Molecular Drivers of Oncotype DX, Prosigna, EndoPredict, and the Breast Cancer Index: A TransATAC Study.

PURPOSE: The Oncotype DX Recurrence Score (RS), Prosigna Prediction Analysis of Microarray 50 (PAM50) Risk of Recurrence (ROR), EndoPredict (EP), and Breast Cancer Index (BCI) are used clinically for estimating risk of distant recurrence for patients receiving endocrine therapy. Discordances in estimates occur between them. We aimed to identify the molecular features that drive the tests and lead to these differences. PATIENTS AND METHODS: Analyses for RS, ROR, EP, and BCI were conducted by the manufacturers in the TransATAC sample collection that consisted of the tamoxifen or anastrozole arms of the ATAC trial. Estrogen receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative cases without chemotherapy treatment were included in which all four tests were available (n = 785). Clinicopathologic features included in some tests were excluded from the comparisons. Estrogen, proliferation, invasion, and HER2 module scores from RS were used to characterize the respective molecular features. Spearman correlation and analysis of variance tests were applied. RESULTS: There were moderate to strong correlations among the four molecular scores (ρ = 0.63-0.74) except for RS versus ROR (ρ = 0.32) and RS versus BCI (ρ = 0.35). RS had strong negative correlation with its estrogen module (ρ = -0.79) and moderate positive correlation with its proliferation module (ρ = 0.36). RS's proliferation module explained 72.5% of ROR's variance, while the estrogen module explained only 0.6%. Most of EP's and BCI's variation was accounted for by the proliferation module (50.0% and 54.3%, respectively) and much less by the estrogen module (20.2% and 2.7%, respectively). CONCLUSION: In contrast to common understanding, RSs are determined more strongly by estrogen-related features and only weakly by proliferation markers. However, the EP, BCI, and particularly ROR scores are determined largely by proliferative features. These relationships help to explain the differences in the prognostic performance of the tests

Use of mitogenic cascade blockers for treatment of C-Raf induced lung adenoma in vivo: CI-1040 strongly reduces growth and improves lung structure

BACKGROUND: Signaling networks promoting cell growth and proliferation are frequently deregulated in cancer. Tumors often are highly dependent on such signaling pathways and may become hypersensitive to downregulation of key components within these signaling cascades. The classical mitogenic cascade transmits stimuli from growth factor receptors via Ras, Raf, MEK and ERK to the cell nucleus and provides attractive molecular targets for cancer treatment. For example, Ras and Raf kinase inhibitors are already in a number of ongoing phase II and phase III clinical trials. In this study the effect of the Raf kinase inhibitor BAY 43-9006 and of the MEK inhibitor CI-1040 (PD184352) on a Raf dependent lung tumor mouse model was analyzed in detail. METHODS: We have generated a lung cancer mouse model by targeting constitutively active C-Raf kinase to the lung. These mice develop adenomas within 4 months of life. At this time-point they received daily intraperitoneal injections of either 100 mg/kg BAY 43-9006 or CI-1040 for additional 21 days. Thereafter, lungs were isolated and the following parameters were analyzed using histology and immunohistochemistry: overall lung structure, frequency of adenoma foci, proliferation rate, ERK activity, caspase-3 activation, and lung differentiation. RESULTS: Both inhibitors were equally effective in vitro using a sensitive Raf/MEK/ERK ELISA. In vivo, the systemic administration of the MEK inhibitor CI-1040 reduced adenoma formation to a third and significantly restored lung structure. The proliferation rate of lung cells of mice treated with CL-1040 was decreased without any obvious effects on differentiation of pneumocytes. In contrast, the Raf inhibitor BAY 43-9006 did not influence adenoma formation in vivo. CONCLUSION: The MEK inhibitor CI-1040 may be used for the treatment of Ras and/or Raf-dependent human malignancies

