Breast Tumor Cells with PI3K Mutation or HER2 Amplification Are Selectively Addicted to Akt Signaling

Dysregulated PI3K/Akt signaling occurs commonly in breast cancers and is due to HER2 amplification, PI3K mutation or PTEN inactivation. The objective of this study was to determine the role of Akt activation in breast cancer as a function of mechanism of activation and whether inhibition of Akt signaling is a feasible approach to therapy.A selective allosteric inhibitor of Akt kinase was used to interrogate a panel of breast cancer cell lines characterized for genetic lesions that activate PI3K/Akt signaling: HER2 amplification or PI3K or PTEN mutations in order to determine the biochemical and biologic consequences of inhibition of this pathway. A variety of molecular techniques and tissue culture and in vivo xenograft models revealed that tumors with mutational activation of Akt signaling were selectively dependent on the pathway. In sensitive cells, pathway inhibition resulted in D-cyclin loss, G1 arrest and induction of apoptosis, whereas cells without pathway activation were unaffected. Most importantly, the drug effectively inhibited Akt kinase and its downstream effectors in vivo and caused complete suppression of the growth of breast cancer xenografts with PI3K mutation or HER2 amplification, including models of the latter selected for resistance to Herceptin. Furthermore, chronic administration of the drug was well-tolerated, causing only transient hyperglycemia without gross toxicity to the host despite the pleiotropic normal functions of Akt.These data demonstrate that breast cancers with PI3K mutation or HER2 amplification are selectively dependent on Akt signaling, and that effective inhibition of Akt in tumors is feasible and effective in vivo. These findings suggest that direct inhibition of Akt may represent a therapeutic strategy for breast and other cancers that are addicted to the pathway including tumors with resistant to Herceptin

Forest landscape ecology and global change: an introduction

Forest landscape ecology examines broad-scale patterns and processes and their interactions in forested systems and informs the management of these ecosystems. Beyond being among the richest and the most complex terrestrial systems, forest landscapes serve society by providing an array of products and services and, if managed properly, can do so sustainably. In this chapter, we provide an overview of the field of forest landscape ecology, including major historical and present topics of research, approaches, scales, and applications, particularly those concerning edges, fragmentation, connectivity, disturbance, and biodiversity. In addition, we discuss causes of change in forest landscapes, particularly land-use and management changes, and the expected structural and functional consequences that may result from these drivers. This chapter is intended to set the context and provide an overview for the remainder of the book and poses a broad set of questions related to forest landscape ecology and global change that need answers

The Notch pathway in ovarian carcinomas and adenomas

Elements of the Notch pathway regulate differentiation; we investigated the expression of such elements in epithelial ovarian tumours. A total of 32 ovarian tumour samples (17 adenocarcinomas, three borderline tumours, 12 adenomas), two human ovarian cancer (A2780, OVCAR3), and one ovarian surface (IOSE 144) cell lines were analysed. The expression of Notch pathway elements was assessed by RT–PCR, real-time PCR (Notch 1), and by immunoblots (Notch 1 extracellular domain (EC), HES1). The proliferation and colony formation of A2780 cells were measured after stable transfection with activated Notch 1 (intracellular domain). Jagged 2, Delta-like-1, Manic Fringe, and TSL1 were expressed more frequently in adenocarcinomas whereas Deltex, Mastermind, and Radical Fringe were more frequent in adenomas. Quantitative PCR revealed decreased Notch 1 mRNA in ovarian adenocarcinomas compared with adenomas. The expression of Notch 1-EC protein was similar in benign and malignant tumours. HES1 protein was strongly expressed in 18/19 ovarian cancers and borderline tumours but not in adenomas. Transfecting A2780 cells with active Notch 1-IC resulted in a proliferative and colony formation advantage compared to mock transfected cells. Thus, Notch pathway elements are expressed in ovarian epithelial tumours and some of them are differentially expressed between adenomas and carcinomas. The Notch pathway could be a target for the development of therapies for ovarian cancer

Residency patterns and migration dynamics of adult bull sharks (Carcharhinus leucas) on the east coast of southern Africa:

