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Breast cancer (BC) is the most common female cancer and the leading cause of cancer death in women worldwide. Alterations in epithelial cadherin (E-cadherin) expression and functions are associated to BC, but the underlying molecular mechanisms have not been fully elucidated. We have previously reported a novel human E-cadherin splice variant (E-cadherin variant) mRNA. Stable transfectants in MCF-7 human BC cells (MCF7Ecadvar) depicted fibroblast-like cell morphology, E-cadherin wild-type downregulation, and other molecular changes characteristic of the epithelial-to-mesenchymal transition process, reduced cell-cell adhesion, and increased cell migration and invasion. In this study, a two-dimensional differential gel electrophoresis (2D-DIGE) combined with mass spectrometry (MS) protein identification and bioinformatics analyses were done to characterize biological processes and canonical pathways affected by E-cadherin variant expression. Fil: Rosso, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Lapyckyj, Lara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Besso, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Monje, Marta. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Reventós, Jaume. Universitat Internacional de Catalunya; España Fil: Canals, Francesc. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Quevedo Cuenca, Jorge Oswaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Matos, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Vazquez, Monica Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Bladder cancer (BC) is the ninth most common cancer worldwide, but molecular changes are still under study. During tumor progression, Epithelial cadherin (E-cadherin) expression is altered and β-catenin may be translocated to the nucleus, where it acts as co-transcription factor of tumor invasion associated genes. This investigation further characterizes E-cadherin and β-catenin associated changes in BC, by combining bioinformatics, an experimental murine cell model (MB49/MB49-I) and human BC samples. In in silico studies, a DisGeNET (gene-disease associations database) analysis identified CDH1 (E-cadherin gene) as one with highest score among 130 BC related-genes. COSMIC mutation analysis revealed CDH1 low mutations rates. Compared to MB49 control BC cells, MB49-I invasive cells showed decreased E-cadherin expression, E- to P-cadherin switch, higher β-catenin nuclear signal and lower cytoplasmic p-Ser33-β-catenin signal, higher Ephrin-B1 ligand and EphB2 receptor expression, higher Phospho-Stat3 and Urokinase-type Plasminogen Activator (UPA), and UPA receptor expression. MB49-I cells transfected with Ephrin-B1 siRNA showed lower migratory and invasive capacity than control cells (scramble siRNA). By immunohistochemistry, orthotopic MB49-I tumors had lower E-cadherin, increased nuclear β-catenin, lower pSer33-β-catenin cytoplasmic signal, and higher Ephrin-B1 expression than MB49 tumors. Similar changes were found in human BC tumors, and 83% of infiltrating tumors depicted a high Ephrin-B1 stain. An association between higher Ephrin-B1 expression and higher stage and tumor grade was found. No association was found between abnormal E-cadherin signal, Ephrin-B1 expression or clinical-pathological parameter. This study thoroughly analyzed E-cadherin and associated changes in BC, and reports Ephrin-B1 as a new marker of tumor aggressiveness. Fil: Mencucci, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Endocrinología Experimental y Aplicada. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Endocrinología Experimental y Aplicada; Argentina Fil: Lapyckyj, Lara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Rosso, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Besso, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Belgorosky, Denise. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Isola, Mariana. Hospital Italiano; Argentina Fil: Vanzulli, Silvia. Academia Nacional de Medicina de Buenos Aires; Argentina Fil: Lodillinsky, Catalina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Eiján, Ana María. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Tejerizo, Juan Carlos. Hospital Italiano; Argentina Fil: González, Matías Ignacio. Hospital Italiano; Argentina Fil: Zubieta, María Ercilia. Hospital Italiano; Argentina Fil: Vazquez, Monica Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Endometrial cancer (EC) is the second most common gynecological cancer worldwide. Myometrial invasion (MI) is a key event in EC dissemination. This study aimed to evaluate FXYD5/dysadherin (FXYD5/Dys) expression in EC tissue and uterine aspirate (UA) biopsies and to assess molecular/functional changes associated with its expression in cellular models. Fil: Besso, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Rosso, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Lapyckyj, Lara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Moiola, Cristian Pablo. