Contrasting Patterns of Rapid Molecular Evolution within the p53 Network across Mammal and Sauropsid Lineages.

Cancer is a threat to multicellular organisms, yet the molecular evolution of pathways that prevent the accumulation of genetic damage has been largely unexplored. The p53 network regulates how cells respond to DNA-damaging stressors. We know little about p53 network molecular evolution as a whole. In this study, we performed comparative genetic analyses of the p53 network to quantify the number of genes within the network that are rapidly evolving and constrained, and the association between lifespan and the patterns of evolution. Based on our previous published data set, we used genomes and transcriptomes of 34 sauropsids and 32 mammals to analyze the molecular evolution of 45 genes within the p53 network. We found that genes in the network exhibited evidence of positive selection and divergent molecular evolution in mammals and sauropsids. Specifically, we found more evidence of positive selection in sauropsids than mammals, indicating that sauropsids have different targets of selection. In sauropsids, more genes upstream in the network exhibited positive selection, and this observation is driven by positive selection in squamates, which is consistent with previous work showing rapid divergence and adaptation of metabolic and stress pathways in this group. Finally, we identified a negative correlation between maximum lifespan and the number of genes with evidence of divergent molecular evolution, indicating that species with longer lifespans likely experienced less variation in selection across the network. In summary, our study offers evidence that comparative genomic approaches can provide insights into how molecular networks have evolved across diverse species.

Immune Signatures Following Single Dose Trastuzumab Predict Pathologic Response to PreoperativeTrastuzumab and Chemotherapy in HER2-Positive Early Breast Cancer.

PURPOSE: Recent data suggest that intrinsic subtype and immune cell infiltration may predict response to trastuzumab-based therapy. We studied the interaction between these factors, changes in immune signatures following brief exposure to trastuzumab, and achievement of pathologic complete response (pCR) to subsequent preoperative trastuzumab and chemotherapy in HER2-positive breast cancer. EXPERIMENTAL DESIGN: In patients enrolled on two multicenter trials (03-311 and 211B), tumor core biopsies were obtained at baseline and after brief exposure to single-agent trastuzumab or nab-paclitaxel. Gene expression profiles were assessed to assign PAM50 subtypes, measure immune cell activation, and were correlated with response. RESULTS: The pCR rate was significantly higher in HER2-enriched tumors in the Discovery, 03-311 (36%, P = 0.043) dataset, as compared with other subtypes, which validated in 211B (50%, P = 0.048). Significant increases in a signature of immune cell admixture (Immune Index) were observed only following brief exposure to trastuzumab in HER2-enriched tumors (Discovery/03-311, P = 0.05; Validation/211B, P = 0.02). Increased Immune Index was predictive of response after brief exposure (03-311, P = 0.03; 211B, P = 0.04), but not at baseline, in addition to increased expression of a CD4(+) follicular helper T-cell signature (03-311, P = 0.05; 211B, P = 0.04). Brief exposure to trastuzumab significantly increased gene expression of the T-cell marker PD-1 in HER2-enriched tumors (Discovery/03-311, P = 0.045) and PD-1 positivity by IHC (Validation/211B, P = 0.035). CONCLUSIONS: Correlations between pCR rates, increases in Immune Index and markers of T-cell activity following brief exposure to trastuzumab in HER2-enriched tumors provide novel insights into the interaction between tumor biology, antitumor immunity, and response to treatment, and suggest potential clinically useful biomarkers in HER2(+) breast cancers. Clin Cancer Res; 22(13); 3249-59. ©2016 AACR.

Physiological indices of stress in wild and captive garter snakes: correlations, repeatability, and ecological variation.

Glucocorticoids and leukocyte ratios have become the most widespread variables employed to test hypotheses regarding physiological stress in wild and captive vertebrates. Little is known, however, regarding how these two indices of stress covary in response to stressors, their repeatability within individuals, and differences in response time upon capture. Furthermore, few studies compare stress indices between captive and wild populations, to assess potential alteration of stress physiology in captivity. To address these issues, we examined corticosterone (CORT) and heterophil to lymphocyte (H:L) ratios in two ecotypes of the garter snake Thamnophis elegans. We found that CORT and H:L ratios were not correlated within individuals, and both variables showed little or no repeatability over a period of months. CORT levels, but not H:L ratios, were higher for individuals sampled after 10min from the time of capture. However, both variables showed similar patterns of ecotypic variation, and both increased over time in gravid females maintained in captivity for four months. We suggest that CORT and H:L ratios are both useful, but disparate indices of stress in this species, and may show complex relationships to each other and to ecological and anthropogenic variables.