Pharmacogenetics of advanced colorectal cancer treatment

Even though treatment of several types of solid tumors has improved in the past few years with the introduction of the monoclonal antibodies against the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), the clinical benefit of these targeted therapies is modest. Pharmacogenetics has the potential to select patients with higher chance of response to agents that target these pathways. In the thesis, we describe the association of the FCGR3A Phe158Val polymorphism with progression-free survival in advanced colorectal cancer patients treated with cetuximab added to chemotherapy and bevacizumab. Following this finding, we found that cetuximab activates type 2 macrophages, which could have a negative effect on the clinical efficacy of cetuximab. Furthermore, we detected a genetic interaction profile consisting of the VEGF +405G>C and TYMS TSER polymorphisms, that was associated with the efficacy of capecitabine, oxaliplatin and bevacizumab in advanced colorectal cancer patients. Finally, we performed a genome wide association study with the same treatment, in which polymorphisms in the proximity of the AGPAT5 gene were associated with progression-free survivalUBL - phd migration 201

Regarding: ‘Explorative study to identify novel candidate genes related to oxaliplatin efficacy and toxicity using a DNA repair array'

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Electrochemistry and spectroelectrochemistry of polymers based on D-A-D and D-D-D bis( N -carbazolyl) monomers, effect of the donor/acceptor core on their properties

In this work we present electropolymerization of monomers of an unusual type using N-linked carbazole units to limit their conjugation. The polymers thus obtained have limited conjugation through the backbone. Using donor-acceptor-donor (D-A-D) and donor-donor-donor (D-D-D) monomers we evaluate the effects of the presence (or absence) of charge transfer states on synthesized electropolymers. The use of a D-A-D monomer resulted in obtaining an ambipolar polymer with quasi-reversible reduction

Near-infrared electroluminescence beyond 940 nm in Pt(N^C^N)X complexes: influencing aggregation with the ancillary ligand X

We present a study of aggregate excited states formed by complexes of the type Pt(N^C^N)X, where N^C^N represents a tridentate cyclometallating ligand, and X = SCN or I. These materials display near-infrared (NIR) photoluminescence in film and electroluminescence in NIR OLEDs with λmaxEL = 720–944 nm. We demonstrate that the use of X = SCN or I modulates aggregate formation compared to the parent complexes where X = Cl. While the identity of the monodentate ligand affects the energy of Pt–Pt excimers in solution in only a subtle way, it strongly influences aggregation in film. Detailed calculations on aggregates of different sizes support the experimental conclusions from steady-state and time-resolved luminescence studies at variable temperatures. The use of X = I appears to limit aggregation to the formation of dimers, while X = SCN promotes the formation of larger aggregates, such as tetramers and pentamers, leading in turn to NIR photo- and electroluminescence > 850 nm. A possible explanation for the contrasting influence of the monodentate ligands is the lesser steric hindrance associated with the SCN group compared to the bulkier I ligand. By exploiting the propensity of the SCN complexes to form extended aggregates, we have prepared an NIR-emitting OLED that shows very long wavelength electroluminescence, with λmaxEL = 944 nm and a maximum EQE = 0.3 ± 0.1%. Such data appear to be unprecedented for a device relying on a Pt(II) complex aggregate as the emitter

Rigidly linked dinuclear platinum( ii ) complexes showing intense, excimer-like, near-infrared luminescence

Many luminescent platinum(ii) complexes undergo face-to-face interactions between neighbouring molecules, leading to bimolecular excited states that may emit at lower energy (dimers and/or excimers). Detailed photophysical studies are reported on dinuclear complexes, in which two NCN-coordinated Pt(ii) units are covalently linked by a xanthene such that intramolecular formation of such dimeric or excimeric states is possible. These complexes display strong excimer-like photoluminescence at low concentrations where their monometallic analogues do not. However, a striking difference emerges between complexes where the Pt(NCN) units are directly connected to the xanthene through the tridentate ligand (denoted Class a) and a new class of compounds reported here (Class b) in which the attachment is through a monodentate acetylide ligand. The former require a substantial geometrical rearrangement to move the metal centres of the Pt(NCN) units to a distance short enough to form excimer-like states. The latter require only a small deformation. Consequently, Class a compounds display negligible excimer-like emission in solid films, as the rigid environment hinders the requisite geometric rearrangement. Class b complexes, in contrast, display strong excimer-like emission in film, even at very low loadings. The new dinuclear molecular architecture may thus offer new opportunities in the quest for efficient NIR-emitting devices

Synergistic Effect of Vitamin C on DNA Damage Induced by Cadmium

Abstract. Salts of divalent cadmium are well-known human mutagens and carcinogens. In the present work, the ability of vitamin C to modulate genotoxic effects of cadmium chloride on human lymphocytes was assessed using single cell gel electrophoresis (comet assay). Vitamin C at 20 and 100 µmol/l and cadmium at 5, 30 and 150 µmol/l significantly increased the tail moment of lymphocytes. Vitamin C also increased the tail moment of cells exposed to cadmium. This effect was concentration-dependent: the higher the vitamin C concentration the greater the tail moment. The combined effects of cadmium and vitamin C were more pronounced at all concentrations tested than the sum of the effects of the compounds applied separately (p < 0.05), so cadmium and vitamin C can be considered to have synergistic effects. The results obtained can be partly explained by the participation of cadmium in the Fenton reaction and reduction of its oxidized form by vitamin C

