Prostaglandin E2 receptor EP4 as the common target on cancer cells and macrophages to abolish angiogenesis, lymphangiogenesis, metastasis, and stem-like cell functions.

We previously established that COX-2 overexpression promotes breast cancer progression and metastasis. As long-term use of COX-2 inhibitors (COX-2i) can promote thrombo-embolic events, we tested an alternative target, prostaglandin E2 receptor EP4 subtype (EP4), downstream of COX-2. Here we used the highly metastatic syngeneic murine C3L5 breast cancer model to test the role of EP4-expressing macrophages in vascular endothelial growth factor (VEGF)-C/D production, angiogenesis, and lymphangiogenesis in situ, the role of EP4 in stem-like cell (SLC) functions of tumor cells, and therapeutic effects of an EP4 antagonist RQ-15986 (EP4A). C3L5 cells expressed all EP receptors, produced VEGF-C/D, and showed high clonogenic tumorsphere forming ability in vitro, functions inhibited with COX-2i or EP4A. Treating murine macrophage RAW 264.7 cell line with COX-2i celecoxib and EP4A significantly reduced VEGF-A/C/D production in vitro, measured with quantitative PCR and Western blots. Orthotopic implants of C3L5 cells in C3H/HeJ mice showed rapid tumor growth, angiogenesis, lymphangiogenesis (CD31/LYVE-1 and CD31/PROX1 immunostaining), and metastasis to lymph nodes and lungs. Tumors revealed high incidence of EP4-expressing, VEGF-C/D producing macrophages identified with dual immunostaining of F4/80 and EP4 or VEGF-C/D. Celecoxib or EP4A therapy at non-toxic doses abrogated tumor growth, lymphangiogenesis, and metastasis to lymph nodes and lungs. Residual tumors in treated mice revealed markedly reduced VEGF-A/C/D and phosphorylated Akt/ERK proteins, VEGF-C/D positive macrophage infiltration, and proliferative/apoptotic cell ratios. Knocking down COX-2 or EP4 in C3L5 cells or treating cells in vitro with celecoxib or EP4A and treating tumor-bearing mice in vivo with the same drug reduced SLC properties of tumor cells including preferential co-expression of COX-2 and SLC markers ALDH1A, CD44, OCT-3/4, β-catenin, and SOX-2. Thus, EP4 is an excellent therapeutic target to block stem-like properties, angiogenesis, and lymphangiogenesis induced by VEGF-A/C/D secreted by cancer cells and tumor infiltrating macrophages. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association

Online Safety in the Pacific: A Report on a Living Lab in Kiribati, Papua New Guinea and Solomon Islands

With cable internet systems rolling out across the Pacific, access to affordable and fast digital connectivity in the region is set to rapidly expand, opening up unprecedented opportunities for children but also potentially exposing them to new risks of harm. Child online safety in the Pacific region thus stands at a critical juncture. However, there is very little rigorous and reliable evidence to guide policy and decision making in relation to children’s digital practices and online safety This report presents the key findings of research undertaken to map the challenges and opportunities that technology presents for children in the Solomon Islands, Kiribati and Papua New Guinea. The project deployed a qualitative, participatory research methodology developed by the Young and Resilient Research Centre and previously deployed in over 70 countries. From December 2019 to March 2020, the Young and Resilient Research Centre at Western Sydney University, ChildFund Australia and Plan International Australia conducted half-day creative workshops conducted separately with 96 children aged 10-18; 58 parents and carers; and 50 representatives of government departments, local and international NGOs, schools, police, telecommunications companies, religious organisations and community leaders. Workshop activities explored key themes relating to each group’s perceptions and experiences of children’s digital media use and online safety, with the overall aim of generating an evidence base for ChildFund Australia’s and Plan International Australia’s future child protection programming in the Pacific region. Activities included writing, discussion, polls, and arts-based tools. Participants were engaged individually, in small groups, and as a whole group. Overall, despite different cultural practices and contexts at play in the three countries that participated in the study, across the sample, there were remarkable similarities in children’s, parents’/carers’ and other adult stakeholders’ experiences of navigating online safety issues for and with children