Bull sharks (Carcharhinus leucas) are globally distributed top predators that play an important ecological role within coastal marine communities. However, little is known about the spatial and temporal scales of their habitat use and associated ecological role. In this study, we employed passive acoustic telemetry to investigate the residency patterns and migration dynamics of 18 adult bull sharks (195–283 cm total length) tagged in southern Mozambique for a period of between 10 and 22 months. The majority of sharks (n = 16) exhibited temporally and spatially variable residency patterns interspersed with migration events. Ten individuals undertook coastal migrations that ranged between 433 and 709 km (mean  = 533 km) with eight of these sharks returning to the study site

A statistical framework for cross-tissue transcriptome-wide association analysis

Transcriptome-wide association analysis is a powerful approach to studying the genetic architecture of complex traits. A key component of this approach is to build a model to impute gene expression levels from genotypes by using samples with matched genotypes and gene expression data in a given tissue. However, it is challenging to develop robust and accurate imputation models with a limited sample size for any single tissue. Here, we first introduce a multi-task learning method to jointly impute gene expression in 44 human tissues. Compared with single-tissue methods, our approach achieved an average of 39% improvement in imputation accuracy and generated effective imputation models for an average of 120% more genes. We describe a summary-statistic-based testing framework that combines multiple single-tissue associations into a powerful metric to quantify the overall gene–trait association. We applied our method, called UTMOST (unified test for molecular signatures), to multiple genome-wide-association results and demonstrate its advantages over single-tissue strategies

Towards Understanding the Origin of Cosmic-Ray Positrons

Precision measurements of cosmic ray positrons are presented up to 1 TeV based on 1.9 million positrons collected by the Alpha Magnetic Spectrometer on the International Space Station. The positron flux exhibits complex energy dependence. Its distinctive properties are (a) a significant excess starting from 25.2 +/- 1.8 GeV compared to the lower-energy, power-law trend, (b) a sharp dropoff above 284(-64)(+91) GeV, (c) in the entire energy range the positron flux is well described by the sum of a term associated with the positrons produced in the collision of cosmic rays, which dominates at low energies, and a new source term of positrons, which dominates at high energies, and (d) a finite energy cutoff of the source term of E-s = 810(-180)(+310) GeV is established with a significance of more than 4 sigma. These experimental data on cosmic ray positrons show that, at high energies, they predominantly originate either from dark matter annihilation or from other astrophysical sources

Properties of Neon, Magnesium, and Silicon Primary Cosmic Rays Results from the Alpha Magnetic Spectrometer

We report the observation of new properties of primary cosmic rays, neon (Ne), magnesium (Mg), and silicon (Si), measured in the rigidity range 2.15 GV to 3.0 TV with 1.8 x 10(6) Ne, 2.2 x 10(6) Mg, and 1.6 x 10(6) Si nuclei collected by the Alpha Magnetic Spectrometer experiment on the International Space Station. The Ne and Mg spectra have identical rigidity dependence above 3.65 GV. The three spectra have identical rigidity dependence above 86.5 GV, deviate from a single power law above 200 GV, and harden in an identical way. Unexpectedly, above 86.5 GV the rigidity dependence of primary cosmic rays Ne, Mg, and Si spectra is different from the rigidity dependence of primary cosmic rays He, C, and O. This shows that the Ne, Mg, and Si and He, C, and O are two different classes of primary cosmic rays

Properties of Cosmic Helium Isotopes Measured by the Alpha Magnetic Spectrometer

Precision measurements by the Alpha Magnetic Spectrometer (AMS) on the International Space Station of He-3 and He-4 fluxes are presented. The measurements are based on 100 million He-4 nuclei in the rigidity range from 2.1 to 21 GV and 18 million He-3 from 1.9 to 15 GV collected from May 2011 to November 2017. We observed that the He-3 and He-4 fluxes exhibit nearly identical variations with time. The relative magnitude of the variations decreases with increasing rigidity. The rigidity dependence of the He-3/He-4 flux ratio is measured for the first time. Below 4 GV, the He-3/He-4 flux ratio was found to have a significant long-term time dependence. Above 4 GV, the He-3/He-4 flux ratio was found to be time independent, and its rigidity dependence is well described by a single power law proportional to R-Delta with Delta = 0.294 0.004. Unexpectedly, this value is in agreement with the B/O and B/C spectral indices at high energies