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Matos, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Mercogliano, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Reventos, Jaume. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Colas, Eva. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Gil Moreno, Antonio. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Wernicke, Alejandra. Hospital Italiano; Argentina Fil: Orti, Roberto. Hospital Italiano; Argentina Fil: Vazquez, Monica Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Epithelial Cadherin (E-cadherin) is involved in calcium-dependent cell-cell adhesion and signal transduction. The E-cadherin decrease/loss is a hallmark of Epithelial to Mesenchymal Transition (EMT), a key event in tumor progression. The underlying molecular mechanisms that trigger E-cadherin loss and consequent EMT have not been completely elucidated. This study reports the identification of a novel human E-cadherin variant mRNA produced by alternative splicing. A bioinformatics evaluation of the novel mRNA sequence and biochemical verifications suggest its regulation by Nonsense-Mediated mRNA Decay (NMD). The novel E-cadherin variant was detected in 29/42 (69%) human tumor cell lines, expressed at variable levels (E-cadherin variant expression relative to the wild type mRNA = 0.05-11.6%). Stable transfection of the novel E-cadherin variant in MCF-7 cells (MCF7Ecadvar) resulted in downregulation of wild type E-cadherin expression (transcript/protein) and EMT-related changes, among them acquisition of a fibroblastic-like cell phenotype, increased expression of Twist, Snail, Zeb1, and Slug transcriptional repressors and decreased expression of ESRP1 and ESRP2 RNA binding proteins. Moreover, loss of cytokeratins and gain of vimentin, N-cadherin and Dysadherin/FXYD5 proteins was observed. Dramatic changes in cell behavior were found in MCF7Ecadvar, as judged by the decreased cell-cell adhesion (Hanging-drop assay), increased cell motility (Wound Healing) and increased cell migration (Transwell) and invasion (Transwell w/Matrigel). Some changes were found in MCF-7 cells incubated with culture medium supplemented with conditioned medium from HEK-293 cells transfected with the E-cadherin variant mRNA. Further characterization of the novel E-cadherin variant will help understanding the molecular basis of tumor progression and improve cancer diagnosis. J. Cell. Physiol. 232: 1368-1386, 2017. © 2016 Wiley Periodicals, Inc.

PLoS One. 2017 Sep 21;12(9):e0184439. doi: 10.1371/journal.pone.0184439. eCollection 2017.E-cadherin: A determinant molecule associated with ovarian cancer progression, dissemination and aggressiveness.Rosso M1, Majem B2, Devis L2, Lapyckyj L1, Besso MJ1, Llauradó M2, Abascal MF1, Matos ML1, Lanau L2, Castellví J3, Sánchez JL4, Pérez Benavente A4, Gil-Moreno A2,4, Reventós J2, Santamaria Margalef A2, Rigau M2, Vazquez-Levin MH1.Author informationAbstractOvarian cancer (OC) is the fifth cancer death cause in women worldwide. The malignant nature of this disease stems from its unique dissemination pattern. Epithelial-to-mesenchymal transition (EMT) has been reported in OC and downregulation of Epithelial cadherin (E-cadherin) is a hallmark of this process. However, findings on the relationship between E-cadherin levels and OC progression, dissemination and aggressiveness are controversial. In this study, the evaluation of E-cadherin expression in an OC tissue microarray revealed its prognostic value to discriminate between advanced- and early-stage tumors, as well as serous tumors from other histologies. Moreover, E-cadherin, Neural cadherin (N-cadherin), cytokeratins and vimentin expression was assessed in TOV-112, SKOV-3, OAW-42 and OV-90 OC cell lines grown in monolayers and under anchorage-independent conditions to mimic ovarian tumor cell dissemination, and results were associated with cell aggressiveness. According to these EMT-related markers, cell lines were classified as mesenchymal (M; TOV-112), intermediate mesenchymal (IM; SKOV-3), intermediate epithelial (IE; OAW-42) and epithelial (E; OV-90). M- and IM-cells depicted the highest migration capacity when grown in monolayers, and aggregates derived from M- and IM-cell lines showed lower cell death, higher adhesion to extracellular matrices and higher invasion capacity than E- and IE-aggregates. The analysis of E-cadherin, N-cadherin, cytokeratin 19 and vimentin mRNA levels in 20 advanced-stage high-grade serous human OC ascites showed an IM phenotype in all cases, characterized by higher proportions of N- to E-cadherin and vimentin to cytokeratin 19. In particular, higher E-cadherin mRNA levels were associated with cancer antigen 125 levels more than 500 U/mL and platinum-free intervals less than 6 months. Altogether, E-cadherin expression levels were found relevant for the assessment of OC progression and aggressiveness. Fil: Rosso, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Majem, Blanca. