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1.  The Enhancement of Bone Regeneration by Gene Activated Matrix Encoding for Platelet Derived Growth Factor 
Biomaterials  2013;35(2):10.1016/j.biomaterials.2013.10.021.
Gene therapy using non-viral vectors that are safe and efficient in transfecting target cells is an effective approach to overcome the shortcomings of protein delivery of growth factors. The objective of this study was to develop and test a non-viral gene delivery system for bone regeneration utilizing a collagen scaffold to deliver polyethylenimine (PEI)-plasmid DNA (pDNA) [encoding platelet derived growth factor-B (PDGF-B)] complexes. The PEI-pPDGF-B complexes were fabricated at amine (N) to phosphate (P) ratio of 10 and characterized for size, surface charge, and in vitro cytotoxicity and transfection efficacy in human bone marrow stromal cells (BMSCs). The influence of the complex-loaded collagen scaffold on cellular attachment and recruitment was evaluated in vitro using microscopic techniques. The in vivo regenerative capacity of the gene delivery system was assessed in 5 mm diameter critical-sized calvarial defects in Fisher 344 rats. The complexes were ~100 nm in size with a positive surface charge. Complexes prepared at an N/P ratio of 10 displayed low cytotoxicity as assessed by a cell viability assay. Confocal microscopy revealed significant proliferation of BMSCs on complex-loaded collagen scaffolds compared to empty scaffolds. In vivo studies showed significantly higher new bone volume/total volume (BV/TV) % in calvarial defects treated with the complex-activated scaffolds following 4 weeks of implantation (14- and 44-fold higher) when compared to empty defects or empty scaffolds, respectively. Together, these findings suggest that non-viral PDGF-B gene-activated scaffolds are effective for bone regeneration and are an attractive gene delivery system with significant potential for clinical translation.
doi:10.1016/j.biomaterials.2013.10.021
PMCID: PMC3855224  PMID: 24161167
Plasmid DNA; Polyethylenimine; Gene Delivery; Scaffold; Platelet Derived Growth Factor; Collagen; Bone regeneration
2.  Phenotypic Diversity in Caucasian Adults with Moderate to Severe Class III Malocclusion 
INTRODUCTION
Class III malocclusion is characterized by a composite of dento-skeletal patterns that lead to the forward positioning of the mandibular teeth in relation to the maxillary teeth and a concave profile. Environmental and genetic factors are associated with this condition, which affects 1% of the US population and imposes significant esthetic and functional burdens on affected individuals. The purpose of this study was to capture the phenotypic variation present in a large sample of white adults with Class III malocclusion by using multivariate reduction methods.
METHODS
Sixty-three lateral cephalometric variables were measured from pre-treatment records of 292 Class II Caucasian adults (126 males, 166 females; ages 16-57 years). Principal component analysis and cluster analysis were used to capture the phenotypic variation and identify the most homogeneous groups of individuals to reduce genetic heterogeneity.
RESULTS
Principal component analysis resulted in 6 principal components that accounted for 81.2% of the variation. The first three components represented variations in mandibular horizontal and vertical position, maxillary horizontal position, and mandibular incisor angulation, respectively. The cluster model identified 5 distinct subphenotypes of Class III malocclusion.
CONCLUSIONS
A spectrum of phenotypic definitions was obtained replicating results of previous studies and supporting the validity of these phenotypic measures in future research of genetic and environmental etiology of Class III malocclusion.
