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The north Andean block evidences by its shallow to intermediate seismicity a juxtaposition of a southern, relatively steeply dipping slab segment with a correlating volcanic arc and a northern flat slab domain, where a margin-parallel volcanic arc became extinct since the Late Miocene. The clear-cut offset of the seismic pattern suggests the presence of a slab tear, which has its correlative morphological expression by a distinct lineament in the Cauca Valley and separates, within the Eastern Cordillera of Colombia, a southern narrow antiformal cordilleran tract from a northern composite belt with an axial depression that constitutes the High Plain of Bogotá. Faults are consistently blind and associated with tight, basement-cored folds with inverted limbs at the mountain front and distinct domes separated by marginal synclines. These structures belong to a young deformation phase as they were superposed on older cylindrical fold trains. Their ductile deformation style may be associated with a thermal anomaly as evidenced by abnormally high Ro data. In order to assess the age of this folding we extracted zircons from a rhyolitic dike that straddles a marginal syncline of a major dome. U-Pb age data indicate a recycling of these crystals from a Neoproterozoic volcanoclastic sequence that composes the basement of this marginal part of the Cordillera. Euhedral overgrowths yield, however, Quaternary ages that we tentatively associate to the advance of the outer bend of the flat slab to its present position.

Trophoblast cells are often compared to highly invasive carcinoma cells due to their capacity to proliferate in hypoxic conditions and to exhibit analogous vascular, proliferative, migratory, and invasive capacities. Thus, genes that are important for tumorigenesis, such as forkhead box M1 ( FOXM1) may also be involved in processes of trophoblast invasion. Indeed, we found Foxm1 protein and messenger RNA (mRNA) levels decreased as gestational age increased in rat's placentae. Accordingly, when mimicking early placental events in vitro, protein and mRNA expression of FOXM1 increased from 21% to 8% O2, reaching its highest expression at 3% oxygen tension, which reflects early implantation environment, and dropping to very low levels at 1% O2. Remarkably, FOXM1 silencing in JEG-3 cells was able to significantly decrease migration by 27.9%, in comparison with those cells transfected with control siRNA. Moreover, angiogenesis was compromised when conditioned media (CM) from FOXM1-siRNA -JEG-3 (3% O2) was added to human umbilical vein endothelial cells (HUVEC) cells; however, when CM of JEG-3 cells overexpressing FOXM1 at 1% O2 was added, the ability of HUVEC to form tubule networks was restored. Additionally, quantitative real-time polymerase chain reaction (PCR) assays of FOXM1 knockdown and overexpression experiments in JEG-3 cells revealed that the depletion of FOXM1 at 3% O2 and overexpression of FOXM1 at 1% O2 led to downregulation and upregulation of vascular endothelial growth factor transcriptional (VEGF) levels, respectively. Conversely, we also observed deregulation of FOXM1 in placentae derived from pregnancies complicated by preeclampsia (PE). Therefore, we demonstrate that FOXM1 may be a new regulatory protein of early placentation processes and that under chronic hypoxic conditions (1% O2) and in patients with severe PE, its levels decrease.

// Rafaela Erices 1, 2 , Sofia Cubillos 2 , Raul Aravena 2, 3 , Felice Santoro 2 , Monica Marquez 2 , Renan Orellana 1, 15 , Carolina Ramirez 2 , Pamela Gonzalez 2, 4 , Patricia Fuenzalida 2 , Maria Loreto Bravo 2, 4, 5 , Barbara Oliva 2, 4 , Sumie Kato 1 , Carolina Ibanez 5, 6, 7 , Jorge Branes 1 , Erasmo Bravo 8 , Catalina Alonso 8 , Karen Garcia 7, 9 , Clemente Arab 10 , Vicente A. Torres 11, 16 , Alejandro S. Godoy 2, 12 , Jaime Pereira 6 , Galdo Bustos 13 , Julio Cesar Cardenas 13, 14 , Mauricio A. Cuello 1 , Gareth I. Owen 2, 4, 5, 7, 16 1 Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile 2 Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Catolica de Chile, Santiago, Chile 3 Universidad Santo Tomas, Santiago, Chile 4 Biomedical Research Consortium of Chile, Santiago, Chile 5 Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Catolica de Chile, Santiago, Chile 6 Hematology and Oncology Department, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile 7 Center UC Investigation in Oncology, Pontificia Universidad Catolica de Chile, Santiago, Chile 8 Hospital Gustavo Fricke, Vina de Mar, Santiago, Chile 9 Hospital Sotero del Rio, Santiago, Chile 10 Hospital Luis Tisne, Santiago, Chile 11 Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile 12 Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA 13 Anatomy and Developmental Biology, Institute of Biomedical Science, Geroscience Center for Brain Health and Metabolism, University of Chile, Santiago, Chile 14 Buck Institute for Research on Aging, Novato, CA, USA 15 Universidad Bernardo OHiggins, Facultad de Salud, Departamento de Ciencias Quimicas y Biologicas, General Gana, Santiago, Chile 16 Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile Correspondence to: Gareth I. Owen, email: gowen@bio.puc.cl Keywords: thrombocytosis, hemostasis, EA.hy926, SKOV3, UCI101 Received: July 27, 2016 Accepted: January 27, 2017 Published: February 15, 2017 ABSTRACT Clinical studies have suggested a survival benefit in ovarian cancer patients with type 2 diabetes mellitus taking metformin, however the mechanism by which diabetic concentrations of metformin could deliver this effect is still poorly understood. Platelets not only represent an important reservoir of growth factors and angiogenic regulators, they are also known to participate in the tumor microenvironment implicated in tumor growth and dissemination. Herein, we investigated if diabetic concentrations of metformin could impinge upon the previously reported observation that platelet induces an increase in the tube forming capacity of endothelial cells (angiogenesis) and upon ovarian cancer cell aggressiveness. We demonstrate that metformin inhibits the increase in angiogenesis brought about by platelets in a mechanism that did not alter endothelial cell migration. In ovarian cancer cell lines and primary cultured cancer cells isolated from the ascitic fluid of ovarian cancer patients, we assessed the effect of combinations of platelets and metformin upon angiogenesis, migration, invasion and cancer sphere formation. The enhancement of each of these parameters by platelets was abrogated by the present of metformin in the vast majority of cancer cell cultures tested. Neither metformin nor platelets altered proliferation; however, metformin inhibited the increase in phosphorylation of focal adhesion kinase induced by platelets. We present the first evidence suggesting that concentrations of metformin present in diabetic patients may reduce the actions of platelets upon both endothelial cells and cancer cell survival and dissemination.

