Interaction of the σ2 Receptor Ligand PB28 with the Human Nucleosome: Computational and Experimental Probes of Interaction with the H2A/H2B Dimer

Sigma‐2 (σ₂) binding sites are an emerging target for anti‐neoplastic agents due to the strong apoptotic effect exhibited by σ₂ agonists in vitro and the overexpression of these sites in tumor cells. Nonetheless, no σ₂ receptor protein has been identified. Affinity chromatography using the high‐affinity σ₂ ligand PB28 and human SK‐N‐SH neuroblastoma cells was previously utilized to identify σ₂ ligand binding proteins, specifically histones H1, H2A, H2B, and H3.3a. To rationalize this finding, homology modeling and automated docking studies were employed to probe intermolecular interactions between PB28 and human nucleosomal proteins. These studies predicted interaction of PB28 with the H2A/H2B dimer at a series of sites previously found to be implicated in chromatin compaction and nucleosomal assembly. To experimentally verify this prediction, a competitive binding assay was performed on the reconstituted H2A/H2B dimer using [³H]PB28 as radioligand, and an IC₅₀ value of 0.50 nM was determined for PB28 binding. In addition, [³H]PB28 was found to accumulate with up to a fivefold excess in nuclear fractions over cytosolic fractions of SK‐N‐SH and MCF7 cells, indicating that PB28 is capable of entering the nucleus to interact with histone proteins. In conjunction with computational results, these data suggest that PB28 may exert its cytotoxic effect through direct interaction with nuclear material.     

New Protocols for the Synthesis of Condensed Heterocyclic Rings Through Palladium-Catalyzed Aryl Coupling Reactions

In the process of developing our aryl coupling methodology according to which aryl iodides are caused to react with aryl bromides under the catalytic action of a dual palladium/norbornene catalyst, we have worked out new protocols to cause appropriate functional groups in the aryl halides to form heterocyclic rings condensed with the first-formed biaryl intermediate. Carbazoles, dibenzopyrans, phenanthridines and azaphenanthrenes have been obtained with good yields in one-pot reactions under mild conditions.     

Building 3D Statistical Shape Models of Horticultural Products

A method to build a 3D statistical shape model of horticultural products is described. The framework consists of two parts. First, the surfaces of the horticultural products, which are extracted from X-ray CT scans, are registered to obtain meaningful correspondences between the surfaces. In the second part, a statistical shape model is built from these corresponded surfaces, which maps out the variability of the surfaces and allows to generate new, realistic surfaces. The proposed shape modelling method is applied to 30 Jonagold apples, 30 bell peppers, and 52 zucchini. The average geometric registration error between the original instance and the deformed reference instance is 0.015 ± 0.011 m m for the apple dataset, 0.106 ± 0.026 m m for the bell pepper dataset, and 0.027 ± 0.007 m m for the Zucchini dataset. All shape models are shown to be an excellent representation of their specific population, as they are compact and able to generalize to an unseen sample of the population.     

A theoretical study of light emission from nanoscale silicon

In comparing our calculated exciton energies with those obtained from pseudopotential calculations (Ref. 27) and from a previous tight binding calculation (Ref. 30), we stated that the differences between the three semi-empirical calculations arise because of different treatment of the nanocrystal surfaces. This appears not to be correct. Subsequent calculations with variable Si-H parameters have shown that the band gap is actually rather insensitive to the actual value of these. Instead, the important feature appears to be the overall quality of the bulk band structure parameterization. References 27 and 30 use more extensive and higher quality empirical parameterizations for bulk Si than the sp³s∗ model used by us. Repeating our time dependent calculations with an improved sp³d⁵ parameterization results in similar values to those of Refs. 27 and 30 for the exciton energies.¹ The agreement of the sp³s∗ values with experimental photoluminescence energies (Fig. 7) cannot, therefore, be regarded as well understood at this time.^1,2     

Recombinant human interleukin-3 hastens trilineage hematopoietic recovery following high-dose (7 g/m2) cyclophosphamide cancer therapy

BACKGROUND: Interleukin-3, a recombinant cytokine with multilineage stimulatory effect on hematopoietic cells, was administered to 22 previously untreated breast cancer patients following high-dose therapy with cyclophosphamide (7 g/m2). PATIENTS AND METHODS: The growth factor, administered through continuous intravenous infusion at 1 (3 patients), 2.5 (3 patients), 5 (10 patients) and 10 micrograms/kg/day (6 patients), was well tolerated up to 5 micrograms/kg/day. RESULTS: Nausea, vomiting, fever and headache prevented administration of the intended dose to all 6 patients in the 10 micrograms/kg/day cohort. At the maximal tolerable dose (5 micrograms/kg/day) the growth factor significantly accelerated granulocyte, platelet and reticulocyte recovery as compared to matched historical controls who received high-dose cyclophosphamide without cytokine infusion. Moreover, no platelet transfusions and fewer erythrocyte transfusions were required in interleukin 3-treated patients. In contrast to GM-CSF and G-CSF, interleukin 3 showed no effect on the mobilization of hematopoietic progenitor cells in the peripheral blood. CONCLUSIONS: Interleukin-3 represents a well-tolerated cytokine, clinically useful for accelerating trilineage hematopoietic recovery following severely myelotoxic treatments such as high-dose cyclophosphamide.     

Diatomite silica nanoparticles for drug delivery

Diatomite is a natural fossil material of sedimentary origin, constituted by fragments of diatom siliceous skeletons. In this preliminary work, the properties of diatomite nanoparticles as potential system for the delivery of drugs in cancer cells were exploited. A purification procedure, based on thermal treatments in strong acid solutions, was used to remove inorganic and organic impurities from diatomite and to make them a safe material for medical applications. The micrometric diatomite powder was reduced in nanoparticles by mechanical crushing, sonication, and filtering. Morphological analysis performed by dynamic light scattering and transmission electron microscopy reveals a particles size included between 100 and 300 nm. Diatomite nanoparticles were functionalized by 3-aminopropyltriethoxysilane and labeled by tetramethylrhodamine isothiocyanate. Different concentrations of chemically modified nanoparticles were incubated with cancer cells and confocal microscopy was performed. Imaging analysis showed an efficient cellular uptake and homogeneous distribution of nanoparticles in cytoplasm and nucleus, thus suggesting their potentiality as nanocarriers for drug delivery.

PACS

87.85.J81.05.Rm; 61.46. + w