doi:10.1016/j.ajodo.2013.02.019
PMCID: PMC3964133  PMID: 23810043
3.  ORGANIZATION, BARRIER FUNCTION AND ANTIMICROBIAL LIPIDS OF THE ORAL MUCOSA 
Synopsis
As one moves from the skin across the vermilion region of the lip and into the oral cavity the oral mucosa is encountered. The oral mucosa consists of connective tissue known as the lamina propria covered by a stratified squamous epithelium. In the regions of the hard palate and gingiva the epithelium is keratinized like the epidermis. In the buccal region, the floor of the mouth and the underside of the tongue the epithelium is nonkeratinized. The epithelium on the dorsum of the tongue is a specialized epithelium but can be approximated as a mosaic of keratinized and nonkeratinized epithelia. The nonkeratinized epithelial regions do not produce a stratum corneum. Nuclei with intact DNA are retained in the superficial cells. In all regions the outer portions of the epithelium provides a protective permeability barrier, which varies regionally. Antimicrobial lipids at the surfaces of the oral mucosa are an integral part of innate immunity.
doi:10.1111/ics.12038
PMCID: PMC3640763  PMID: 23320785
mouth mucosa; keratinocytes; keratin; cell envelope; ceramide; permeability
4.  Factors Associated with Dental Caries Experience in 1-Year-Old Children 
Objectives
Dental caries in early childhood is an important public health problem. Previous studies have examined risk factors, but they have focused on children during the later stages of the disease process. The purpose of this study was to assess the factors associated with caries in children aged 6 to 24 months as part of a cross-sectional analysis.
Methods
Two hundred twelve mothers with children 6 to 24 months of age were recruited from Special Supplemental Nutrition Program for Women, Infants, and Children clinic sites in southeastern Iowa for participation in a longitudinal study of dental caries. Baseline assessments included detailed questions regarding the children’s beverage consumption, oral hygiene, and family socioeconomic status. Dental caries examinations using the d1d2-3f criteria and semiquantitative assessments of salivary mutans streptococci (MS) levels of mother and child were also conducted. Counts of the number of teeth with visible plaque were recorded for maxillary and mandibular molars and incisors.
Results
Of the 212 child/mother pairs, 187 children had teeth. Among these children, the mean age was 14 months, and 23 of the children exhibited either d1, d2-3, or filled lesions. Presence of caries was significantly associated with older age, presence of MS in children, family income <$25,000 per year, and proportion of teeth with visible plaque.
Conclusions
Results suggest that not only microbial measures, including MS and plaque levels, are closely associated with caries in very young children, but that other age-related factors may also be associated with caries. Continued study is necessary to more fully assess the risk factors for caries prevalence and incidence in preschool children.
doi:10.1111/j.1752-7325.2007.00068.x
PMCID: PMC2562928  PMID: 18221314
dental caries; early childhood caries; sugar consumption; mutans streptococci; plaque
5.  Sphingoid bases are taken up by Escherichia coli and Staphylococcus aureus and induce ultrastructural damage 
Sphingoid bases found in the outer layers of the skin exhibit antimicrobial activity against Gram-positive and Gram-negative bacteria. We investigated the uptake of several sphingoid bases by Escherichia coli and Staphylococcus aureus, and assessed subsequent ultrastructural damage. E. coli and S. aureus were incubated with D-sphingosine, dihydrosphingosine, or phytosphingosine at ten times their MIC for 0.5 h and 4 h, respectively, to kill 50% of viable bacteria. Treated bacterial cells were immediately prepared for SEM, TEM, and analyzed for lipid content by QTLC. E. coli and S. aureus treated with sphingoid bases were distorted and their surfaces were concave and rugate. Significant differences were observed in the visual surface area relative to controls for both E. coli and S. aureus when treated with dihydrosphingosine and sphingosine (p<0.0001) but not phytosphingosine. While sphingoid base-treated S. aureus exhibited disruption and loss of cell wall and membrane, E. coli cytoplasmic membranes appeared intact and the outer envelope uncompromised. Both E. coli and S. aureus cells contained unique internal inclusion bodies, likely associated with cell death. QTLC demonstrated extensive uptake of sphingoid bases by the bacteria. Hence, sphingoid bases induce both extracellular and intracellular damage and cause intracellular inclusions that may reflect lipid uptake.
doi:10.1159/000343175
PMCID: PMC3634627  PMID: 23128426
Antimicrobial lipids; sphingoid bases; sphingolipids; Escherichia coli; Staphylococcus aureus; ultrastructure; electron microscopy
6.  Dental Caries in a Cohort of Very Young American Indian Children 
OBJECTIVES
This paper reports the prevalence and severity of caries in a group of 16-month-old American Indian children.