Introduction The development of placenta plays a central role in determining the outcome of pregnancy. Extravillous trophoblast invasion is a fundamental component of human placentation. However, the transcriptional networks responsible for controlling the extent of trophoblast invasion are not well defined. Trophoblast cells are often compared to highly invasive carcinoma cells due to their capacity to proliferate and invade and to exhibit similar gene expression signatures. Thus, the transcriptional regulation of genes associated with cancer metastasis and trophoblast invasion may also be shared. The transcription factor forkhead box M1 (FOXM1), which is one of a few genes shown to be upregulated during early cancer development, possibly fits this scenario. FOXM1 has been shown to play a crucial role in the regulation of cell proliferation, cell cycle progression, angiogenesis, metastasis and DNA damage repair. Objective our objective in this study was to evaluate the role of FOXM1 in normal placental development. Method To evaluate the expression of FOXM1 throughout pregnancy Sprague Dawley dams were sacrificed at E14, E15, E18, E19 and E20 and protein and total RNA was isolated from one placenta per dam. Changes in placental protein expression were analyzed by western blot and mRNA expression was analyzed by qPCR. The influence of FOXM1 on trophoblast proliferation and migration was evaluated by Sulforhodamine B colorimetric (SRB) assay and wound healing assay, respectively, in JEG cell lines following silencing of FOXM1 via RNA interference under 21%, 8% and 3% oxygen conditions. Results The transcription regulator FOXM1 was expressed during early-mid gestation (E14) but its expression decreased as gestational age increased (E14 to E18 there was a decrease in 0.29 fold and E14 to E21 0.04 fold). Compared to trophoblast cells expressing control non-specific siRNA, FOXM1 knockdown resulted in a significant reduction of migration at 21%, 8% and 3% O 2 , whereas silencing of FOXM1 slows down the proliferation of JEG-3 cells at 21% O 2 but it does not alter its proliferative capacity at 8% or 3% O 2 . Conclusions Our data is suggestive that FOXM1 modulates trophoblast migration but not proliferative potential at 8% and 3% O 2 , which coincides with oxygen tension in the placenta in early pregnancy and the results of the rat placenta indicate that FOXM1 may play a role in early placentation events. However, more studies are required to fully understand the exact role of FOXM1 in placenta development.

Background An increase in circulating platelets, or thrombocytosis, is recognized as an independent risk factor of bad prognosis and metastasis in patients with ovarian cancer; however the complex role of platelets in tumor progression has not been fully elucidated. Platelet activation has been associated with an epithelial to mesenchymal transition (EMT), while Tissue Factor (TF) protein expression by cancer cells has been shown to correlate with hypercoagulable state and metastasis. The aim of this work was to determine the effect of platelet-cancer cell interaction on TF and “Metastasis Initiating Cell (MIC)” marker levels and migration in ovarian cancer cell lines and cancer cells isolated from the ascetic fluid of ovarian cancer patients. Methods With informed patient consent, ascitic fluid isolated ovarian cancer cells, cell lines and ovarian cancer spheres were co-cultivated with human platelets. TF, EMT and stem cell marker levels were determined by Western blotting, flow cytometry and RT-PCR. Cancer cell migration was determined by Boyden chambers and the scratch assay. Results The co-culture of patient-derived ovarian cancer cells with platelets causes: 1) a phenotypic change in cancer cells, 2) chemoattraction and cancer cell migration, 3) induced MIC markers (EMT/stemness), 3) increased sphere formation and 4) increased TF protein levels and activity. Conclusions We present the first evidence that platelets act as chemoattractants to cancer cells. Furthermore, platelets promote the formation of ovarian cancer spheres that express MIC markers and the metastatic protein TF. Our results suggest that platelet-cancer cell interaction plays a role in the formation of metastatic foci. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1304-z) contains supplementary material, which is available to authorized users.