2013-2014 project "New Ultrafast Spectroscopy Experiments for Shared Facilities", the Spanish Government (CTQ2015-70164-P and BES-2013-066566) are also acknowledged.Li, M.; Yan, Z.; Zhu, R.; Phillips, DL.; Aparici-Espert, MI.; Lhiaubet, VL.; Miranda Alonso, MÁ. (2018). Enhanced Drug Photosafety by Interchromophoric Interaction Due to Intramolecular Charge Separation. Chemistry - A European Journal. 24(25):6654-6659. https://doi.org/10.1002/chem.201800716S665466592425Patel, S. (2013). Long-term efficacy of imatinib for treatment of metastatic GIST. Cancer Chemotherapy and Pharmacology, 72(2), 277-286. doi:10.1007/s00280-013-2135-8Lydon, N. (2009). Attacking cancer at its foundation. Nature Medicine, 15(10), 1153-1157. doi:10.1038/nm1009-1153Bucci, M., Goodman, C., & Sheppard, T. L. (2010). A decade of chemical biology. Nature Chemical Biology, 6(12), 847-854. doi:10.1038/nchembio.489Yang, J. C., Niu, D., Karsten, B. P., Lima, F., & Buchwald, S. L. (2016). Use of a «Catalytic» Cosolvent, N
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-Dimethyl Octanamide, Allows the Flow Synthesis of Imatinib with no Solvent Switch. Angewandte Chemie International Edition, 55(7), 2531-2535. doi:10.1002/anie.201509922Yang, J. C., Niu, D., Karsten, B. P., Lima, F., & Buchwald, S. L. (2016). Use of a «Catalytic» Cosolvent, N
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-Dimethyl Octanamide, Allows the Flow Synthesis of Imatinib with no Solvent Switch. Angewandte Chemie, 128(7), 2577-2581. doi:10.1002/ange.201509922Ōmura, S. (2016). A Splendid Gift from the Earth: The Origins and Impact of the Avermectins (Nobel Lecture). Angewandte Chemie International Edition, 55(35), 10190-10209. doi:10.1002/anie.201602164Ōmura, S. (2016). Ein vortreffliches Geschenk der Erde: Ursprünge und Auswirkungen der Avermectine (Nobel-Aufsatz). Angewandte Chemie, 128(35), 10344-10364. doi:10.1002/ange.201602164Korch, K. M., Eidamshaus, C., Behenna, D. C., Nam, S., Horne, D., & Stoltz, B. M. (2014). Enantioselective Synthesis of α-Secondary and α-Tertiary Piperazin-2-ones and Piperazines by Catalytic Asymmetric Allylic Alkylation. Angewandte Chemie International Edition, 54(1), 179-183. doi:10.1002/anie.201408609Korch, K. M., Eidamshaus, C., Behenna, D. C., Nam, S., Horne, D., & Stoltz, B. M. (2014). Enantioselective Synthesis of α-Secondary and α-Tertiary Piperazin-2-ones and Piperazines by Catalytic Asymmetric Allylic Alkylation. Angewandte Chemie, 127(1), 181-185. doi:10.1002/ange.201408609Lydon, N. B., & Druker, B. J. (2004). Lessons learned from the development of imatinib. Leukemia Research, 28, 29-38. doi:10.1016/j.leukres.2003.10.002AMITAY-LAISH, I., STEMMER, S. M., & LACOUTURE, M. E. (2011). Adverse cutaneous reactions secondary to tyrosine kinase inhibitors including imatinib mesylate, nilotinib, and dasatinib. Dermatologic Therapy, 24(4), 386-395. doi:10.1111/j.1529-8019.2011.01431.xRousselot, P., Larghero, J., Raffoux, E., Calvo, F., Tulliez, M., Giraudier, S., & Rybojad, M. (2003). Photosensitization in chronic myelogenous leukaemia patients treated with imatinib mesylate. British Journal of Haematology, 120(6), 1091-1092. doi:10.1046/j.1365-2141.2003.04208_3.xBrazzelli, V., Muzio, F., Manna, G., Moggio, E., Vassallo, C., Orlandi, E., … Borroni, G. (2011). Photoinduced dermatitis and oral lichenoid reaction in a chronic myeloid leukemia patient treated with imatinib mesylate. Photodermatology, Photoimmunology & Photomedicine, 28(1), 2-5. doi:10.1111/j.1600-0781.2011.00621.xAtalay, F., Kızılkılıç, E., & Ada, R. S. (2013). Imatinib-Induced Psoriasis. Turkish Journal of Hematology, 30(2), 216-218. doi:10.4274/tjh.2012.0147Valeyrie, L., Bastuji-Garin, S., Revuz, J., Bachot, N., Wechsler, J., Berthaud, P., … Giraudier, S. (2003). Adverse cutaneous reactions to imatinib (STI571) in Philadelphia chromosome-positive leukemias: A prospective study of 54 patients. Journal of the American Academy of Dermatology, 48(2), 201-206. doi:10.1067/mjd.2003.44Heidary, N., Naik, H., & Burgin, S. (2008). Chemotherapeutic agents and the skin: An update. Journal of the American Academy of Dermatology, 58(4), 545-570. doi:10.1016/j.jaad.2008.01.001Timmer-de Mik, L., Kardaun, S. H., Kramer, M. H. H., Hayes, D. P., & Bousema, M. T. (2009). Imatinib-induced pseudoporphyria. Clinical and Experimental Dermatology, 34(6), 705-707. doi:10.1111/j.1365-2230.2008.02985.xBaskaynak, G., Kreuzer, K.