PaxVax (United States)

Both primary and metastatic brain tumors rely on signals from the surrounding environment for their survival and progression. In particular, the most common and lethal brain cancer, glioblastoma (GBM), derived from glial cells (astrocytes or microglia), has been shown to integrate into synaptic networks and to receive paracrine signals from neighbouring tumor microenvironment (TME) cells. There is increasing evidence that metastatic disease in the brain exhibits similar behavior. The TME both maintains malignant cells and is maintained by them, a process that relies on cancer stem cells (CSCs). These stem cells and their signaling mechanisms, including in the case of GBM, “GSCs,” provide possible novel targets for immunotherapy. In this review, we will discuss the integration of primary and malignant brain tumors into normal synaptic networks, the role of tumor stem cells and the TME in this integration, and the potential for immunotherapeutic targeting of these processes.

<title>Abstract</title> Background The COVID-19 pandemic highlighted the critical need for drug repurposing to rapidly identify therapeutic options. While computational graph-based approaches show promise, conventional single analytical methods often fail to capture the complex pathological mechanisms needed for clinical translation. Methods We developed a Graph Attention Autoencoder (GATE) framework with multilayered validation integrating computational prediction, real-world data, and phenome analyses. Network-based embeddings identified drug candidates through latent space similarity analysis within biomedical knowledge graphs. Clinical potential was assessed via disproportionality analysis (DPA) using adverse event reporting system, and biological plausibility was evaluated through gene expression profiling and pathway analyses. Results Our GATE framework identified 17 drug candidates, including 13 with known clinical effects on COVID-19 symptoms, validating model performance. Four novel candidates (cilastatin, megestrol, drotrecogin alfa, and ethacrynic acid) with minimal prior COVID-19 associations were identified. DPA further narrowed these to two promising candidates with significant protective signals: cilastatin (reporting odds ratio [ROR]: 0.19, 95% confidence interval [CI]: 0.09–0.43) and megestrol (ROR: 0.63, 95% CI: 0.42–0.94). Pathway profiling confirmed that both drugs share molecular signatures with drugs investigated in COVID-19 clinical trials. Gene expression analyses suggest that cilastatin may have anti-viral and anti-inflammatory effects via suppression of splicing, ribosomal function and mitochondrial pathway, through DPEP1 inhibition. Conclusions This study presents the first systematic integration of GATE-based computational prediction, real-world evidence from adverse event databases, and phenome-level pathway profiling for COVID-19 drug repurposing. This multilayered approach enabled multidimensional candidate validation unattainable by single analytical methods alone. The identification of clinically approved drugs with established safety profiles may facilitate accelerated clinical evaluation. Furthermore, the pathway and gene expression analyses provide mechanistic working hypotheses that can streamline subsequent preclinical validation. Although preclinical and clinical validation remain essential, this framework offers a generalizable strategy for rapid candidate identification during pandemics and for diseases with unmet therapeutic needs.

The development of new approaches to cholera control relies on an accurate understanding of cholera epidemiology. However, most information on cholera incidence lacks laboratory confirmation and instead relies on surveillance systems reporting medically attended acute watery diarrhea. If recent infections could be identified using serological markers, cross-sectional serosurveys would offer an alternative approach to measuring incidence. Here, we used 1569 serologic samples from a cohort of cholera cases and their uninfected contacts in Bangladesh to train machine learning models to identify recent Vibrio cholerae O1 infections. We found that an individual’s antibody profile contains information on the timing of V. cholerae O1 infections in the previous year. Our models using six serological markers accurately identified individuals in the Bangladesh cohort infected within the last year [cross-validated area under the curve (AUC), 93.4%; 95% confidence interval (CI), 92.1 to 94.7%], with a marginal performance decrease using models based on two markers (cross-validated AUC, 91.0%; 95% CI, 89.2 to 92.7%). We validated the performance of the two-marker model on data from a cohort of North American volunteers challenged with V. cholerae O1 (AUC range, 88.4 to 98.4%). In simulated serosurveys, our models accurately estimated annual incidence in both endemic and epidemic settings, even with sample sizes as small as 500 and annual incidence as low as two infections per 1000 individuals. Cross-sectional serosurveys may be a viable approach to estimating cholera incidence.

BackgroundCholera is an acute voluminous dehydrating diarrheal disease caused by toxigenic strains of Vibrio cholerae O1 and occasionally O139. A growing body of evidence indicates that immune responses targeting the O-specific polysaccharide (OSP) of V. cholerae are involved in mediating protection against cholera. We therefore assessed whether antibody responses against OSP occur after vaccination with live attenuated oral cholera vaccine CVD 103-HgR, and whether such responses correlate with protection against cholera.MethodologyWe assessed adult North American volunteers (n = 46) who were vaccinated with 5 × 108 colony-forming units (CFU) of oral cholera vaccine CVD 103-HgR and then orally challenged with approximately 1 × 105 CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961, either 10 or 90 days post-vaccination.Principal findingsVaccination was associated with induction of significant serum IgM and IgA anti-OSP and vibriocidal antibody responses within 10 days of vaccination. There was significant correlation between anti-OSP and vibriocidal antibody responses. IgM and IgA anti-OSP responses on day 10 following vaccination were associated with lower post-challenge stool volume (r = −0.44, P = 0.002; r = −0.36, P = 0.01; respectively), and none of 27 vaccinees who developed a ≥1.5 fold increase in any antibody isotype targeting OSP on day 10 following vaccination compared to baseline developed moderate or severe cholera following experimental challenge, while 5 of 19 who did not develop such anti-OSP responses did (P = 0.01).ConclusionOral vaccination with live attenuated cholera vaccine CVD 103-HgR induces antibodies that target V. cholerae OSP, and these anti-OSP responses correlate with protection against diarrhea following experimental challenge with V. cholerae O1.Trial registrationClinicalTrials.gov NCT01895855

Rio Bravo virus (RBV) is a member of the family Flaviviridae, genus Flavivirus. It belongs to a group of viruses in the genus with no known vector. In this report, we analyze the complete genome of the prototype RBV, strain M64.