Communication of BRCA1 and BRCA2 genetic test results to health care providers following genetic testing at a tertiary care center.

Individuals at high risk for hereditary cancers often receive genetic counseling and testing at tertiary care centers; however, they may receive care for long-term management of their cancer risk in community settings. Communication of genetic test results to health care providers outside of tertiary care settings can facilitate the long-term management of high risk individuals. This study assessed women's communication of BRCA1/BRCA2 genetic test results to health care providers outside of tertiary care settings (termed "outside" health care providers, or OHCPs) and women's perceptions regarding communication of results. Women (n = 312) who underwent BRCA1/BRCA2 genetic counseling and testing completed a questionnaire assessing whether or not they shared test results with OHCPs and perceptions regarding the communication of test results to OHCPs. Most (72%) shared genetic test results with OHCPs. Women with no personal history of cancer were more likely to have shared results compared to women with a personal history of cancer. Mutation status did not significantly predict sharing of genetic information. Most reported positive perceptions regarding the disclosure of genetic test results to OHCPs. The majority did not report any concerns about potential insurance discrimination (88%) and indicated that OHCPs were able to appropriately address their questions (81%). Although most women shared their genetic test results with OHCPs, those with a personal history of cancer may need further encouragement to share this information. Tertiary care centers should facilitate outreach and education with OHCPs in order to assure appropriate long-term cancer risk management for high risk populations.

Immunosuppressant PG490 (triptolide) inhibits T-cell interleukin-2 expression at the level of purine-box/nuclear factor of activated T-cells and NF-kappaB transcriptional activation.

PG490 (triptolide) is a diterpene triepoxide with potent immunosuppressive and antiinflammatory properties. PG490 inhibits interleukin(IL)-2 expression by normal human peripheral blood lymphocytes stimulated with phorbol 12-myristate 13-acetate (PMA) and antibody to CD3 (IC50 of 10 ng/ml), and with PMA and ionomycin (Iono, IC50 of 40 ng/ml). In Jurkat T-cells, PG490 inhibits PMA/Iono-stimulated IL-2 transcription. PG490 inhibits the induction of DNA binding activity at the purine-box/antigen receptor response element (ARRE)/nuclear factor of activated T-cells (NF-AT) target sequence but not at the NF-kappaB site. PG490 can completely inhibit transcriptional activation at the purine-box/ARRE/NF-AT and NF-kappaB target DNA sequences triggered by all stimuli examined (PMA, PMA/Iono, tumor necrosis factor-alpha). PG490 also inhibits PMA-stimulated activation of a chimeric transcription factor in which the C-terminal TA1 transactivation domain of NF-kappaB p65 is fused to the DNA binding domain of GAL4. In 16HBE human bronchial epithelial cells, IL-8 expression is regulated predominantly by NF-kappaB, and PG490 but not cyclosporin A can completely inhibit expression of IL-8. The mechanism of PG490 inhibition of cytokine gene expression differs from cyclosporin A and involves nuclear inhibition of transcriptional activation of NF-kappaB and the purine-box regulator operating at the ARRE/NF-AT site at a step after specific DNA binding.

Human airway epithelial cells express interleukin-2 in vitro.

Human airway epithelial cells (AEC) produce the T cell growth factor interleukin (IL)-2 that likely modulates the T cell lung inflammatory response. IL-2 mRNA from cultured AEC and from Jurkat T cells was analyzed by reverse transcription-polymerase chain reaction and Northern hybridization. IL-2 mRNA is present constitutively in AEC and is enhanced twofold after stimulation with phorbol 12-myristate 13-acetate (PMA; 20 ng/ml) + histamine (2 mM). Normal human AEC secrete IL-2 at rest (7 pg/ml), and IL-2 secretion is increased threefold after stimulation with PMA + histamine; this increase is inhibited by dexamethasone and diphenhydramine. Transcriptional regulation of IL-2 was investigated with a transgenic human AEC line, 16HBE/IL-2 luciferase; there is constitutive IL-2 transcription at rest, and IL-2 transcription is enhanced 8-fold by PMA and 25-fold by PMA + histamine. IL-2 regulation differs fundamentally between AEC and Jurkat T cells. AEC IL-2 likely promotes local proliferation of T cells and may contribute to pathological airway inflammation in asthma.