Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers.

There are considerable challenges in directly targeting the mutant p53 protein, given the large heterogeneity of p53 mutations in the clinic. An alternative approach is to exploit the altered fitness of cells imposed by loss-of-wild-type p53. Here we identify niclosamide through a HTS screen for compounds selectively killing p53-deficient cells. Niclosamide impairs the growth of p53-deficient cells and of p53 mutant patient-derived ovarian xenografts. Metabolome profiling reveals that niclosamide induces mitochondrial uncoupling, which renders mutant p53 cells susceptible to mitochondrial-dependent apoptosis through preferential accumulation of arachidonic acid (AA), and represents a first-in-class inhibitor of p53 mutant tumors. Wild-type p53 evades the cytotoxicity by promoting the transcriptional induction of two key lipid oxygenation genes, ALOX5 and ALOX12B, which catalyzes the dioxygenation and breakdown of AA. Therefore, we propose a new paradigm for targeting cancers defective in the p53 pathway, by exploiting their vulnerability to niclosamide-induced mitochondrial uncoupling.

Patterns of spread of head and neck adenoid cystic carcinoma.

We present a review of head and neck adenoid cystic carcinoma (ACC). Imaging features of the primary tumour, patterns of locoregional spread, and distant metastasis with emphasis on perineural extension and imaging pitfalls are discussed with illustrated examples.

Synthesis of (+)-obtusenyne.

An enantioselective synthesis of the halogenated medium-ring ether natural product (+)-obtusenyne is reported which uses the ring expansion of a seven-membered ketene acetal by means of a Claisen rearrangement to construct the core nine-membered oxygen heterocycle. The trans substituents across the ether linkage were established by using a transition-metal-catalyzed intramolecular hydrosilation reaction of an exo-cyclic enol ether. In addition, a formal synthesis of ent-obtusenyne from 2-deoxy-D-ribose is reported. A number of interesting points regarding the chemistry of medium-ring oxygen heterocycles are highlighted.

In-vitro study of medial strain distribution in the femur during impaction grafting.

Impaction bone grafting (IBG) is widely used for revision hip surgery to compensate for bone stock loss. It is performed by impacting morsellized allograft into the femoral canal and acetabulum prior to cementing new total hip components. Per- and post-operative femoral fractures and post-operative implant subsidence are major complications in IBG. The aim of this study was to investigate the strain distribution on the medial side of the femur during impaction grafting and the subsequent stability of the stem under uniaxial cyclic loading. The Exeter IBG technique was used in conjunction with Howmedica X-change instrumentation. Sawbones composite femora were used. An impactometer, which provides a known impaction energy and momentum, was used to standardize the impaction process. Three drop heights, 130, 260, and 390 mm, were used for proximal impaction. In-vitro medial hoop strains and the number of impacts were recorded. A drop height of 260 mm was found to provide sufficient energy for impaction without introducing excessive strains to achieve implant stability. Furthermore, a feasibility study was performed on the use of a proximal impaction cap (PIC) to restrain extrusion of the graft during impaction. Although no significant difference in impaction strains or stem stability in uniaxial cylic loading was found by using a PIC, it is postulated that the design of a proximal impactor could be improved to assist with proximal stem alignment and graft containment.

An XML-Java system for HL7-based healthcare informatics.

Health-Level (HL) 7 message semantics allows effective functional implementation of Electronic Medical Record (EMR)--encompassing both clinical and administrative (i.e. demographic and financial) information--interchange systems, at the expense of complexity with respect the Protocol Data Unit (PDU) structure and the client-side application architecture. In this paper we feature the usage of the Extensible Markup Language (XML) document-object modelling and Java client-server connectivity towards the implementation of a Web-based system for EMR transaction processing. Our solution features an XML-based description of EMR templates, which are subsequently transcribed into a Hypertext Markup Language (HTML)-Javascript form. This allows client-side user interfaceability and server-side functionality--i.e. message validation, authentication and database connectivity--to be handled through standard Web client-server mechanisms, the primary assumption being availability of a browser capable of XML documents and the associated stylesheets. We assume usage of the Internet as the interchange medium, hence the necessity for authentication and data privacy mechanisms, both of which can be constructed using standard Java-based building blocks.

Mature T cell reactivity altered by peptide agonist that induces positive selection.

Recent studies have investigated how defined peptides influence T cell development. Using a T cell receptor-transgenic beta2-microglobulin-deficient model, we have examined T cell maturation in fetal thymic organ cultures in the presence of various peptides containing single-alanine substitutions of the strong peptide agonist, p33. Cocultivation with the peptide A4Y, which contains an altered T cell contact residue, resulted in efficient positive selection. Several in vitro assays demonstrated that A4Y was a moderate agonist relative to p33. Although A4Y promoted positive selection over a wide concentration range, high doses of this peptide could not induce clonal deletion. Thymocytes maturing in the presence of A4Y were no longer able to respond to A4Y, but could proliferate against p33. These studies demonstrate that (a) peptides that induce efficient positive selection at high concentrations are not exclusively antagonists; (b) some agonists do not promote clonal deletion; (c) positive selection requires a unique T cell receptor-peptide-major histocompatibility complex interaction; and (d) interactions with selecting peptides during T cell ontogeny may define the functional reactivity of mature T cells.