METHODS
The study is an ongoing longitudinal study of risk factors for caries in children from a Northern Plains Tribal community. Children were examined for caries and risk factor data collected at approximately 1, 4, 8, 12 and 16 months of age. Surface-specific caries data were collected and the presence of pre-cavitated “white spot” lesions was recorded at the subject level.
RESULTS
The mean age was 15.4 months for the sample of 232 children. Caries prevalence was 31.9%, while an additional 29.3% had white spot lesions only. Mean dmfs was 1.57, and ranged from 0 to 44 surfaces. Nearly 3% of all erupted tooth surfaces were affected and maxillary central incisors had the highest prevalence of caries (22%).
CONCLUSIONS
Among the very youngest children, dental caries prevalence was very high among these American Indian children.
doi:10.1111/j.1752-7325.2012.00372.x
PMCID: PMC3509261  PMID: 23017107
7.  Oral mucosal lipids are antibacterial against Porphyromonas gingivalis, induce ultrastructural damage, and alter bacterial lipid and protein compositions 
Oral mucosal and salivary lipids exhibit potent antimicrobial activity for a variety of Gram-positive and Gram-negative bacteria; however, little is known about their spectrum of antimicrobial activity or mechanisms of action against oral bacteria. In this study, we examine the activity of two fatty acids and three sphingoid bases against Porphyromonas gingivalis, an important colonizer of the oral cavity implicated in periodontitis. Minimal inhibitory concentrations, minimal bactericidal concentrations, and kill kinetics revealed variable, but potent, activity of oral mucosal and salivary lipids against P. gingivalis, indicating that lipid structure may be an important determinant in lipid mechanisms of activity against bacteria, although specific components of bacterial membranes are also likely important. Electron micrographs showed ultrastructural damage induced by sapienic acid and phytosphingosine and confirmed disruption of the bacterial plasma membrane. This information, coupled with the association of treatment lipids with P. gingivalis lipids revealed via thin layer chromatography, suggests that the plasma membrane is a likely target of lipid antibacterial activity. Utilizing a combination of two-dimensional in-gel electrophoresis and Western blot followed by mass spectroscopy and N-terminus degradation sequencing we also show that treatment with sapienic acid induces upregulation of a set of proteins comprising a unique P. gingivalis stress response, including proteins important in fatty acid biosynthesis, metabolism and energy production, protein processing, cell adhesion and virulence. Prophylactic or therapeutic lipid treatments may be beneficial for intervention of infection by supplementing the natural immune function of endogenous lipids on mucosal surfaces.
