Synthesis and Biological Activity Evaluations of Novel Heterobimetallic Platinum(II)–Gold(I) Complexes as Bio-imaging Agents.

Introduction: Platinum-based drugs have become a mainstay of cancer therapy, approximately half of all patients undergoing chemotherapeutic treatment receive a platinum drug. Despite the pervasiveness of platinum drugs in cancer treatment regimens, a number of attendant disadvantages such as resistance to some cancer types and side effects exist. Gold complexes are also emerging as a new class of metal complexes with outstanding cytotoxic properties and are presently being evaluated as potential antitumor agents. Methods and Results: Here, some novel heterobimetallic platinum(II)–gold(I) complexes were synthesized and their cytotoxic activities against different human cancer cell lines such as A549 (human lung cancer), SKOV3 (human ovarian cancer) and MDA-MB-231 (human breast cancer) were evaluated. Electrophoresis mobility shift assay and molecular modeling investigations have been performed to determine the specific binding mode or the binding orientation of these compounds to DNA. Molecular docking studies of them on DNA were performed by means of AutoDock 4.2. Fluorescence emission properties of them were assessed using fluorescent microscopy imaging. In comparison to cis-platin, these compounds displayed significantly higher in vitro cytotoxicity on the studied cell lines. They enter SKOV3 cells rapidly, retaining their phosphorescence and localise simultaneously in cytoplasm, especially in perinuclear regions. So they are suitable candidates for time resolved emission imaging microscopy (TREM). Electrophoresis mobility shift assay showed a little shift and little interaction with plasmid DNA, though this shift is not as much as cis-platin. They may exert their cytotoxic effect through a different mechanism. Conclusions: According to the results, careful drug design would result in producing potential antitumor agents with high efficacy. These Pt(II)-Au(I) complexes can be used in biological labelling and cellular imaging studies, due to desirable absorption and emission of them in solution under ambient conditions. Hence, they had a potential value for drug development as anticancer agents

On fiber dispersion models: exclusion of compressed fibers and spurious model comparisons

Fiber dispersion in collagenous soft tissues has an important influence on the mechanical response, and the modeling of the collagen fiber architecture and its mechanics has developed significantly over the last few years. The purpose of this paper is twofold, first to develop a method for excluding compressed fibers within a dispersion for the generalized structure tensor (GST) model, which several times in the literature has been claimed not to be possible, and second to draw attention to several erroneous and misleading statements in the literature concerning the relative values of the GST and the angular integration (AI) models. For the GST model we develop a rather simple method involving a deformation dependent dispersion parameter that allows the mechanical influence of compressed fibers within a dispersion to be excluded. The theory is illustrated by application to simple extension and simple shear in order to highlight the effect of exclusion. By means of two examples we also show that the GST and the AI models have equivalent predictive power, contrary to some claims in the literature. We conclude that from the theoretical point of view neither of these two models is superior to the other. However, as is well known and as we now emphasize, the GST model has proved to be very successful in modeling the data from experiments on a wide range of tissues, and it is easier to analyze and simpler to implement than the AI approach, and the related computational effort is much lower

Cyclometalated platinum(II) complexes of 2,2'-bipyridine N-oxide containing 1,1'-bis(diphenylphosphino)ferrocene ligand: Structural, computational and electrochemical studies

