Chemoresistance and chemosensitization in cholangiocarcinoma

One of the main difficulties in the management of patients with advanced cholangiocarcinoma (CCA) is their poor response to available chemotherapy. This is the result of powerful mechanisms of chemoresistance (MOC) of quite diverse nature that usually act synergistically. The problem is often worsened by altered MOC gene expression in response to pharmacological treatment. Since CCA includes a heterogeneous group of cancers their genetic signature coding for MOC genes is also diverse; however, several shared traits have been defined. Some of these characteristics are shared with other types of liver cancer, namely hepatocellular carcinoma and hepatoblastoma. An important goal in modern oncologic pharmacology is to develop novel strategies to overcome CCA chemoresistance either by increasing drug specificity, such as in targeted therapies aimed to inhibit receptors with tyrosine kinase activity, or to increase the amounts of active agents inside CCA cells by enhancing drug uptake or reducing efflux through export pumps. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.     

Chronicle of an impact foretold: the fate and effect of the introduced <Emphasis Type="Italic">Formica paralugubris</Emphasis> ant

Starting in 1958, red wood ants (Formica rufa group) from the Alps were transplanted to several Apennine forests along the Italian peninsula to be employed as biological control agents for tree insect pests. In the Campigna Biogenetic Nature Reserve, central Italy, hundreds of mounds of the dominant Formica paralugubris were repeatedly introduced, creating several populations that still survive today. In this study, we analyzed the temporal dynamics and the ecological impact of five of these populations. Their present state was assessed by censusing the total number of nest mounds and their volumes, while past changes were reconstructed from literature records. We also evaluated the impact of this species on autochthonous arthropod communities by comparing impacted and non-impacted areas and performing predation experiments. The density of nests and their volume remained stable or declined for a few years after transplant, and then they began to grow steadily. Local arthropods were severely affected, since almost all collected groups were significantly less represented in impacted than in non-impacted sites. Additionally, experiments with live bait demonstrated that potential prey have a significantly greater probability of being consumed in the areas occupied by F. paralugubris. These results prompt a thorough assessment of the fate of the introduced red wood ant populations, since their role as biological control agents has to be traded against the ecological impact on native arthropod communities. This is particularly relevant for highly biodiverse areas, such as the Campigna forest, that are home of several invertebrate species with conservation interest.     

Sugars Communicate through Water: Oriented Glycans Induce Water Structuring

Cells are coated with a glycocalyx—a layer of carbohydrate-containing biomolecules, such as glycoproteins. Although the structure and orientation of the cell-surface glycans are frequently regarded as being random, we have found, using α-1-acid glycoprotein and antitrypsin as model systems for surface glycans, that this is not the case. A glycoprotein monolayer was adsorbed onto hydrophilic and hydrophobic substrates. Surface-force measurements revealed that the orientation of the glycans with respect to the aqueous solution has a profound effect on the structure of vicinal water. The glycan antennae of the surface-adsorbed glycoproteins apparently impose an ordering on the water, resulting in a strong repulsive force over some tens of nanometers with superposed film-thickness transitions ranging from ≈0.7 to 1.8 nm. When the glycan orientation is modified by chemical means, this long-range repulsion disappears. These results may provide an explanation as to why the multiantennary structure is ubiquitous in glycoproteins. Although direct, specific interactions between glycans and other biomolecules are essential for their functionality, these results indicate that glycans’ long-range structuring of water may also influence their ability to interact with biomolecules in their vicinity.     

Sequence-Specific Transcription Factor NF-Y Displays Histone-like DNA Binding and H2B-like Ubiquitination

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Highlights? 3D structure of NF-Y/CCAAT shows close relationships to core histones H2A/H2B ? NF-YA displays a sequence-specific DNA minor groove-binding module ? Histone H2B and NF-YB share a functional posttranslational modification ? NF-Y binding and monoubiquitination are early events in gene activation     

Mechanical aspects of CO2 angiography

The aim of this paper is to clarify some physical–mechanical aspects involved in the carbon dioxide angiography procedure (CO₂ angiography), with a particular attention to a possible damage of the vascular wall.CO₂ angiography is widely used on patients with iodine intolerance. The injection of a gaseous element, in most cases manually performed, requires a long training period. Automatic systems allow better control of the injection and the study of the mechanical behaviour of the gas.CO₂ injections have been studied by using manual and automatic systems. Pressures, flows and jet shapes have been monitored by using a cardiovascular mock. Photographic images of liquid and gaseous jet have been recorded in different conditions, and the vascular pressure rises during injection have been monitored.The shape of the liquid jet during the catheter washing phase is straight in the catheter direction and there is no jet during gas injection. Gas bubbles are suddenly formed at the catheter’s hole and move upwards: buoyancy is the only governing phenomenon and no bubbles fragmentation is detected. The pressure rise in the vessel depends on the injection pressure and volume and in some cases of manual injection it may double the basal vascular pressure values.CO₂ angiography is a powerful and safe procedure which diffusion will certainly increase, although some aspects related to gas injection and chamber filling are not jet well known. The use of an automatic system permits better results, shorter training period and limitation of vascular wall damage risk.     

