Mechanistic studies of the modulation of cleavage activity of topoisomerase I by DNA adducts of mono- and bi-functional PtII complexes

Using electrophoresis and replication mapping, we show that the presence of DNA adducts of bifunctional antitumor cisplatin or monodentate [PtCl(dien)]Cl (dien = diethylenetriamine) in the substrate DNA inhibits eukaryotic topoisomerase 1 (top1) action, the adducts of cisplatin being more effective. The presence of camptothecin in the samples of platinated DNA markedly enhances effects of Pt–DNA adducts on top1 activity. Interestingly, the effects of Pt–DNA adducts on the catalytic activity of top1 in the presence of camptothecin differ depending on the sequence context. A multiple metallation of the short nucleotide sequences on the scissile strand, immediately downstream of the cleavage site impedes the cleavage by top1. On the other hand, DNA cleavage by top1 at some cleavage sites which were not platinated in their close proximity is notably enhanced as a consequence of global platination of DNA. We suggest that this enhancement of DNA cleavage by top1 may consist in its inability to bind to other cleavage sites platinated in their close neighborhood; thus, more molecules of top1 may become available for cleavage at the sites where top1 normally cleaves and where platination does not interfere

Euphol, a tetracyclic triterpene, from Euphorbia tirucalli induces autophagy and sensitizes temozolomide cytotoxicity on glioblastoma cells

Glioblastoma (GBM) is the most frequent and aggressive type of brain tumor. There are limited therapeutic options for GBM so that new and effective agents are urgently needed. Euphol is a tetracyclic triterpene alcohol, and it is the main constituent of the sap of the medicinal plant Euphorbia tirucalli. We previously identified anti-cancer activity in euphol based on the cytotoxicity screening of 73 human cancer cells. We now expand the toxicological screening of the inhibitory effect and bioactivity of euphol using two additional glioma primary cultures. Euphol exposure showed similar cytotoxicity against primary glioma cultures compared to commercial glioma cells. Euphol has concentration-dependent cytotoxic effects on cancer cell lines, with more than a five-fold difference in the IC50 values in some cell lines. Euphol treatment had a higher selective cytotoxicity index (0.64-3.36) than temozolomide (0.11-1.13) and reduced both proliferation and cell motility. However, no effect was found on cell cycle distribution, invasion and colony formation. Importantly, the expression of the autophagy-associated protein LC3-II and acidic vesicular organelle formation were markedly increased, with Bafilomycin A1 potentiating cytotoxicity. Finally, euphol also exhibited antitumoral and antiangiogenic activity in vivo, using the chicken chorioallantoic membrane assay, with synergistic temozolomide interactions in most cell lines. In conclusion, euphol exerted in vitro and in vivo cytotoxicity against glioma cells, through several cancer pathways, including the activation of autophagy-associated cell death. These findings provide experimental support for further development of euphol as a novel therapeutic agent for GBM, either alone or in combination chemotherapy.The work was supported by the Amazonia Fitomedicamentos (FITO05/2012) Ltda. and Barretos Cancer Hospital, all from Brazil

Search for dark matter in the form of hidden photons and axion-like particles in the XMASS detector

Hidden photons and axion-like particles are candidates for cold dark matter if they were produced non-thermally in the early universe. We conducted a search for both of these bosons using 800 live-days of data from the XMASS detector with 327 kg of liquid xenon in the fiducial volume. No significant signal was observed, and thus we set constraints on the α´/α parameter related to kinetic mixing of hidden photons and the coupling constant gAe of axion-like particles in the mass range from 40 to 120 keV/c2, resulting in α´/α < 6 × 10−26 and gAe < 4 × 10−13. These limits are the most stringent over this mass range derived from both direct and indirect searches to date

Triangulation supports agricultural spread of the Transeurasian languages

The origin and early dispersal of speakers of Transeurasian languages, i.e., Japanese, Korean, Tungusic, Mongolic and Turkic, is among the most disputed issues of Eurasian population history. A key problem is the relationship between linguistic dispersals, agricultural expansions and population movements. Here we address this question through ‘triangulating’ genetics, archaeology and linguistics in a unified perspective. We report new, wide-ranging datasets from these disciplines, including the most comprehensive Transeurasian agropastoral and basic vocabulary presented to date, an archaeological database of 255 Neolithic and Bronze Age sites from Northeast Asia, and the first collection of ancient genomes from Korea, the Ryukyu islands and early cereal farmers in Japan, complementing previously published genomes from East Asia. Challenging the traditional ‘Pastoralist Hypothesis’, we show that the common ancestry and primary dispersals of Transeurasian languages can be traced back to the first farmers moving across Northeast Asia from the Early Neolithic onwards, but that this shared heritage has been masked by extensive cultural interaction since the Bronze Age. As well as marking significant progress in the three individual disciplines, by combining their converging evidence, we show that the early spread of Transeurasian speakers was driven by agriculture.Introduction Linguistics Archaeology Genetics Discussion: Triangulation Method

Direct dark matter search in XMASS-I

A search for dark matter using an underground single-phase liquid xenon detector was conducted at the Kamioka Observatory in Japan, particularly for Weakly Interacting Massive Particles (WIMPs). We have used 705.9 live days of data in a fiducial volume containing 97 kg of liquid xenon at the center of the detector. The event rate in the fiducial volume after the data reduction was (4.2 ± 0.2) × 10−3 day−1 kg−1 keVee−1 at 5 keVee, with a signal efficiency of 20%. All the remaining events are consistent with our background evaluation, mostly of the “mis-reconstructed events” originated from 210Pb in the copper plates lining the detector’s inner surface. The obtained upper limit on a spin-independent WIMP-nucleon cross section was 2.2 × 10−44 cm2 for a WIMP mass of 60 GeV/c2 at the 90% confidence level, which was the most stringent limit among results from single-phase liquid xenon detectors

Improved search for two-neutrino double electron capture on 124Xe and 126Xe using particle identification in XMASS-I

We conducted an improved search for the simultaneous capture of two K-shell electrons on the 124Xe and 126Xe nuclei with emission of two neutrinos using 800.0 days of data from the XMASS-I detector. A novel method to discriminate γ-ray/X-ray or double electron capture signals from β-ray background using scintillation time profiles was developed for this search. No significant signal was found when fitting the observed energy spectra with the expected signal and background. Therefore, we set the most stringent lower limits on the half-lives at 2.1×1022 and 1.9×1022 years for 124Xe and 126Xe, respectively, with 90% confidence level. These limits improve upon previously reported values by a factor of 4.5