Regulation of extracellular matrix degradation and metastatic spread by IQGAP1 through endothelin-1 receptor signalling in ovarian cancer.

Abstract The invasive phenotype of serous ovarian cancer (SOC) cells is linked to the formation of actin-based protrusions, invadopodia, operating extracellular matrix (ECM) degradation and metastatic spread. Growth factor receptors might cause engagement of integrin-related proteins, like the polarity protein IQ-domain GTPase-activating protein 1 (IQGAP1), to F-actin core needed for invadopodia functions. Here, we investigated whether IQGAP1 forms a signalosome with endothelin-1 (ET-1)/β-arrestin1 (β-arr1) network, as signal-integrating module for adhesion components, cytoskeletal remodelling and ECM degradation. In SOC cells, ET-1 receptor (ET-1R) activation, besides altering IQGAP1 expression and localization, coordinates the binding of IQGAP1 with β-arr1, representing a "hotspot" for ET-1R-induced invasive signalling. We demonstrated that the molecular interaction of IQGAP1 with β-arr1 affects relocalization of focal adhesion components, as vinculin, and cytoskeleton dynamics, through the regulation of invadopodia-related pathways. In particular, ET-1R deactivates Rac1 thereby promoting RhoA/C activation for the correct functions of invasive structures. Silencing of either IQGAP1 or β-arr1, or blocking ET-1R activation with a dual antagonist macitentan, prevents matrix metalloproteinase (MMP) activity, invadopodial function, transendothelial migration and cell invasion. In vivo, targeting ET-1R/β-arr1 signalling controls the process of SOC metastasis, associated with reduced levels of IQGAP1, as well as other invadopodia effectors, such as vinculin, phospho-cortactin and membrane type 1-MMP. High expression of ET A R/β-arr1/IQGAP1 positively correlates with poor prognosis, validating the clinical implication of this signature in early prognosis of SOC. These data establish the ET-1R-driven β-arr1/IQGAP1 interaction as a prerequisite for the dynamic integration of pathways in fostering invadopodia and metastatic process in human SOC

Endothelin-1 cooperates with hypoxia to induce vascular-like structures through vascular endothelial growth factor-C, -D and -A in lymphatic endothelial cells.

Abstract Aims Lymphangiogenesis refers to the formation of new lymphatic vessels and is thought to constitute conduits for the tumor cells to metastasize. We previously demonstrated that endothelin (ET)-1 through its binding with ETB receptor (ET B R) expressed on lymphatic endothelial cells (LEC), induced cell growth and invasiveness. Since vascular endothelial growth factor (VEGF)-A/-C/-D, and hypoxia play key role in lymphatic differentiation, in this study we investigated the involvement of these growth factors and hypoxia in ET-1-induced lymphangiogenesis. Main methods Real time PCR and ELISA were used to quantify VEGF-A/-C/-D. LEC morphological differentiation was analyzed by tube formation assay on Matrigel. Key findings Hypoxia, as well as ET-1, induced an increase in VEGF-A/-C and -D expression that was reduced in the presence of a selective ET B R antagonist, BQ788, and enhanced when ET-1 was administered under hypoxic conditions. We analyzed the role of hypoxia on LEC morphological differentiation, and found that hypoxia increased the formation of vascular-like structures on Matrigel and that in combination with ET-1 this effect was markedly enhanced. The use of specific antibodies neutralizing VEGF-A, or recombinant VEGFR-3/(Flt-4)/Fc that block VEGF-C/-D, inhibited the effect of ET-1 as well that of hypoxia. Significance These results demonstrated that ET-1 and hypoxia act, at list in part, through VEGF to induce lymphangiogenic events and that these two stimuli may cooperate to induce VEGF-A/-C/-D expression and lymphatic differentiation. These data further support the role of ET-1 as potent lymphangiogenic factor that relies on the interplay with hypoxic microenvironment and with VEGF family members

