Increased level of phosphorylated akt measured by chemiluminescence-linked immunosorbent assay is a predictor of poor prognosis in primary breast cancer overexpressing ErbB-2

INTRODUCTION: Akt1, Akt2 and Akt3 kinases are downstream components of phosphoinositol 3-kinase derived signals from receptor tyrosine kinases, which influence cell growth, proliferation and survival. Akt2 overexpression and amplification have been described in breast, ovarian and pancreatic cancers. The present study was designed to investigate the prognostic significance of activated Akt in primary breast cancer and its association with other tumour biomarkers. METHODS: Using a two-site chemiluminescence-linked immunosorbent assay, we measured the quantitative expression levels of total phosphorylated (P-S473) Akt (Akt1/Akt2/Akt3) on cytosol fractions obtained from fresh frozen tissue samples of 156 primary breast cancer patients. RESULTS: Akt phosphorylation was not associated with nodal status or ErbB-2 protein expression levels. High levels of phosphorylated Akt correlated (P < 0.01) with poor prognosis, and the significance of this correlation increased (P < 0.001) in the subset of patients with ErbB-2 overexpressing tumours. In addition, phosphorylated Akt was found to be associated with mRNA expression levels of several proliferation markers (e.g. thymidylate synthase), measured using quantitative real-time RT-PCR. CONCLUSION: Our findings demonstrate that, in breast cancer patients, Akt activation is associated with tumour proliferation and poor prognosis, particularly in the subset of patients with ErbB2-overexpressing tumours

Low E2F1 transcript levels are a strong determinant of favorable breast cancer outcome

INTRODUCTION: We investigated whether mRNA levels of E2F1, a key transcription factor involved in proliferation, differentiation and apoptosis, could be used as a surrogate marker for the determination of breast cancer outcome. METHODS: E2F1 and other proliferation markers were measured by quantitative RT-PCR in 317 primary breast cancer patients from the Stiftung Tumorbank Basel. Correlations to one another as well as to the estrogen receptor and ERBB2 status and clinical outcome were investigated. Results were validated and further compared with expression-based prognostic profiles using The Netherlands Cancer Institute microarray data set reported by Fan and colleagues. RESULTS: E2F1 mRNA expression levels correlated strongly with the expression of other proliferation markers, and low values were mainly found in estrogen receptor-positive and ERBB2-negative phenotypes. Patients with low E2F1-expressing tumors were associated with favorable outcome (hazard ratio = 4.3 (95% confidence interval = 1.8-9.9), P = 0.001). These results were consistent in univariate and multivariate Cox analyses, and were successfully validated in The Netherlands Cancer Institute data set. Furthermore, E2F1 expression levels correlated well with the 70-gene signature displaying the ability of selecting a common subset of patients at good prognosis. Breast cancer patients' outcome was comparably predictable by E2F1 levels, by the 70-gene signature, by the intrinsic subtype gene classification, by the wound response signature and by the recurrence score. CONCLUSION: Assessment of E2F1 at the mRNA level in primary breast cancer is a strong determinant of breast cancer patient outcome. E2F1 expression identified patients at low risk of metastasis irrespective of the estrogen receptor and ERBB2 status, and demonstrated similar prognostic performance to different gene expression-based predictors

Holocene hydro-climatic variability in the Mediterranean: A synthetic multi-proxy reconstruction

Here we identify and analyze proxy data interpreted to reflect hydro-climatic variability over the last 10,000 years from the Mediterranean region to (1) outline millennial and multi-centennial-scale trends and (2) identify regional patterns of hydro-climatic variability. A total of 47 lake, cave, and marine records were transformed to z-scores to allow direct comparisons between sites, put on a common time scale, and binned into 200-year time slices. Six different regions were identified based on numerical and spatial analyzes of z-scores: S Iberia and Maghreb, N Iberia, Italy, the Balkans, Turkey, and the Levant, and the overall hydro-climate history of each region was reconstructed. N Iberia is largely decoupled from the five other regions throughout the Holocene. Wetter conditions occur in the five other regions between 8500 and 6100 yr BP. After 6000 yr BP, climate oscillated until around 3000 ± 300 yr BP, which seems to have been the overall driest period in the eastern Mediterranean and North Africa. In contrast, Italy and N Iberia seem to have remained wetter during this period. In addition, non-metric multidimensional scaling (nMDS) was applied to 18 long, continuous climate z-score records that span the majority of the Holocene. nMDS axes 1 and 2 illustrate the main trends in the z-score data. The first axis captures a long-term development of drier condition in the Mediterranean from 7900 to 3700 yr BP. Rapid shifts occur in nMDS axis 2 at 6700–6300 BP, 4500–4300 BP, and 3500–3300 BP indicating centennial-scale climate change. Our synthesis highlights a dominant south/east versus north/west Mediterranean hydro-climate dipole throughout the Holocene and therefore confirms that there was no single climate trajectory characterizing the whole Mediterranean basin during the last 10 millennia

Comparison of gene expression profiles in core biopsies and corresponding surgical breast cancer samples

