A prolonged methoxymorpholino doxorubicin (PNU-152243 or MMRDX) infusion schedule in patients with solid tumours: a phase 1 and pharmacokinetic study

The aim of this phase I study was to assess feasibility, pharmacokinetics and toxicity of methoxymorpholino doxorubicin (MMRDX or PNU-152243) administered as a 3 h intravenous infusion once every 4 weeks. Fourteen patients with intrinsically anthracycline-resistant tumours received 37 cycles of MMRDX. The first cohort of patients was treated with 1 mg m−2of MMRDX. The next cohorts received 1.25 mg m−2and 1.5 mg m−2respectively. Common toxicity criteria (CTC) grade III/IV nausea and vomiting were observed in 1/18 cycles at 1.25 mg m−2and in 2/11 cycles at 1.5 mg m−2. Transient elevation in transaminases up to CTC grade III was observed in 2/16 cycles at 1.25 mg m−2and 4/11 cycles at 1.5 mg m−2. No cardiotoxicity was observed. At 1.25 mg m−2CTC grade IV neutropenia occurred in 1/17 cycles. At 1.5 mg m−2CTC grade III neutropenia was seen in 2/7 and grade IV in 3/7 evaluable cycles. Thrombocytopenia grade III was observed in 2/9 and grade IV in 1/9 evaluable cycles. One patient treated at 1.5 mg m−2died with neutropenic fever. Therefore, dose-limiting toxicity was reached and 1.25 mg m−2was considered the maximum tolerated dose for MMRDX as 3 h infusion. No tumour responses were observed. Pharmacokinetic parameters showed a rapid clearance of MMRDX from the circulation by an extensive tissue distribution. Renal excretion of the drug and its metabolite was negligible. In conclusion, prolongation of MMRDX infusion to 3 h does not improve the toxicity profile as compared with bolus administration. © 2000 Cancer Research Campaig

Structural correlations in heterogeneous electron transfer at monolayer and multilayer graphene electrodes

As a new form of carbon, graphene is attracting intense interest as an electrode material with widespread applications. In the present study, the heterogeneous electron transfer (ET) activity of graphene is investigated using scanning electrochemical cell microscopy (SECCM), which allows electrochemical currents to be mapped at high spatial resolution across a surface for correlation with the corresponding structure and properties of the graphene surface. We establish that the rate of heterogeneous ET at graphene increases systematically with the number of graphene layers, and show that the stacking in multilayers also has a subtle influence on ET kinetics. © 2012 American Chemical Society

PerBrain: a multimodal approach to personalized tracking of evolving state-of-consciousness in brain-injured patients: protocol of an international, multicentric, observational study

BACKGROUND: Disorders of consciousness (DoC) are severe neurological conditions in which consciousness is impaired to various degrees. They are caused by injury or malfunction of neural systems regulating arousal and awareness. Over the last decades, major efforts in improving and individualizing diagnostic and prognostic accuracy for patients affected by DoC have been made, mainly focusing on introducing multimodal assessments to complement behavioral examination. The present EU-funded multicentric research project “PerBrain” is aimed at developing an individualized diagnostic hierarchical pathway guided by both behavior and multimodal neurodiagnostics for DoC patients. METHODS: In this project, each enrolled patient undergoes repetitive behavioral, clinical, and neurodiagnostic assessments according to a patient-tailored multi-layer workflow. Multimodal diagnostic acquisitions using state-of-the-art techniques at different stages of the patients’ clinical evolution are performed. The techniques applied comprise well-established behavioral scales, innovative neurophysiological techniques (such as quantitative electroencephalography and transcranial magnetic stimulation combined with electroencephalography), structural and resting-state functional magnetic resonance imaging, and measurements of physiological activity (i.e. nasal airflow respiration). In addition, the well-being and treatment decision attitudes of patients’ informal caregivers (primarily family members) are investigated. Patient and caregiver assessments are performed at multiple time points within one year after acquired brain injury, starting at the acute disease phase. DISCUSSION: Accurate classification and outcome prediction of DoC are of crucial importance for affected patients as well as their caregivers, as individual rehabilitation strategies and treatment decisions are critically dependent on the latter. The PerBrain project aims at optimizing individual DoC diagnosis and accuracy of outcome prediction by integrating data from the suggested multimodal examination methods into a personalized hierarchical diagnosis and prognosis procedure. Using the parallel tracking of both patients’ neurological status and their caregivers’ mental situation, well-being, and treatment decision attitudes from the acute to the chronic phase of the disease and across different countries, this project aims at significantly contributing to the current clinical routine of DoC patients and their family members. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04798456. Registered 15 March 2021 – Retrospectively registered

