Abelian subgroups of \Out(F_n)

We classify abelian subgroups of Out(F_n) up to finite index in an algorithmic and computationally friendly way. A process called disintegration is used to canonically decompose a single rotationless element \phi into a composition of finitely many elements and then use these elements to generate an abelian subgroup A(\phi) that contains \phi. The main theorem is that up to finite index every abelian subgroup is realized by this construction. As an application we classify, up to finite index, abelian subgroups of Out(F_n) and of IA with maximal rank.Comment: 56 page

In1-ghrelin splicing variant is associated with reduced disease-free survival of breast cancer patients and increases malignancy of breast cancer cells lines

OXFORD UNIVERSITY: This is a pre-copyedited, author-produced version of an article accepted for publication in Carcinogenesis following peer review. The version of record David Rincón-Fernández, Michael D Culler, Natia Tsomaia, Gema Moreno-Bueno, Raúl M Luque, Manuel D Gahete, Justo P Castaño; In1-ghrelin splicing variant is associated with reduced disease-free survival of breast cancer patients and increases malignancy of breast cancer cells lines, Carcinogenesis, Volume 39, Issue 3, 8 March 2018, Pages 447–457, https://doi.org/10.1093/carcin/bgx146Ghrelin gene generates several variants that regulate multiple pathophysiological functions, including tumor-related processes. In1-ghrelin is a splicing variant that was previously shown to be overexpressed in breast cancer (BCa), where it correlated with proliferation markers; however, its possible association with clinical outcome of BCa patients and underlying mechanisms are still unknown. To address this issue, expression levels and clinical associations of In1-ghrelin were analyzed in a cohort of 117 BCa samples. Additionally, a battery of cellular and molecular assays was implemented using two BCa cell lines (MCF-7 and MDA-MB-231), wherein the role of In1-ghrelin on proliferation, migration, dedifferentiation and signaling pathways was explored. The results generated revealed that high expression of In1-ghrelin in BCa samples was associated with lymph node metastasis and reduced disease-free survival. Indeed, In1-ghrelin overexpression stimulated proliferation and migration in MCF-7 and MDA-MB-231 cells. Similar results were found by treating MDA-MB-231 and MCF-7 with In1- ghrelin-derived peptides. Conversely, In1-ghrelin silencing decreased proliferation and migration capacities of MDA-MB-231. Furthermore, In1-ghrelin (but not ghrelin) overexpression increased the capacity to form mammospheres in both cell lines. These effects could be associated with activation of MAPK-ERK, Jag1/Notch, Wnt/β-catenin and/or TGF-β1 pathways. Altogether, our data indicate that In1-ghrelin could play relevant functional roles in the regulation of BCa development and progression and may provide insights to identify novel biomarkers and new therapeutic approaches for this pathology.BIO-0139, CTS-1406, PI-639-2012, PI-0541-2013 (Junta de Andalucia), BFU2013-43282-R, BFU2016-80360-R (MINECO), PI13-00651, PI16/00264 (Proyectos de Investigación en Salud FIS, funded by Instituto de Salud Carlos III), GETNE Grant 2014, Merck Serono Grant 2013 and CIBERobn (to RML and JPC); PI13/00132, RETICC RD12/0036/0007, CIBERonc and S2010/BMD-2303 (to GMB

Somatostatin analogue treatment primarily induce miRNA expression changes and up-regulates growth inhibitory miR-7 and miR-148a in neuroendocrine cells

Somatostatin (SST) analogues are used to control the proliferation and symptoms of neuroendocrine tumors (NETs). MicroRNAs (miRNA) are small non-coding RNAs that modulate posttranscriptional gene expression. We wanted to characterize the miRNAs operating under the control of SST to elucidate to what extent they mediate STT actions. NCI-H727 carcinoid cell line was treated with either a chimeric SST/dopamine analogue; a SST or dopamine analogue for proliferation assays and for identifying differentially expressed miRNAs using miRNA microarray. The miRNAs induced by SST analogue treatment are investigated in carcinoid cell lines NCI-H727 and CNDT2 using in situ hybridization, qPCR and proliferation assays. SST analogues inhibited the growth of carcinoid cells more potently compared to the dopamine analogue. Principal Component Analysis (PCA) of the samples based on miRNA expression clearly separated the samples based on treatment. Two miRNAs which were highly induced by SST analogues, miR-7 and miR-148a, were shown to inhibit the proliferation of NCI-H727 and CNDT2 cells. SST analogues also produced a general up-regulation of the let-7 family members. SST analogues control and induce distinct miRNA expression patterns among which miR-7 and miR-148a both have growth inhibitory properties