Trail laying during tandem-running recruitment in the ant Temnothorax albipennis

Tandem running is a recruitment strategy whereby one ant leads a single naïve nest mate to a resource. While tandem running progresses towards the goal, the leader ant and the follower ant maintain contact mainly by tactile signals. In this paper, we investigated whether they also deposit chemical signals on the ground during tandem running. We filmed tandem-running ants and analysed the position of the gasters of leaders and followers. Our results show that leader ants are more likely to press their gasters down to the substrate compared to follower ants, single ants and transporter ants. Forward tandem-run leaders (those moving towards a new nest site) performed such trail-marking procedures three times more often than reverse tandem leaders (those moving towards an old nest site). That leader ants marked the trails more often during forward tandem runs may suggest that it is more important to maintain the bond with the follower ant on forward tandem runs than on reverse tandem runs. Marked trails on the ground may serve as a safety line that improves both the efficiency of tandem runs and their completion rates. © 2014 Springer-Verlag Berlin Heidelberg

HER2 status predicts for upfront AI benefit: A TRANS-AIOG meta-analysis of 12,129 patients from ATAC, BIG 1-98 and TEAM with centrally determined HER2

The BIG 1-98 trial was financed by Novartis and coordinated by the IBCSG [clinicaltrials.gov IDs = NCT00004205], including the design of the trial, data management, medical review, pathology review, and statistical support. The ATAC Trial was funded by AstraZeneca [clinicaltrials.gov IDs = NCT00849030] and Cancer Research UK. The TEAM trial was funded by Pharmacia/Pfizer [clinicaltrials.gov IDs = NCT00279448] and aspects of the biomarker work was funded by Cancer Research UK. John Bartlett was supported by funding from OICR which is provided through the Ontario Ministry of Research, Innovation and Science

Migration control: A distance compensation strategy in ants

©The Author(s) 2016. This article is published with open access at Springerlink.com. Migratory behaviour forms an intrinsic part of the life histories of many organisms but is often a high-risk process. Consequently, varied strategies have evolved to negate such risks, but empirical data relating to their functioning are limited. In this study, we use the model system of the househunting ant Temnothorax albipennis to demonstrate a key strategy that can shorten migration exposure times in a group of social insects. Colonies of these ants frequently migrate to new nest sites, and due to the nature of their habitat, the distances over which they do so are variable, leading to fluctuating potential costs dependent on migration parameters. We show that colonies of this species facultatively alter the dynamics of a migration and so compensate for the distance over which a given migration occurs. Specifically, they achieve this by modulating the rate of ‘tandem running’, in which workers teach each other the route to a new nest site. Using this method, colonies are able to engage a larger number of individuals in the migration process when the distance to be traversed is greater, and furthermore, the system appears to be based on perceived encounter rate at the individual level. This form of decentralised control highlights the adaptive nature of a behaviour of ecological importance, and indicates that the key to its robustness lies in the use of simple rules. Additionally, our results suggest that such coordinated group reactions are central to achieving the high levels of ecological success seen in many eusocial organisms

Male circumcision and penile cancer: a systematic review and meta-analysis

OBJECTIVE: We systematically reviewed the evidence of an association between male circumcision and penile cancer. METHODS: Databases were searched using keywords and text terms for the epidemiology of penile cancer. Random effects meta-analyses were used to calculate summary odds ratios (ORs) and 95% confidence intervals (CI). RESULTS: We identified eight papers which evaluated the association of circumcision with penile cancer, of which seven were case-control studies. There was a strong protective effect of childhood/adolescent circumcision on invasive penile cancer (OR = 0.33; 95% CI 0.13-0.83; 3 studies). In two studies, the protective effect of childhood/adolescent circumcision on invasive cancer no longer persisted when analyses were restricted to boys with no history of phimosis. In contrast, there was some evidence that circumcision in adulthood was associated with an increased risk of invasive penile cancer (summary OR = 2.71; 95% CI 0.93-7.94; 3 studies). There was little evidence for an association of penile intra-epithelial neoplasia and in situ penile cancer with circumcision performed at any age. CONCLUSIONS: Men circumcised in childhood/adolescence are at substantially reduced risk of invasive penile cancer, and this effect could be mediated partly through an effect on phimosis. Expansion of circumcision services in sub-Saharan Africa as an HIV prevention strategy may additionally reduce penile cancer risk