doi:10.1038/ijos.2013.28
PMCID: PMC3967327  PMID: 23867843
antimicrobial lipid; fatty acid; Porphyromonas gingivalis; sphingoid base; sphingolipid; ultrastructure
8.  Antibacterial Activity of Sphingoid Bases and Fatty Acids against Gram-Positive and Gram-Negative Bacteria 
There is growing evidence that the role of lipids in innate immunity is more important than previously realized. How lipids interact with bacteria to achieve a level of protection, however, is still poorly understood. To begin to address the mechanisms of antibacterial activity, we determined MICs and minimum bactericidal concentrations (MBCs) of lipids common to the skin and oral cavity—the sphingoid bases d-sphingosine, phytosphingosine, and dihydrosphingosine and the fatty acids sapienic acid and lauric acid—against four Gram-negative bacteria and seven Gram-positive bacteria. Exact Kruskal-Wallis tests of these values showed differences among lipid treatments (P < 0.0001) for each bacterial species except Serratia marcescens and Pseudomonas aeruginosa. d-Sphingosine (MBC range, 0.3 to 19.6 μg/ml), dihydrosphingosine (MBC range, 0.6 to 39.1 μg/ml), and phytosphingosine (MBC range, 3.3 to 62.5 μg/ml) were active against all bacteria except S. marcescens and P. aeruginosa (MBC > 500 μg/ml). Sapienic acid (MBC range, 31.3 to 375.0 μg/ml) was active against Streptococcus sanguinis, Streptococcus mitis, and Fusobacterium nucleatum but not active against Escherichia coli, Staphylococcus aureus, S. marcescens, P. aeruginosa, Corynebacterium bovis, Corynebacterium striatum, and Corynebacterium jeikeium (MBC > 500 μg/ml). Lauric acid (MBC range, 6.8 to 375.0 μg/ml) was active against all bacteria except E. coli, S. marcescens, and P. aeruginosa (MBC > 500 μg/ml). Complete killing was achieved as early as 0.5 h for some lipids but took as long as 24 h for others. Hence, sphingoid bases and fatty acids have different antibacterial activities and may have potential for prophylactic or therapeutic intervention in infection.
doi:10.1128/AAC.05151-11
PMCID: PMC3294957  PMID: 22155833
9.  PRESENCE OF WAX ESTERS AND SQUALENE IN HUMAN SALIVA 
Archives of oral biology  2011;56(6):588-591.
Objective
The purpose of this study was to determine the presence and relative composition of neutral lipids in human saliva.
Design
Whole unstimulated saliva was collected from 12 subjects ranging from 21 to 29 years old. Samples were lyophilized, and lipids were extracted using chloroform-methanol. Lipids were analyzed by thin-layer chromatography.
Results
Human saliva contains cholesterol, fatty acids, triglycerides, wax esters, cholesterol esters and squalene. The mean total neutral lipid content was 12.1 +/− 6.3 µg/ml.
Conclusions
This lipids in human saliva closely resemble the lipids found on the skin surface. These salivary lipids are most likely produced by the sebaceous follicles in the oral mucosa and sebaceous glands associated with major salivary glands.
doi:10.1016/j.archoralbio.2010.12.002
PMCID: PMC3095707  PMID: 21247555
10.  Comparison of perceptions of oral health-related quality of life in adolescents affected with ectodermal dysplasias relative to caregivers 
The objective of this study was to assess the perceived oral health-related quality of life (OHQoL) of adolescents affected with one of the ectodermal dysplasias (EDs).
Data were collected from 2003 to 2007 in a cross-sectional study of a convenience sample of individuals affected by ED (n=35) using the Child Perceptions Questionnaire(CPQ11–14)for children and the Parent-Caregiver Perceptions Questionnaire (P-CPQ) for their caregivers. The main findings of this study were that individuals who were affected with ED in the older age group (15–19 years old) perceived more functional problems than younger individuals (11–14 years old) (p=0.04). Females with ED (n= 13) perceived more emotional problems than males (n=22; p=0.01). Although caregivers tended to report slightly higher OHQoL scores (indicating worse OHQoL), no significant differences were observed between children’s and parents’ total OHQoL and individual domains’ median scores (p>0.05). Thus, the perceptions of oral health and well-being may vary by age and gender for children who have ED. Caution is warranted concerning using parents as proxies for their children when assessing the child’s OHQoL.