New Technologies, New Identities, and the Growth of Mass Opposition in the Arab Spring

The recent revolutions known as the Arab Spring have been characterized as the products of social media. However, there is an alternative view that revolution takes place on the street or the battlefield and that the role of social media has been overstated. We argue that some new technologies can serve to facilitate rapid social change when they provide ways to overcome restrictions on the freedoms of expression and association. In doing so, communication technologies enable the formation of new social identities that can challenge existing social orders by promoting the growth of a social movement that is positioned as loyal to the nation and its people but opposed to the government. Our analyses focus on the role of social media in spreading video images of dissent and the links between this video material, satellite television, and mobile telephones in Tunisia and Egypt

Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model

We reported that cyclo-oxygenase (COX)-2 expression in human breast cancer stimulated cancer cell migration and invasiveness, production of vascular endothelial growth factor (VEGF)-C and lymphangiogenesis in situ, largely from endogenous PGE2-mediated stimulation of prostaglandin E (EP)1 and EP4 receptors, presenting them as candidate therapeutic targets against lymphatic metastasis. As human breast cancer xenografts in immuno-compromised mice have limitations for preclinical testing, we developed a syngeneic murine breast cancer model of spontaneous lymphatic metastasis mimicking human and applied it for mechanistic and therapeutic studies. We tested the roles of COX-2 and EP receptors in VEGF-C and-D production by a highly metastatic COX-2 expressing murine breast cancer cell line C3L5. These cells expressed all EP receptors and produced VEGF-C and-D, both inhibited with COX-2 inhibitors or EP4 (but not EP1, EP2 or EP3) antagonists. C3H/HeJ mice, when implanted SC in both inguinal regions with C3L5 cells suspended in growth factor-reduced Matrigel, exhibited rapid tumor growth, tumor-associated angiogenesis and lymphangiogenesis (respectively measured with CD31 and LYVE-1 immunostaining), metastasis to the inguinal and axillary lymph nodes and the lungs. Chronic oral administration of COX-1/COX-2 inhibitor indomethacin, COX-2 inhibitor celecoxib and an EP4 antagonist ONO-AE3-208, but not an EP1 antagonist ONO-8713 at nontoxic doses markedly reduced tumor growth, lymphangiogenesis, angiogenesis, and metastasis to lymph nodes and lungs. Residual tumors in responding mice revealed reduced VEGF-C and-D proteins, AkT phosphorylation and increased apoptotic/proliferative cell ratios consistent with blockade of EP4 signaling. We suggest that EP4 antagonists deserve clinical testing for chemo-intervention of lymphatic metastasis in human breast cancer. © 2012 USCAP, Inc All rights reserved

Online Safety Perceptions, Needs, and Expectations of Young People in Southeast Asia: Consultations with Young People in Indonesia, Malaysia, Thailand, and Vietnam

Globally, children and young people's access to digital devices and online spaces are fundamental to what it means to be a young person in the contemporary context. Young people's access to digital technology earlier in life, and in greater numbers, has resulted in increased societal awareness and concern about ensuring their safety and wellbeing online. One manifestation of that concern is through calls for online platforms to take greater responsibility for safeguarding users' privacy and wellbeing. A growing body of work asserts the importance of technology industries adopting a human-centric approach when designing their online platforms and services to ensure those products are safer for the people who use them. In Southeast Asia in particular, penetration and use of online technologies among young people is rapidly advancing. It follows then that young people in this region should be included in discourses about and practices for online safety. This report describes outcomes of a project that explored online experiences of children and young people in four countries in Southeast Asia - Indonesia, Malaysia, Thailand, Vietnam - showing how young people in these countries perceive and experience key elements of their lives online. The report also presents young participants' ideas and aspirations about how to ensure they and their peers remain safe online, reinforcing the value of such ideas for key stakeholders when planning, developing, and operationalising their online products and services

PGE2 promotes breast cancer-associated lymphangiogenesis by activation of EP4 receptor on lymphatic endothelial cells