Endothelin-1 regulates hypoxia-inducible factor-1α and -2α stability through prolyl hydroxylase domain 2 inhibition in human lymphatic endothelial cells

n/

Endothelin-1 drives invadopodia and interaction with mesothelial cells through ILK

Summary Cancer cells use actin-based membrane protrusions, invadopodia, to degrade stroma and invade. In serous ovarian cancer (SOC), the endothelin A receptor (ETAR) drives invadopodia by a not fully explored coordinated function of β-arrestin1 (β-arr1). Here, we report that β-arr1 links the integrin-linked kinase (ILK)/βPIX complex to activate Rac3 GTPase, acting as a central node in the adhesion-based extracellular matrix (ECM) sensing and degradation. Downstream, Rac3 phosphorylates PAK1 and cofilin and promotes invadopodium-dependent ECM proteolysis and invasion. Furthermore, ETAR/ILK/Rac3 signaling supports the communication between cancer and mesothelial cells, favoring SOC cell adhesion and transmigration. In vivo, ambrisentan, an ETAR antagonist, inhibits the adhesion and spreading of tumor cells to intraperitoneal organs, and invadopodium marker expression. As prognostic factors, high EDNRA/ILK expression correlates with poor SOC clinical outcome. These findings provide a framework for the ET-1R/β-arr1 pathway as an integrator of ILK/Rac3-dependent adhesive and proteolytic signaling to invadopodia, favoring cancer/stroma interactions and metastatic behavior

Ovarian Cancer-Driven Mesothelial-to-Mesenchymal Transition is Triggered by the Endothelin-1/ß-arr1 Axis

Transcoelomic spread of serous ovarian cancer (SOC) results from the cooperative interactions between cancer and host components. Tumor-derived factors might allow the conversion of mesothelial cells (MCs) into tumor-associatedMCs, providing a favorable environment for SOC cell dissemination. However, factors and molecular mechanisms involved in this process are largely unexplored. Herewe investigated the tumor-related endothelin-1 (ET-1) as an inducer of changes inMCs supporting SOC progression. Here, we report a significant production of ET-1 from MCs associatedwith the expression of its cognate receptors, ETA and ETB, along with the protein β-arrestin1. ET-1 triggers MC proliferation via β-arrestin1-dependentMAPK and NF-kB pathways and increases the release of cancer-related factors. The ETA/ETB receptor activation supports the genetic reprogramming of mesothelial-to-mesenchymal transition (MMT), with upregulation of mesenchymal markers, as fibronectin, α-SMA, N-cadherin and vimentin, NFkB-dependent Snail transcriptional activity and downregulation of E-cadherin and ZO-1, allowing to enhanced MC migration and invasion, and SOC transmesothelial migration. These effects are impaired by either blockade of ETAR and ETB R or by β-arrestin1 silencing. Notably, in peritoneal metastases both ETAR and ETBR are co-expressed with MMT markers compared to normal control peritoneum. Collectively, our report shows that the ET-1 axis may contribute to the early stage of SOC progression by modulating MC prometastatic behaviour via MMTAssociazione Italiana Ricerca sul Cancro (AIRC) to LR grant number AIRC 21372 and partially by Agencia Estatal de Investigación Project to ML-P “PID 2019-110132RBI00/AEI/10.13039/50110001103

Tracing a Route and Finding a Shortcut: The Working Memory, Motivational, and Personality Factors Involved

Wayfinding (WF) is the ability to move around efficiently and find the way from a starting point to a destination. It is a component of spatial navigation, a coordinate and goal-directed movement of one\u2019s self through the environment. In the present study, the relationship between WF tasks (route tracing and shortcut finding) and individual factors were explored with the hypothesis that WF tasks would be predicted by different types of cognitive, affective, motivational variables, and personality factors. A group of 116 university students (88 F.) were conducted along a route in a virtual environment and then asked first to trace the same route again, and then to find a shortcut between the start and end points. Several instruments assessing visuospatial working memory, mental rotation ability, self-efficacy, spatial anxiety, positive attitude to exploring, and personality traits were administered. The results showed that a latent spatial ability factor (measured with the visuospatial working memory and mental rotations tests) \u2013 controlled for gender \u2013 predicted route-tracing performance, while self-report measures of anxiety, efficacy, and pleasure in exploring, and some personality traits were more likely to predict shortcut-finding performance. We concluded that both personality and cognitive abilities affect WF performance, but differently, depending on the requirements of the task

