Hypoxia Sensitive Metal β-Ketoiminate Complexes Showing Induced Single Strand DNA Breaks and Cancer Cell Death by Apoptosis

A series of ruthenium and iridium complexes have been synthesised and characterised with 20 novel crystal structures discussed. The library of β-ketoiminate complexes has been shown to be active against MCF-7 (human breast carcino-ma), HT-29 (human colon carcinoma), A2780 (human ovarian carcinoma) and A2780cis (cisplatin resistant human ovarian carcinoma) cell lines, with selected complexes being more than three times as active as cisplatin against the A2780cis cell line. Complexes have also been shown to be highly active under hypoxic conditions, with the activities of some complexes increasing with a decrease in O2 concentration. The enzyme thioredoxin reductase is over-expressed in cancer cells and complexes reported herein have the advantage of inhibiting this enzyme, with IC50 values measured in the nanomolar range. The anti-cancer activity of these complexes was further investigated to determine whether activity is due to effects on cellular growth or cell survival. The complexes were found to induce significant cancer cell death by apoptosis with levels induced correlating closely with activity in chemosensitivity studies. As a possible cause of cell death, the ability of the complexes to induce damage to cellular DNA was also assessed. The complexes failed to induce double strand DNA break or DNA crosslinking but induced significant levels of single DNA strand breaks indi-cating a different mechanism of action to cisplatin

Microstates and power envelope hidden Markov modeling probe bursting brain activity at different timescales

State modeling of whole-brain electroencephalography (EEG) or magnetoencephalography (MEG) allows to investigate transient, recurring neurodynamical events. Two widely-used techniques are the microstate analysis of EEG signals and hidden Markov modeling (HMM) of MEG power envelopes. Both reportedly lead to similar state lifetimes on the 100 ms timescale, suggesting a common neural basis. To investigate whether microstates and power envelope HMM states describe the same neural dynamics, we used simultaneous MEG/EEG recordings at rest and compared the spatial signature and temporal activation dynamics of microstates and power envelope HMM states obtained separately from EEG and MEG. Results showed that microstates and power envelope HMM states differ both spatially and temporally. Microstates reflect sharp events of neural synchronization, whereas power envelope HMM states disclose network-level activity with 100–200 ms lifetimes. Further, MEG microstates do not correspond to the canonical EEG microstates but are better interpreted as split HMM states. On the other hand, both MEG and EEG HMM states involve the (de)activation of similar functional networks. Microstate analysis and power envelope HMM thus appear sensitive to neural events occurring over different spatial and temporal scales. As such, they represent complementary approaches to explore the fast, sub-second scale bursting electrophysiological dynamics in spontaneous human brain activity

Comparing MEG and high-density EEG for intrinsic functional connectivity mapping

Available online 20 January 2020.Magnetoencephalography (MEG) has been used in conjunction with resting-state functional connectivity (rsFC) based on band-limited power envelope correlation to study the intrinsic human brain network organization into resting-state networks (RSNs). However, the limited availability of current MEG systems hampers the clinical applications of electrophysiological rsFC. Here, we directly compared well-known RSNs as well as the whole-brain rsFC connectome together with its state dynamics, obtained from simultaneously-recorded MEG and high-density scalp electroencephalography (EEG) resting-state data. We also examined the impact of head model precision on EEG rsFC estimation, by comparing results obtained with boundary and finite element head models. Results showed that most RSN topographies obtained with MEG and EEG are similar, except for the fronto-parietal network. At the connectome level, sensitivity was lower to frontal rsFC and higher to parieto-occipital rsFC with MEG compared to EEG. This was mostly due to inhomogeneity of MEG sensor locations relative to the scalp and significant MEG-EEG differences disappeared when taking relative MEG-EEG sensor locations into account. The default-mode network was the only RSN requiring advanced head modeling in EEG, in which gray and white matter are distinguished. Importantly, comparison of rsFC state dynamics evidenced a poor correspondence between MEG and scalp EEG, suggesting sensitivity to different components of transient neural functional integration. This study therefore shows that the investigation of static rsFC based on the human brain connectome can be performed with scalp EEG in a similar way than with MEG, opening the avenue to widespread clinical applications of rsFC analyses.This study was supported by the Action de Recherche Concert ee Consolidation (ARCC, “Characterizing the spatio-temporal dynamics and the electrophysiological bases of resting state networks”, ULB, Brussels, Belgium), the Fonds Erasme (Research Convention “Les Voies du Savoir”, Brussels, Belgium) and the Fonds de la Recherche Scientifique (Research Convention: T.0109.13, F.R.S. - FNRS, Brussels, Belgium). Nicolas Coquelet has been supported by the ARCC and is supported by the Fonds Erasme (Research Convention “Les Voies du Savoir”, Brussels, Belgium). Xavier De Ti ege is Postdoctorate Clinical Master Specialist at the FRSFNRS. Florian Destoky and Mathieu Bourguignon are supported by the program Attract of Innoviris (Research Grant 2015-BB2B-10, Brussels, Belgium). Mathieu Bourguignon is also supported by the Marie Sklodowska-Curie Action of the European Commission (Research Grant: 743562) and by the Spanish Ministery of Economy and Competitiveness (Research Grant: PSI2016-77175-P). Lillia Roshchupkina is F.R.S. - FNRS Research Fellow and was previously supported by a ULB Mini-ARC grant. The MEG project at the CUB H^opital Erasme is financially supported by the Fonds Erasme (Research Convention “Les Voies du Savoir”, Brussels, Belgium). The high-density EEG project at the CUB H^opital Erasme has been financially supported by the CUB H^opital Erasme (Medical Council Research Grant) and by the F.R.S. - FNRS. The authors would like to thank Maribel Pulgarin Montoya for her help in part of the simultaneous MEG and high-density EEG recordings

Evaluation of the short-term efficacy and safety of biological agents in different rheumatic diseases: a multidisciplinary therapeutic hospital"s experience

There has been a substantial expansion in the possibilities of current therapy for rheumatic diseases (RD) primarily due to the use of genetically engineered biological agents (GEBA). Objective: to evaluate the short-term efficacy and safety of GEBA in patients with different RD. Subjects and methods. The trial included all RD patients receiving GEBA: rituximab (RTM), infliximab (INF), adalimumab, etanercept, tocilizumab, abatacept in 2009-2012. Therapeutic efficiency and safety were evaluated 6 months later. The effect of GEBA was determined as “remission”, “improvement”, and “no response”, by using the parameters peculiar to specific diseases (such as BVAS, DAS28, BASDAI). Results. The trial enrolled 107 patients (49 men and 58 women; mean age 41.5 years) with rheumatoid arthritis (n=34), ANCA-associated vasculitis (n = 34), systemic lupus erythematosus (n=16), cryoglobulinemic vasculitis (n=11), ankylosing spondyloarthritis (n = 8), systemic vasculitis with large artery involvement (n=6), and other RD. All the cases showed severe systemic autoimmune disease refractory to standard immunosuppressive therapy. RTM (n=66) and INF (n = 31) were most frequently used. The high rate of RTM prescription was due to the fact that this drug was given to all patients with ANCA-associated vasculitis, systemic lupus erythematosus, and cryoglobulinemic vasculitis who totaled more than half of the patients included into the trial. The vast majority of them received GEBA for the first time. After the treatment, there was remission in 62 (57.9%) and improvement in 42 (39.3%) cases. Mild or moderate adverse reactions were observed in 22 (20.6%) patients and severe ones were seen in 6 (5.6%). Conclusion. GEBA therapy ensures a significant improvement in a substantial proportion of patients with different RD refractory to standard immunosuppressive therapy