The Proteolipid Protein Promoter Drives Expression outside of the Oligodendrocyte Lineage during Embryonic and Early Postnatal Development

The proteolipid protein (Plp) gene promoter is responsible for driving expression of one of the major components of myelin – PLP and its splice variant DM-20. Both products are classically thought to express predominantly in oligodendrocytes. However, accumulating evidence suggests Plp expression is more widespread than previously thought. In an attempt to create a mouse model for inducing oligodendrocyte-specific gene deletions, we have generated transgenic mice expressing a Cre recombinase cDNA under control of the mouse Plp promoter. We demonstrate Plp promoter driven Cre expression is restricted predominantly to mature oligodendrocytes of the central nervous system (CNS) at postnatal day 28. However, crosses into the Rosa26LacZ and mT/mG reporter mouse lines reveal robust and widespread Cre activity in neuronal tissues at E15.5 and E10.5 that is not strictly oligodendrocyte lineage specific. By P28, all CNS tissues examined displayed high levels of reporter gene expression well outside of defined white matter zones. Importantly, our study reinforces the emerging idea that Plp promoter activity is not restricted to the myelinating cell lineage, but rather, has widespread activity both during embryonic and early postnatal development in the CNS. Specificity of the promoter to the oligodendrocyte cell lineage, as shown through the use of a tamoxifen inducible Plp-CreERt line, occurs only at later postnatal stages. Understanding the temporal shift in Plp driven expression is of consequence when designing experimental models to study oligodendrocyte biology

Trail laying during tandem-running recruitment in the ant Temnothorax albipennis

Tandem running is a recruitment strategy whereby one ant leads a single naïve nest mate to a resource. While tandem running progresses towards the goal, the leader ant and the follower ant maintain contact mainly by tactile signals. In this paper, we investigated whether they also deposit chemical signals on the ground during tandem running. We filmed tandem-running ants and analysed the position of the gasters of leaders and followers. Our results show that leader ants are more likely to press their gasters down to the substrate compared to follower ants, single ants and transporter ants. Forward tandem-run leaders (those moving towards a new nest site) performed such trail-marking procedures three times more often than reverse tandem leaders (those moving towards an old nest site). That leader ants marked the trails more often during forward tandem runs may suggest that it is more important to maintain the bond with the follower ant on forward tandem runs than on reverse tandem runs. Marked trails on the ground may serve as a safety line that improves both the efficiency of tandem runs and their completion rates. © 2014 Springer-Verlag Berlin Heidelberg

Marine probiotics: increasing coral resistance to bleaching through microbiome manipulation

Although the early coral reef-bleaching warning system (NOAA/USA) is established, there is no feasible treatment that can minimize temperature bleaching and/or disease impacts on corals in the field. Here, we present the first attempts to extrapolate the widespread and well-established use of bacterial consortia to protect or improve health in other organisms (e.g., humans and plants) to corals. Manipulation of the coral-associated microbiome was facilitated through addition of a consortium of native (isolated from Pocillopora damicornis and surrounding seawater) putatively beneficial microorganisms for corals (pBMCs), including five Pseudoalteromonas sp., a Halomonas taeanensis and a Cobetia marina-related species strains. The results from a controlled aquarium experiment in two temperature regimes (26 °C and 30 °C) and four treatments (pBMC; pBMC with pathogen challenge – Vibrio coralliilyticus, VC; pathogen challenge, VC; and control) revealed the ability of the pBMC consortium to partially mitigate coral bleaching. Significantly reduced coral-bleaching metrics were observed in pBMC-inoculated corals, in contrast to controls without pBMC addition, especially challenged corals, which displayed strong bleaching signs as indicated by significantly lower photopigment contents and Fv/Fm ratios. The structure of the coral microbiome community also differed between treatments and specific bioindicators were correlated with corals inoculated with pBMC (e.g., Cobetia sp.) or VC (e.g., Ruegeria sp.). Our results indicate that the microbiome in corals can be manipulated to lessen the effect of bleaching, thus helping to alleviate pathogen and temperature stresses, with the addition of BMCs representing a promising novel approach for minimizing coral mortality in the face of increasing environmental impacts