The preparation and characterization of new heteronuclear-platinum(II) complexes containing 1,1'-bis(diphenylphosphino)ferrocene (dppf) ligand are described. The reaction of the known starting complex [PtMe(κ2N,C-bipyO-H)(SMe2)], A, in which bipyO-H is a cyclometalated “rollover” 2,2'-bipyridine N-oxide, with the dppf ligand in a 2 : 1 ratio or an equimolar ratio led to the formation of corresponding binuclear complex [Pt2Me2(κ2N,C-bipyO-H)2(µ-dppf)], 1, or mononuclear complex [PtMe(κ1C-bipyO-H)(dppf)], 2, respectively. According to the reaction conditions, the dppf ligand in 1 and 2 behaves as either a bridging or chelateing ligand. All complexes were characterized by NMR spectroscopy. The solid-state structure of 2 was determined by single-crystal X-ray diffraction method and it was shown that the chelateing dppf ligand in this complex was arranged “synclinal-staggered” conformation. Also, the occurrence of intermolecular C–HCp…ObipyO-H interactions in the solid-state gave rise to an extended 1-D network. The electronic absorption spectra and the electrochemical behavior of these complexes are discussed. Density functional theory (DFT) was used for geometry optimization of the singlet states in solution and for electronic structure calculations. The analysis of the molecular orbital (MO) compositions in terms of occupied and unoccupied fragment orbitals in 2 was performed

QSAR, Molecular Docking and protein ligand interaction fingerprint studies of N-phenyl dichloroacetamide derivatives as anticancer agents

Dichloroacetate (DCA) is a pyruvate mimetic compound that stimulates the activity of the enzyme pyruvate dehydrogenase (PDH) through inhibition of the enzyme pyruvate dehydrogenase kinases (PDK1-4). DCA works by turning on the apoptosis which is suppressed in tumor cells, hence let them to die on their own. Here, in this paper a series of DCA analogues were applied to quantitative structure–activity relationship (QSAR) analysis. A collection of chemometrics methods such as multiple linear regression (MLR), factor analysis–based multiple linear regression (FA-MLR), principal component regression (PCR), simple Free-Wilson analysis (FWA) and partial least squared combined with genetic algorithm for variable selection (GA-PLS) were conducted to make relations between structural features and cytotoxic activities of a variety of DCA derivatives. The best multiple linear regression equation obtained from genetic algorithms partial least squares which predict 91% of variances. On the basis of the produced model, an in silico-screening study was also employed and new potent lead compounds based on new structural patterns were suggested. Docking studies of these compounds were also investigated and promising results were obtained. The docking results were also conducted to protein ligand interaction fingerprints (PLIF) studies using self-organizing map (SOM) in order to evaluate the predictive ability in suggesting new potent compounds and some compounds were introduced as a good candidates for synthesis.</p

Tensile and Compressive Mechanical Behaviour of Human Blood Clot Analogues

Endovascular thrombectomy procedures are significantly influenced by the mechanical response of thrombi to the multi-axial loading imposed during retrieval. Compression tests are commonly used to determine compressive ex vivo thrombus and clot analogue stiffness. However, there is a shortage of data in tension. This study compares the tensile and compressive response of clot analogues made from the blood of healthy human donors in a range of compositions. Citrated whole blood was collected from six healthy human donors. Contracted and non-contracted fibrin clots, whole blood clots and clots reconstructed with a range of red blood cell (RBC) volumetric concentrations (5–80%) were prepared under static conditions. Both uniaxial tension and unconfined compression tests were performed using custom-built setups. Approximately linear nominal stress–strain profiles were found under tension, while strong strain-stiffening profiles were observed under compression. Low- and high-strain stiffness values were acquired by applying a linear fit to the initial and final 10% of the nominal stress–strain curves. Tensile stiffness values were approximately 15 times higher than low-strain compressive stiffness and 40 times lower than high-strain compressive stiffness values. Tensile stiffness decreased with an increasing RBC volume in the blood mixture. In contrast, high-strain compressive stiffness values increased from 0 to 10%, followed by a decrease from 20 to 80% RBC volumes. Furthermore, inter-donor differences were observed with up to 50% variation in the stiffness of whole blood clot analogues prepared in the same manner between healthy human donors

Cyclometalated platinum(II) complexes of 2,2'-bipyridine N-oxide containing 1,1'-bis(diphenylphosphino)ferrocene ligand: Structural, computational and electrochemical studies

Two cycloplatinated rollover complexes containing dppf ligand were synthesized and characterized.</p