Pegaso: an ultra-light long duration stratospheric

Launched from the Mario Zuccelli Station (Baia Terra Nova) in Antarctica during the 2005/06 austral summer, the PEGASO-D payload lifted into the stratospheric anticyclone over the southern polar region. This effort marks the first Long Duration Scientific payload to be launched from this location and is the fourth such payload launched in the polar regions. Performing in the framework of the NOBILE/AMUNDSEN collaborative LDB development between ASI-ARR. The Italian Institute of Geophysics and Volcanology (INGV), with the sponsorship of the Italian Antarctic Program (PNRA) and the Italian Space Agency (ASI),designed and built the Ultra-Light system together with three Universities in Italy. The Pegaso program has been created to investigate the Earth magnetic field and provide a precursor series of small payload launches for the bigger LDB program such as OLIMPO, BOOMERanG and BArSPOrt through this collaboration between ASI and ARR. The Italian scientific community, aware of the big advantages that LDB balloons can offer to their experiments, proposed to extend the LDB program to Southern polar regions, besides performing launches from the newly initiated Nobile/Amundsen Stratospheric Balloon Center in Svalbard, Norway.Three PEGASO (Polar Explorer for Geomagnetics And other Scientific Observations) payloads have been launched from the Svalbard (No) in collaboration with Andoya Rocket Range, ASI and ISTAR (Operations and logistics) during the past two northern summers. These stratospheric (altitude m.35000) small 10kmc balloons have floated in the stratosphere between 14 to 39 days measuring the magnetic field of polar regions, by means of a 3-axys-fluxgate magnetometer, during a three year campaign. The study of the magnetic field and its variations is done through permanent observatories. They provide us with high quality data but their spatial distribution is not quite regular, specially in Antarctica due to logistic difficulties. The coverage is improved through marine and aeromagnetic surveys, and also through satellite missions. There exists nevertheless a gap in the wavelengths of the magnetic field represented by these kind of measurements. Satellite data are too far away from Earth's surface to individuate wavelengths lower than 1000 km, and near-ground sur- veys are not able to represent wavelengths longer than the dimensions of the surveyed area. Moreover, there is a region empty of data around the geographical pole for the satellite measurements. The size of these gaps depends on the orbital parameters, but it can reach up to 10 degrees around the pole. PEGASO allows to bridge this gap in the measurements of the magnetic field. Surveys carried out at 35 km height allow the study of crustal anomalies in the range between, we can say, 60 and 1000 km. Taking into account that pathfinders (smaller non-recoverable balloon systems) are usually sent to explore the atmospheric currents, the use of PEGASO as pathfinder allows us to obtain all these results at a very affordable cost. The PEGASO payload was also developed as a single source system integrating science, housekeeping and operational control of the entire balloon borne configuration.Satellite telemetry sent the scientific (magnetometric) data, house-keeping (temperature, solar panel voltage and current, altitude and time) and telecommand (four ballast, two parachute release system, system reset), and powered the terminate system. Data flows through the IRIDIUM telephone service. The onboard systems were kept inside a vessel (white painted and pressurizzed vessel due to power dissipation) except for external flexible solar panels and magnetometer, attached to an external boom. Two redundant tracking systems have been used: a first GPS was integrated inside the on-board telemetry system, necessary to reconstruct position and time of scientific data, while an independent GPS-ARGOS system gave the balloon trajectory, including its descent. Continuous trajectory predictions were made during the missions; they have been necessary, in particular, for the flight safety requirements of the northern hemisphere. The evaluation of the statistical error is proposed. The PEGASO payload was developed to be a light, cost effective way to explore the potential of Ultra-Light Long Duration Ballooning for science as well as an introduction to the earth-space possibilities for students.PublishedBeijing, China1A. Geomagnetismo e Paleomagnetism

