Sharing the Patient Experience: A "Talk Story" Intervention for Heart Failure Management in Native Hawaiians.

BACKGROUND: Native Hawaiians (NHs) suffer disproportionately from cardiovascular disease morbidity and mortality. OBJECTIVE: To test a narrative intervention of patient stories to support heart disease self-management in NHs. METHOD: Six NH storyteller videos were developed with community feedback following established methods. The NH participants with heart failure (N = 35) were recruited from a major medical center in Hawai'i. Participants completed demographic questionnaires, watched videos via iPad, and described experiences. Follow-up was 4 weeks later. RESULTS: Mean participant age was 57.0 years (standard deviation [SD]:13.0) and 31% (11) were female. On a scale of 1 (worst) to 4 (best), respondents rated the videos 3.7 (SD: 0.5) in relevance for helping them manage their heart disease and 3.6 (SD: 0.5) in their experience using these videos. When asked what they liked best, the most common response was that they are "like me" (from 14 respondents, ranging from a 43-year-old woman to an 84-year-old man). Of those completing follow-up (n = 15), 87% said videos helped them. CONCLUSION: Our narrative "talk story" intervention showed promise as a culturally relevant method to share patient experiences and reduce health disparities.

ß+-Thalassemia trait due to a novel mutation in the ß-globin gene promoter: -26 (A>C) [HBB c.-76A>C].

We report the case of a woman with ß(+)-thalassemia (ß(+)-thal) trait, in which there were two sequence variants within the ß-globin gene promoter: -54 (G>A) [HBB c.-104G>A] and -26 (A>C) [HBB c.-76A>C]. Data from other patients indicate that the -54 substitution is a non pathogenic sequence variant. Therefore, the ß-thal phenotype is most likely due to the -26 mutation that is adjacent to the conserved ATAA box.

Three new beta-thalassemia mutations with varying degrees of severity.

We report the identification of three, new beta-thalassemia (beta-thal) mutations with varying degrees of severity. The most severe mutation, a frameshift mutation in exon 3 of the beta-globin gene [codon 120 (-A)], was associated with a dominant beta-thal phenotype. A second frameshift mutation, codon 50 (-T), resulted in a phenotype of typical high Hb A(2) beta-thal trait. The mildest mutation was IVS-II-2 (T > C), which changes the splice donor sequence of IVS-II from GT to GC. This transition mutation resulted in a slight reduction in beta-globin gene expression and could be considered a mild beta(+)-thal allele.

Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing.

Antibody-drug conjugates are targeted anticancer agents consisting of a cytotoxic drug covalently linked to a monoclonal antibody for tumor antigen-specific activity. Once bound to the target cell-surface antigen, the conjugate must be processed to release an active form of the drug, which can reach its intracellular target. Here, we used both biological and biochemical methods to better define this process for antibody-maytansinoid conjugates. In particular, we examined the metabolic fate in cells of huC242-maytansinoid conjugates containing either a disulfide linker (huC242-SPDB-DM4) or a thioether linker (huC242-SMCC-DM1). Using cell cycle analysis combined with lysosomal inhibitors, we showed that lysosomal processing is required for the activity of antibody-maytansinoid conjugates, irrespective of the linker. We also identified and characterized the released maytansinoid molecules from these conjugates, and measured their rate of release compared with the kinetics of cell cycle arrest. Both conjugates are efficiently degraded in lysosomes to yield metabolites consisting of the intact maytansinoid drug and linker attached to lysine. The lysine adduct is the sole metabolite from the thioether-linked conjugate. However, the lysine metabolite generated from the disulfide-linked conjugate is reduced and S-methylated to yield the lipophilic and potently cytotoxic metabolite, S-methyl-DM4. These findings provide insight into the mechanism of action of antibody-maytansinoid conjugates in general, and more specifically, identify a biochemical mechanism that may account for the significantly enhanced antitumor efficacy observed with disulfide-linked conjugates.

An anti-insulin-like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation.

An antagonistic monoclonal antibody, designated EM164, has been developed which binds specifically to the human insulin-like growth factor I receptor (IGF-IR) and inhibits the proliferation and survival functions of the receptor in cancer cells. EM164 was initially selected by a rapid cell-based screen of hybridoma supernatants to identify antibodies that bind to IGF-IR but not to the homologous insulin receptor and that show maximal inhibition of IGF-I-stimulated autophosphorylation of IGF-IR. EM164 binds tightly to IGF-IR with a dissociation constant K(d) of 0.1 nM, inhibits binding of IGF-I and antagonizes its effects on cells completely, and has no agonistic activity on its own. EM164 inhibits IGF-I-, IGF-II-, and serum-stimulated proliferation and survival of diverse human cancer cell lines in vitro, including breast, lung, colon, cervical, ovarian, pancreatic, melanoma, prostate, neuroblastoma, rhabdomyosarcoma, and osteosarcoma cancer lines. It also suppresses the autocrine or paracrine proliferation of several cancer cell lines. EM164 was the most potent antagonistic anti-IGF-IR antibody tested when compared with several commercially available antibodies. The in vitro inhibitory effect could be extended to in vivo tumor models, where EM164 caused regression of established BxPC-3 human pancreatic tumor xenografts in SCID mice. The antitumor effect of treatment with EM164 could be enhanced by combining it with the cytotoxic agent gemcitabine. These data support the development of EM164 as a candidate therapeutic agent that targets IGF-IR function in cancer cells.