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Devis, Laura. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Lapyckyj, Lara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Besso, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Llauradó, Marta. University of British Columbia; Canadá Fil: Abascal, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Matos, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Lanau, Lucia. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Castellví, Josep. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Sanchez, José Luis. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Perez Benavente, Asunción. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Gil Moreno, Antonio. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Reventós, Jaumé. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Santamaria Margalef, Anna. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Rigau, Marina. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Vazquez, Monica Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Fil: Rosso, Marina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Instituto de Biologia y Medicina Experimental (i); Argentina

Epithelial Cadherin (E-cadherin) is involved in calcium-dependent cell-cell adhesion and signal transduction. The E-cadherin decrease/loss is a hallmark of Epithelial to Mesenchymal Transition (EMT), a key event in tumor progression. The underlying molecular mechanisms that trigger E-cadherin loss and consequent EMT have not been completely elucidated. This study reports the identification of a novel human E-cadherin variant mRNA produced by alternative splicing. A bioinformatics evaluation of the novel mRNA sequence and biochemical verifications suggest its regulation by Nonsense-Mediated mRNA Decay (NMD). The novel E-cadherin variant was detected in 29/42 (69%) human tumor cell lines, expressed at variable levels (E-cadherin variant expression relative to the wild type mRNA = 0.05-11.6%). Stable transfection of the novel E-cadherin variant in MCF-7 cells (MCF7Ecadvar) resulted in downregulation of wild type E-cadherin expression (transcript/protein) and EMT-related changes, among them acquisition of a fibroblastic-like cell phenotype, increased expression of Twist, Snail, Zeb1, and Slug transcriptional repressors and decreased expression of ESRP1 and ESRP2 RNA binding proteins. Moreover, loss of cytokeratins and gain of vimentin, N-cadherin and Dysadherin/FXYD5 proteins was observed. Dramatic changes in cell behavior were found in MCF7Ecadvar, as judged by the decreased cell-cell adhesion (Hanging-drop assay), increased cell motility (Wound Healing) and increased cell migration (Transwell) and invasion (Transwell w/Matrigel). Some changes were found in MCF-7 cells incubated with culture medium supplemented with conditioned medium from HEK-293 cells transfected with the E-cadherin variant mRNA. Further characterization of the novel E-cadherin variant will help understanding the molecular basis of tumor progression and improve cancer diagnosis. J. Cell. Physiol. 232: 1368-1386, 2017. © 2016 Wiley Periodicals, Inc.

Acetaminophen (APAP) is an analgesic-antipyretic drug widely used in children. In the present study, we used an in vivo model of APAP-induced nephrotoxicity in male Wistar rats. We analyzed whether toxic doses of APAP could induce heat shock protein 70 (HSP70) in the kidney and whether HSP70 could be detected in urine. Renal function and histological evaluation of the kidneys were performed at different times after APAP administration (1,000 mg/kg body weight i.p.). Cellular injury was assessed by Triton X-100 solubilization of Na(+)/K(+) ATPase. Renal and hepatic glutathione levels were also measured. Urinary N-acetyl-beta-D glucosaminidase (NAG) excretion increased 4 h after intoxication. At this time, urea and creatinine were at control levels and a slight degree of histological alteration was detected. Kidney microscopic evaluation, Na(+)/K(+) ATPase solubility, creatinine, and urea levels and NAG excretion did not differ from those of controls 48 h after APAP administration. HSP70 was detected in urine obtained from 4 to 24 h after APAP administration. HSP70 abundance in renal cortex was increased at early time points and 48 h after APAP administration. Urinary HSP70 excretion would be a marker of its renal induction combined with the loss of tubule integrity. NAG would be a suitable early biomarker of APAP-induced nephrotoxicity.