Didattica e inclusione scolastica - Inklusion im Bildungsbereich

The inequalities in education, which have also been exposed by the pandemic, highlight the need for alternatives and new horizons. The seventh edition of the conference series "Didattica e Inclusione Scolastica – Inclusion in Education", which was organized for the first time under the direction of the Competence Center for Inclusion in Education of the Free University of Bozen-Bolzano, offered a space to deal with the priorities of a just and inclusive education during this time. This volume opens up a dialogue on inclusive didactics, which builds a bridge between german- and Italian-speaking traditions through its multilingual and intercultural orientation. The twelve contributions open up from different perspectives theoretical references, methods and instruments for the development of an inclusive school with a special focus on didactics.Die Ungleichheiten im Bildungsbereich, die auch durch die Pandemie zutage getreten sind, verdeutlichen die Notwendigkeit von Alternativen und neuen Horizonten. Die siebte Ausgabe der Tagungsreihe „Didattica e Inclusione Scolastica – Inklusion im Bildungsbereich“, welche erstmals unter der Leitung des Kompetenzzentrums für Inklusion im Bildungsbereich der Freien Universität Bozen veranstaltet wurde, bot einen Raum zur Auseinandersetzung mit den Prioritäten einer gerechten und inklusiven Bildung in dieser Zeit. Dieser Band eröffnet einen Dialog über inklusive Didaktik, der durch seine mehrsprachige und interkulturelle Ausrichtung eine Brücke zwischen deutsch- und italienischsprachigen Traditionen schlägt. Die zwölf Beiträge erschließen aus unterschiedlichen Blickwinkeln theoretische Bezüge, Methoden und Instrumente für die Entwicklung einer inklusiven Schule mit besonderem Augenmerk auf die Didaktik.Le disuguaglianze in ambito educativo, emerse anche a causa della pandemia, indicano la necessità di alternative e nuovi orizzonti. La settima edizione del Convegno “Didattica e Inclusione Scolastica – Inklusion im Bildungsbereich”, organizzato per la prima volta dal Centro di Competenza per l’Inclusione Scolastica della Libera Università di Bolzano, ha voluto creare uno spazio per mettere a fuoco le priorità per un’educazione equa ed inclusiva in questo tempo. Con questo volume si dà avvio ad un dialogo sulla didattica inclusiva che si fa plurilingue ed interculturale, creando un ponte fra le tradizioni di lingua italiana e tedesca. I dodici contributi presenti delineano, da prospettive diverse, riferimenti teorici, metodologie e strumenti per lo sviluppo della scuola inclusiva, con un’attenzione particolare alla dimensione didattica

ITALIAN CANCER FIGURES - REPORT 2015: The burden of rare cancers in Italy = I TUMORI IN ITALIA - RAPPORTO 2015: I tumori rari in Italia