doi:10.1111/j.1754-4505.2011.00189.x
PMCID: PMC3105356  PMID: 21592162
ectodermal dysplasias; oral health-related quality of life; children; teenagers; parents; perceptions
11.  Targeted antimicrobial activity of a specific IgG–SMAP28 conjugate against Porphyromonas gingivalis in a mixed culture 
Antimicrobial peptides coupled to a ligand, receptor or antibody for a specific pathogenic bacteria could be used to develop narrow-spectrum pharmaceuticals with ‘targeted’ antimicrobial activity void of adverse reactions often associated with the use of broad-spectrum antibiotics. To assess the feasibility of this approach, in this study sheep myeloid antimicrobial peptide (SMAP) 28 was linked to affinity- and protein G-purified rabbit immunoglobulin G (IgG) antibodies specific to the outer surface of Porphyromonas gingivalis strain 381. The selective activity of the P. gingivalis IgG–SMAP28 conjugate was then assessed by adding it to an artificially generated microbial community containing P. gingivalis, Aggregatibacter actinomycetemcomitans and Peptostreptococcus micros. The specificity of the P. gingivalis IgG–SMAP28 conjugate in this mixed culture was concentration-dependent. The conjugate at 50 μg protein/mL lacked specificity and killed P. gingivalis, A. actinomycetemcomitans and P. micros. The conjugate at 20 μg protein/mL was more specific and killed P. gingivalis. This is an initial step to develop a selective antimicrobial agent that can eliminate a specific periodontal pathogen, such as P. gingivalis, from patients with periodontal disease without harming the normal commensal flora.
doi:10.1016/j.ijantimicag.2008.05.021
PMCID: PMC3169388  PMID: 18778918
Porphyromonas gingivalis; Aggregatibacter actinomycetemcomitans; Peptostreptococcus micros; Cathelicidins; Targeted antimicrobial activity; SMAP28
12.  Communication: Antimicrobial Activity of SMAP28 with a Targeting Domain for Porphyromonas gingivalis 
Antibiotic therapy is often used with mechanical therapy to treat periodontal disease. However, complications associated with antibiotic use can occur. A ‘bacteria-specific’ targeted approach would eliminate some of these complications and kill specific periodontopathogens without harming the commensal bacteria. One such approach is to couple antimicrobial peptides to a ligand, pheromone, or antibody specific for the periodontopathogen, Porphyromonas gingivalis. To assess the feasibility of this approach, we attached PQGPPQ, a peptide from proline-rich protein 1 to either the N-terminus of SMAP28 (peptide ZS37-37) or the C-terminus of SMAP28 (peptide ZS37-38) to see whether it has potential as a carrier ligand to deliver SMAP28 to the surface of P. gingivalis. For Escherichia coli and Aggregatibacter actinomycetemcomitans, the median minimal inhibitory concentration (MIC) of ZS37-37 was higher than the median of SMAP28 alone, although the median MIC of ZS37-38 was lower than that of SMAP28 alone. For P. gingivalis, there was no difference in the median MIC values. For S. aureus, the median MIC was higher for ZS37-37 and ZS37-38 compared to SMAP28 alone, particularly for ZS37-38. For Fusobacterium nucleatum, the median MIC values were equal for ZS37-37 and ZS37-38 and higher than the median MIC for SMAP28 alone. Attaching PQGPPQ to SMAP28 did not greatly increase the antimicrobial activity of ZS37-37 or ZS37-38 for P. gingivalis nor substantially decrease the antimicrobial activity of ZS37-37 or ZS37-38 for the four other microorganisms tested. This is an initial step to develop a selective antimicrobial agent that has ‘targeted’ antimicrobial activity without adverse reactions often associated with the use of broad-spectrum antibiotics.
doi:10.1007/s12602-009-9028-5
PMCID: PMC2863077  PMID: 20454638
Porphyromonas gingivalis; SMAP28; Periodontal disease; Targeted antimicrobial activity
13.  Sunburns and risk of cutaneous melanoma, does age matter: a comprehensive meta-analysis 
Annals of epidemiology  2008;18(8):614-627.
Purpose
Sunburns are an important risk factor for melanoma and those occurring in childhood are often cited as posing the greatest risk. We conducted a meta-analysis to quantify the magnitude of association for melanoma and sunburns during childhood, adolescence, adulthood and over a lifetime.