Cancer is a group of diseases that causes millions of deaths worldwide. Among cancers, Solid Tumors (ST) stand-out due to their high incidence and mortality rates. Disruption of cell–cell adhesion is highly relevant during tumor progression. Epithelial-cadherin (protein: E-cadherin, gene: CDH1) is a key molecule in cell–cell adhesion and an abnormal expression or/and function(s) contributes to tumor progression and is altered in ST. A systematic study was carried out to gather and summarize current knowledge on CDH1/E-cadherin and ST using bioinformatics resources. The DisGeNET database was exploited to survey CDH1-associated diseases. Reported mutations in specific ST were obtained by interrogating COSMIC and IntOGen tools. CDH1 Single Nucleotide Polymorphisms (SNP) were retrieved from the dbSNP database. DisGeNET analysis identified 609 genes annotated to ST, among which CDH1 was listed. Using CDH1 as query term, 26 disease concepts were found, 21 of which were neoplasms-related terms. Using DisGeNET ALL Databases,172 disease concepts were identified. Of those, 80 ST disease-related terms were subjected to manual curation and 75/80 (93.75%) associations were validated. On selected ST, 489 CDH1 somatic mutations were listed in COSMIC and IntOGen databases. Breast neoplasms had the highest CDH1- mutation rate. CDH1 was positioned among the 20 genes with highest mutation frequency and was confirmed as driver gene in breast cancer. Over 14,000 SNP for CDH1 were found in the dbSNP database. This report used DisGeNET to gather/compile current knowledge on gene-disease association for CDH1/E-cadherin and ST; data curation expanded the number of terms that relate them. An updated list of CDH1 somatic mutations was obtained with COSMIC and IntOGen databases and of SNP from dbSNP. This information can be used to further understand the role of CDH1/E-cadherin in health and disease. Fil: Abascal, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Besso, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Rosso, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Mencucci, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Aparicio, Evangelina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Szapiro, Gala. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Furlong, Laura Ines. Universitat Pompeu Fabra; España Fil: Vazquez, Monica Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Fibroblast growth factors receptors (FGFRs) have been widely characterized in somatic cells, but there is scarce evidence of their expression and function in mammalian gametes. The objective of the present study was to evaluate the expression of FGFRs in human male germ cells, to determine sperm FGFR activation by the FGF2 ligand and their participation in the regulation of sperm motility. The expression of FGFR1, 2, 3 and 4 mRNAs and proteins in human testis and localization of these receptors in germ cells of the seminiferous epithelium was demonstrated. In ejaculated sperm, FGFRs were localized to the acrosomal region and flagellum. Sperm exposure to FGF2 caused an increase in flagellar FGFR phosphorylation and activation of extracellular signal-regulated kinase (ERK) and protein kinase B (PKB or Akt) signaling pathways. Incubation with FGF2 led to a significant increase in the percentage of total and progressive sperm motility, as well as in sperm kinematics. All responses were prevented by sperm preincubation with BGJ398, a specific inhibitor of FGFR tyrosine kinase activity. In addition to confirming the expression of FGFRs in germ cells of the human testis, our study describes for the first time the presence, localization and functionality of human sperm FGFRs, and provides evidence of the beneficial effect of FGF2 upon sperm motility.

Multistage flash (MSF) desalination plants are among the major sources of potable water in the world, in particular in the Arab Gulf area [1]. These are very large, complex and expensive plants, in which large amounts of seawater and energy are consumed. Accordingly, big quantities of concentrated brine are disposed of after the desalination treatment. These characteristics of MSF plants make issues such as optimization of the operation and minimization of the corresponding environmental impact of the greatest importance. To the aim of addressing all these aspects, mathematical models provide a very useful tool. This work describes a steady-state mathematical model developed to analyze the MSF desalination process. It is based on a detailed physicochemical representation of the process, including all the fundamental elementary phenomena. In particular, the model accounts for the geometry of the stages, the variation of the physical properties of water with temperature and salinity, the different non-idealities involved in the process, the mechanism of heat transfer and the role of fouling. The developed model allows to analyze the role of operating and design variables in determining the process performances in terms of steady-state behavior. These information are used not only for design purposes, but also to support the development of a dynamical model through which the time-dependent behavior of the plant can be studied.