The carbonic anhydrase of Clostridium autoethanogenum represents a new subclass of β-carbonic anhydrases

Carbonic anhydrase catalyses the interconversion of carbon dioxide and water to bicarbonate and protons. It was unknown if the industrial relevant acetogen Clostridium autoethanogenum possesses these enzymes. We identified two putative carbonic anhydrase genes in its genome, one of the β class and one of the γ class. Carbonic anhydrase activity was found for the purified β class enzyme, but not the γ class candidate. Functional complementation of an Escherichia coli carbonic anhydrase knock-out mutant showed that the β class carbonic anhydrase could complement this activity, but not the γ class candidate gene. Phylogenetic analysis showed that the β class carbonic anhydrase of Clostridium autoethanogenum represents a novel sub-class of β class carbonic anhydrases that form the F-clade. The members of this clade have the shortest primary structure of any known carbonic anhydrase

Testing models of dental development in the earliest bony vertebrates, Andreolepis and Lophosteus

Theories on the development and evolution of teeth have long been biased by the fallacy that chondrichthyans reflect the ancestral condition for jawed vertebrates. However, correctly resolving the nature of the primitive vertebrate dentition is challenged by a dearth of evidence on dental development in primitive osteichthyans. Jaw elements from the Silurian–Devonian stem-osteichthyans Lophosteus and Andreolepis have been described to bear a dentition arranged in longitudinal rows and vertical files, reminiscent of a pattern of successional development. We tested this inference, using synchrotron radiation X-ray tomographic microscopy (SRXTM) to reveal the pattern of skeletal development preserved in the sclerochronology of the mineralized tissues. The tooth-like tubercles represent focal elaborations of dentine within otherwise continuous sheets of the dermal skeleton, present in at least three stacked generations. Thus, the tubercles are not discrete modular teeth and their arrangement into rows and files is a feature of the dermal ornamentation that does not reflect a polarity of development or linear succession. These fossil remains have no bearing on the nature of the dentition in osteichthyans and, indeed, our results raise questions concerning the homologies of these bones and the phylogenetic classification of Andreolepis and Lophosteus

Fleshing out your text: How elaboration and contextualization moves differentially predict writing quality

This study explores the relation between writing quality and contextualization and elaboration moves, two kinds of textual expansion devices crucial for building common ground between writers and readers. We ask whether elaboration and contextualization features differentially predict writing quality and whether their quality contributions differ between genres. We also ask to what extent elaboration and contextualization are tied to individual writers, and can be explained by writer characteristics. To examine these issues, we annotated descriptive and argumentative texts of Dutch adolescents. Text quality was rated holistically, using benchmark scales. As regards elaboration, depth affects quality more than breadth does. It also contributes across genres, whereas breadth only contributes in argumentations. Depth shows a large individual consistency across tasks, which is substantially related to students’ school type, grade and gender. Breadth shows weaker links to individual writers and their characteristics. With regard to contextualization, opening and closing moves play a modest role in text quality. Initial support moves contribute to quality across tasks; concluding moves contribute more in argumentations. Concluding moves are most consistent within writers; however, for all contextualization moves, the writer variance is substantially explained by writer characteristics. This study opens up new avenues for explicating writing quality and writing skill

Zirconium-based metal–organic frameworks as acriflavine cargos in the battle against coronaviruses : a theoretical and experimental approach

[Image: see text] In this study, we present a complementary approach for obtaining an effective drug, based on acriflavine (ACF) and zirconium-based metal–organic frameworks (MOFs), against SARS-CoV-2. The experimental results showed that acriflavine inhibits the interaction between viral receptor-binding domain (RBD) of spike protein and angiotensin converting enzyme-2 (ACE2) host receptor driving viral cell entry. The prepared ACF@MOF composites exhibited low (MOF-808 and UiO-66) and high (UiO-67 and NU-1000) ACF loadings. The drug release profiles from prepared composites showed different release kinetics depending on the local pore environment. The long-term ACF release with the effective antiviral ACF concentration was observed for all studied ACF@MOF composites. The density functional theory (DFT) calculations allowed us to determine that π–π stacking together with electrostatic interaction plays an important role in acriflavine adsorption and release from ACF@MOF composites. The molecular docking results have shown that acriflavine interacts with several possible binding sites within the RBD and binding site at the RBD/ACE2 interface. The cytotoxicity and ecotoxicity results have confirmed that the prepared ACF@MOF composites may be considered potentially safe for living organisms. The complementary experimental and theoretical results presented in this study have confirmed that the ACF@MOF composites may be considered a potential candidate for the COVID-19 treatment, which makes them good candidates for clinical trials