OBJECTIVES: This collaborative study, based on data collected by the network of Italian Cancer Registries (AIRTUM), describes the burden of rare cancers in Italy. Estimated number of new rare cancer cases yearly diagnosed (incidence), proportion of patients alive after diagnosis (survival), and estimated number of people still alive after a new cancer diagnosis (prevalence) are provided for about 200 different cancer entities. MATERIALS AND METHODS: Data herein presented were provided by AIRTUM population- based cancer registries (CRs), covering nowadays 52% of the Italian population. This monograph uses the AIRTUM database (January 2015), which includes all malignant cancer cases diagnosed between 1976 and 2010. All cases are coded according to the International Classification of Diseases for Oncology (ICD-O-3). Data underwent standard quality checks (described in the AIRTUM data management protocol) and were checked against rare-cancer specific quality indicators proposed and published by RARECARE and HAEMACARE (www.rarecarenet.eu; www.haemacare.eu). The definition and list of rare cancers proposed by the RARECAREnet "Information Network on Rare Cancers" project were adopted: rare cancers are entities (defined as a combination of topographical and morphological codes of the ICD-O-3) having an incidence rate of less than 6 per 100,000 per year in the European population. This monograph presents 198 rare cancers grouped in 14 major groups. Crude incidence rates were estimated as the number of all new cancers occurring in 2000-2010 divided by the overall population at risk, for males and females (also for gender-specific tumours).The proportion of rare cancers out of the total cancers (rare and common) by site was also calculated. Incidence rates by sex and age are reported. The expected number of new cases in 2015 in Italy was estimated assuming the incidence in Italy to be the same as in the AIRTUM area. One- and 5-year relative survival estimates of cases aged 0-99 years diagnosed between 2000 and 2008 in the AIRTUM database, and followed up to 31 December 2009, were calculated using complete cohort survival analysis. To estimate the observed prevalence in Italy, incidence and follow-up data from 11 CRs for the period 1992-2006 were used, with a prevalence index date of 1 January 2007. Observed prevalence in the general population was disentangled by time prior to the reference date (≤2 years, 2-5 years, ≤15 years). To calculate the complete prevalence proportion at 1 January 2007 in Italy, the 15-year observed prevalence was corrected by the completeness index, in order to account for those cancer survivors diagnosed before the cancer registry activity started. The completeness index by cancer and age was obtained by means of statistical regression models, using incidence and survival data available in the European RARECAREnet data. RESULTS: In total, 339,403 tumours were included in the incidence analysis. The annual incidence rate (IR) of all 198 rare cancers in the period 2000-2010 was 147 per 100,000 per year, corresponding to about 89,000 new diagnoses in Italy each year, accounting for 25% of all cancer. Five cancers, rare at European level, were not rare in Italy because their IR was higher than 6 per 100,000; these tumours were: diffuse large B-cell lymphoma and squamous cell carcinoma of larynx (whose IRs in Italy were 7 per 100,000), multiple myeloma (IR: 8 per 100,000), hepatocellular carcinoma (IR: 9 per 100,000) and carcinoma of thyroid gland (IR: 14 per 100,000). Among the remaining 193 rare cancers, more than two thirds (No. 139) had an annual IR <0.5 per 100,000, accounting for about 7,100 new cancers cases; for 25 cancer types, the IR ranged between 0.5 and 1 per 100,000, accounting for about 10,000 new diagnoses; while for 29 cancer types the IR was between 1 and 6 per 100,000, accounting for about 41,000 new cancer cases. Among all rare cancers diagnosed in Italy, 7% were rare haematological diseases (IR: 41 per 100,000), 18% were solid rare cancers. Among the latter, the rare epithelial tumours of the digestive system were the most common (23%, IR: 26 per 100,000), followed by epithelial tumours of head and neck (17%, IR: 19) and rare cancers of the female genital system (17%, IR: 17), endocrine tumours (13% including thyroid carcinomas and less than 1% with an IR of 0.4 excluding thyroid carcinomas), sarcomas (8%, IR: 9 per 100,000), central nervous system tumours and rare epithelial tumours of the thoracic cavity (5%with an IR equal to 6 and 5 per 100,000, respectively). The remaining (rare male genital tumours, IR: 4 per 100,000; tumours of eye, IR: 0.7 per 100,000; neuroendocrine tumours, IR: 4 per 100,000; embryonal tumours, IR: 0.4 per 100,000; rare skin tumours and malignant melanoma of mucosae, IR: 0.8 per 100,000) each constituted <4% of all solid rare cancers. Patients with rare cancers were on average younger than those with common cancers. Essentially, all childhood cancers were rare, while after age 40 