Discovery of novel inhibitors of human 11β-hydroxysteroid dehydrogenase type 1

International audienc

Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors

Purpose: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and heterogeneous tumors, and their biological behavior is not well known. We studied the presence and potential functional roles of somatostatin receptors (sst1-5), focusing particularly on the truncated variants (sst5TMD4, sst5TMD5) and on their relationships with the angiogenic system (Ang/Tie-2 and VEGF) in human GEP-NETs. Experimental Design: We evaluated 42 tumor tissue samples (26 primary/16 metastatic) from 26 patients with GEP-NETs, and 30 non-tumoral tissues (26 from adjacent non-tumor regions and 4 from normal controls) from a single center. Expression of sst1-5, sst5TMD4, sst5TMD5, Ang1-2, Tie-2 and VEGF was analyzed using real-time qPCR, immunofluorescence and immunohistochemistry. Expression levels were associated with tumor characteristics and clinical outcomes. Functional role of sst5TMD4 was analyzed in GEP-NET cell lines. Results: sst1 exhibited the highest expression in GEP-NET, whilst sst2 was the most frequently observed sst-subtype (90.2%). Expression levels of sst1, sst2, sst3, sst5TMD4, and sst5TMD5 were significantly higher in tumor tissues compared to their adjacent non-tumoral tissue. Lymph-node metastases expressed higher levels of sst5TMD4 than in its corresponding primary tumor tissue. sst5TMD4 was also significantly higher in intestinal tumor tissues from patients with residual disease of intestinal origin compared to those with non-residual disease. Functional assays demonstrated that the presence of sst5TMD4 was associated to enhanced malignant features in GEP-NET cells. Angiogenic markers correlated positively with sst5TMD4, which was confirmed by immunohistochemical/fluorescence studies. Conclusions: sst5TMD4 is overexpressed in GEP-NETs and is associated to enhanced aggressiveness, suggesting its potential value as biomarker and target in GEP-NETs.This work has received the following grants: Proyectos de Investigación en Salud (FIS) PI13-01414, and PIE-0041 (funded by Instituto de Salud Carlos III) and S2011/BMD-2328 TIRONET (funded by Comunidad de Madrid) (to MM). BIO-0139, CTS-5051, CTS-1406, PI-0369-2012, BFU2010-19300, BFU2013-43282-R, PI13/00651, CIBERobn and Ayuda Merck Serono 2013 (to RML and JPC). Fellowship CTS-5051 (to AIC). “Sara Borrell” program CD11/00276 (to MDG

The Novel Somatostatin Receptor 2/Dopamine Type 2 Receptor Chimeric Compound BIM-23A758 Decreases the Viability of Human GOT1 Midgut Carcinoid Cells

The majority of neuroendocrine tumors (NETs) of thegastro-enteropancreatic system coexpress sornatostatin receptors (SSTRs)and dopamine type 2 receptors (D2R), thus providing a rationale for theuse of novel SSTR2/D2R chimeric compounds in NET disease. Here weinvestigate the antitumor potential of the SSTR2/D2R chimeric compoundsBIM-23A760 and BIM-23A758 in comparison to the selective SSTR2 agonistBIM-23023 and the selective D2R agonist BIM-53097 on human NET celllines of heterogeneous origin. While having only minor effects on humanpancreatic and bronchus carcinoid cells (BONI and NCI-H727), BIM-23A758induced significant antitumor effects in human midgut carcinoid cells(GOT1). These effects involved apoptosis induction as well as inhibitionof mitogen-activated protein kinase and Akt signaling. Consistent withtheir antitumor response to BIM-23A758, GOT1 cells showed relativelyhigh expression levels of SSTR2 and D2R mRNA. In particular, GOT1 cellshighly express the short transcript variant of D2R. In contrast toBIM-23A758, the SSTR2/D2R chimeric compound BIM-23A760 as well as theindividual SSTR2 and D2R agonistic compounds BIM-23023 and BIM-53097induced no or only minor antitumor responses in the examined NET celllines. Taken together, our findings suggest that the novel SSTR2/D2Rchimeric compound BIM-23A758 might be a promising substance for thetreatment of NETs highly expressing SSTR2 and D2R. In particular, asufficient expression of the short transcript variant of DR2 might playa pivotal role for effective treatment