Synthesis and characterization of the tetranuclear iron(III) complex of a new asymmetric multidentate ligand. A structural model for purple acid phosphatases

The ligand, 2-((2-hydroxy-5-methyl-3-((pyridin-2-ylmethylamino)methyl)benzyl)(2-hydroxybenzyl)amino)acetic acid (H(3)HPBA), which contains a donor atom set that mimics that of the active site of purple acid phosphatase is described. Reaction of H(3)HPBA with iron(III) or iron(II) salts results in formation of the tetranuclear complex, [Fe-4(HPBA)(2)(OAc)(2)(mu-O)(mu-OH)(OH2)(2)]ClO4 center dot 5H(2)O. X-Ray structural analysis reveals the cation consists of four iron(III) ions, two HPBA(3-) ligands, two bridging acetate ligands, a bridging oxide ion and a bridging hydroxide ion. Each binucleating HPBA(3-) ligand coordinates two structurally distinct hexacoordinate iron(III) ions. The two metal ions coordinated to a HPBA(3-) ligand are linked to the two iron(III) metal ions of a second, similar binuclear unit by intramolecular oxide and hydroxide bridging moieties to form a tetramer. The complex has been further characterised by elemental analysis, mass spectrometry, UV-vis and MCD spectroscopy, X- ray crystallography, magnetic susceptibility measurements and variable-temperature Mossbauer spectroscopy

Ecto-5’-nucleotidase: Structure function relationships

Ecto-5’-nucleotidase (ecto-5’-NT) is attached via a GPI anchor to the extracellular membrane, where it hydrolyses AMP to adenosine and phosphate. Related 5’-nucleotidases exist in bacteria, where they are exported into the periplasmic space. X-ray structures of the 5’-nucleotidase from E. coli showed that the enzyme consists of two domains. The N-terminal domain coordinates two catalytic divalent metal ions, whereas the C-terminal domain provides the substrate specificity pocket for the nucleotides. Thus, the substrate binds at the interface of the two domains. Here, the currently available structural information on ecto-5’NT is reviewed in relation to the catalytic properties and enzyme function

Increased sensitivity to TRAIL-induced apoptosis occurs during the adenoma to carcinoma transition of colorectal carcinogenesis

The death ligand TRAIL (Apo2L) has potential for cancer therapy, since tumour cells are thought to be more sensitive than normal cells. We investigated whether sensitivity to TRAIL increases during the adenoma to carcinoma transition of colorectal carcinogenesis. Under the same culture conditions, we compared the extent of TRAIL-induced apoptosis in four premalignant adenoma and three carcinoma cell lines. Although TRAIL induced some apoptosis in adenoma cultures, the carcinoma cell lines were significantly more sensitive (P<0.001). This finding was recapitulated in an in vitro model of tumour progression in which conversion of the adenoma cell line AA/C1 to a tumorigenic phenotype was associated with increased TRAIL sensitivity (P<0.001). Increased TRAIL sensitivity during colorectal carcinogenesis has been previously attributed to changes in the balance between TRAIL receptors TRAIL-R1 and -R2 and ‘decoy' receptors TRAIL-R3 and -R4 during malignant progression. To address this, cell surface receptor expression was measured by flow cytometry. In summary, during colorectal carcinogenesis, there is a marked increase in sensitivity to TRAIL-induced apoptosis associated with progression from benign to malignant tumour that could be exploited for colon cancer therapy, but alterations in cell surface TRAIL receptor expression may not be the primary reason for this change

A New Heterobinuclear FeIIICuII Complex with a Single Terminal FeIII–O(phenolate) Bond. Relevance to Purple Acid Phosphatases and Nucleases

A novel heterobinuclear mixed valence complex [Fe^IIICu^II(BPBPMP)(OAc)_2]ClO_4, 1, with the unsymmetrical N_5O_2 donor ligand 2-bis[{(2-pyridylmethyl)aminomethyl}-6-{(2-hydroxybenzyl)(2-pyridylmethyl)} aminomethyl]-4-methylphenol (H_2BPBPMP) has been synthesized and characterized. A combination of data from mass spectrometry, potentiometric titrations, X-ray absorption and electron paramagnetic resonance spectroscopy, as well as kinetics measurements indicates that in ethanol/water solutions an [Fe^III-(nu)OH-Cu^IIOH_2]+ species is generated which is the likely catalyst for 2,4-bis(dinitrophenyl)phosphate and DNA hydrolysis. Insofar as the data are consistent with the presence of an Fe_III-bound hydroxide acting as a nucleophile during catalysis, 1 presents a suitable mimic for the hydrolytic enzyme purple acid phosphatase. Notably, 1 is significantly more reactive than its isostructural homologues with different metal composition (Fe^IIIM^II, where M^II is Zn^II, Mn^II, Ni^II,or Fe^II). Of particular interest is the observation that cleavage of double-stranded plasmid DNA occurs even at very low concentrations of 1 (2.5 nuM), under physiological conditions (optimum pH of 7.0), with a rate enhancement of 2.7 x 10^7 over the uncatalyzed reaction. Thus, 1 is one of the most effective model complexes to date, mimicking the function of nucleases

