A design tool for use in simulation and training of sinus surgery

The traditional approaches to training surgeons are becoming increasingly difficult to apply to modern surgical procedures. The development of Minimally Invasive Surgery (MIS) techniques demands new and complex psychomotor skills, and means that the apprentice-based system described by “see one, do one, teach one” can no longer be expected to fully prepare surgeons for operations on real patients, placing patient safety at risk. The use of cadavers and animals in surgical training raises issues of ethics, cost and anatomical similarity to live humans. Endoscopic sinus surgery involves further risk to the patient due to the proximity of vital structures such as the brain, eyes, optic nerve and internal carotid artery. In recent years, simulation has been used to overcome these problems, exposing surgeons to complex procedures in a safe environment, similarly to its use in aviation. However, the cases simulated in this manner may not be customised by training staff to present desired pathology. This thesis describes the design and development of a new tool for the creation of customised cases for the training of sinus surgery. Users who are inexperienced and non-skilled in the use of three-dimensional (3D) Computer Aided Design (CAD) modelling software may use the tool to implement pathology to the virtual sinus model, which was constructed from real CT data. Swelling is applied in five directions (four horizontal, one vertical) to the cavity lining of the frontal and sphenoid sinuses. Tumours are individually customised and positioned in the frontal, sphenoid and ethmoid sinuses. The customised CAD model may then be latterly manufactured using Three-Dimensional Printing (3DP) to produce the complex anatomy of the sinuses in a full colour physical part for the realistic simulation of surgical procedures. An investigation into the colouring of the physical model is also described, involving the study of endoscopic videos to ascertain realistic shades. The program was evaluated by a group of medical professionals from a range of fields, and their feedback was taken into account in subsequent redevelopment of the program, and to suggest further work

Stereoselective Synthesis of the C9–C19 Fragment of Lyngbyaloside B and C via Ether Transfer

A stereoselective synthesis of the C9–C19 fragment of lyngbyaloside B and C highlighted, by an extension of our ether transfer methodology, enables the formation of tertiary ethers. 2-Naphthylmethyl ethers have been shown to proceed efficiently through ether transfer with high stereoselectivity and are easily deprotected by DDQ oxidation. Variation of the workup conditions results in the stereoselective formation of <i>syn</i>-1,3-diol mono- or diethers

Toward an Enantioselective Synthesis of (−)-Zampanolide: Preparation of the C9–C20 Region

Progress toward the synthesis of the microtubule-stabilizing agent, (−)-zampanolide, is reported. Construction of the 2,6-<i>cis-</i>tetrahydropyran ring was accomplished utilizing <i>ether transfer</i> methodology in conjunction with an intramolecular radical cyclization reaction. Efficient installation of the C16–C20 side chain relied on a one-pot cross-metathesis/olefination sequence, Sharpless epoxidation, and selective reduction of a vinyl epoxide

Rapid Access to Conformational Analogues of (+)-Peloruside A

An efficient synthetic strategy for rapid access to analogues of peloruside A has been demonstrated. The synthetic route was highlighted by a simple esterification-based fragment coupling and a late stage ring-closing metathesis reaction. This convergent route has provided access to rationally designed analogues inspired by the solution conformational preferences of peloruside A

Conformational Preferences of Zampanolide and Dactylolide

The solution conformation behavior of the macrolide core of microtubule-stabilizing agents (−)-zampanolide and (−)-dactylolide has been determined through a combination of high-field NMR experiments and computational modeling. Taken together, the results demonstrate that in solution both molecules exist as a mixture of three interconverting conformational families, one of which bears strong resemblance to zampanolide’s tubulin-bound conformation

Elucidation of Gephyronic Acid Biosynthetic Pathway Revealed Unexpected SAM-Dependent Methylations

Gephyronic acid, a cytostatic polyketide produced by the myxobacterium <i>Cystobacter violaceus</i> Cb vi76, exhibits potent and selective eukaryotic protein synthesis inhibition. Next-generation sequencing of the <i>C. violaceus</i> genome revealed five type I polyketide synthases and post-PKS tailoring enzymes including an <i>O</i>-methyltransferase and a cytochrome P450 monooxygenase. Seven methyltransferase (MT) domains embedded within the PKS subunits were found to install the methyl branches throughout the gephyronic acid skeleton. A rare loading domain from the GNAT superfamily also contains an embedded MT domain that catalyzes the in situ production of an isobutyryl starter unit. Phylogenetic analysis identified new motifs that distinguish MT domains located in PKS pathways with <i>in cis</i> acyltransferase (AT) domains from MT domains located in PKS pathways with <i>trans</i> AT enzymes. The identification of the gene cluster sets the stage for the generation of a heterologous expression system, which will allow further investigation of selective eukaryotic protein synthesis inhibitors through the generation of gephyronic acid analogues

Bicistronic reporter systems in KB-3-1 cells allowing to compare cap-dependent translation directly to cap-independent in the same environment.

<p>GA inhibited the translation of the polio IRES sequence (a) but not that of the CrPV IRES (b). DMDA-pateamine A which targets eIF4A also inhibited the polio IRES and not the CrPV IRES mediated translation. Cycloheximide, which targets the elongation phase, inhibited translation from both IRES sequences. All experiments were run in triplicates. The error bars show standard deviations.</p

Inhibition of translation in two <i>in vitro</i> systems.

<p>(a) GA (■) inhibited the translation in a rabbit reticulocyte lysate more efficiently than cycloheximide (●). The error bars show standard deviations. (b) GA also inhibited a wheat germ lysate translation system. Here, the relative standard deviations were < 5%. The error bars do not exceed the square symbols. All experiments were run in triplicates.</p

Activity of GA in primary and transformed cells.

<p>Human dermal fibroblasts (NHDF; □) and cancerous KB-3-1 cells (■) were incubated with different concentrations of GA and measured for viability after 48 hours. NHDFs were less sensitive than KB-3-1 cancer cells.</p

Biotinylation of GA methylester 2.

<p>Steglich esterification resulted the two biotinylated derivatives <b>4a</b> and <b>4b</b>.</p