Development of a bispecific immune engager using a recombinant malaria protein

As an immune evasion and survival strategy, the Plasmodium falciparum malaria parasite has evolved a protein named VAR2CSA. This protein mediates sequestration of infected red blood cells in the placenta through the interaction with a unique carbohydrate abundantly and exclusively present in the placenta. Cancer cells were found to share the same expression of this distinct carbohydrate, termed oncofetal chondroitin sulfate on their surface. In this study we have used a protein conjugation system to produce a bispecific immune engager, V-aCD3, based on recombinant VAR2CSA as the cancer targeting moiety and an anti-CD3 single-chain variable fragment linked to a single-chain Fc as the immune engager. Conjugation of these two proteins resulted in a single functional moiety that induced immune mediated killing of a broad range of cancer cells in vitro and facilitated tumor arrest in an orthotopic bladder cancer xenograft model.Subject terms: Drug development, Preclinical research     

Extensions of the probabilistic ranking metrics of competing treatments in network meta-analysis to reflect clinically important relative differences on many outcomes

One of the key features of network meta-analysis is ranking of interventions according to outcomes of interest. Ranking metrics are prone to misinterpretation because of two limitations associated with the current ranking methods. First, differences in relative treatment effects might not be clinically important and this is not reflected in the ranking metrics. Second, there are no established methods to include several health outcomes in the ranking assessments. To address these two issues, we extended the P-score method to allow for multiple outcomes and modified it to measure the mean extent of certainty that a treatment is better than the competing treatments by a certain amount, for example, the minimum clinical important difference. We suggest to present the tradeoff between beneficial and harmful outcomes allowing stakeholders to consider how much adverse effect they are willing to tolerate for specific gains in efficacy. We used a published network of 212 trials comparing 15 antipsychotics and placebo using a random effects network meta-analysis model, focusing on three outcomes; reduction in symptoms of schizophrenia in a standardized scale, all-cause discontinuation, and weight gain.     

Pathogenicity of clinical Salmonella enterica serovar Typhimurium isolates from Thailand in a mouse colitis model

Salmonella enterica serovar Typhimurium (S. Typhimurium [STM]) is a leading cause of nontyphoidal salmonellosis (NTS) worldwide. The pathogenesis of NTS has been studied extensively using a streptomycin-pretreated mouse colitis model with the limited numbers of laboratory STM strains. However, the pathogenicity of the clinically isolated STM (STMC) strains endemic in Thailand in mice has not been explored. The aim of this study was to compare the pathogenicity of STMC strains collected from Northern Thailand with the laboratory STM (IR715) in mice. Five STMC isolates were obtained from the stool cultures of patients with acute NTS admitted to Maharaj Nakorn Chiang Mai Hospital in 2016 and 2017. Detection of virulence genes and sequence type (ST) of the strains was performed. Female C57BL/6 mice were pretreated with streptomycin sulfate 1 day prior to oral infection with STM. On Day 4 postinfection, mice were euthanized, and tissues were collected to analyze the bacterial numbers, tissue inflammation, and cecal histopathological score. We found that all five STMC strains are ST34 and conferred the same or reduced pathogenicity compared with that of IR715 in mice. A strain-specific effect of ST34 on mouse gut colonization was also observed. Thailand STM ST34 exhibited a significant attenuated systemic infection in mice possibly due to the lack of spvABC-containing virulence plasmid.     

Modéliser les interactions moléculaires par la théorie des réseaux de jeux

We present a method to model biological systems, the theory of games networks. It extends game theory by multiplying the number of games, and by allowing agents to play several games simultaneously. Some important notions of biological systems, such as locality of interactions and modularity, can then be modelled. To cite this article: M. Manceny et al., C. R. Biologies 329 (2006).     

Citric acid arrest and stabilization of nucleoside incorporation into cultured cells

Either citric acid or ascorbic acid (0.23 m final concentration) quickly arrests incorporation of tritiated thymidine or uridine upon addition to cultures of animal cells. The incorporated radioactivity is totally preserved for a day at 37°C without further manipulations. In contrast, radioactivity is extensively lost from cultured cells at 37°C after they are arrested by the conventional method of trichloroacetic acid precipitation following removal of medium and rinsing. The cells arrested with citric or ascorbic acid preserve their morphology and are suitable for autoradiography. The new method has considerable advantages of convenience and accuracy over treatment with trichloroacetic acid.