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. 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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

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