Epithelial cadherin (E-cadherin) is involved in cell-cell adhesion through its extracellular domain, whereas the intracellular domain interacts with adaptor proteins, i.e. β-catenin, links E-cadherin to the actin cytoskeleton and participates in signal transduction events. E-cadherin protects mammary epithelial cells from apoptosis and its loss during tumour progression has been documented. Secretory Leukocyte Protease Inhibitor (SLPI) has anti- and pro-tumourigenic activities but its role in breast cancer has not been fully elucidated. Notwithstanding its relevance, how SLPI affects E-cadherin in breast cancer is still unknown. This study evaluated the effect of SLPI upon E-cadherin/β-catenin expression and apoptosis-related markers in murine (F3II) and human (MCF-7) breast tumour cells either treated with exogenous recombinant human SLPI (rhSLPI) or stably transfected with a plasmid encoding its sequence.Addition of rhSLPI to F3II cells caused a decrease (P0.05) in E-cadherin transcript and protein levels. Similar results were observed in SLPI-stable F3II transfectants (2C1), and treatment of 2C1 cells with a siRNA toward SLPI restored E-cadherin to control levels. SLPI-expressing cells showed disruption of E-cadherin/β-catenin complex and increased (P0.05) percentage of cells depicting nuclear β-catenin localisation. Associated to these changes, 2C1 cells showed increased Bax/Bcl-2 ratio and p21 protein levels, decreased c-Myc protein levels and decreased Cyclin D1 and Claudin-1 transcript levels. No differences in N- and P-cadherin were observed between SLPI-transfected cells and controls. Addition of rhSLPI to MCF-7 cells or stable transfection with SLPI caused a decrease (P0.05) in E-cadherin expression (transcript/protein) and its redistribution to the cytoplasm, as well as β-catenin re-localisation to the cell nucleus.Expression of SLPI was associated to a decrease in E-cadherin expression and re-localisation of E-cadherin to the cell cytoplasm and β-catenin to the cell cytoplasm and nucleus, and had pro-apoptotic and cell cycle-arrest effects.

Cancer is a complex disease characterized by abnormal proliferation of different cell types among which solid tumors (ST) stand out due to their high incidence and mortality rates. Of many ST, breast cancer (BC) is the 2nd most common cancer worldwide and the most frequent among women (∼1.67 million new cases in 2012). Ductal breast cancer (DBC) and lobular breast cancer (LBC) are the most frequent BC types. The human gene CDH1 encodes Epithelial Cadherin (ECad), a calcium-dependent cell-cell adhesion molecule defined as tumor suppressor since its absence prevents adherens junctions and associates to tumor progression and poor patient outcome. In cancer research, a great deal of data is available in the literature, providing an abundant source of knowledge for biomedical research, although the information is disaggregated. The use of bioinformatics tools (BT) dedicated to text mining (TM) and network biology has become very useful to study cancer pathology from a global perspective since integrate the vast amount of data available. In this study, we have implemented BT (DisGeNET, Cytoscape, COSMIC, Hippie, PANTHER, String) to systematically assess the relationship between CDH1/ECad and ST and to identify potential biomarkers for DBC and LBC. To identify CDH1 related diseases, a gene-disease network analysis was performed using DisGeNET/Cytoscape. In a query restricted to curated databases, CDH1 was associated (biomarker/genetic variation/ therapeutic target) to 29 diseases among which 20 were ST. When all databases (curated, predicted and literature) were included, the terms related to CDH1 expanded to 173 diseases (98 ST). A manual term-curation related to CDH1 (80 ST) was performed, with a total of 286 publications reviewed. In 199/286 (70%) reports, the association between CDH1 and ST was confirmed (67/286 (23%) inconclusive, 20/286 (7%) unconfirmed). As a result, 75/80 ST terms were validated as related to CDH1. An analysis done with the COSMIC BT led to the identification of 376 somatic mutations on the CDH1 gene in 11/20 ST terms from the DisGeNET output (curated databases). For BC, 3045 genes were found using TM tools as related to this term (CDH1: biomarker/genetic variation). For DBC, 42 genes were related with proven evidence (high score: BAG1, CDH1, ATF4, CLDN4, PTGER1, SERPINB5). To analyze protein-protein interaction (PPI), the HIPPIE BT was used. A selected DBC biomarkers were identified from a PPI network of 448 nodes, among which HDAC1, SKP2, CFTR, HSPA8, SMAD7, TGM2, ATF2, MDM2 were listed as putative biomarkers based on the ´Linkage method´. For LBC, 28 genes were found as associated (3 with proven evidence) and generate a PPI network of 216 nodes; ERBB2IP, SRC, EGFR, EP300 y HDAC1 were listed as potential biomarkers. Altogether, BT allowed a systematic assessment of current knowledge of CDH1/ECad and led to the identification of novel putative biomarkers for DBC and LBC. Citation Format: Maria F. Abascal, Maria J. Besso, Evangelina Aparicio, Marina Rosso, Victoria Mencucci, Laura I. Furlong, Monica H. Vazquez-Levin. A bioinformatics approach to evaluate the involvement of CDH1/E-cadherin in solid tumors and to identify breast cancer biomarkers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1085. doi:10.1158/1538-7445.AM2015-1085