Background: Lymphatic metastasis, facilitated by lymphangiogenesis is a common occurrence in breast cancer, the molecular mechanisms remaining incompletely understood. We had earlier shown that cyclooxygenase (COX)-2 expression by human or murine breast cancer cells promoted lymphangiogenesis and lymphatic metastasis by upregulating VEGF-C/D production by tumor cells or tumor-associated macrophages primarily due to activation of the prostaglandin receptor EP4 by endogenous PGE2. It is not clear whether tumor or host-derived PGE2 has any direct effect on lymphangiogenesis, and if so, whether EP4 receptors on lymphatic endothelial cells (LEC) play any role. Methods: Here, we address these questions employing in vitro studies with a COX-2-expressing and VEGF-C/D-producing murine breast cancer cell line C3L5 and a rat mesenteric (RM) LEC line and in vivo studies in nude mice. Results: RMLEC responded to PGE2, an EP4 agonist PGE1OH, or C3L5 cell-conditioned media (C3L5-CM) by increased proliferation, migration and accelerated tube formation on growth factor reduced Matrigel. Native tube formation by RMLEC on Matrigel was abrogated in the presence of a selective COX-2 inhibitor or an EP4 antagonist. Addition of PGE2 or EP4 agonist, or C3L5-CM individually in the presence of COX-2 inhibitor, or EP4 antagonist, restored tube formation, reinforcing the role of EP4 on RMLEC in tubulogenesis. These results were partially duplicated with a human dermal LEC (HMVEC-dLyAd) and a COX-2 expressing human breast cancer cell line MDA-MB-231. Knocking down EP4 with shRNA in RMLEC abrogated their tube forming capacity on Matrigel in the absence or presence of PGE2, EP4 agonist, or C3L5-CM. RMLEC tubulogenesis following EP4 activation by agonist treatment was dependent on PI3K/Akt and Erk signaling pathways and VEGFR-3 stimulation. Finally in a directed in vivo lymphangiogenesis assay (DIVLA) we demonstrated the lymphangiogenic as well as angiogenic capacity of PGE2 and EP4 agonist in vivo. Discussion/conclusions: These results demonstrate the roles of tumor as well as host-derived PGE2 in inducing lymphangiogenesis, at least in part, by activating EP4 and VEGFR-3 on LEC. EP4 being a common target on both tumor and host cells contributing to tumor-associated lymphangiogenesis reaffirms the therapeutic value of EP4 antagonists in the intervention of lymphatic metastasis in breast cancer

Child-centred Indicators for Violence Prevention: Summary Report on a Living Lab in the City of Valenzuela, Philippines

In 2015, world leaders made a commitment to end all forms of violence against children by 2030, as part of the Sustainable Development Goals (SDGs). To achieve the aspirations of the SDG global targets, Governments set targets, taking into account national circumstances, to reduce children’s risk and be responsive to local contexts. Prevention and response efforts need to be grounded in the best available evidence to achieve measurable reductions in violence, and if the needs of children are to be foregrounded, strategies to end violence must respect not only children’s protection rights but also their participation rights. Moreover, it is critical that the processes for monitoring and measuring impacts centre children’s needs, aspirations and experiences. If children themselves report that violence is reducing in their personal lives, in their communities and in their countries, we will know that efforts to address violence, abuse and neglect are succeeding. This report describes a project undertaken in collaboration with End Violence, the City of Valenzuela, the Young and Resilient Research Centre and other partners to develop child-centred indicators for violence prevention in the City of Valenzuela in greater Manila, Philippines. Child and adult stakeholders worked together in a series of 14 participatory workshops to creatively explore children’s experiences and perceptions of violence, to map their aspirations for change, to ideate strategies for addressing violence in their communities, and to develop child-centred indicators against which violence reduction can be measured. This project found that children’s perspectives are a vital resource for efforts to localise INSPIRE strategies and that the deployment of child-centred indicators usefully augments and complements the INSPIRE measurement framework. Beyond the City of Valenzuela, there is opportunity to scale the use of these child-centred indicators to other parts of the Philippines and globally. The report also offers reflections on the key strengths and limitations of the Living Lab process for engaging a wide range of stakeholders, including children themselves, in the project of ending violence against children