A new view of electrochemistry at highly oriented pyrolytic graphite

Major new insights on electrochemical processes at graphite electrodes are reported, following extensive investigations of two of the most studied redox couples, Fe(CN)64–/3– and Ru(NH3)63+/2+. Experiments have been carried out on five different grades of highly oriented pyrolytic graphite (HOPG) that vary in step-edge height and surface coverage. Significantly, the same electrochemical characteristic is observed on all surfaces, independent of surface quality: initial cyclic voltammetry (CV) is close to reversible on freshly cleaved surfaces (>400 measurements for Fe(CN)64–/3– and >100 for Ru(NH3)63+/2+), in marked contrast to previous studies that have found very slow electron transfer (ET) kinetics, with an interpretation that ET only occurs at step edges. Significantly, high spatial resolution electrochemical imaging with scanning electrochemical cell microscopy, on the highest quality mechanically cleaved HOPG, demonstrates definitively that the pristine basal surface supports fast ET, and that ET is not confined to step edges. However, the history of the HOPG surface strongly influences the electrochemical behavior. Thus, Fe(CN)64–/3– shows markedly diminished ET kinetics with either extended exposure of the HOPG surface to the ambient environment or repeated CV measurements. In situ atomic force microscopy (AFM) reveals that the deterioration in apparent ET kinetics is coupled with the deposition of material on the HOPG electrode, while conducting-AFM highlights that, after cleaving, the local surface conductivity of HOPG deteriorates significantly with time. These observations and new insights are not only important for graphite, but have significant implications for electrochemistry at related carbon materials such as graphene and carbon nanotubes

Electron transfer kinetics on natural crystals of MoS2 and graphite

Here, we evaluate the electrochemical performance of sparsely studied natural crystals of molybdenite and graphite, which have increasingly been used for fabrication of next generation monolayer molybdenum disulphide and graphene energy storage devices. Heterogeneous electron transfer kinetics of several redox mediators, including Fe(CN)63−/4−, Ru(NH3)63+/2+ and IrCl62−/3− are determined using voltammetry in a micro-droplet cell. The kinetics on both materials are studied as a function of surface defectiveness, surface ageing, applied potential and illumination. We find that the basal planes of both natural MoS2 and graphite show significant electroactivity, but a large decrease in electron transfer kinetics is observed on atmosphere-aged surfaces in comparison to in situ freshly cleaved surfaces of both materials. This is attributed to surface oxidation and adsorption of airborne contaminants at the surface exposed to an ambient environment. In contrast to semimetallic graphite, the electrode kinetics on semiconducting MoS2 are strongly dependent on the surface illumination and applied potential. Furthermore, while visibly present defects/cracks do not significantly affect the response of graphite, the kinetics on MoS2 systematically accelerate with small increase in disorder. These findings have direct implications for use of MoS2 and graphene/graphite as electrode materials in electrochemistry-related applications

Electrochemical properties of CVD grown pristine graphene: monolayer- vs. quasi-graphene

We report the electrochemical properties of pristine monolayer, double layer and few-layer (termed quasi-) graphene grown via CVD and transferred using PMMA onto an insulating substrate (silicon dioxide wafers). Characterisation has been performed by Raman spectroscopy, optical spectroscopy, Atomic Force Microscopy and X-ray Photoelectron Spectroscopy, revealing ‘true’ pristine single-layer graphene (O/C of 0.05) at the former and pristine quasi-graphene at the latter (O/C of 0.07); the term “quasi-graphene” is coined due to the surface comprising on average 4-graphene-layers. The graphene electrodes are electrochemically characterised using both inner-sphere and outer-sphere redox probes with electrochemical performances of the graphene electrodes compared to other available graphitic electrodes, namely that of basal- and edge- plane pyrolytic graphite electrodes constructed from Highly Ordered Pyrolytic Graphite (HOPG), with information on heterogeneous rate constants (ko) obtained. The electrochemical rate constants are predominantly influenced by the electronic properties of the graphene surfaces. Monolayer graphene is found to exhibit slow heterogeneous electron transfer (HET) kinetics towards the redox probes studied, with HET rates ca. 2 and 8 times faster at quasi-graphene and HOPG respectively, relative to that of the monolayer graphene electrode. Critically contrasting the performance of monolayer graphene to quasi-graphene and HOPG electrodes reveals that increasing the number of graphene layers results in improved electrochemical properties, where in terms of the electrochemical reversibility of the probes studied: monolayer-graphene < quasi-graphene < HOPG, as governed by the respective HET electrochemical rate constants. Given that edge plane sites are the predominant origin of fast electron transfer kinetics at graphitic materials, the slow HET rates at pristine single-layer graphene electrodes are likely due to graphene’s fundamental geometry, which comprises a small edge plane and large basal plane contribution. In the case of quasi-graphene and HOPG, they possess increasing global coverage of electrochemically reactive edge plane sites (respectively) and thus exhibit superior electrochemical performances over that of monolayer graphene. Last, the case of a double-layer graphene electrode is considered, which as a result of its fabrication possesses a large global coverage of edge plane like- sites/defects. In agreement with the former conclusions, the doublelayered defect-graphene electrode is found to exhibit fast/favourable electrochemical properties, which is attributed to its large edge plane content (i.e. defect abundant graphene) and thus is further evidence that the electrochemical response is dependent on the density of edge plane sites at graphene based electrodes (influenced by the coverage of graphene-defects and the number of graphene layers)