Ovarian cancer (OC) is the 5th leading cause of cancer deaths in women worldwide due to late symptoms and its diagnosis at advanced stages. Epithelial to mesenchymal transition (EMT) is an important step in cancer invasion/metastasis and downregulation of Epithelial cadherin (Ecad) is a critical feature of this process. Ecad expression was evaluated in 100 OC tissue sections, finding a decreased Ecad signal along tumor stage, with highest expression in stage I/II (no invasive) and lowest in stage IV (invasive) tumors. These results are in agreement with previous reports showing reduced Ecad expression in correlation with poor prognosis in OC patients. In some cases, Ecad downregulation is accompanied by increased Neural cadherin (Ncad) expression and acquisition of migratory/mesenchymal features. Although this cadherin “switch” has been reported in OC, current data is inconclusive. Expression of Ecad, Ncad and other EMT markers was studied in 4 OC cell lines and according to their levels they were classified as epithelial (OV90), intermediate epithelial (OAW42), intermediate mesenchymal (SKOV3) and mesenchymal (TOV112) cells. The mechanisms underlying regulation of Ecad levels were evaluated by assessing expression of its transcriptional repressors Twist, Snail, Slug, Zeb1. Migration properties were also studied, being significantly higher in TOV112 and SKOV3 cells. It has been proposed that OC cells shed from the primary tumor aggregate as spheroids in the ascites, maintain cellular contacts and survive in suspension. To mimic ovarian tumor cell dissemination through the ascites and to evaluate the role of the cadherin “switch” in this process, cell lines were grown under anchorage-independent conditions. The aggregates number/area was analyzed, being the SKOV3 spheroids the most compacted. When Ecad, Ncad and EMT markers expression was determined similar findings were obtained when spheroids were compared to monolayers, suggesting an intrinsic cell gene expression pattern rather than a response to a cell culture growth condition. The OC spheroids survival was assessed by estimating cell death, finding a positive correlation between high Ncad levels and cell aggregates with low% cell death. Spheroid adhesion/dissemination in extracellular matrices and 3D-spheroid matrigel assays were done to assess invasion at a secondary site. Spheroids from cells with mesenchymal/intermediate mesenchymal phenotypes adhered to extracellular matrices and invaded more than cells with intermediate epithelial/epithelial phenotypes. Finally, Ecad/Ncad expression studies done on primary cultures derived from tumor and ascitic cells from patients with OC revealed a diminished Ecad and a higher Ncad expression in ascitic cells compared to primary tumor cells. Altogether, the data here presented reveals an association between OC cell aggressiveness and a mesenchymal-like molecular profile; and it depends on the expression of Ecad and Ncad markers. Citation Format: Marina Rosso, Blanca Majem, Laura Devis, Lara Lapyckyj, Marta Llauradó, Lucía Lanau, María Florencia Abascal, María Laura Matos, María José Besso, Josep Castellví, Jose Luís Sanchez-Iglesias, Asunción Pérez-Benavente, Antonio Gil-Moreno, Jaume Reventós, Marina Rigau, Mónica Vazquez-Levin. Cadherin “switch” and ovarian cancer: Studies using in vitro models and patient samples. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4093. doi:10.1158/1538-7445.AM2015-4093

A model for the dynamic simulation of multistage flash desalination units has been developed, based on a detailed description of the fundamental elementary phenomena involved in the process. It takes into account stage geometry, physico-chemical and transport properties of water, vapor and brine and the different non-idealities of the process. In this work the model is used to describe the behavior of the MSF plant under different kinds of process disturbances, thus showing some of its nonlinear dynamic features. Further applications of the model may deal with the analysis of steady-state stability and the development of optimal control strategies and start-up/shut-down procedures.