Weight loss reversed obesity-induced HGF/c-Met pathway and basal-like breast cancer progression

Epidemiologic studies demonstrate that obesity is associated with an aggressive subtype of breast cancer called basal-like breast cancer (BBC). Using the C3(1)-TAg murine model of BBC, we previously demonstrated that mice displayed an early onset of tumors when fed obesogenic diets in the adult window of susceptibility. Obesity was also shown to elevate mammary gland expression and activation of hepatocyte growth factor (HGF)/c-Met compared to lean controls, a pro-tumorigenic pathway associated with BBC in patients. Epidemiologic studies estimate that weight loss could prevent a large proportion of BBC. We sought to investigate whether weight loss in adulthood prior to tumor onset would protect mice from accelerated tumorigenesis observed in obese mice. Using a life-long model of obesity, C3(1)-TAg mice were weaned onto and maintained on an obesogenic high-fat diet. Obese mice displayed significant elevations in tumor progression, but not latency or burden. Tumor progression was significantly reversed when obese mice were induced to lose weight by switching to a control low-fat diet prior to tumor onset compared to mice maintained on obesogenic diet. We investigated the HGF/c-Met pathway known to regulate tumorigenesis. Importantly, HGF/c-Met expression in normal mammary glands and c-Met in tumors was elevated with obesity and was significantly reversed with weight loss. Changes in tumor growth could not be explained by measures of HGF action including phospho-AKT or phospho-S6. Other mediators associated with oncogenesis such as hyperinsulinemia and a high leptin:adiponectin ratio were elevated by obesity and reduced with weight loss. In sum, weight loss significantly blunted the obesity-responsive pro-tumorigenic HGF/c-Met pathway and improved several metabolic risk factors associated with BBC, which together may have contributed to the dramatic reversal of obesity-driven tumor progression. Future research aims to evaluate the role of obesity and the HGF/c-Met pathway in basal-like breast cancer progression

cMET inhibitor crizotinib impairs angiogenesis and reduces tumor burden in the C3(1)-Tag model of basal-like breast cancer

Epidemiologic studies have associated obesity with increased risk of the aggressive basal-like breast cancer (BBC) subtype. Hepatocyte growth factor (HGF) signaling through its receptor, cMET, is elevated in obesity and is a pro-tumorigenic pathway strongly associated with BBC. We previously reported that high fat diet (HFD) elevated HGF, cMET, and phospho-cMET in normal mammary gland, with accelerated tumor development, compared to low fat diet (LFD)-fed lean controls in a murine model of BBC. We also showed that weight loss resulted in a significant reversal of HFD-induced effects on latency and elevation of HGF/cMET signaling in normal mammary and cMET in normal mammary and tumors. Here, we sought to inhibit BBC tumor progression in LFD- and HFD-fed C3(1)-Tag BBC mice using a small molecule cMET inhibitor, and began crizotinib treatment (50 mg/kg body weight by oral gavage) upon identification of the first palpable tumor. We next investigated if administering crizotinib in a window prior to tumor development would inhibit or delay BBC tumorigenesis. Treatment: Crizotinib significantly reduced mean tumor burden by 27.96 and 37.29 %, and mean tumor vascularity by 35.04 and 33.52 %, in our LFD- and HFD-fed C3(1)-Tag BBC mice, respectively. Prevention: Crizotinib significantly accelerated primary tumor progression in both diet groups but had no effect on total tumor progression or total tumor burden. In sum, cMET inhibition by crizotinib limited tumor development and microvascular density in basal-like tumor-bearing mice but did not appear to be an effective preventive agent for BBC

