Metformin inhibits androgen-induced IGF-IR up-regulation in prostate cancer cells by disrupting membrane-initiated androgen signaling.

We have previously demonstrated that, in prostate cancer cells, androgens up-regulate IGF-I receptor (IGF-IR) by inducing cAMP-response element-binding protein (CREB) activation and CREB-dependent IGF-IR gene transcription through androgen receptor (AR)-dependent membrane-initiated effects. This IGF-IR up-regulation is not blocked by classical antiandrogens and sensitizes cells to IGF-I-induced biological effects. Metformin exerts complex antitumoral functions in various models and may inhibit CREB activation in hepatocytes. We, therefore, evaluated whether metformin may affect androgen-dependent IGF-IR up-regulation. In the AR(+) LNCaP prostate cancer cells, we found that metformin inhibits androgen-induced CRE activity and IGF-IR gene transcription. CRE activity requires the formation of a CREB-CREB binding protein-CREB regulated transcription coactivator 2 (CRTC2) complex, which follows Ser133-CREB phosphorylation. Metformin inhibited Ser133-CREB phosphorylation and induced nuclear exclusion of CREB cofactor CRTC2, thus dissociating the CREB-CREB binding protein-CRTC2 complex and blocking its transcriptional activity. Similarly to metformin action, CRTC2 silencing inhibited IGF-IR promoter activity. Moreover, metformin blocked membrane-initiated signals of AR to the mammalian target of rapamycin/p70S6Kinase pathway by inhibiting AR phosphorylation and its association with c-Src. AMPK signals were also involved to some extent. By inhibiting androgen-dependent IGF-IR up-regulation, metformin reduced IGF-I-mediated proliferation of LNCaP cells. These results indicate that, in prostate cancer cells, metformin inhibits IGF-I-mediated biological effects by disrupting membrane-initiated AR action responsible for IGF-IR up-regulation and suggest that metformin could represent a useful adjunct to the classical antiandrogen therapy

Machine Learning-based GPS Jamming and Spoofing Detection

The increasing reliance on Global Positioning System (GPS) technology across various sectors has exposed vulnerabilities to malicious attacks, particularly GPS jamming and spoofing. This thesis presents an analysis into detection and mitigation strategies for enhancing the resilience of GPS receivers against jamming and spoofing attacks. The research entails the development of a simulated GPS signal and a receiver model to accurately decode and extract information from simulated GPS signals. The study implements the generation of jammed and spoofed signals to emulate potential threats faced by GPS receivers in practical settings. The core innovation lies in the integration of machine learning techniques to detect and differentiate genuine GPS signals from jammed and spoofed ones. By leveraging the machine learning capability of the Support Vector Machine (SVM) algorithm to classify signal attributes as nominal or abnormal and an Artificial Immune System (AIS) framework to create an optimized Health Management System (HMS), the system adapts and learns from various signal characteristics, enabling it to make informed decisions regarding the authenticity of the received signals. After conducting training, validation, and fault detection, the model successfully returned an average 95.3% spoofed signal detection rate. The proposed machine-learning-based detection mechanism is expected to enhance the robustness of GPS receivers against evolving spoofing techniques

Judicial diplomacy: international courts and legitimation

Observers of international courts (ICs) note that several ICs carry out a broad range of non-judicial activities, ranging from legal training workshops and public seminars to visits with public officials. Despite the growing prominence of these activities, they have received little attention from scholars. Seeking to fill this gap, this article examines these activities as a form of 'judicial diplomacy', asking how and why ICs employ judicial diplomacy. The article argues that ICs use judicial diplomacy as a means of legitimation. They seek to boost institutional legitimacy through their judicial diplomacy by targeting the public and communicating norm-referential narratives about their processes and outcomes. This argument bears out in case studies on the judicial diplomacy of the African Court of Human and Peoples' Rights and the Caribbean Court of Justice. Both courts are shown to have judicial diplomacy that is public-oriented and people-centred. This argument has important implications for literature on international courts and the legitimacy of international institutions

Could Covid-19 herald the renewal of international cooperation?

