Utility of poly(ethylene glycol) conjugation to create prodrugs of amphotericin B

This paper reports on the synthesis, safety, and efficacy of a series of water-soluble derivatives of poly(ethylene glycol) (PEG)-conjugated amphotericin B (AmB). PEG 40 000 attached to the sugar amino group of AmB via labile carbamate and carbonate linkages was examined. The synthetic program conducted for this investigation provided a series of disubstituted PEG-AmB derivatives which had in vitro PEG half-life of hydrolyses rates in rat plasma varying between 1 and 3 h. Importantly, all conjugates demonstrated less than 6% hydrolysis following 24 h incubation in pH 7.4 phosphate buffer at 25 degrees C and showed solubilities greater than 46 mg/mL in aqueous solutions. The solubility of AmB in the conjugates increased up to approximately 200 times compared to unmodified AmB in saline. As a major finding, this investigation demonstrated that conjugation of PEG to AmB could produce conjugates that were significantly (6x) less toxic than AmB-deoxycholate and maintained, or even had enhanced, in vivo antifungal activity.     

High-throughput identification of inhibitors of human mitochondrial peptide deformylase

The human mitochondrial peptide deformylase (HsPDF) provides a potential new target for broadly acting antiproliferative agents. To identify novel nonpeptidomimetic and nonhydroxamic acid-based inhibitors of HsPDF, the authors have developed a high-throughput screening (HTS) strategy using a fluorescence polarization (FP)-based binding assay as the primary assay for screening chemical libraries, followed by an enzymatic-based assay to confirm hits, prior to characterization of their antiproliferative activity against established tumor cell lines. The authors present the results and performance of the established strategy tested in a pilot screen of 2880 compounds and the identification of the 1st inhibitors. Two common scaffolds were identified within the hits. Furthermore, cytotoxicity studies revealed that most of the confirmed hits have antiproliferative activity. These findings demonstrate that the designed strategy can identify novel functional inhibitors and provide a powerful alternative to the use of functional assays in HTS and support the hypothesis that HsPDF inhibitors may constitute a new class of antiproliferative agent.     

The association of wall mechanics and morphology: a case study of abdominal aortic aneurysm growth

The purpose of this study is to evaluate the potential correlation between peak wall stress (PWS) and abdominal aortic aneurysm (AAA) morphology and how it relates to aneurysm rupture potential. Using in-house segmentation and meshing software, six 3-dimensional (3D) AAA models from a single patient followed for 28 months were generated for finite element analysis. For the AAA wall, both isotropic and anisotropic materials were used, while an isotropic material was used for the intraluminal thrombus (ILT). These models were also used to calculate 36 geometric indices characteristic of the aneurysm morphology. Using least squares regression, seven significant geometric features (p?相似文献   

Choriocarcinoma metastatic to the lung. A cytologic study with identification of human choriogonadotropin with an immunoperoxidase technique

A case of choriocarcinoma metastatic to the lung following a previous hydatidiform mole is presented. It was possible to make definitive identification of trophoblastic elements on a needle aspiration biopsy using an immunoperoxidase staining technique, thus avoiding diagnostic thoracotomy prior to therapeutic intervention. A method of immunoperoxidase staining of previously fixed and Papanicolaou-stained needle aspiration biopsy specimens is also described, and other uses of the immunoperoxidase technique on needle biopsy specimens are discussed.     

Bilateral otolith contribution to spatial coding in the vestibular system

Recent work on the coding of spatial information in central otolith neurons has significantly advanced our knowledge of signal transformation from head-fixed otolith coordinates to space-centered coordinates during motion. In this review, emphasis is placed on the neural mechanisms by which signals generated at the bilateral labyrinths are recognized as gravity-dependent spatial information and in turn as substrate for otolithic reflexes. We first focus on the spatiotemporal neuronal response patterns (i.e. one- and two-dimensional neurons) to pure otolith stimulation, as assessed by single unit recording from the vestibular nucleus in labyrinth-intact animals. These spatiotemporal features are also analyzed in association with other electrophysiological properties to evaluate their role in the central construction of a spatial frame of reference in the otolith system. Data derived from animals with elimination of inputs from one labyrinth then provide evidence that during vestibular stimulation signals arising from a single utricle are operative at the level of both the ipsilateral and contralateral vestibular nuclei. Hemilabyrinthectomy also revealed neural asymmetries in spontaneous activity, response dynamics and spatial coding behavior between neuronal subpopulations on the two sides and as a result suggested a segregation of otolith signals reaching the ipsilateral and contralateral vestibular nuclei. Recent studies have confirmed and extended previous observations that the recovery of resting activity within the vestibular nuclear complex during vestibular compensation is related to changes in both intrinsic membrane properties and capacities to respond to extracellular factors. The bilateral imbalance provides the basis for deranged spatial coding and motor deficits accompanying hemilabyrinthectomy. Taken together, these experimental findings indicate that in the normal state converging inputs from bilateral vestibular labyrinths are essential to spatiotemporal signal transformation at the central otolith neurons during low-frequency head movements.