A recently discovered enzyme system produces antibacterial hypothiocyanite (OSCN − ) in the airway lumen by oxidizing the secreted precursor thiocyanate (SCN − ). Airway epithelial cultures have been shown to secrete SCN − in a CFTR-dependent manner. Thus, reduced SCN − availability in the airway might contribute to the pathogenesis of cystic fibrosis (CF), a disease caused by mutations in the CFTR gene and characterized by an airway host defense defect. We tested this hypothesis by analyzing the SCN − concentration in the nasal airway surface liquid (ASL) of CF patients and non-CF subjects, and in the tracheobronchial ASL of CFTR-ΔF508 homozygous pigs and control littermates. In the nasal ASL, the SCN − concentration was ~30-fold higher than in

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Ras expression in human epithelial cells with integrated HPV genomes has been shown to cause tumorigenic transformation. The effects of Ras in cells representing early stage HPV-associated disease (i.e., when HPV is extrachromosomal and the oncogenes are under control of native promoters) have not been examined. Here, we used human cervical keratinocyte cell lines containing stably replicating extrachromosomal HPV-16 and present the novel finding that these cells resist transformation by oncogenic H-Ras. Ras expression consistently diminished anchorage-independent growth (AI), reduced E6 and E7 expression, and caused p53 induction in these cells. Conversely, AI was enhanced or maintained in Ras-transduced cervical cells that were immortalized with a 16E6/E7 retrovirus, and minimal effects on E6 and E7 expression were observed. Ras expression with either episomal HPV-16 or LXSN-E6/E7 was insufficient for tumorigenic growth suggesting that other events are needed for tumorigenic transformation. In conclusion, our results indicate that Ras-mediated transformation depends on the context of HPV oncogene expression and that this is an important point to address when developing HPV tumor models.

Introduction: The aim of this study was to determine if laterality of an absent umbilical artery (AUA) is associated with specific sonographic findings, chromosomal defects or postpartum birth defects. Materials and Methods: In this retrospective cohort study, ultrasound reports and medical records of patients who received an obstetric ultrasound at the University of Iowa Hospitals and Clinics with an identified laterality of the AUA from 1989 to 2007 (n = 405) were reviewed. Rates of sonographic abnormalities between fetuses with a right versus left AUA were compared using Fisher’s exact test. Adjustments for confounding were made using logistic regression modeling. The significance level was set at 0.05. Results: Right AUAs on ultrasound demonstrate higher unadjusted rates of ultrasound abnormalities with a higher percentage of fetuses with >1 additional abnormality (51.1 vs. 37.0%; p = 0.0043). The left AUA group had a significantly higher percentage of isolated AUA (63.0 vs. 48.8%; p = 0.004). In a multivariate analysis, a sonographic right AUA was significantly associated with gastrointestinal (GI) and genitourinary (GU) abnormalities. No other ultrasonographic and umbilical artery Doppler abnormalities, chromosomal defects or postpartum birth defects were significantly associated with a specific laterality of the AUA. Discussion: Our study identified a significant association between a right AUA and concomitant fetal GI and GU abnormalities. Contrary to previous reports, we conclude that laterality of the AUA may prove to be an easily identified early marker of fetal abnormalities.

Adjuvants modulate protective CD8+ T cell responses generated by cancer vaccines. We have previously shown that immunostimulatory CpG ODN significantly augments tumor protection in mice given adenovirus cancer vaccines. Here, we examined the impact of chitosan, another candidate vaccine adjuvant, on protection conferred by adenovirus cancer vaccines. Unexpectedly, immunization of mice with adenovirus cancer vaccines in combination with chitosan provided little protection against tumor challenge. This directly correlated with reduced detection of Ag-specific CD8+ T cells, IFN-γ production and cytotoxic T cell activity. We ruled out immunosuppressive regulatory T cells since frequency did not change regardless of whether chitosan was delivered. In mammalian cell lines, chitosan did not interfere with adenovirus transgene expression. However, infection of primary murine bone marrow-derived dendritic cells with adenovirus complexed with chitosan significantly reduced viability, transgene expression and upregulation of MHC class I and CD86. Our in vitro observations indicate that chitosan dramatically inhibits adenovirus-mediated transgene expression and antigen presenting cell activation, without which CD8+ T cell activation cannot occur in vivo. These surprising data demonstrate for the first time that chitosan vaccine formulations can negatively impact the induction of CD8+ T cell responses via its effect on dendritic cells, which is clinically important since consideration of chitosan as an adjuvant for vaccine formulations is growing.

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Preeclampsia annually kills 76,000 mothers and 500,000 babies worldwide often due to delay in diagnosis secondary to the lack ofsimple, early gestation tests. Elevated circulating copeptin (CPP), the pro-segment of vasopressin, is associated with preeclampsia (PreE). We have demonstrated that CPP is robustly predictive of PreE as early as the 6 th week of gestation in all mothers. Development of PreE is increased 3 fold by a history of PreE. Currently, no test robustly predicts PreE in women without a history of PreE. To evaluate if CPP is predictive in this low risk setting when a predictor is most needed, a nested case-control study was performed to evaluate the predictive characteristics of CPP of women with and without a history of PreE. Maternal plasma CPP concentrations throughout gestation were measured by ELISA. Univariate comparisons were performed. Receiver operating characteristic (ROC curves were constructed to determine sensitivity, specificity, positive and negative predictive values for particular cutoffs. Multivariable logistic regression was performed to control for confounding to examine if CPP was significantly predictive of PreE. Apart from a difference in prior history of PreE, no significant demographic or clinical differences were observed between groups. In all trimesters, CPP predicted PreE similarly or better in women with no history of PreE as evidenced by an elevated ROC Area Under the Curve in comparison to values of women with a history of Pre (1 st trimester: 0.96 vs. 0.85; 2 nd trimester: 0.95 vs. 0.94 ; 3 rd trimester: 0.82 vs. 0.67; p<0.05). Despite controlling for significant covariates such as maternal age, BMI, diabetes, chronic hypertension, and twin gestation, logistic modeling demonstrate that trimester specific CPP cutoffs throughout gestation are significantly associated with the development of PreE in women with no history of PreE (all models p< 0.001). Our data clearly support copeptin as an early predictor of preeclampsia in a low risk cohort. The ability to predict PreE in a low risk cohort with CPP is clinically significant as women in whom the diagnosis of preeclampsia is delayed or missed may now receive the appropriate interventions.

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