years, the common cancers (breast, prostate, colon, rectum, and lung) became increasingly more frequent. For 254,821 rare cancers diagnosed in 2000-2008, 5-year RS was on average 55%, lower than the corresponding figures for patients with common cancers (68%). RS was lower for rare cancers than for common cancers at 1 year and continued to diverge up to 3 years, while the gap remained constant from 3 to 5 years after diagnosis. For rare and common cancers, survival decreased with increasing age. Five-year RS was similar and high for both rare and common cancers up to 54 years; it decreased with age, especially after 54 years, with the elderly (75+ years) having a 37% and 20% lower survival than those aged 55-64 years for rare and common cancers, respectively. We estimated that about 900,000 people were alive in Italy with a previous diagnosis of a rare cancer in 2010 (prevalence). The highest prevalence was observed for rare haematological diseases (278 per 100,000) and rare tumours of the female genital system (265 per 100,000). Very low prevalence (<10 prt 100,000) was observed for rare epithelial skin cancers, for rare epithelial tumours of the digestive system and rare epithelial tumours of the thoracic cavity. COMMENTS: One in four cancers cases diagnosed in Italy is a rare cancer, in agreement with estimates of 24% calculated in Europe overall. In Italy, the group of all rare cancers combined, include 5 cancer types with an IR>6 per 100,000 in Italy, in particular thyroid cancer (IR: 14 per 100,000).The exclusion of thyroid carcinoma from rare cancers reduces the proportion of them in Italy in 2010 to 22%. Differences in incidence across population can be due to the different distribution of risk factors (whether environmental, lifestyle, occupational, or genetic), heterogeneous diagnostic intensity activity, as well as different diagnostic capacity; moreover heterogeneity in accuracy of registration may determine some minor differences in the account of rare cancers. Rare cancers had worse prognosis than common cancers at 1, 3, and 5 years from diagnosis. Differences between rare and common cancers were small 1 year after diagnosis, but survival for rare cancers declined more markedly thereafter, consistent with the idea that treatments for rare cancers are less effective than those for common cancers. However, differences in stage at diagnosis could not be excluded, as 1- and 3-year RS for rare cancers was lower than the corresponding figures for common cancers. Moreover, rare cancers include many cancer entities with a bad prognosis (5-year RS <50%): cancer of head and neck, oesophagus, small intestine, ovary, brain, biliary tract, liver, pleura, multiple myeloma, acute myeloid and lymphatic leukaemia; in contrast, most common cancer cases are breast, prostate, and colorectal cancers, which have a good prognosis. The high prevalence observed for rare haematological diseases and rare tumours of the female genital system is due to their high incidence (the majority of haematological diseases are rare and gynaecological cancers added up to fairly high incidence rates) and relatively good prognosis. The low prevalence of rare epithelial tumours of the digestive system was due to the low survival rates of the majority of tumours included in this group (oesophagus, stomach, small intestine, pancreas, and liver), regardless of the high incidence rate of rare epithelial cancers of these sites. This AIRTUM study confirms that rare cancers are a major public health problem in Italy and provides quantitative estimations, for the first time in Italy, to a problem long known to exist. This monograph provides detailed epidemiologic indicators for almost 200 rare cancers, the majority of which (72%) are very rare (IR<0.5 per 100,000). These data are of major interest for different stakeholders. Health care planners can find useful information herein to properly plan and think of how to reorganise health care services. Researchers now have numbers to design clinical trials considering alternative study designs and statistical approaches. Population-based cancer registries with good quality data are the best source of information to describe the rare cancer burden in a population

Dispositional bases of self-serving positive evaluations

Positive orientation (POS) is the name given to the latent dimension common to self-esteem, optimism and life satisfaction. Earlier findings attest to the trait-like nature of POS and to its unique contribution to well-adjustment across domains of functioning. The present study investigates the extent to which POS accounts for individuals' tendency to distort their self-assessment in a positive direction. Taking a class of students (N=190) at the beginning of their academic year, POS predicted the individuals' tendency to perform academically better-than-average (BTA) peers. POS accounted for BTA beyond what is merely due to self-esteem, life satisfaction and optimism. (C) 2013 Elsevier Ltd. All rights reserved