Human papillomavirus and oropharyngeal cancer: what you need to know in 2009.

OPINION STATEMENT: Oropharyngeal cancer has demonstrated a steady increase in incidence over the past 20 years in contrast to declining numbers of head and neck squamous cell carcinoma (HNSCC) overall. Recent evidence has found that high-risk strains of human papillomavirus (HPV) are the likely cause of the changing epidemiology of oropharyngeal cancer. HPV-associated oropharyngeal cancer has a molecular, epidemiological, and clinical profile that is distinct from non-HPV HNSCC. Clinicians managing oropharyngeal HNSCC need to be aware of differences in the HPV HNSCC population which may impact treatment outcomes. Testing of HNSCC tumor tissue for HPV using validated and precise techniques should be performed when feasible.

Complex adenovirus-mediated expression of West Nile virus C, PreM, E, and NS1 proteins induces both humoral and cellular immune responses.

West Nile Virus (WNV), a member of the family Flaviviridae, was first identified in Africa in 1937. In recent years, it has spread into Europe and North America. The clinical manifestations of WNV infection range from mild febrile symptoms to fatal encephalitis. Two genetic lineages (lineages I and II) are recognized; lineage II is associated with mild disease, while lineage I has been associated with severe disease, including encephalitis. WNV has now spread across North America, significantly affecting both public and veterinary health. In the efforts to develop an effective vaccine against all genetic variants of WNV, we have studied the feasibility of inducing both neutralizing and cellular immune responses by de novo synthesis of WNV antigens using a complex adenoviral vaccine (CAdVax) vector. By expressing multiple WNV proteins from a single vaccine vector, we were able to induce both humoral and cellular immune responses in vaccinated mice. Neutralization assays demonstrated that the antibodies were broadly neutralizing against both lineages of WNV, with a significant preference for the homologous lineage II virus. The results from this study show that multiple antigens synthesized de novo from a CAdVax vector are capable of inducing both humoral and cellular immune responses against WNV and that a multiantigen approach may provide broad protection against multiple genetic variants of WNV.

Impact of nutrients on insulin-like growth factor-I, insulin-like growth factor binding protein-3 and their ratio in African American and white males.

OBJECTIVE: Higher levels of insulin-like growth factor-I (IGF-I) and lower levels of IGF binding protein-3 (IGFBP-3) have been associated with an increased risk of prostate cancer. Nutrition is known to partially regulate IGF levels and it is possible that nutritional factors mediate the impact of IGF levels on prostate cancer risk. DESIGN: A cross-sectional analysis of the impact of nutritional factors measured by a dietary questionnaire on plasma levels of IGF-I, IGFBP-3 and their molar ratio. Multiple linear regression analysis was used to test for effects of nutrients on IGF levels. SETTING: Prostate cancer screening at the Hollings Cancer Center in Charleston, South Carolina. SUBJECTS: Ninety-five African American and 138 white males aged 33-83 years attending the screening. RESULTS: In whites, intakes of total, saturated and monounsaturated fats were positively associated with an increase in the molar ratio, while there was no association in African Americans. In African Americans, we found that increasing intake of calcium and dairy servings was positively associated with IGF-I levels. Increased vegetable intake was positively associated with IGFBP-3 in African Americans, while there was no effect in whites. A higher percentage of alcohol in the total diet was significantly associated with a decrease in the molar ratio and an increase in IGFBP-3 in both groups. CONCLUSIONS: Our results confirm previous findings of nutritional determinants of IGF levels. Additionally, we found the impact of several nutrients on IGF levels to be different in whites and African Americans, which warrants further investigation.

Racial and anthropometric differences in plasma levels of insulin-like growth factor I and insulin-like growth factor binding protein-3.

