A pilot randomized trial of an educational intervention to increase genetic counseling and genetic testing among Latina breast cancer survivors.

Latinas are less likely to participate in genetic counseling (GC) and genetic testing (GT) than non-Hispanic Whites. A multisite, randomized pilot study tested a culturally targeted educational intervention to increase uptake of GC/GT among Latina breast cancer (BC) survivors (N = 52). Participants were recruited in Tampa, FL and Ponce, PR and randomized to: (a) fact sheet about BC survivorship (control) or (b) a culturally targeted educational booklet about GC/GT (intervention). Participants in the intervention condition were also offered no-cost telephone GC followed by free GT with mail-based saliva sample collection. Participants self-reported hereditary breast and ovarian cancer (HBOC) knowledge and emotional distress at baseline and 1- and 3-month follow-ups. We used logistic regression to examine differences in GC/GT uptake by study arm (primary outcome) and repeated measures ANOVA to examine the effects of study arm and time on HBOC knowledge and emotional distress (secondary outcomes). Compared to the control arm, intervention participants were more likely to complete GC (ORIntervention  = 13.92, 95% CI = 3.06-63.25, p < .01) and GT (ORIntervention  = 12.93, 95% CI = 2.82-59.20, p < .01). Study site did not predict uptake of GC (p = .08) but Ponce participants were more likely to complete GT (ORPonce  = 4.53, 95% CI = 1.04-19.72, p = .04). ANOVAs demonstrated an increase in HBOC knowledge over time across both groups (F(2,88) = 12.24, p < .01, ηp2  = 0.22). We also found a significant interaction of study arm and time, such that intervention participants demonstrated a greater and sustained (to the 3-month follow-up) increase in knowledge than control participants (F(2,88) = 3.66, p = .03, ηp2  = 0.08). No other main or interaction effects were significant (all p's> .15). Study findings demonstrate the potential of our culturally targeted print intervention. Lessons learned from this multisite pilot study for enhancing GC/GT in Latinas include the need to attend to both access to GC/GT and individual factors such as attitudes and knowledge.

Discovery of potent calpain inhibitors based on the azolo-imidazolidenone scaffold.

A series of new azolopyrimidine-peptide hybrids and indolomethylideneimidazolones were obtained and evaluated as calpain inhibitors. The hybrid compounds were inactive, whereas some members of the initial azolomethylideneimidazolone series showed interesting calpain inhibitory activity. By using 4b as a hit compound, a new series of analogs were synthesized by an efficient synthetic procedure based on a multicomponent reaction followed by an unprecedented reaction at the methylene position of the molecule. The best inhibitor found for calpain I (IC50 = 20 nM) was about 20 times more potent than the hit compound. Studies on 4b showed that its inhibition is consistent with an uncompetitive inhibition mode. This compound did not exhibit cellular toxicity at any of the doses tested (0.1-10 µM) and further studies indicated that it was capable of blockading chemical ischemia induction of apoptosis by preventing sodium azide-dependent calpain activation in intact human kidney tubular epithelial cells. The results of molecular modeling studies rationalized the inhibitory activity found for this series and account, from a structural point of view, for the most active compound identified (4j).

Benzo[f]azino[2,1-a]phthalazinium cations: novel DNA intercalating chromophores with antiproliferative activity.

New azaquinolizinium-type cations have been obtained from isochromane. The synthesis was completed over seven steps and included as the key feature an intramolecular Westphal condensation. This first example of the intramolecular process allowed the preparation of benzo[f]pyrido[2,1-a]phthalazinium and benzo[f]quino[2,1-a]phthalazinium salts, which were evaluated as DNA intercalators, DNA topoisomerase I inhibitors, and antiproliferative compounds. Both cationic systems behave as DNA intercalators and exhibit antiproliferative activity. The pentacyclic benzo[f]quino[2,1-a]phthalazinium cations also have an inhibitory effect on the catalytic activity of DNA topoisomerase I, without trapping of cleavage complexes. Structural characterization using density functional theory indicates that the fused ring systems are slightly nonplanar, and additional molecular modeling studies suggest a preferred orientation for the intercalating chromophores within a typical CpG or TpG intercalation site.