Diagnosing Norms Surrounding Sexual Harassment at a Jordanian University

Sexual harassment (SH) is a form of gender-based violence (GBV) that negatively impacts women’s physical, mental, social, and financial well-being. Although SH is a global phenomenon, it also is a contextualized one, with local and institutional norms influencing the ways in which harassment behavior manifests. As more women attend institutions of higher education in Jordan, these women are at increased risk of experiencing SH in university settings, with potential implications for their health and future employment. Social norms theory, which examines the informal rules governing individual behavior within groups, has been a useful framework for understanding and developing interventions against GBV globally. We sought to apply a social-norms lens to the understanding and prevention of SH at a Jordanian university. To gain a comprehensive and nuanced picture of social norms surrounding SH, we collected qualitative data using three complementary methods: focus group discussions (n = 6) with male and female students (n = 33); key informant interviews with staff and faculty (n = 5); and a public, participatory event to elicit anonymous short responses from students (n = 317). Using this data, we created a codebook incorporating social-norms components and emergent themes. As perceived by participants, SH was unacceptable yet common, characterized as a weak norm primarily because negative sanctioning of harassers was unlikely. Distal norms related to gender and tribal affiliation served to weaken further norms against SH by blaming the victim, preventing reporting, discouraging bystander intervention, and/or protecting the perpetrator. The complexity of the normative environment surrounding SH perpetration will necessitate the use of targeted, parallel approaches to change harmful norms. Strengthening weak norms against SH will require increasing the likelihood of sanctions, by revising university policies and procedures to increase accountability, increasing the acceptability of bystander intervention and reporting, and fostering tribal investment in sanctioning members who harass women. Creating dialogue that emphasizes the harmful nature of SH behaviors and safe spaces to practice positive masculinity also may be an effective strategy to change how male students interact in the presence of peers. Any social norms change intervention will need to consider the various reference groups that dictate and enforce norms surrounding SH

The Monarch Initiative in 2019: an integrative data and analytic platform connecting phenotypes to genotypes across species.

In biology and biomedicine, relating phenotypic outcomes with genetic variation and environmental factors remains a challenge: patient phenotypes may not match known diseases, candidate variants may be in genes that haven’t been characterized, research organisms may not recapitulate human or veterinary diseases, environmental factors affecting disease outcomes are unknown or undocumented, and many resources must be queried to find potentially significant phenotypic associations. The Monarch Initiative (https://monarchinitiative.org) integrates information on genes, variants, genotypes, phenotypes and diseases in a variety of species, and allows powerful ontology-based search. We develop many widely adopted ontologies that together enable sophisticated computational analysis, mechanistic discovery and diagnostics of Mendelian diseases. Our algorithms and tools are widely used to identify animal models of human disease through phenotypic similarity, for differential diagnostics and to facilitate translational research. Launched in 2015, Monarch has grown with regards to data (new organisms, more sources, better modeling); new API and standards; ontologies (new Mondo unified disease ontology, improvements to ontologies such as HPO and uPheno); user interface (a redesigned website); and community development. Monarch data, algorithms and tools are being used and extended by resources such as GA4GH and NCATS Translator, among others, to aid mechanistic discovery and diagnostics

The Human Phenotype Ontology in 2024: phenotypes around the world

\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs

The Human Phenotype Ontology in 2024: phenotypes around the world.

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs

D2D mobile relaying for efficient throughput-reliability delivering in 5G

Abstract Ensuring high reliability is one of the major goals of 5G systems. This work investigates the problem of cooperative relaying and the optimal number of devices to be directly connected to the base station, in order to meet best uplink performance in terms of throughput and reliability. We first propose a D2D-relaying system where devices cooperate forming groups of cellular devices serving as relays to other groups of D2D transmitters. Second we adopt a Markov chain framework, where the states are defined as the numbers of D2D-relays present in the network. Based on that, we derive the average network throughput and reliability. Next, we show that there exists an optimal device distribution, that maximizes the overall reliability and throughput. This number is strongly related to the switching probabilities of the devices and the network parameters such as the orthogonality factor, the cooperation level of D2D-transmitter, the network density and the cluster’s radius. Simulation results illustrate the optimal switching probabilities and the average number of D2D-relays that maximize the overall throughput and reliability

Une complication inhabituelle de la ligature des varicesoesophagiennes : accolement irréversible du cylindre à la varice

Les auteurs rapportent une complication inhabituelle de ligature des varices oesophagiennes. Au cours de cette procédure, le cylindre de plastique s’est détaché de l’endoscope pour se coller à la varice, obligeant l’opérateur à cesser l’intervention et à attendre 48 heures avant de pouvoir retirer ce cylindre