A Bio-Conjugated Fullerene as a Subcellular-Targeted and Multifaceted Phototheranostic Agent

Fullerenes are candidates for theranostic applications because of their high photodynamic activity and intrinsic multimodal imaging contrast. However, fullerenes suffer from low solubility in aqueous media, poor biocompatibility, cell toxicity, and a tendency to aggregate. C70@lysozyme is introduced herein as a novel bioconjugate that is harmless to a cellular environment, yet is also photoactive and has excellent optical and optoacoustic contrast for tracking cellular uptake and intracellular localization. The formation, water-solubility, photoactivity, and unperturbed structure of C70@lysozyme are confirmed using UV-visible and 2D 1H, 15N NMR spectroscopy. The excellent imaging contrast of C70@lysozyme in optoacoustic and third harmonic generation microscopy is exploited to monitor its uptake in HeLa cells and lysosomal trafficking. Last, the photoactivity of C70@lysozyme and its ability to initiate cell death by means of singlet oxygen (1O2) production upon exposure to low levels of white light irradiation is demonstrated. This study introduces C70@lysozyme and other fullerene-protein conjugates as potential candidates for theranostic applications

Value of Screening Asymptomatic Carotid Artery Stenosis Prior to Coronary Artery Bypass Grafting: Analysis of the E-CABG Registry

Background and aim: The aim of this study was to evaluate the prognostic impact of asymptomatic carotid artery stenosis(CAS) in patients undergoing isolated coronary artery bypass grafting(CABG). Methods:Patients from the multicenter, prospective E-CABG registry without history of stroke or transient ischemic attack and screened by duplex ultrasound for CAS before isolated CABG were included in this analysis. Results:Among 2813 patients screened by duplex ultrasound for asymptomatic CAS, 11.1% had a CAS of 50-59%, 6.0% of 60-69%, 3.1% of 70-79%, 1.4% of 80-89%, 0.5% of 90-99%, and 1.1% had carotid occlusion. Postoperative stroke occurred in 25 patients(0.9%). Lesions were bilateral in five patients(25%) and ipsilateral to a CAS 6550% in six patients(30%). In univariate analysis, the severity of CAS was associated with a significantly increased risk of stroke(p<0.0001). In multivariate analysis, a CAS of 90-99%(OR 12.03, 95%CI 1.34-108.23) and the presence of an occluded internal carotid artery(OR 8.783, 95%CI 1.820-42.40) were independent predictors of stroke along with urgency of the procedure, severe-massive bleeding according to the E-CABG classification and the presence of a porcelain ascending aorta. Conclusions: Among patients with asymptomatic CAS, the risk of stroke is significant only in patients with a stenosis 6590%. Since this condition has a low prevalence and when left untreated is associated with a relatively low rate of stroke, preoperative screening of asymptomatic CAS before CABG may not be justified. Instead, avoiding manipulation of diseased ascending aorta and prevention of excessive bleeding may be more effective measures to prevent stroke after CABG

Comparative Analysis of Prothrombin Complex Concentrate and Fresh Frozen Plasma in the Management of Perioperative Bleeding after Coronary Artery Bypass Grafting

Background and Aim: Recent studies suggested that prothrombin complex concentrate (PCC) might be more effective than fresh frozen plasma (FFP) to reduce red blood cell (RBC) transfusion requirement after cardiac surgery. The benefits and risks associated with the use of PCC over FFP have been investigated in this study including patients undergoing isolated coronary artery bypass grafting(CABG) from a prospective, multicenter registry. Methods: This is a comparative analysis of 416 patients who received postoperatively FFP and 119 patients who received PCC with or without FFP after isolated CABG. Results: Mixed-effects regression analyses adjusted for multiple covariates and participating centers showed that PCC significantly decreased RBC transfusion (67.2% vs. 87.5%, adjusted OR 0.319, 95%CI 0.136-0.752) and platelet transfusion requirements (11.8% vs. 45.2%, adjusted OR 0.238, 95%CI 0.097-0.566) compared with FFP. The PCC cohort received a mean of 2.7\ub13.7 (median, 2.0, IQR 4) units of RBC and the FFP cohort received a mean of 4.9\ub16.3 (median, 3.0, IQR 4) units of RBC (adjusted coefficient, -1.926, 95%CI -3.357-0.494). The use of PCC increased the risk of KDIGO acute kidney injury (41.4% vs. 28.2%, adjusted OR 2.300, 1.203-4.400), but not of KDIGO acute kidney injury stage 3 (6.0% vs. 8.0%, OR 0.850, 95%CI 0.258-2.796) when compared with the FFP cohort. Conclusions: These results suggest that the use of PCC compared with FFP may reduce the need of blood transfusion after CABG. In view of the observational nature of this study, these results shoul

The Italian arm of the PREPARE study: an international project to evaluate and license a maternal vaccine against group B streptococcus.