INTRODUCTION: Gene expression profiling has been successfully used to classify breast cancer into clinically distinct subtypes, and to predict the risk of recurrence and treatment response. The aim of this study was to investigate whether the gene expression profile (GEP) detected in a core biopsy (CB) is representative for the entire tumor, since CB is an important tool in breast cancer diagnosis. Moreover, we investigated whether performing CBs prior to the surgical excision could influence the GEP of the respective tumor. METHODS: We quantified the RNA expression of 60 relevant genes by quantitative real-time PCR in paired CBs and surgical specimens from 22 untreated primary breast cancer patients. Subsequently, expression data were compared with independent GEPs obtained from tumors of 317 patients without preceding CB. RESULTS: In 82% of the cases the GEP detected in the CB correlated very well with the corresponding profile in the surgical sample (r(s )≥ 0.95, p < 0.001). Gene-by-gene analysis revealed four genes significantly elevated in the surgical sample compared to the CB; these comprised genes mainly involved in inflammation and the wound repair process as well as in tumor invasion and metastasis. CONCLUSION: A GEP detected in a CB are representative for the entire tumor and is, therefore, of clinical relevance. The observed alterations of individual genes after performance of CB deserve attention since they might impact the clinical interpretation with respect to prognosis and therapy prediction of the GEP as detected in the surgical specimen following CB performance

Pollen-inferred regional vegetation patterns and demographic change in Southern Anatolia through the Holocene

Southern Anatolia is a highly significant area within the Mediterranean, particularly in terms of understanding how agriculture moved into Europe from neighbouring regions. This study uses pollen, palaeoclimate and archaeological evidence to investigate the relationships between demography and vegetation change, and to explore how the development of agriculture varied spatially. Data from 21 fossil pollen records have been transformed into forested, parkland and open vegetation types using cluster analysis. Patterns of change have been explored using non-metric multidimensional scaling (nMDS) and through analysis of indicator groups, such as an Anthropogenic Pollen Index, and Simpson’s Diversity. Settlement data, which indicate population densities, and summed radiocarbon dates for archaeological sites have been used as a proxy for demographic change. The pollen and archaeological records confirm that farming can be detected earlier in Anatolia in comparison with many other parts of the Mediterranean. Dynamics of change in grazing indicators and the OJCV (Olea, Juglans, Castanea and Vitis) index for cultivated trees appear to match cycles of population expansion and decline. Vegetation and land use change is also influenced by other factors, such as climate change. Investigating the early impacts of anthropogenic activities (e.g. woodcutting, animal herding, the use of fire and agriculture) is key to understanding how societies have modified the environment since the mid–late Holocene, despite the capacity of ecological systems to absorb recurrent disturbances. The results of this study suggest that shifting human population dynamics played an important role in shaping land cover in central and southern Anatolia

Evaluating model outputs using integrated global speleothem records of climate change since the last glacial

Although quantitative isotopic data from speleothems has been used to evaluate isotope-enabled model simulations, currently no consensus exists regarding the most appropriate methodology through which to achieve this. A number of modelling groups will be running isotope-enabled palaeoclimate simulations in the framework of the Coupled Model Intercomparison Project Phase 6, so it is timely to evaluate different approaches to use the speleothem data for data-model comparisons. Here, we illustrate this using 456 globally-distributed speleothem δ18O records from an updated version of the Speleothem Isotopes Synthesis and Analysis (SISAL) database and palaeoclimate simulations generated using the ECHAM5-wiso isotope-enabled atmospheric circulation model. We show that the SISAL records reproduce the first-order spatial patterns of isotopic variability in the modern day, strongly supporting the application of this dataset for evaluating model-derived isotope variability into the past. However, the discontinuous nature of many speleothem records complicates procuring large numbers of records if data-model comparisons are made using the traditional approach of comparing anomalies between a control period and a given palaeoclimate experiment. To circumvent this issue, we illustrate techniques through which the absolute isotopic values during any time period could be used for model evaluation. Specifically, we show that speleothem isotope records allow an assessment of a model’s ability to simulate spatial isotopic trends. Our analyses provide a protocol for using speleothem isotopic data for model evaluation, including screening the observations to take into account the impact of speleothem mineralogy on 18O values, the optimum period for the modern observational baseline, and the selection of an appropriate time-window for creating means of the isotope data for palaeo time slices

The SISAL database: a global resource to document oxygen and carbon isotope records from speleothems

Stable isotope records from speleothems provide information on past climate changes, most particularly information that can be used to reconstruct past changes in precipitation and atmospheric circulation. These records are increasingly being used to provide “out-of-sample” evaluations of isotope-enabled climate models. SISAL (Speleothem Isotope Synthesis and Analysis) is an international working group of the Past Global Changes (PAGES) project. The working group aims to provide a comprehensive compilation of speleothem isotope records for climate reconstruction and model evaluation. The SISAL database contains data for individual speleothems, grouped by cave system. Stable isotopes of oxygen and carbon (δ 18O, δ 13C) measurements are referenced by distance from the top or bottom of the speleothem. Additional tables provide information on dating, including information on the dates used to construct the original age model and sufficient information to assess the quality of each data set and to erect a standardized chronology across different speleothems. The metadata table provides location information, information on the full range of measurements carried out on each speleothem and information on the cave system that is relevant to the interpretation of the records, as well as citations for both publications and archived data. The compiled data are available at https://doi.org/10.17864/1947.147

Climatic Changes and Their Impacts in the Mediterranean during the First Millennium AD

Many events and developments in human history have been suspected to be, at least partly, influenced by climate and environmental changes. In order to investigate climate impacts on societies, reliable palaeoclimatic data of adequate dating precision, resolution, spatial representativeness, and so on, are needed. This paper presents a survey and analysis of published palaeoclimatic data of the Mediterranean for the 1st millennium AD, and identifies regional patterns of hydro-climate variability, useful for comparison with archaeological/historical studies. It also provides general guidelines to palaeoclimatic data for archaeologists/historians interested in climatic change. We conclude with a discussion of how the emerging patterns of regional climate histories may have had an impact on Mediterranean societies in Late Antiquity