Chimeric mouse tumor models reveal differences in pathway activation between ERBB family- and KRAS-dependent lung adenocarcinomas.

To recapitulate the stochastic nature of human cancer development, we have devised a strategy for generating mouse tumor models that involves stepwise genetic manipulation of embryonic stem (ES) cells and chimera generation. Tumors in the chimeric animals develop from engineered cells in the context of normal tissue. Adenocarcinomas arising in an allelic series of lung cancer models containing HER2 (also known as ERBB2), KRAS or EGFR oncogenes exhibit features of advanced malignancies. Treatment of EGFR(L858R) and KRAS(G12V) chimeric models with an EGFR inhibitor resulted in near complete tumor regression and no response to the treatment, respectively, accurately reflecting previous clinical observations. Transcriptome and immunohistochemical analyses reveal that PI3K pathway activation is unique to ERBB family tumors whereas KRAS-driven tumors show activation of the JNK/SAP pathway, suggesting points of therapeutic intervention for this difficult-to-treat tumor category.

Inhaled nitric oxide for modulation of ischemia-reperfusion injury in lung transplantation.

BACKGROUND: The prophylactic administration of inhaled nitric oxide (NO) during reperfusion after lung transplantation has been shown to reduce neutrophil-induced injury in animal models. There remain questions regarding efficacy in the clinical setting and concerns regarding increased free radical injury. We sought to assess the efficacy of NO in reducing neutrophil infiltration and associated injury if administered from the very onset of reperfusion in clinical lung transplantation. METHODS: Twenty bilateral sequential lung transplant recipients were randomized to receive 20-ppm inhaled NO (NO group) or a standard anesthetic gas mixture (control group) from the onset of ventilation. Bronchoalveolar lavage was performed immediately prior to implantation and after 30 minutes of reperfusion and analyzed for inflammatory cytokine levels and free radical surrogates. Primary graft dysfunction (PGD) scoring was performed prospectively for 72 hours post-transplant. RESULTS: The prophylactic administration of NO during the first 30 minutes of reperfusion had no statistically significant effect on the development of Grade II to III PGD (5 of 10 in NO group and 7 of 10 in control group, p = 0.36) or gas exchange (area under the curve: 429 +/- 296 vs 336 +/- 306; p = 0.64) in the NO and control groups, respectively. Pulmonary neutrophil sequestration, as measured by the transpulmonary arteriovenous neutrophil difference, was not influenced by the administration of NO. Prophylactic NO did not significantly alter the concentration of interleukin-8, myeloperoxidase or nitrotyrosine during transplantation. CONCLUSIONS: This study could not demonstrate a significant effect of inhaled NO during the first 30 minutes of reperfusion in the prevention of neutrophil injury and primary graft dysfunction after lung transplantation.

Validity of the parent young mania rating scale in a community mental health setting.

The objective of this study was to examine the potential of using the Parent Young Mania Rating Scale (P-YMRS) to distinguish pediatric bipolar disorder from other psychiatric conditions. The design of the study was a retrospective chart review. The setting of the study was community mental health. Participants included 130 children and adolescents. Measurements were based on P-YMRS scores. An ANOVA revealed a significant difference between mean scores of patients with and without bipolar disorder. A receiver operating characteristic (ROC) analysis revealed that the P-YMRS is very good at predicting group membership and suggested a cutoff of 18 or higher for the presence of bipolar disorder. The authors conclude that the P-YMRS should be useful to differentiate pediatric bipolar disorder from other mental health conditions.

Measurement of human interleukin 11.

This unit describes an ELISA and a cell proliferation assay that can be used, respectively, to measure the protein level or biologic activity of human and murine interleukin 11 (IL-11). The bioassay is based on the ability of IL-11 to support growth of the B9-11 cell line, a subline of B9 that has traditionally been used to measure levels of IL-6. B9-11 is substantially more responsive to IL-11 than the T10 line used in older protocols. This new bioassay therefore provides improved sensitivity, with a detection limit of 20 pg/ml. An alternate procedure is provided that employs neutralizing antibodies in the cell proliferation bioassay to use to ensure that the activity of the desired molecule (IL-11) is being measured in samples containing multiple cytokines. A describes maintenance of B9-11 cells.