Computational approaches to predicting drug induced toxicity

Errors and issues requiring clarification are included as a separate document (January 2016).Novel approaches and models for predicting drug induced toxicity in silico are presented. Typically, these were based on Quantitative Structure-Activity Relationships (QSAR). The following endpoints were modelled: mutagenicity, carcinogenicity, inhibition of the hERG ion channel and the associated arrhythmia - Torsades de Pointes. A consensus model was developed based on Derek for WindowsTM and Toxtree and used to filter compounds as part of a collaborative effort resulting in the identification of potential starting points for anti-tuberculosis drugs. Based on the careful selection of data from the literature, binary classifiers were generated for the identification of potent hERG inhibitors. These were found to perform competitively with, or better than, those computational approaches previously presented in the literature. Some of these models were generated using Winnow, in conjunction with a novel proposal for encoding molecular structures as required by this algorithm. The Winnow models were found to perform comparably to models generated using the Support Vector Machine and Random Forest algorithms. These studies also emphasised the variability in results which may be obtained when applying the same approaches to different train/test combinations. Novel approaches to combining chemical information with Ultrafast Shape Recognition (USR) descriptors are introduced: Atom Type USR (ATUSR) and a combination between a proposed Atom Type Fingerprint (ATFP) and USR (USR-ATFP). These were applied to the task of predicting protein-ligand interactions - including the prediction of hERG inhibition. Whilst, for some of the datasets considered, either ATUSR or USR-ATFP was found to perform marginally better than all other descriptor sets to which they were compared, most differences were statistically insignificant. Further work is warranted to determine the advantages which ATUSR and USR-ATFP might offer with respect to established descriptor sets. The first attempts to construct QSAR models for Torsades de Pointes using predicted cardiac ion channel inhibitory potencies as descriptors are presented, along with the first evaluation of experimentally determined inhibitory potencies as an alternative, or complement to, standard descriptors. No (clear) evidence was found that 'predicted' ('experimental') 'IC-descriptors' improve performance. However, their value may lie in the greater interpretability they could confer upon the models. Building upon the work presented in the preceding chapters, this thesis ends with specific proposals for future research directions

Radiology corner

Two patients presented with multiple concentric calcifications superimposed over the mandibular ramus region. The first patient was a 41-year-old male who presented to the dental clinic requesting a partial denture (Figure 1A). The calcifications were detected incidentally on panoramic radiography. The second patient was a 15- year-old female who presented with a left facial swelling that had been present for 7 years (Figure 1B). What is your diagnostic hypothesis for both patients

South Africa’s contribution in the field of Forensic Odontology - A textbook review

This textbook represents an up-to-date, comprehensive compilation of the field of Forensic Odontology. The chapters have been uniquely structured to take the reader through all aspects of this discipline in a methodical and logical approach. Authors for each section were carefully selected as being internationally recognised experts and renowned amongst their peers in their particular field of Forensic Odontology. The material in this textbook is presented in a manner that is both interesting and clear for novices in the discipline, while at the same time offering highly informative, cutting-edge information for experts practising Forensic Odontology. The book begins with a chronology of the origin of Forensic Odontology dating back to 1477, using intriguing real-life cases to set the theme for the rest of the book

Maxillofacial Radiology 192

A 64-year-old male patient, who is human immunodeficiency virus (HIV) positive on treatment, presented with atwo-year history of a painful swelling involving the left parotid gland. Cone beam computerised tomographic (CBCT) imaging was performed (Figures A-D). What are the pertinent radiological findings and your diagnostic hypothesis

Maxillofacial Radiology 205

A 5-year-old healthy female patient presented with a one-year history of a slow-growing swelling of the right mandible. The patient reported that the swelling was slightly tender. Intraoral examination revealed a grossly carious lower right primary molar (tooth 85). A panoramic radiograph showed bony expansion of the inferior mandibular border with a lamellated or ‘onion-skin’ appearance. The trabecular bone in the vicinity had a sclerotic appearance. What is your diagnostic hypothesis

Maxillofacial Radiology 202

A 30-year-old male patient, RVD-reactive on treatment, presented with a fast-growing, painful swelling involving the mandible of unknown duration. A panoramic radiograph (PR) and cone-beam computed tomography (CBCT) imaging were performed. What are the pertinent radiological features and your diagnostic hypothesis

Maxillofacial Radiology 201

Two female patients presented with multiple radiolucent lesions noted on panoramic radiography. Cone-beam computed tomography (CBCT) scans confirmed multiple “punched-out” lesions affecting the skull

Maxillofacial Radiology 198

Two paediatric male patients presented with painless bilateral facial swellings (Figures 1 and 2A&B). What are the pertinent radiological findings and your diagnostic hypothesis

You can run, but you can’t hide - A bitemark analysis

All names and places have been changed to protect innocent victims in this case report. A young woman was returning home after work when she was accosted by a man wielding a knife. She was dragged into a nearby bush where the suspect attempted to rape her. She put up a substantial fight and was able to flee the scene. She went directly to the nearest police station to report the case. She was asked by the police to accompany them in the hope that she might recognise the suspect at the local taxi rank, which was near the scene of the crime. She did in fact recognise the suspect who was duly arrested. He denied any knowledge of the crime for which he was being apprehended. The victim informed the police that she had remembered biting the suspect on his right shoulder during the attack and ensuing struggle. The suspect was asked to roll up his right sleeve where a possible bitemark wound was observed. The suspect was taken into custody for further investigations. Fortunately, the police officer in charge of the case had attended a lecture on bitemarks given by the second author some weeks before the incident and was therefore well-versed in the protocol for the collection of evidence in a bitemark case. The officer arranged that photographs and impressions of the possible bitemark were taken for forensic analysis. Unfortunately, swobs of the bitemark were not conducted, therefore DNA and ABO blood group antigen analysis could not be performed. Impressions of the victim’s dentition were also taken from which plaster models were constructed. All dental materials used in this case were mixed according to the manufacturer’s instructions and were within their expiry dates. This evidence was submitted to the forensic odontology unit at the University of Pretoria for examination and comparative analysi