Exploration of Antagonist Efficacy for LPrA2 Like Peptide

Leptin is a small protein hormone that controls satiety and is produced by adipocytes. Obese people have increased levels of circulating leptin. Excessive leptin levels cause a break down in the control of leptin signaling pathways leading to increased angiogenesis, proliferation, cell migration, invasion, and anti-apoptotic events. Obesity and leptin signaling have been linked to cancer progression. Literature shows that LPrA2 is an effective leptin antagonist as it decreases proliferation of breast cancer cells in vitro. This project compares the effectiveness of LPrA2 like compounds in breast cancer cell-line MDA-MB-468 (M-468 BCs). We hypothesize that the new peptide antagonists have shorter sequences than LPrA2 and could be more advantageous inhibitors of leptin signaling in BCs than the original LPrA2. During this study, we first tested toxicity of LPrA2 like peptides in MCF10-A cell-line. Then we tested the effectiveness to inhibit leptin induce S-phase in BCs and compared them to LPrA2. M-468 BCs were treated with various compounds for 48 hours. Cell cycle staging was determined using a cellometer. Our results show that two of the new peptide antagonists were more effective in S-phase inhibition than LPrA2. We also expect that a combination of the new peptide antagonist and chemotherapy drug will inhibit proliferation in vitro. This study could lead to the development of future studies that test the efficacy of C6 and C8 using an in vivo mouse model

Pancreatic Cancer, Leptin, and Chemoresistance: Current Challenges

Pancreatic cancer (PC) remains a leading cause of cancer-related deaths. Currently, conventional chemotherapies have showed only limited benefits for PC patients. Main factors affecting PC treatment failures are due to late detection, lack of early symptoms and biomarkers, and the development of desmoplasia and chemoresistance. Various mechanisms have been implicated in PC chemoresistance that includes stem cells, epigenetic changes, and alteration of signaling pathways, among others. Obesity is a modifiable factor for PC risk, which is characterized by high levels of the adipokine leptin that is a proinflammatory, proangiogenic, survival factor that affects chemotherapy effectiveness. Here, we will discuss on the mechanisms of PC chemoresistance and the influence of obesity and leptin signaling. Furthermore, the potential use of nontoxic leptin antagonists as a novel sensitization strategy for PC chemotherapeutics will also be discussed

Vascular Endothelial Growth Factor Receptor-2 Couples Cyclo-Oxygenase-2 with Pro-Angiogenic Actions of Leptin on Human Endothelial Cells

The adipocyte-derived hormone leptin influences the behaviour of a wide range of cell types and is now recognised as a pro-angiogenic and pro-inflammatory factor. In the vasculature, these effects are mediated in part through its direct leptin receptor (ObRb)-driven actions on endothelial cells (ECs) but the mechanisms responsible for these activities have not been established. In this study we sought to more fully define the molecular links between inflammatory and angiogenic responses of leptin-stimulated human ECs../Akt/COX-2 signalling axis is required for leptin's pro-angiogenic actions and that this is regulated upstream by ObRb-dependent activation of VEGFR2. These studies identify a new function for VEGFR2 as a mediator of leptin-stimulated COX-2 expression and angiogenesis and have implications for understanding leptin's regulation of the vasculature in both non-obese and obese individuals

Current Status of the EU-VGOS Project

The EU-VGOS project began in 2018 with\ua0the aim of using the VGOS infrastructure in Europe\ua0to investigate methods for VGOS data processing. The\ua0project is now structured into Working Groups dealing\ua0with operations (stations), e-transfer, correlation and\ua0post-processing, and analysis. This is a report on the\ua0status of the project

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Stress and worry in the 2020 coronavirus pandemic: Relationships to trust and compliance with preventive measures across 48 countries in the COVIDiSTRESS global survey

The COVIDiSTRESS global survey collects data on early human responses to the 2020 COVID-19 pandemic from 173 429 respondents in 48 countries. The open science study was co-designed by an international consortium of researchers to investigate how psychological responses differ across countries and cultures, and how this has impacted behaviour, coping and trust in government efforts to slow the spread of the virus. Starting in March 2020, COVIDiSTRESS leveraged the convenience of unpaid online recruitment to generate public data. The objective of the present analysis is to understand relationships between psychological responses in the early months of global coronavirus restrictions and help understand how different government measures succeed or fail in changing public behaviour. There were variations between and within countries. Although Western Europeans registered as more concerned over COVID-19, more stressed, and having slightly more trust in the governments' efforts, there was no clear geographical pattern in compliance with behavioural measures. Detailed plots illustrating between-countries differences are provided. Using both traditional and Bayesian analyses, we found that individuals who worried about getting sick worked harder to protect themselves and others. However, concern about the coronavirus itself did not account for all of the variances in experienced stress during the early months of COVID-19 restrictions. More alarmingly, such stress was associated with less compliance. Further, those most concerned over the coronavirus trusted in government measures primarily where policies were strict. While concern over a disease is a source of mental distress, other factors including strictness of protective measures, social support and personal lockdown conditions must also be taken into consideration to fully appreciate the psychological impact of COVID-19 and to understand why some people fail to follow behavioural guidelines intended to protect themselves and others from infection. The Stage 1 manuscript associated with this submission received in-principle acceptance (IPA) on 18 May 2020. Following IPA, the accepted Stage 1 version of the manuscript was preregistered on the Open Science Framework at https://osf.io/g2t3b. This preregistration was performed prior to data analysis

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Combined fit to the spectrum and composition data measured by the Pierre Auger Observatory including magnetic horizon effects

The measurements by the Pierre Auger Observatory of the energy spectrum and mass composition of cosmic rays can be interpreted assuming the presence of two extragalactic source populations, one dominating the flux at energies above a few EeV and the other below. To fit the data ignoring magnetic field effects, the high-energy population needs to accelerate a mixture of nuclei with very hard spectra, at odds with the approximate E$^{-2}$ shape expected from diffusive shock acceleration. The presence of turbulent extragalactic magnetic fields in the region between the closest sources and the Earth can significantly modify the observed CR spectrum with respect to that emitted by the sources, reducing the flux of low-rigidity particles that reach the Earth. We here take into account this magnetic horizon effect in the combined fit of the spectrum and shower depth distributions, exploring the possibility that a spectrum for the high-energy population sources with a shape closer to E$^{-2}$ be able to explain the observations