-A., Schwarz, M., Zuber, J., Audring, H., Riess, H., … Le Coutre, P. (2003). Squamous cutaneous epithelial cell carcinoma in two CML patients with progressive disease under imatinib treatment. European Journal of Haematology, 70(4), 231-234. doi:10.1034/j.1600-0609.2003.00044.xNardi, G., Lhiaubet-Vallet, V., & Miranda, M. A. (2014). Photosensitization by Imatinib. A Photochemical and Photobiological Study of the Drug and Its Substructures. Chemical Research in Toxicology, 27(11), 1990-1995. doi:10.1021/tx500328qDeria, P., Yu, J., Smith, T., & Balaraman, R. P. (2017). Ground-State versus Excited-State Interchromophoric Interaction: Topology Dependent Excimer Contribution in Metal–Organic Framework Photophysics. Journal of the American Chemical Society, 139(16), 5973-5983. doi:10.1021/jacs.7b02188Liu, B., Zhao, J., Luo, C., Lu, F., Tao, S., & Tong, Q. (2016). A novel bipolar phenanthroimidazole derivative host material for highly efficient green and orange-red phosphorescent OLEDs with low efficiency roll-off at high brightness. Journal of Materials Chemistry C, 4(10), 2003-2010. doi:10.1039/c5tc04393jFang, C., Frontiera, R. R., Tran, R., & Mathies, R. A. (2009). Mapping GFP structure evolution during proton transfer with femtosecond Raman spectroscopy. Nature, 462(7270), 200-204. doi:10.1038/nature08527Nicolaou, K. C. (2014). Advancing the Drug Discovery and Development Process. Angewandte Chemie International Edition, 53(35), 9128-9140. doi:10.1002/anie.201404761Nicolaou, K. C. (2014). Advancing the Drug Discovery and Development Process. Angewandte Chemie, 126(35), 9280-9292. doi:10.1002/ange.201404761Li, M.-D., Hanway, P. J., Albright, T. R., Winter, A. H., & Phillips, D. L. (2014). Direct Spectroscopic Observation of Closed-Shell Singlet, Open-Shell Singlet, and Triplet p-Biphenylyloxenium Ion. Journal of the American Chemical Society, 136(35), 12364-12370. doi:10.1021/ja505447qLi, M.-D., Albright, T. R., Hanway, P. J., Liu, M., Lan, X., Li, S., … Phillips, D. L. (2015). Direct Spectroscopic Detection and EPR Investigation of a Ground State Triplet Phenyl Oxenium Ion. Journal of the American Chemical Society, 137(32), 10391-10398. doi:10.1021/jacs.5b06302Du, L., Qiu, Y., Lan, X., Zhu, R., Phillips, D. L., Li, M.-D., … Winter, A. H. (2017). Direct Detection of the Open-Shell Singlet Phenyloxenium Ion: An Atom-Centered Diradical Reacts as an Electrophile. Journal of the American Chemical Society, 139(42), 15054-15059. doi:10.1021/jacs.7b07512Li, M.-D., Ma, J., Su, T., Liu, M., Yu, L., & Phillips, D. L. (2012). Direct Observation of Triplet State Mediated Decarboxylation of the Neutral and Anion Forms of Ketoprofen in Water-Rich, Acidic, and PBS Solutions. 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Methylation levels of a novel genetic element, EgNB3 as a candidate biomarker associated with the embryogenic competency of oil palm
The association between DNA methylation status and embryogenic competency in oil palm tissue culture was examined through Representational Difference Analysis (RDA) approach, using methylation-sensitive restriction endonucleases. "Difference Products" (DPs) of RDA derived from palms of similar genetic backgrounds but exhibiting different embryogenesis rates during the regeneration process were isolated. The DPs were sequenced using a pyrosequencing platform. To our knowledge, this is the first study profiling partial HpaII methylation sites in oil palm young leaf tissues which are potentially associated with embryogenic amenability through a genomic subtractive approach. Quantitative real-time PCR analysis demonstrated that the methylation status of a novel fragment, EgNB3, was higher in highly embryogenic leaf explants compared to low embryogenesis rate materials. These differences are likely to be contributed by the 5′-mCCGG-3′ and/or 5′-mCmCGG-3′ methylation patterns. Our data suggest that the differentially methylated site in EgNB3 has potential as a molecular biomarker for the screening of oil palm leaf explants for their embryogenic potentials
Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma
Epidermal growth factor receptor (EGFR) and tumour growth factor alpha (TGFα) are frequently overexpressed in renal cell carcinoma (RCC) yet responses to single-agent EGFR inhibitors are uncommon. Although von Hippel–Lindau (VHL) mutations are predominant, RCC also develops in individuals with tuberous sclerosis (TSC). Tuberous sclerosis mutations activate mammalian target of rapamycin (mTOR) and biochemically resemble VHL alterations. We found that RCC cell lines expressed EGFR mRNA in the near-absence of other ErbB family members. Combined EGFR and mTOR inhibition synergistically impaired growth in a VHL-dependent manner. Iressa blocked ERK1/2 phosphorylation specifically in wt-VHL cells, whereas rapamycin inhibited phospho-RPS6 and 4E-BP1 irrespective of VHL. In contrast, phospho-AKT was resistant to these agents and MYC translation initiation (polysome binding) was similarly unaffected unless AKT was inhibited. Primary RCCs vs cell lines contained similar amounts of phospho-ERK1/2, much higher levels of ErbB-3, less phospho-AKT, and no evidence of phospho-RPS6, suggesting that mTOR activity was reduced. A subset of tumours and cell lines expressed elevated eIF4E in the absence of upstream activation. Despite similar amounts of EGFR mRNA, cell lines (vs tumours) overexpressed EGFR protein. In the paired cell lines, PRC3 and WT8, EGFR protein was elevated post-transcriptionally in the VHL mutant and EGF-stimulated phosphorylation was prolonged. We propose that combined EGFR and mTOR inhibitors may be useful in the subset of RCCs with wt-VHL. However, apparent differences between primary tumours and cell lines require further investigation
Single-cell protein induction dynamics reveals a period of vulnerability to antibiotics in persister bacteria
In-vivo-modified gonococcal plasmid pJD1. A model system for analysis of restriction enzyme sensitivity to DNA modifications
Management and outcomes of sellar, suprasellar, and parasellar masses in low-and middle- income countries: a scoping review
Background: There are several studies which describe the current management strategies and outcomes of SMs in High-Income Countries (HICs). However, there is little known the situation regarding SMs in Low and Middle-Income Countries (LMICs) apart from studies describing the experience from tertiary centres. With this study, we identified the epidemiology, diagnosis, management, and outcomes of SMs, SSMs, and PSMs in LMICs while reviewing and synthesising the relevant literature.
Methods: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis extension for Scoping Review (PRISMA-ScR) guidelines were used to report the findings. MEDLINE, Embase, Global Index Medicus, and African Journals OnLine were the databases of choice. Cases were included if the pathology was related to the sellar, parasellar or suprasellar regions. The dataset was analysed using descriptive statistics via SPSS.
Results: We have includedn=16589 patients from 49 LMICs. LMICs with the most studies were in China (n=49, 4.9%). Headache was the most reported symptomn=3995 with a mean of 29.82 cases per study (Range 0–130). Most reported tumour location was the sellar regionn=12933 (85%). Somatotroph adenomas was the most diagnosed pituitary adenoma (n=3297). The most frequently diagnosed non-pituitary adenomatous mass was arachnoid cysts (n=282). Endoscopic approaches were far more utilised compared to microsurgical approaches, n=3418 and n=1730, respectively. Hormonal therapies with Cabergoline were administered in 1700 patients with prolactinoma. Radiosurgery was performed in n=357 patients. The average follow-up duration was 33.26 months.
Conclusion: Neuro-oncology and pituitary research in LMICs remains under-reported. Our understanding of the current landscape of the management and outcomes of sellar, suprasellar and parasellar masses show that there is similarity to the management approaches utilised compared to HICs. The surgical outcomes, although largely underreported, were worse in LMICs compared to HICs, highlighting the need for more research and education