BACKGROUND: Group B streptococcus (GBS) is a leading cause of sepsis, pneumonia and meningitis in infants, with long term neurodevelopmental sequelae. GBS may be associated with poor pregnancy outcomes, including spontaneous abortion, stillbirth and preterm birth. Intrapartum antibiotic prophylaxis (IAP) is currently the only way to prevent early-onset disease (presenting at 0 to 6 days of life), although it has no impact on the disease presenting over 6 days of life and its implementation is challenging in resource poor countries. A maternal vaccine against GBS could reduce all GBS manifestations as well as improve pregnancy outcomes, even in low-income countries. MAIN BODY: The term "PREPARE" designates an international project aimed at developing a maternal vaccination platform to test vaccines against neonatal GBS infections by maternal immunization. It is a non-profit, multi-center, interventional and experimental study (promoted by the St George University of London. [UK]) with the aim of developing a maternal vaccination platform, determining pregnancy outcomes, and defining the extent of GBS infections in children and mothers in Africa. PREPARE also aims to estimate the protective serocorrelates against the main GBS serotypes that cause diseases in Europe and Africa and to conduct two trials on candidate GBS vaccines. PREPARE consists of 6 work packages. In four European countries (Italy, UK, Netherlands, France) the recruitment of cases and controls will start in 2020 and will end in 2022. The Italian PREPARE network includes 41 centers. The Italian network aims to collect: GBS isolates from infants with invasive disease, maternal and neonatal sera (cases); cord sera and GBS strains from colonized mothers whose infants do not develop GBS infection (controls). SHORT CONCLUSION: PREPARE will contribute information on protective serocorrelates against the main GBS serotypes that cause diseases in Europe and Africa. The vaccine that will be tested by the PREPARE study could be an effective strategy to prevent GBS disease

Inside and out: the activities of senescence in cancer.

The core aspect of the senescent phenotype is a stable state of cell cycle arrest. However, this is a disguise that conceals a highly active metabolic cell state with diverse functionality. Both the cell-autonomous and the non-cell-autonomous activities of senescent cells create spatiotemporally dynamic and context-dependent tissue reactions. For example, the senescence-associated secretory phenotype (SASP) provokes not only tumour-suppressive but also tumour-promoting responses. Senescence is now increasingly considered to be an integrated and widespread component that is potentially important for tumour development, tumour suppression and the response to therapy.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/nrc377

BioMAX the first macromolecular crystallography beamline at MAX IV Laboratory

BioMAX is the first macromolecular crystallography beamline at the MAX IV Laboratory 3 GeV storage ring, which is the first operational multi bend achromat storage ring. Due to the low emittance storage ring, BioMAX has a parallel, high intensity X ray beam, even when focused down to 20 mm 5 mm using the bendable focusing mirrors. The beam is tunable in the energy range 5 25 keV using the in vacuum undulator and the horizontally deflecting doublecrystal monochromator. BioMAX is equipped with an MD3 diffractometer, an ISARA high capacity sample changer and an EIGER 16M hybrid pixel detector. Data collection at BioMAX is controlled using the newly developed MXCuBE3 graphical user interface, and sample tracking is handled by ISPyB. The computing infrastructure includes data storage and processing both at MAX IV and the Lund University supercomputing center LUNARC. With state of the art instrumentation, a high degree of automation, a user friendly control system interface and remote operation, BioMAX provides an excellent facility for most macromolecular crystallography experiments. Serial crystallography using either a high viscosity extruder injector or the MD3 as a fixedtarget scanner is already implemented. The serial crystallography activities at MAX IV Laboratory will be further developed at the microfocus beamline MicroMAX, when it comes into operation in 2022. MicroMAX will have a 1 mm x 1 mm beam focus and a flux up to 10 15 photons s 1 with main applications in serial crystallography, room temperature structure determinations and time resolved experiment

mTOR: from growth signal integration to cancer, diabetes and ageing

In all eukaryotes, the target of rapamycin (TOR) signalling pathway couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress and, in metazoans, growth factors. Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt. In the past few years, a significant advance in our understanding of the regulation and functions of mTOR has revealed the crucial involvement of this signalling pathway in the onset and progression of diabetes, cancer and ageing.National Institutes of Health (U.S.)Howard Hughes Medical InstituteWhitehead Institute for Biomedical ResearchJane Coffin Childs Memorial Fund for Medical Research (Postdoctoral Fellowship)Human Frontier Science Program (Strasbourg, France

Imaging biomarker roadmap for cancer studies.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.Development of this roadmap received support from Cancer Research UK and the Engineering and Physical Sciences Research Council (grant references A/15267, A/16463, A/16464, A/16465, A/16466 and A/18097), the EORTC Cancer Research Fund, and the Innovative Medicines Initiative Joint Undertaking (grant agreement number 115151), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution