Anti-DLD monoclonal antibody, clone FQS7745(C)

Targeted thorium-227 conjugates (TTCs) represent a novel class of therapeutic radiopharmaceuticals for the treatment of cancer. TTCs consist of the alpha particle emitter thorium-227 complexed to a 3,2-hydroxypyridinone chelator conjugated to a tumor-targeting monoclonal antibody. The high energy and short range of the alpha particles induce potent and selective anti-tumor activity driven by the induction of DNA damage in the target cell. Methods: The efficacy of human epidermal growth factor receptor 2 (HER2)-TTC was tested in combination in vitro and in vivo with the poly ADP ribose polymerase (PARP) inhibitor (PARPi), olaparib, in the human colorectal adenocarcinoma isogenic cell line pair DLD-1 and the knockout variant DLD-1 BRCA2 -/- Results: The in vitro combination effects were determined to be synergistic in DLD-1 BRCA2 -/- and additive in DLD-1 parental cell lines. Similarly, the in vivo efficacy of the combination was determined to be synergistic only in the DLD-1 BRCA2 -/- xenograft model, with statistically significant tumor growth inhibition at a single TTC dose of 120 kBq/kg body weight (bw) and 50 mg/kg bw olaparib (daily, i.p. for 4 weeks), demonstrating comparable tumor growth inhibition to a single TTC dose of 600 kBq/kg bw. Conclusions: This study supports the further investigation of DNA damage response inhibitors in combination with TTCs as a new strategy for the effective treatment of mutation-associated cancers.

To improve early identification of autism spectrum disorder (ASD), we need objective, reliable, and accessible measures. To that end, a previous study demonstrated that a tablet-based application (app) that assessed several autism risk behaviors distinguished between toddlers with ASD and non-ASD toddlers. Using vocal data collected during this study, we investigated whether vocalizations uttered during administration of this app can distinguish among toddlers aged 16-31 months with typical development (TD), language or developmental delay (DLD), and ASD. Participant's visual and vocal responses were recorded using the camera and microphone in a tablet while toddlers watched movies designed to elicit behaviors associated with risk for ASD. Vocalizations were then coded offline. Results showed that (a) children with ASD and DLD were less likely to produce words during app administration than TD participants; (b) the ratio of syllabic vocalizations to all vocalizations was higher among TD than ASD or DLD participants; and (c) the rates of nonsyllabic vocalizations were higher in the ASD group than in either the TD or DLD groups. Those producing more nonsyllabic vocalizations were 24 times more likely to be diagnosed with ASD. These results lend support to previous findings that early vocalizations might be useful in identifying risk for ASD in toddlers and demonstrate the feasibility of using a scalable tablet-based app for assessing vocalizations in the context of a routine pediatric visit. Lay Summary Although parents often report symptoms of autism spectrum disorder (ASD) in infancy, we are not yet reliably diagnosing ASD until much later in development. A previous study tested a tablet-based application (app) that recorded behaviors we know are associated with ASD to help identify children at risk for the disorder. Here we measured how children vocalize while they watched the movies presented on the tablet. Children with ASD were less likely to produce words, less likely to produce speechlike sounds, and more likely to produce atypical sounds while watching these movies. These measures, combined with other behaviors measured by the app, might help identify which children should be evaluated for ASD.