Fix My Food: Children's Views on Transforming Food Systems

Sustainable food systems are critical to ensuring that all children and adolescents are able to access nutritious, safe, affordable, and sustainable foods. However, current food systems are failing children and adolescents. Globally, two out of three young children do not consume a diet of minimal diversity and three in four adolescents in low-income and middle-income countries do not consume enough fruit and vegetables. At the same time, in the same settings, children and adolescents often have ready access to cheap, nutrient-poor processed and ultra-processed foods. Urgent action to radically transform food systems and deliver on children’s right to good nutrition is needed. UNICEF partnered with the Young and Resilient Research Centre at Western Sydney University to bring the voices of children to the forefront through participatory food systems dialogues in 18 countries around the world. Over 700 children and adolescents aged 10-19 from significantly diverse backgrounds participated in two-and-a-half-hour workshops to share their lived experiences, insights, and perspectives on food systems. The workshops help understand children’s views and perspectives on food systems; the key challenges to attaining nutritious, safe, desirable, and sustainable food; and how children want food systems to change. Additionally, UNICEF conducted U-Report polls involving 22,561 children and youth in 23 countries who reported on their experiences of food systems and food environments. Workshop findings exposed how children are knowledgeable about the importance of food and what it means to them and their communities. They understand how food is produced and how it travels from farm to mouth. They are clear about the main barriers – physical and financial – to nutritious, safe, and sustainable diets and are concerned about the links between current food systems, environmental degradation, and climate change. U-Report data demonstrated that cost and safety of food (32%) followed by taste (25%) were the biggest influence on food choice. During workshop activities children expressed a strong desire to be engaged in dialogue and action to transform their food systems and to address food poverty, food quality, environmental degradation, and climate change. Children voiced two key recommendations to aid food system transformation 1) improve the availability, accessibility and affordability of nutritious foods; and 2) reduce the impact of food systems on environmental degradation and climate change. Children call on political leaders and public/private-sector stakeholders to work across all levels of society to strengthen food systems; from implementing effective regulation of food industries to promoting individual and community behaviour change. Doing so will support people to sustain themselves while also sustaining the environment. Children call on governments and other stakeholders to work with them during this process to create platforms for their ongoing participation in the process of food systems transformation

DIE AREALE DER IKAVISCHEN, EKAVISCHEN UND IJEKAVISCHEN MUNDARTEN IM SLAVONISCHEN DIALEKT

Der Author hat in diesem Artikel die Areale aller Mundarten des slavonisehen Dialekts in Detail dargestellt und auch eine Karte hinzugefügt wo man die Grenzen der besprechenden Mundarten sehen kann

Anticoagulation in Patients With COVID-19: JACC Review Topic of the Week.

Clinical, laboratory, and autopsy findings support an association between coronavirus disease-2019 (COVID-19) and thromboembolic disease. Acute COVID-19 infection is characterized by mononuclear cell reactivity and pan-endothelialitis, contributing to a high incidence of thrombosis in large and small blood vessels, both arterial and venous. Observational studies and randomized trials have investigated whether full-dose anticoagulation may improve outcomes compared with prophylactic dose heparin. Although no benefit for therapeutic heparin has been found in patients who are critically ill hospitalized with COVID-19, some studies support a possible role for therapeutic anticoagulation in patients not yet requiring intensive care unit support. We summarize the pathology, rationale, and current evidence for use of anticoagulation in patients with COVID-19 and describe the main design elements of the ongoing FREEDOM COVID-19 Anticoagulation trial, in which 3,600 hospitalized patients with COVID-19 not requiring intensive care unit level of care are being randomized to prophylactic-dose enoxaparin vs therapeutic-dose enoxaparin vs therapeutic-dose apixaban. (FREEDOM COVID-19 Anticoagulation Strategy [FREEDOM COVID]; NCT04512079).Dr Farkouh has received research grants from Amgen, Novo Nordisk, and Novartis. Dr Stone has received speaker honoraria from Infraredx; has served as a consultant to Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Miracor, Neovasc, Abiomed, Ancora, Vectorious, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Cardiomech, Gore, and Amgen; and has equity/ options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter. Dr Godoy is supported by the Frederick Banting and Charles Best Canada Graduate Scholarship (Doctoral Research Award) from the Canadian Institutes of Health Research. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.S