Methods
After reviewing over 1300 article titles and evaluating 270 articles in detail, we pooled ORs from 51 independent study populations for “ever” sunburned and risk of cutaneous melanoma. Among these, 26 studies reported results from dose-response analyses. Dose-response analyses were examined using both fixed-effects models and Bayesian random-effects models.
Results
An increased risk of melanoma was seen with increasing number of sunburns for all time-periods (childhood, adolescence, adulthood and lifetime). In an attempt to understand how risk between life-periods compares, we also report these same linear models on a scale of 5 sunburns per decade for each life-period. The magnitude of risk for 5 sunburns per decade is highest for adult and lifetime sunburns.
Conclusions
Overall, these results show an increased risk of melanoma with increasing number of sunburns during all life-periods, not just childhood. Prevention efforts should focus on reducing sunburns during all life-periods.
doi:10.1016/j.annepidem.2008.04.006
PMCID: PMC2873840  PMID: 18652979
adolescent; adult; child; intermittent sun exposure; melanoma; meta-analysis; odds ratio; sunburn; sun sensitivity
14.  A Longitudinal Study of Dental Caries Risk among Very Young Low SES Children 
Objectives
Early childhood caries is a challenging public health problem in the United States and elsewhere; however, there is limited information concerning risk factors in very young children. The purpose of this study was to assess baseline risk factors for 18-month caries prevalence as part of a longitudinal study of high-risk children.
Methods
212 children 6–24 months of age were recruited from a rural community in Iowa. Subjects were enrolled in the WIC program, which provides nutritional support for low-income families with children. Dental examinations using d1d2-3 criteria were conducted at baseline and after 18 months. Caries prevalence was determined at the frank decay level (d2-3 or filled surfaces), as well as at the non-cavitated level (d1), and combined (d1, d2-3 or f surfaces). Risk factor data were collected at baseline and after 9- and 18- months. These data included beverage consumption data, presence of visible plaque, and use of fluoride toothpaste for children as well as mutans streptococci (MS) levels of mothers and children and family socio-demographic factors.
Results
128 children (60%) remained in the study after 18 months. Among these children, prevalence of d-1d2-3/f level caries increased from 9% to 77%, while d2-3/f level caries increased from 2% to 20%. Logistic regression models for baseline predictors of d2-3f caries at the 18-month follow-up found presence of MS in children (OR=4.4; 95% CI: 1.4, 13.9) and sugar-sweetened beverages (OR=3.0; 95% CI: 1.1, 8.6) to be the only significant risk factors. Socio-demographic factors and use of fluoride toothpaste were not significant in these models.
Conclusions
Results suggest that early colonization by MS and consumption of sugar-sweetened beverages are significant predictors of early childhood caries in high-risk populations.
doi:10.1111/j.1600-0528.2008.00447.x
PMCID: PMC2661009  PMID: 19046332
Dental caries; primary dentition; children; risk factors; mutans streptococci
15.  When to Tell and Test for Genetic Carrier Status: Perspectives of Adolescents and Young Adults from Fragile X Families 
We report here our findings from adolescent and young adult females (ages 14–25) with a family history of fragile X syndrome regarding their perceptions of the optimal ages for 1) learning fragile X is inherited, 2) learning one could be a carrier for fragile X, and 3) offering carrier testing for fragile X. Three groups were enrolled: those who knew they were carriers or noncarriers and those who knew only they were at-risk to be a carrier. Only two of the 53 participants felt that offering carrier testing should be delayed until the age of 18 years. Participants who knew only that they were at-risk to be a carrier provided older optimal ages for offering carrier testing than those who knew their actual carrier status. Participants did not express regret or negative emotions about the timing of the disclosure of genetic risk information regarding their own experiences. Participants’ reasoning behind reported ages for informing about genetic risk and offering carrier testing varied depending on what type of information was being disclosed, which carrier status group the participant belonged to, and the preferred age for learning the information. Study findings suggest that decisions regarding the timing to inform about genetic risk and offer testing should be tailored to the individual needs of the child and his/her family.