The fabrication, characterisation and electrochemical investigation of screen-printed graphene electrodes

We report the fabrication, characterisation (SEM, Raman spectroscopy, XPS and ATR) and electrochemical implementation of novel screen-printed graphene electrodes. Electrochemical characterisation of the fabricated graphene electrodes is undertaken using an array of electroactive redox probes and biologically relevant analytes, namely: potassium ferrocyanide(II), hexaammine-ruthenium(III) chloride, N,N,N0 ,N0-tetramethyl-pphenylenediamine (TMPD), b-nicotinamide adenine dinucleotide (NADH), L-ascorbic acid (AA), uric acid (UA) and dopamine hydrochloride (DA). The electroanalytical capabilities of the fabricated electrodes are also considered towards the sensing of AA and DA. The electrochemical and (electro)analytical performances of the fabricated screen-printed graphene electrodes are considered with respect to the relative surface morphologies and material compositions (elucidated via SEM, Raman, XPS and ATR spectroscopy), the density of electronic states (% global coverage of edge-plane like sites/defects) and the specific fabrication conditions utilised. Comparisons are made between two screen-printed graphene electrodes and alternative graphite based screen-printed electrodes. The graphene electrodes are fabricated utilising two different commercially prepared ‘graphene’ inks, which have long screen ink lifetimes (43 hours), thus this is the first report of a true mass-reproducible screen-printable graphene ink. Through employment of appropriate controls/comparisons we are able to report a critical assessment of these screen-printed graphene electrodes. This work is of high importance and demonstrates a proof-of-concept approach to screen-printed graphene electrodes that are highly reproducible, paving the way for mass-producible graphene sensing platforms in the future

The fabrication, characterisation and electrochemical investigation of screen-printed graphene electrodes

We report the fabrication, characterisation (SEM, Raman spectroscopy, XPS and ATR) and electrochemical implementation of novel screen-printed graphene electrodes. Electrochemical characterisation of the fabricated graphene electrodes is undertaken using an array of electroactive redox probes and biologically relevant analytes, namely: potassium ferrocyanide(II), hexaammine-ruthenium(III) chloride, N,N,N0 ,N0-tetramethyl-pphenylenediamine (TMPD), b-nicotinamide adenine dinucleotide (NADH), L-ascorbic acid (AA), uric acid (UA) and dopamine hydrochloride (DA). The electroanalytical capabilities of the fabricated electrodes are also considered towards the sensing of AA and DA. The electrochemical and (electro)analytical performances of the fabricated screen-printed graphene electrodes are considered with respect to the relative surface morphologies and material compositions (elucidated via SEM, Raman, XPS and ATR spectroscopy), the density of electronic states (% global coverage of edge-plane like sites/defects) and the specific fabrication conditions utilised. Comparisons are made between two screen-printed graphene electrodes and alternative graphite based screen-printed electrodes. The graphene electrodes are fabricated utilising two different commercially prepared ‘graphene’ inks, which have long screen ink lifetimes (43 hours), thus this is the first report of a true mass-reproducible screen-printable graphene ink. Through employment of appropriate controls/comparisons we are able to report a critical assessment of these screen-printed graphene electrodes. This work is of high importance and demonstrates a proof-of-concept approach to screen-printed graphene electrodes that are highly reproducible, paving the way for mass-producible graphene sensing platforms in the future