CYP 17 and CYP 19 Inhibitors. Evaluation of Fluorine Effects on the Inhibiting Activity of Regioselectively Fluorinated 1-(Naphthalen-2-ylmethyl)imidazoles

Regioselectively fluorinated 1-(naphth-2-ylmethyl)imidazoles 1a–h have been synthesized starting from the corresponding (naphth-2-yl)methanols (2). 2a–d have been obtained by LiAlH4-promoted reduction of fluorinated 1-methyl-2-naphthaldehydes. The latter were easily prepared in fairly good overall yields by ceric ammonium nitrate (CAN)-promoted oxidative addition of the suitable 3-(fluoroaryl)-1-trimethylsilyloxy-1-butenes to ethyl vinyl ether in methanol followed by cyclization of the resulting acetals in strongly acidic medium in the presence of DDQ. 2e–h were prepared by LiAlH4-promoted reduction of the corresponding fluorinated methyl 2-naphthoates. The latter were more profitably obtained by reacting the suitable benzyl bromide with the sodium salt of dimethyl 2-(2,2-dimethoxyethyl)malonate in DMF followed by demethoxycarbonylation and acid catalysed cyclization of the resulting acetals. Compared with the non-fluorinated parent compounds 1i–l, fluorinated 1-(naphth-2-yl)methylimidazoles 1a–h turned out to be potent inhibitors of CYP17 and CYP19 enzymes. The most active inhibitor of CYP17 is 1c, whereas CYP19 is strongly inhibited by 1b, 1e, and 1g. Interestingly, 1g is a potent dual inhibitor also being very active towards CYP19.     

Ecological and evolutionary implications of food subsidies from humans

Human activities are the main current driver of global change. From hunter‐gatherers through to Neolithic societies–and particularly in contemporary industrialised countries–humans have (voluntarily or involuntarily) provided other animals with food, often with a high spatio‐temporal predictability. Nowadays, as much as 30–40% of all food produced in Earth is wasted. We argue here that predictable anthropogenic food subsidies (PAFS) provided historically by humans to animals has shaped many communities and ecosystems as we see them nowadays. PAFS improve individual fitness triggering population increases of opportunistic species, which may affect communities, food webs and ecosystems by altering processes such as competition, predator–prey interactions and nutrient transfer between biotopes and ecosystems. We also show that PAFS decrease temporal population variability, increase resilience of opportunistic species and reduce community diversity. Recent environmental policies, such as the regulation of dumps or the ban of fishing discards, constitute natural experiments that should improve our understanding of the role of food supply in a range of ecological and evolutionary processes at the ecosystem level. Comparison of subsidised and non‐subsidised ecosystems can help predict changes in diversity and the related ecosystem services that have suffered the impact of other global change agents.     

Synthesis,HPLC Enantioresolution,and X‐ray Analysis of a New Series of C5‐methyl Pyridazines as N‐Formyl Peptide Receptor (FPR) Agonists

The synthesis of three racemates and the corresponding non‐chiral analogues of a C5‐methyl pyridazine series is described here, as well as the isolation of pure enantiomers and their absolute configuration assignment. In order to obtain optically active compounds, direct chromatographic methods of separation by HPLC‐UV were investigated using four chiral stationary phases (CSPs: Lux Amylose‐2, Lux Cellulose‐1, Lux Cellulose‐2 and Lux Cellulose‐3). The best resolution was achieved using amylose tris(5‐chloro‐2‐methylphenylcarbamate) (Lux Amylose‐2), and single enantiomers were isolated on a semipreparative scale with high enantiomeric excess, suitable for biological assays. The absolute configuration of optically active compounds was unequivocally established by X‐ray crystallographic analysis and comparative chiral HPLC‐UV profile. All compounds of the series were tested for formyl peptide receptor (FPR) agonist activity, and four were found to be active, with EC₅₀ values in the micromolar range. Chirality 25:400–408, 2013. © 2013 Wiley Periodicals, Inc.     

Practical considerations over spectral quality in solid state NMR spectroscopy of soluble proteins

Great theoretical and methodological advances are pushing the limits of resolution and sensitivity in solid state NMR (SSNMR). However, sample preparation remains a critical issue for the success of an experiment. The factors affecting spectral quality in SSNMR samples are discussed, examining cases encountered in the literature and presenting new experimental data. A discussion on resolution and sensitivity in sedimented solutes is framed in this context.     

Susceptibility of Human Placenta Derived Mesenchymal Stromal/Stem Cells to Human Herpesviruses Infection

Fetal membranes (FM) derived mesenchymal stromal/stem cells (MSCs) are higher in number, expansion and differentiation abilities compared with those obtained from adult tissues, including bone marrow. Upon systemic administration, ex vivo expanded FM-MSCs preferentially home to damaged tissues promoting regenerative processes through their unique biological properties. These characteristics together with their immune-privileged nature and immune suppressive activity, a low infection rate and young age of placenta compared to other sources of SCs make FM-MSCs an attractive target for cell-based therapy and a valuable tool in regenerative medicine, currently being evaluated in clinical trials. In the present study we investigated the permissivity of FM-MSCs to all members of the human Herpesviridae family, an issue which is relevant to their purification, propagation, conservation and therapeutic use, as well as to their potential role in the vertical transmission of viral agents to the fetus and to their potential viral vector-mediated genetic modification. We present here evidence that FM-MSCs are fully permissive to infection with Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), Varicella zoster virus (VZV), and Human Cytomegalovirus (HCMV), but not with Epstein-Barr virus (EBV), Human Herpesvirus-6, 7 and 8 (HHV-6, 7, 8) although these viruses are capable of entering FM-MSCs and transient, limited viral gene expression occurs. Our findings therefore strongly suggest that FM-MSCs should be screened for the presence of herpesviruses before xenotransplantation. In addition, they suggest that herpesviruses may be indicated as viral vectors for gene expression in MSCs both in gene therapy applications and in the selective induction of differentiation.