doi:10.1002/ajmg.a.32840
PMCID: PMC2756686  PMID: 19449413
Carrier testing; minors; adolescent; genetic risk communication; fragile X syndrome; X-linked disorders
16.  Living with Genetic Risk: Effect on Adolescent Self-Concept 
The purpose of this study is to describe the interplay of adolescent girls’ self-concept, coping behaviors, and adjustment associated with knowledge of genetic risk for fragile X syndrome. We will report here findings on self concept. Using a multi-group cross-sectional design this study focused on girls ages 14–25 years from families previously diagnosed with fragile X syndrome, who knew they were 1) carriers (n = 20; mean age 18.35 years s.d. 2.5), or 2) noncarriers (n =18; mean age 17.78 years s.d. 2.69), or 3) at-risk to be carriers (n = 15; mean age 17.87 s.d. 3.18). The girls completed the Tennessee Self Concept Scale (TSCS:2), a visual analog scale, and a guided interview. Total and all subscale scores on the TSCS:2 were in the normal range for all three groups. However, threats to self concept were found in personal self (physical self, genetic identity, and parental role), social self, and family self (family genetic identity) as they specifically related to the meaning of genetic information and varied based on risk status. Our findings suggest that risk information itself is threatening and for some girls, may be as threatening as learning one is a carrier. Certainty related to genetic risk status appears to make a positive difference for some girls by allowing them the opportunity to face the challenge of their genetic risk status and to begin to consider the meaning of this information.
doi:10.1002/ajmg.c.30161
PMCID: PMC2756030  PMID: 18200514
Fragile X syndrome; self concept; genetic testing in children; genetic counseling; carrier testing; parental role; adolescents
17.  Lipopolysaccharide-Squamous Cell Carcinoma-Monocyte Interactions Induce Cancer-Supporting Factors Leading to Rapid STAT3 Activation 
Head and neck pathology  2008;2(1):1-12.
Oral and oro-pharyngeal squamous cell carcinomas (OSCC) exhibit surface breach, and recent studies have demonstrated bacterial contamination of primary and metastatic OSCC. Increasing concentrations of inflammatory products, such as interleukin (IL)-6 and vascular endothelial growth factor (VEGF), correlate with, and contribute to, cancer progression, but their regulation in OSCC is poorly understood. We hypothesized that monocyte-lineage cells and bacterial contamination may contribute important inflammatory products that can support OSCC progression. We found that relative to non-specific chronic mucositis, oral carcinoma-in-situ/superficially-invasive OSCC contained more monocyte-lineage cells. In vitro, we used lipopolysaccharide (LPS) to model bacterial contamination, and evaluated the effects of oral and oropharyngeal (O)SCC-monocyte interactions and of LPS on OSCC cells and on the production of IL-6 and VEGF. OSCC cell lines varied in constitutive cytokine and chemokine production, and OSCC-monocyte interactions in the absence of LPS stimulated IL-6 and VEGF occasionally, while LPS-OSCC-monocyte interactions were always strongly stimulatory. Importantly, LPS independently stimulated some OSCC lines to secrete monocyte-dendritic cell chemoattractants CCL2 and/or CCL20, as well as IL-6 and/or VEGF. While very little constitutive Y705-STAT3 phosphorylation (pY705-STAT3) was detectable in HNSCC lines, IL-6 rapidly induced pY705-STAT3 in OSCC lines that produced little IL-6 constitutively. Supernatants from LPS-OSCC-monocyte co-cultures always rapidly and strongly activated STAT3, which was partly due to IL-6. We conclude that monocytes and microbial contamination have the potential to contribute to OSCC progression, as STAT3 activation in OSCC cells depends on soluble factors, which are consistently available through LPS-OSCC-monocyte interactions.
doi:10.1007/s12105-007-0038-x
PMCID: PMC2709294  PMID: 19603082
Oral squamous cell carcinoma; Lipopolysaccharide; Monocytes/macrophages; STAT3; Inflammation; Cytokines; Interleukin-6; Vascular endothelial growth factor; Toll-like receptor
18.  Human α- and β-Defensins Bind to Immobilized Adhesins from Porphyromonas gingivalis▿  
Infection and Immunity  2008;76(12):5714-5720.
