Antiangiogenic therapy of glioblastoma (GBM) with bevacizumab, a VEGFA-blocking antibody, may accelerate tumor cell invasion and induce alternative angiogenic pathways. Here we investigate the roles of the proangiogenic apelin receptor APLNR and its cognate ligand apelin in VEGFA/VEGFR2 antiangiogenic therapy against distinct subtypes of GBM. In proneural GBM, apelin levels were downregulated by VEGFA or VEGFR2 blockade. A central role for apelin/APLNR in controlling GBM vascularization was corroborated in a serial implantation model of the angiogenic switch that occurs in human GBM. Apelin and APLNR are broadly expressed in human GBM, and knockdown or knockout of APLN in orthotopic models of proneural or classical GBM subtypes significantly reduced GBM vascularization compared with controls. However, reduction in apelin expression led to accelerated GBM cell invasion. Analysis of stereotactic GBM biopsies from patients as well as from in vitro and in vivo experiments revealed increased dissemination of APLNR-positive tumor cells when apelin levels were reduced. Application of apelin-F13A, a mutant APLNR ligand, blocked tumor angiogenesis and GBM cell invasion. Furthermore, cotargeting VEGFR2 and APLNR synergistically improved survival of mice bearing proneural GBM. In summary, we show that apelin/APLNR signaling controls GBM angiogenesis and invasion and that both pathologic features are blunted by apelin-F13A. We suggest that apelin-F13A can improve the efficiency and reduce the side effects of established antiangiogenic treatments for distinct GBM subtypes.Significance: Pharmacologic targeting of the APLNR acts synergistically with established antiangiogenic treatments in glioblastoma and blunts therapy resistance to current strategies for antiangiogenesis.
IntroductionViolence against women is a pressing global health problem that is being met with a new intervention strategy—mobile applications. With this systematic review, we provide an initial analysis and functional categorisation of apps addressing violence against women.MethodsWe conducted a systematic online search conforming with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify apps addressing violence against women in five World Bank regions (Europe and Central Asia; North America, Latin America and the Caribbean; Middle East and North Africa; South Asia; and sub-Saharan Africa). Applications with location of initiation in mentioned regions and ≥100 downloads were included. Data on sector, target group(s), year of release, location of initiation and implementation were extracted. By means of a structured qualitative content analysis, applications were then categorised according to their main functions.ResultsOf 327 relevant applications, 171 were included into the systematic review and assigned to one of five identified categories of main functions, respectively: emergency, avoidance, education, reporting and evidence building, and supporting apps. The largest proportion (46.78%) consisted of emergency apps, followed by education, reporting and evidence building, supporting and avoidance apps in descending order. With regards to the geographical distribution of app categories, significant (χ2(20)=58.172; p=0.000) differences among the included regions were found.ConclusionA vast proportion of apps addressing violence against women primarily draw on one-time emergency or avoidance solutions, as opposed to more preventative approaches. Further research is necessary, critically considering questions of data security, personal safety and efficacy of such mobile health interventions.
Mobile applications (apps) have gained significant popularity as a new intervention strategy responding to violence against women and girls. Despite their growing relevance, an assessment from the perspective of public health ethics is still lacking.Here, we base our discussion on the understanding of violence against women and girls as a multidimensional, global public health issue on structural, societal and individual levels and situate it within the theoretical framework of structural injustice, including epistemic injustice. Based on a systematic app review we previously conducted, we evaluate the content and functions of apps through the lens of structural injustice. We argue that technological solutions such as apps may be a useful tool in the fight against violence against women and girls but have to be situated within the broader frame of public health that considers the structural dimensions of such violence. Ultimately, the concerns raised by structural injustice are-alongside key concerns of safety, data privacy, importance of human supportive contact, and so forth-crucial dimensions in the ethical assessment of such apps.
While some COVID-19 patients maintain SARS-CoV-2-specific serum IgGs for more than 6 months post-infection, others eventually lose IgG levels. We assessed the persistence of SARS-CoV-2-specific B cells in 17 patients, five of whom had lost specific IgGs after 5–8 months. Differentiation of blood-derived B cells in vitro revealed persistent SARS-CoV-2-specific IgG B-cells in all patients, whereas IgA-B cells were maintained in 11. Antibodies derived from cultured B cells blocked binding of viral receptor-binding domain (RBD) to the cellular receptor ACE-2, had neutralizing activity to authentic virus and recognized the RBD of the variant of concern Alpha similarly to the wild-type, while reactivity to Beta and Gamma were decreased. Thus, differentiation of memory B-cells could be more sensitive for detecting previous infection than measuring serum antibodies. Understanding the persistence of SARS-CoV-2 specific B cells even in the absence of specific serum IgG will help to promote long-term immunity.
Background and ObjectivesTo investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-NMDA receptor (anti-NMDAR) encephalitis.MethodsWe performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls, followed by a colocalization analysis to identify putatively causal genes.ResultsWe identified 2 independent risk loci harboring genome-wide significant variants (p < 5 × 10−8, OR ≥ 2.2), 1 on chromosome 15, harboring only the LRRK1 gene, and 1 on chromosome 11 centered on the ACP2 and NR1H3 genes in a larger region of high linkage disequilibrium. Colocalization signals with expression quantitative trait loci for different brain regions and immune cell types suggested ACP2, NR1H3, MADD, DDB2, and C11orf49 as putatively causal genes. The best candidate genes in each region are LRRK1, encoding leucine-rich repeat kinase 1, a protein involved in B-cell development, and NR1H3 liver X receptor alpha, a transcription factor whose activation inhibits inflammatory processes.DiscussionThis study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the human leukocyte antigen (HLA) region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism.
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