Monitoring Monoclonal Antibody Delivery in Oncology: The Example of Bevacizumab

Developing therapeutic monoclonal antibodies paves the way for new strategies in oncology using targeted therapy which should improve specificity. However, due to a lack of biomarkers, a personalized therapy scheme cannot always be applied with monoclonal antibodies. As a consequence, the efficacy or side effects associated with this type of treatment often appear to be sporadic. Bevacizumab is a therapeutic monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF). It is used to limit tumor vascularization. No prognosis or response biomarker is associated with this antibody, we therefore assessed whether the administration protocol could be a possible cause of heterogeneous responses (or variable efficacy). To do this, we developed a bevacizumab assay with a broad sensitivity range to measure blood bevacizumab concentrations. We then analyzed bevacizumab concentrations in 17 patients throughout the first quarter of treatment. In line with previously published data, average blood concentrations were 88+/−27 mg/L following the first dose administered, and 213+/−105 mg/L after the last (6^th) dose administered. However, the individual values were scattered, with a mean 4-fold difference between the lowest and the highest concentration for each dose administered. We demonstrated that the bevacizumab administration schedule results in a high inter-individual variability in terms of blood concentrations. Comparison of assay data with clinical data indicates that blood concentrations above the median are associated with side effects, whereas values below the median favor inefficacy. In conclusion, bevacizumab-based therapy could benefit from a personalized administration schedule including follow-up and adjustment of circulating bevacizumab concentrations.     

Zoo soundscape: Daily variation of low-to-high-frequency sounds

Most studies assessing the impact of noises on zoo animal welfare did not measure sound frequencies outside of the human-hearing range (infrasounds and ultrasounds). Many nonhuman mammals can hear these frequencies, and because loud and variable soundscapes are potentially detrimental for animal welfare, this overlooked aspect of their acoustic environment could have important consequences. This study evaluated the soundscape of an urban zoo in a large frequency range (17.5–90,510 Hz) by measuring its average sound levels (L_eq) and variability (the difference between highest and lowest peaks). Sound data were collected for 24 hr in 25 locations (e.g., indoor, outdoor, near the amusement park). The soundscape was not considered problematic for animal welfare when looking at the average sound levels in most locations (<77-dB sound pressure level [SPL]), except for a few indoor areas and near the water park. Ultrasounds were rare, had low average sound levels, and were less variable in time. Infrasounds were always present and were the loudest and most variable sound frequencies. The soundscape was louder and more variable during the day and when visitors were present, suggesting that human-related activities were the sources of these augmentations. Indoor environments were generally louder than outdoor environments and touristic features; however, the water park was near 85-dB SPL during the day. On the basis of results, we suggest a series of mitigation actions to minimize noise-related stress in captive animals.     

The Golgi Protein ACBD3, an Interactor for Poliovirus Protein 3A,Modulates Poliovirus Replication

We have shown that the circulating vaccine-derived polioviruses responsible for poliomyelitis outbreaks in Madagascar have recombinant genomes composed of sequences encoding capsid proteins derived from poliovaccine Sabin, mostly type 2 (PVS2), and sequences encoding nonstructural proteins derived from other human enteroviruses. Interestingly, almost all of these recombinant genomes encode a nonstructural 3A protein related to that of field coxsackievirus A17 (CV-A17) strains. Here, we investigated the repercussions of this exchange, by assessing the role of the 3A proteins of PVS2 and CV-A17 and their putative cellular partners in viral replication. We found that the Golgi protein acyl-coenzyme A binding domain-containing 3 (ACBD3), recently identified as an interactor for the 3A proteins of several picornaviruses, interacts with the 3A proteins of PVS2 and CV-A17 at viral RNA replication sites, in human neuroblastoma cells infected with either PVS2 or a PVS2 recombinant encoding a 3A protein from CV-A17 [PVS2-3A(CV-A17)]. The small interfering RNA-mediated downregulation of ACBD3 significantly increased the growth of both viruses, suggesting that ACBD3 slowed viral replication. This was confirmed with replicons. Furthermore, PVS2-3A(CV-A17) was more resistant to the replication-inhibiting effect of ACBD3 than the PVS2 strain, and the amino acid in position 12 of 3A was involved in modulating the sensitivity of viral replication to ACBD3. Overall, our results indicate that exchanges of nonstructural proteins can modify the relationships between enterovirus recombinants and cellular interactors and may thus be one of the factors favoring their emergence.     

Silent,generic and plant kairomone sensitive odorant receptors from the Southern house mosquito

The Southern house mosquito Culex quinquefasciatus has the largest repertoire of odorant receptors (ORs) of all mosquitoes and dipteran species whose genomes have been sequenced to date. Previously, we have identified and de-orphanized two ORs expressed in female antennae, CquiOR2 and CquiOR10, which are sensitive to oviposition attractants. In view of a new nomenclature for the Culex genome (VectorBase) we renamed these ORs as CquiOR21 (formerly CquiOR10) and CquiOR121 (CquiOR2). In addition, we selected ORs from six different phylogenetic groups for deorphanization. We cloned four of them by using cDNA from female antennae as a template. Attempts to clone CquiOR87 and CquiOR110 were unsuccessful either because they are pseudogenes or are not expressed in adult female antennae, the main olfactory tissue. By contrast, CquiOR1, CquiOR44, CquiOR73, and CquiOR161 were highly expressed in female antennae. To de-orphanize these ORs, we employed the Xenopus oocyte recording system. CquiORx–CquiOrco-expressed oocytes were challenged with a panel of 90 compounds, including known oviposition attractants, human and vertebrate host odorants, plant kairomones, and naturally occurring repellents. While CquiOR161 did not respond to any test compound in two different laboratories, CquiOR1 showed the features of a generic OR, with strong responses to 1-octen-3-ol and other ligands. CquiOR44 and CquiOR73 showed preference to plant-derived terpenoids and phenolic compounds, respectively. While fenchone was the best ligand for the former, 3,5-dimethylphenol elicited the strongest responses in the latter. The newly de-orphanized ORs may be involved in reception of plant kairomones and/or natural repellents.     

Effect of mineral oil on Potato virus Y acquisition by Rhopalosiphum padi

Seed potato crops are currently sprayed weekly with mineral oil to prevent transmission of the Potato virus Y (PVY; Potyviridae: Potyvirus), one of the most prevalent and important non‐persistent viruses affecting potato production. In spite of its wide usage as inhibitor of virus transmission, the mode of action for mineral oil is poorly known. The objective of this study was to quantify the effect of dosage and time from application of mineral oil on the inhibition of PVY acquisition. The bird cherry‐oat aphid, Rhopalosiphum padi (L.) (Hemiptera: Aphididae), known as vector of PVY, was used in all the experiments. The results indicated that mineral oil efficiently decreased PVY acquisition by 75 and 70% 1 day after application of 5 and 10 l ha^?1, respectively. The inhibition effect decreased with time from application; mineral oil inhibits acquisition for less than 4 days at 5 l ha^?1 and between 8 and 12 days at 10 l ha^?1. As mineral oil was detected in the body of fewer aphids when they fed on plants 1 day after oil application, a change in the aphid probing behaviour on mineral oil‐treated plants was deduced. These results support the hypothesis that mineral oil physically inhibits the binding of the virus at the tip of the stylets.