Human neutrophil peptide α-defensins (HNPs) and human β-defensins (HBDs) are small well-characterized peptides with broad antimicrobial activities and a diversity of innate immune functions. Although the interactions of defensins with bacteria and their membranes have been well characterized, the interactions of defensins with bacterial adhesins have not. Here we determine if HNPs and HBDs bind to the immobilized adhesins of Porphyromonas gingivalis strain 381, recombinant hemagglutinin B (rHagB) and recombinant fimbrillin A (rFimA), by surface plasmon resonance spectroscopy. Association of HNPs and HBDs with rHagB or rFimA was dose dependent and defensin specific. HBD3, HNP-2, and HNP-1 bound more readily to immobilized rHagB than HBD2 and HBD1 did. HNP-2, HNP-1, and HBD3 bound more readily to immobilized rFimA than HBD1 and HBD2 did. Binding of defensins to adhesins may serve to prevent microbial adherence to tissues, attenuate proinflammatory cytokine responses, and facilitate delivery of bound antigen to antigen-presenting cells with defensin receptors.
doi:10.1128/IAI.00997-08
PMCID: PMC2583589  PMID: 18852241
19.  Lipopolysaccharide-Squamous Cell Carcinoma-Monocyte Interactions Induce Cancer-Supporting Factors Leading to Rapid STAT3 Activation 
Head and Neck Pathology  2008;2(1):1-12.
Oral and oro-pharyngeal squamous cell carcinomas (OSCC) exhibit surface breach, and recent studies have demonstrated bacterial contamination of primary and metastatic OSCC. Increasing concentrations of inflammatory products, such as interleukin (IL)-6 and vascular endothelial growth factor (VEGF), correlate with, and contribute to, cancer progression, but their regulation in OSCC is poorly understood. We hypothesized that monocyte-lineage cells and bacterial contamination may contribute important inflammatory products that can support OSCC progression. We found that relative to non-specific chronic mucositis, oral carcinoma-in-situ/superficially-invasive OSCC contained more monocyte-lineage cells. In vitro, we used lipopolysaccharide (LPS) to model bacterial contamination, and evaluated the effects of oral and oropharyngeal (O)SCC-monocyte interactions and of LPS on OSCC cells and on the production of IL-6 and VEGF. OSCC cell lines varied in constitutive cytokine and chemokine production, and OSCC-monocyte interactions in the absence of LPS stimulated IL-6 and VEGF occasionally, while LPS-OSCC-monocyte interactions were always strongly stimulatory. Importantly, LPS independently stimulated some OSCC lines to secrete monocyte-dendritic cell chemoattractants CCL2 and/or CCL20, as well as IL-6 and/or VEGF. While very little constitutive Y705-STAT3 phosphorylation (pY705-STAT3) was detectable in HNSCC lines, IL-6 rapidly induced pY705-STAT3 in OSCC lines that produced little IL-6 constitutively. Supernatants from LPS-OSCC-monocyte co-cultures always rapidly and strongly activated STAT3, which was partly due to IL-6. We conclude that monocytes and microbial contamination have the potential to contribute to OSCC progression, as STAT3 activation in OSCC cells depends on soluble factors, which are consistently available through LPS-OSCC-monocyte interactions.
doi:10.1007/s12105-007-0038-x
PMCID: PMC2709294  PMID: 19603082
Oral squamous cell carcinoma; Lipopolysaccharide; Monocytes/macrophages; STAT3; Inflammation; Cytokines; Interleukin-6; Vascular endothelial growth factor; Toll-like receptor

Results 1-19 (19)