<i>MYCN</i> amplification drives an aggressive form of spinal ependymoma

Spinal ependymal tumors form a histologically and molecularly heterogeneous group of tumors with generally good prognosis. However, their treatment can be challenging if infiltration of the spinal cord or dissemination throughout the central nervous system (CNS) occurs and, in these cases, clinical outcome remains poor. Here, we describe a new and relatively rare subgroup of spinal ependymal tumors identified using DNA methylation profiling that is distinct from other molecular subgroups of ependymoma. Copy number variation plots derived from DNA methylation arrays showed MYCN amplification as a characteristic genetic alteration in all cases of our cohort (n = 13), which was subsequently validated using fluorescence in situ hybridization. The histological diagnosis was anaplastic ependymoma (WHO Grade III) in ten cases and classic ependymoma (WHO Grade II) in three cases. Histological re-evaluation in five primary tumors and seven relapses showed characteristic histological features of ependymoma, namely pseudorosettes, GFAP- and EMA positivity. Electron microscopy revealed cilia, complex intercellular junctions and intermediate filaments in a representative sample. Taking these findings into account, we suggest to designate this molecular subgroup spinal ependymoma with MYCN amplification, SP-EPN-MYCN. SP-EPN-MYCN tumors showed distinct growth patterns with intradural, extramedullary localization mostly within the thoracic and cervical spine, diffuse leptomeningeal spread throughout the whole CNS and infiltrative invasion of the spinal cord. Dissemination was observed in 100% of cases. Despite high-intensity treatment, SP-EPN-MYCN showed significantly worse median progression free survival (PFS) (17 months) and median overall survival (OS) (87 months) than all other previously described molecular spinal ependymoma subgroups. OS and PFS were similar to supratentorial ependymoma with RELA-fusion (ST-EPN-RELA) and posterior fossa ependymoma A (PF-EPN-A), further highlighting the aggressiveness of this distinct new subgroup. We, therefore, propose to establish SP-EPN-MYCN as a new molecular subgroup in ependymoma and advocate for testing newly diagnosed spinal ependymal tumors for MYCN amplification

Recurrent stroke: the role of thrombophilia in a large international pediatric stroke population

Risk factors for arterial ischaemic stroke in children include vasculopathy and prothrombotic risk factors but their relative importance to recurrent stroke is uncertain. Data on recurrent stroke from the databases held in Canada (Toronto), Germany (Kiel-Lubeck/Munster), and UK (London/Southampton) were pooled. Data were available from 894 patients aged 1 month to 18 years at first stroke (median age 6 years) with a median follow-up of 35 months. 160/894 patients (17.9%) had recurrence from 1 day to 136 months after first stroke (median 3.1 months). Among 288 children with vasculopathy, recurrence was significantly more common (hazard ratio (HR) 2.5, 95% confidence intervals (CI) 1.92-3.5) compared to children without vasculopathy. Adjusting for vasculopathy, isolated antithrombin deficiency (HR 3.9; 95%CI 1.4-10.9), isolated elevated lipoprotein (a) (HR 2.3; 95%CI 1.3-4.1), and the presence of more than one prothrombotic risk (HR 1.9; 95%CI 1.12-3.2) were independently associated with an increased risk of recurrence. Recurrence rates calculated per 100 person-years were 10 (95%CI 3-24) for antithrombin deficiency, 6 (95%CI 4-9) for elevated lipoprotein (a), and 13 (95%CI 7-20) for the presence of more than one prothrombotic risk. Identifying children at increased for second stroke events is important in intensifying measures aimed at preventing recurrent stroke

Fog and Dew as Potable Water Resources: Maximizing Harvesting Potential and Water Quality Concerns

Fog and dew are often viewed as economic nuisances causing significant financial losses in the transportation industry and agricultural sector. However, they are also critical components of the hydrological cycle, especially in water scarce environments. Water scarcity is one of the major threats to mankind in the 21st century, and this can be due to development pressures, pollution, and/or expanding populations. In water scarce environments, fog and dew represent potentially exploitable ancillary water resources that could ameliorate the water scarce situation, if efficiently harvested. However, two important issues are often overlooked in relation to fog and dew harvesting and potability. First, current fog and dew harvesting technologies are low yielding with great potential for improvements. Second and more importantly, the potability of these water resources is often based on simple analyses that often omit trace metal and biological analyses. The few studies that report trace metal or biological measurements suggest elevated trace metal concentrations or biological contamination that could be of concern to public health. We discuss the potential for fog and dew harvesting technologies and the need for trace metal and biological analyses of these waters before use