Critical Reviews in Oral Biology & Medicine

Discrepancies in size and shape of the jaws are the underlying etiology in many orthodontic and orthognathic surgery patients. Genetic factors combined with environmental interactions have been postulated to play a causal or contributory role in these craniofacial abnormalities. Along with the soon-to-be-available complete human and mouse genomic sequence data, mouse mutants have become a valuable tool in the functional mapping of genes involved in the development of human maxillofacial dysmorphologies. We review two powerful methods in such efforts: N-ethyl-N-nitrosourea (ENU) large-scale mutagenesis and quantitative trait linkage (QTL) analysis. The former aims at producing a plethora of novel variants of particular trait(s), and ultimately mapping the point mutations responsible for the appearance of these new traits. In contrast, the latter applies intensive breeding and mapping techniques to identify multiple loci (and, subsequently, genes) contributing to the phenotypic difference between the tested strains. A prerequisite for either approach to studying variations in the traits of interest is the application of effective mouse cephalometric phenotype analysis and rapid DNA mapping techniques. These approaches will produce a wealth of new data on critical genes that influence the size and shape of the human face.

This review will focus on the impact of molecular genetic approaches on elucidating the bacterial etiology of oral diseases from an historical perspective. Relevant results from the pre- and post-recombinant DNA periods will be highlighted, including the roles of gene cloning, mutagenesis, and nucleotide sequencing in this area of research. Finally, the impact of whole-genome sequencing on deciphering the virulence mechanisms of oral pathogens, along with new approaches to control these organisms, will be discussed.

High-risk genotypes of the human papillomavirus (HPV), particularly HPV type 16, are found in a distinct subset of head and neck squamous cell carcinomas (HNSCC). Thus, these HPV-associated HNSCC may be prevented or treated by vaccines designed to induce appropriate HPV virus-specific immune responses. Infection by HPV may be prevented by neutralizing antibodies specific for the viral capsid proteins. In clinical trials, vaccines comprised of HPV virus-like particles (VLPs) have shown great promise as prophylactic HPV vaccines. However, given that capsid proteins are not expressed at detectable levels by infected basal keratinocytes, vaccines with therapeutic potential must target other non-structural viral antigens. Two HPV oncogenic proteins, E6 and E7, are important in the induction and maintenance of cellular transformation and are co-expressed in the majority of HPV-containing carcinomas. Therefore, therapeutic vaccines targeting these proteins may have potential to control HPV-associated malignancies. Various candidate therapeutic HPV vaccines are currently being tested whereby E6 and/or E7 is administered in live vectors, in peptides or protein, in nucleic acid form, as components of chimeric VLPs, or in cell-based vaccines. Encouraging results from experimental vaccination systems in animal models have led to several prophylactic and therapeutic vaccine clinical trials. Should they fulfill their promise, these vaccines may prevent HPV infection or control its potentially life-threatening consequences in humans.

Field cancerization was first described in 1953 as histologically altered epithelium surrounding tumor samples taken from the upper aerodigestive tract. Since then, the term has been used to describe multiple patches of pre-malignant disease, a higher-than-expected prevalence of multiple local second primary tumors, and the presence of synchronous distant tumors within the upper aerodigestive tract. Molecular techniques such as karyotype analysis, microsatellite analysis, p53 mutation screening, and X-chromosome inactivation studies have further refined the relationship among these lesions. While there are differences in the techniques used to identify the clonal origins of the lesions, these studies indicate that there is often lateral clonal spread of pre-malignant or malignant disease, and a significant portion of local second primary tumors are in fact genetically related. Distant second primary tumors found in the esophagus are often not related to concurrent head and neck cancer, whereas synchronous squamous lung tumors with a head and neck primary are often, in fact, metastases, rather than independently arising malignancies. These observations help to explain the high incidence of recurrent disease, despite excision or other therapy—pre-malignant or malignant clones often have the ability to migrate and persist outside of the field of treatment. Therefore, alternative means of prevention or therapy that can affect the entire head and neck region may be of benefit to such patients. Future studies will further refine the relationship among these lesions and perhaps identify key molecular alterations to be used as targets for gene therapy.

Proteins found in mineralized tissues act as nature’s crystal engineers, where they play a key role in promoting or inhibiting the growth of minerals such as hydroxyapatite (bones/teeth) and calcium oxalate (kidney stones). Despite their importance in hard-tissue formation and remodeling, and in pathological processes such as stone formation and arterial calcification, there is little known of the protein structure-function relationships that govern hard-tissue engineering. Here we review early studies that have utilized solid-state NMR (ssNMR) techniques to provide in situ secondary-structure determination of statherin and statherin peptides on their biologically relevant hydroxyapatite (HAP) surfaces. In addition to direct structural study, molecular dynamics studies have provided considerable insight into the protein-binding footprint on hydroxyapatite. The molecular insight provided by these studies has also led to the design of biomimetic fusion peptides that utilize nature’s crystal-recognition mechanism to display accessible and dynamic bioactive sequences from the HAP surface. These peptides selectively engage adhesion receptors and direct specific outside-in signaling pathway activation in osteoblast-like cells.

Oral fungal infections (mycoses) have come into particular prominence since the advent of infection with Human Immunodeficiency Virus (HIV), and recognition of the Acquired Immune Deficiency Syndrome (AIDS), as well as the phenomenal increase in world travel with increased exposure to infections endemic in the tropics. Paracoccidioidomycosis is a rare mycosis worldwide but common in Brazil and some other areas in Latin America. It can be life-threatening and can manifest with a spectrum of clinical presentations, including frequent oral lesions. This paper reviews the more recent information on Paracoccidioidomycosis, emphasizing those areas most relevant in dental science.