The COVID-19 crisis has exposed what some scholars of international organizations have been noticing in recent years: a retrenchment from international cooperation and multilateral approaches to problem-solving. While the Trump administration’s admonishment of the World Health Organization is a political manoeuvre to brandish a scapegoat for the administration’s abysmal failures, it also a telltale sign of broader efforts to withdraw from and undermine international cooperation. However, could COVID-19 herald the renewal of international cooperation,asks Theresa Squatrito (LSE)

SELF-EXPANDABLE METAL STENT PLACEMENT FOR CLOSURE OF A LEAK AFTER TOTAL GASTRECTOMY FOR GASTRIC CANCER: REPORT ON THREE CASES AND REVIEW OF THE LITERATURE

consequently the management of this problem has become more critically focused than was previously possible. We report here three cases of placement of a partially silicone-coated SEMS (Evolution Controlled Release Esophageal Stent System, CookMedical, Winston-Salem, NC, USA) in patients who underwent total gastrectomy with Roux-en-Y end-to-side esophagojejunostomy for a gastric adenocarcinoma. The promising results of our report, despite the small number of patients, suggest that early stenting (through a partially silicone-coated SEMS) is a feasible alternative to surgical treatment in this subset of patients. In fact, in the treatment of leakage after total gastrectomy, plastic stents and totally covered metallic stents may not adhere sufficiently to the esophagojejunal walls and, as a result, migrate beyond the anastomosis. However, prospective studies with a larger number of patients might assess the real effectiveness and safety of this procedure

DESIGN-DRIVEN INNOVATION OF BIO-BASED CIRCULAR MATERIALS

In recent years, design has turned its attention toward the Circular Economy where material issues are central. More and more companies and designers are turning their research towards ‘circular materials’ from the recycling of ‘technical materials’ or created from an organic base of processing/production or consumption waste and reintegrating into the biological cycle. The paper focused on ‘bio-based circular materials’, presents the first phase of research in progress, with the aim of mapping and systematizing the strategies used for the conception, development, design, production, and distribution of new materials and related products

CLINICAL OUTCOMES OF SELF-EXPAMDABLE METALLIC STENTS IN PALLIATION OF MALIGNANT ANASTOMOTIC STRICTURES: A SINGLE CENTER EXPERIENCE

Background: self-expandable metallic stents (SEMS) are employed as the preferred non surgical palliative treatment for gastric outlet obstruction due to malignancies. Metallic stents are often employed to treat malignant anastomotic obstructions after surgicsl interventions as esophagojejunostomy, gastrojejunostomy and esophagogastrojejunostomy. Methods: this case series reports prospectively the clinical outcomes of SEMS in the palliative care of malignant anastomotic strictures caused by the recurrence gastric cancer follwing gastric surgery as oncological curative treatment, in a series of nine consecutive patients, treated between January 2009 and december 2012 in our center. Results: Nine patients (M:F=8:1) were enrolled in the study. The operation was a total gastrectomy with esophagogastrojejunostomy (n=4), subtotal gastrectomy with Bilroth-II reconstruction (n=4), subtotal gastrectomy with Billroth-II reconstruction (n=3), and subtotal gastrectomy with esophagogastrostomy (n=2). The technical success rate was 88,9%, and the clinical success rate was 88.9%. The reostruction of the stent, due to the ingrowth of the tumor, occurred in 1 patient (11,1%) within 1 month after stent placement. the migration of the stent occurred after the placement of a covered stent in 1 patient who underwent a subtotal gastrectomy (with Billroth-II reconstruction). A case o partial stent dislodgement was treated with the placement of a second stent. The median survival period was 180 days (range, 30-240 days) and the median stent patency was 45 days 8range, 30-90 days). Conclusions: Although the number of the patients treated with SEMS results, in this series, almost small to certainly judge the safety and feasibility of SEMS, we believe that the endoscopic insertion of SEMS seems to be a safe, easily feasible, and effective treatment in the palliative care of malignant anastomotic strictures caused by the recurrence of gastric cancer following gastric surgery. The technical and clinical success, and the onset of complications of this procedure are influenced by several factors, such as the type of anastomosis, the technical features of the stent, and the extent of the underlying tumor