OBJECTIVES: To analyze the differences in the plasma levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and their ratio between black and white men while controlling for factors that could confound the relationship between IGF levels and race. Furthermore, we analyzed the association between age, height, prostate-specific antigen level, digital rectal examination status, and current smoking status on IGF levels separately in black and white men. Greater levels of IGF-I and lower levels of IGFBP-3 have been associated with an increased risk of prostate cancer in many studies. METHODS: A cross-sectional analysis was performed on 171 white and 130 black men aged 40 to 80 years. Multiple linear regression analysis was used to model the data separately for blacks and whites. A chi-square global test was used to test for racial differences in regression curves. RESULTS: Our results indicated that black men have lower levels of IGFBP-3 and IGF-I and a greater IGF-I/IGFBP-3 ratio than white men across all ages younger than 70, with and without an adjustment for height. We found racial differences in the effect of age and height on levels of IGF-I, IGFBP-3, and the molar ratio. Age had an inverse correlation with IGF-I and IGFBP-3 levels in whites, but no such relationship in blacks. CONCLUSIONS: The differences in IGF levels between blacks and whites may explain some of the racial disparity in prostate cancer risk. Because age and height affect IGF levels differently in black and white men, future analysis exploring the determinants of IGF levels may need to be stratified by race.

Development of a thermally regulated broad-spectrum promoter system for use in pathogenic gram-positive species.

Selectively regulating gene expression is an essential molecular tool that is lacking for many pathogenic gram-positive bacteria. In this report, we describe the evaluation of a series of promoters regulated by the bacteriophage P1 temperature-sensitive C1 repressor in Enterococcus faecium, Enterococcus faecalis, and Staphylococcus aureus. Using the lacZ gene to monitor gene expression, we examined the strength, basal expression, and induced expression of synthetic promoters carrying C1 operator sites. The promoters exhibited extremely low basal expression and, under inducing conditions, gave high levels of expression (100- to 1,000-fold induction). We demonstrate that the promoter system could be modulated by temperature and showed rapid induction and that the mechanism of regulation occurred at the level of transcription. Controlled expression with the same constructs was also demonstrated in the gram-negative bacterium Escherichia coli. However, low basal expression and the ability to achieve derepression were dependent on both the number of mismatches in the C1 operator sites and the promoter driving c1 expression. Since the promoters were designed to contain conserved promoter elements from gram-positive species and were constructed in a broad-host-range plasmid, this system will provide a new opportunity for controlled gene expression in a variety of gram-positive bacteria.

Doxorubicin pretreatment sensitizes prostate cancer cell lines to TRAIL induced apoptosis which correlates with the loss of c-FLIP expression.

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL/Apo2L) can induce receptor-mediated apoptosis in prostate cancer cell lines that have been co-treated with the chemotherapeutic agent doxorubicin (Voelkel-Johnson C, et al. Cancer Gene Therapy 2002; 9:164-172). In this study, we report that pretreatment with doxorubicin is sufficient to sensitize cells to TRAIL. To identify possible targets of doxorubicin, we analyzed levels of several Bcl-2 family members, TRAIL receptors and the anti-apoptotic protein c-FLIP. Doxorubicin did not affect steady state levels of Bax, Bcl-2 and Bcl-X(L) in the majority of the prostate cancer cell lines. TRAIL receptor mRNAs (DR4, DR5, and DcR2) were induced by doxorubicin but these changes were not reflected at the protein level. In contrast, in response to doxorubicin, levels of c-FLIP, particularly FLIP(S), decreased in all cell lines tested. The decrease in c-FLIP(S) correlated with onset and magnitude of caspase-8 and PARP cleavage in PC3 cells. In two TRAIL resistant cell lines, DU145 and LNCaP, treatment with TRAIL alone resulted in processing of c-FLIP(L) and initiated abortive caspase-8 proteolysis. TRAIL treatment did not affect levels of c-FLIP(S) in Du145 and LNCaP cells and did not result in PARP cleavage. Therefore, our results suggest that doxorubicin- mediated down regulation of c-FLIP(S) predisposes cells to TRAIL-induced apoptosis.