Mechanical characterization of thrombi retrieved with endovascular thrombectomy in patients with acute ischemic stroke

Background and Purpose: Mechanical properties of thromboemboli play an important role in the efficacy of endovascular thrombectomy (EVT) for acute ischemic stroke. However, very limited data on mechanical properties of human stroke thrombi are available. We aimed to mechanically characterize thrombi retrieved with EVT, and to assess the relationship between thrombus composition and thrombus stiffness. Methods: Forty-one thrombi from 19 patients with acute stroke who underwent EVT between July and October 2019 were mechanically analyzed, directly after EVT. We performed unconfined compression experiments and determined tangent modulus at 75% strain (E-t75) as a measure for thrombus stiffness. Thrombi were histologically analyzed for fibrin/platelets, erythrocytes, leukocytes, and platelets, and we assessed the relationship between histological components and E-t75 with univariable and multivariable linear mixed regression. Results: Median E-t75 was 560 (interquartile range, 393-1161) kPa. In the multivariable analysis, fibrin/platelets were associated with increased E-t75 (a beta, 9 [95% CI, 5 to 13]) kPa, erythrocytes were associated with decreased E-t75% (a beta, -9 [95% CI, -5 to -13]) kPa. We found no association between leukocytes and E-t75. High platelet values were strongly associated with increased E-t75 (a beta, 56 [95% CI, 38-73]). Conclusions: Fibrin/platelet content of thrombi retrieved with EVT for acute ischemic stroke is strongly associated with increased thrombus stiffness. For thrombi with high platelet values, there was a very strong relationship with thrombus stiffness. Our data provide a basis for future research on the development of next-generation EVT devices tailored to thrombus composition.Neuro Imaging Researc

A simplified mesoscale 3D model for characterizing fibrinolysis under flow conditions

One of the routine clinical treatments to eliminate ischemic stroke thrombi is injecting a biochemical product into the patient’s bloodstream, which breaks down the thrombi’s fibrin fibers: intravenous or intravascular thrombolysis. However, this procedure is not without risk for the patient; the worst circumstances can cause a brain hemorrhage or embolism that can be fatal. Improvement in patient management drastically reduced these risks, and patients who benefited from thrombolysis soon after the onset of the stroke have a significantly better 3-month prognosis, but treatment success is highly variable. The causes of this variability remain unclear, and it is likely that some fundamental aspects still require thorough investigations. For that reason, we conducted in vitro flow-driven fibrinolysis experiments to study pure fibrin thrombi breakdown in controlled conditions and observed that the lysis front evolved non-linearly in time. To understand these results, we developed an analytical 1D lysis model in which the thrombus is considered a porous medium. The lytic cascade is reduced to a second-order reaction involving fibrin and a surrogate pro-fibrinolytic agent. The model was able to reproduce the observed lysis evolution under the assumptions of constant fluid velocity and lysis occurring only at the front. For adding complexity, such as clot heterogeneity or complex flow conditions, we propose a 3-dimensional mesoscopic numerical model of blood flow and fibrinolysis, which validates the analytical model’s results. Such a numerical model could help us better understand the spatial evolution of the thrombi breakdown, extract the most relevant physiological parameters to lysis efficiency, and possibly explain the failure of the clinical treatment. These findings suggest that even though real-world fibrinolysis is a complex biological process, a simplified model can recover the main features of lysis evolution.</p

Global, regional, and national burden of colorectal cancer and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Funding: F Carvalho and E Fernandes acknowledge support from Fundação para a Ciência e a Tecnologia, I.P. (FCT), in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy i4HB; FCT/MCTES through the project UIDB/50006/2020. J Conde acknowledges the European Research Council Starting Grant (ERC-StG-2019-848325). V M Costa acknowledges the grant SFRH/BHD/110001/2015, received by Portuguese national funds through Fundação para a Ciência e Tecnologia (FCT), IP, under the Norma Transitória DL57/2016/CP1334/CT0006.proofepub_ahead_of_prin