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Pediatric brain tumors are the leading cause of cancer-related death in children. Patient-derived orthotopic xenografts (PDOX) of childhood brain tumors have recently emerged as a biologically faithful vehicle for testing novel and more effective therapies. Herein, we provide the histopathological and molecular analysis of 37 novel PDOX models generated from pediatric brain tumor patients treated at St. Jude Children’s Research Hospital. Using a combination of histopathology, whole-genome and whole-exome sequencing, RNA-sequencing, and DNA methylation arrays, we demonstrate the overall fidelity and inter-tumoral molecular heterogeneity of pediatric brain tumor PDOX models. These models represent frequent as well as rare childhood brain tumor entities, including medulloblastoma, ependymoma, atypical teratoid rhabdoid tumor, and embryonal tumor with multi-layer rosettes. PDOX models will be valuable platforms for evaluating novel therapies and conducting pre-clinical trials to accelerate progress in the treatment of brain tumors in children. All described PDOX models and associated datasets can be explored using an interactive web-based portal and will be made freely available to the research community upon request.

ABT-751 is a novel antimitotic agent that binds tubulin at the colchicine binding site. ABT-751 is undergoing Phase I trials in children, but has not been evaluated against a range of pediatric tumor models in vivo. ABT-751 was evaluated against 27 subcutaneously implanted xenograft models of childhood cancer including neuroblastoma [4], osteosarcoma [4], Ewing sarcoma [2] rhabdomyosarcoma [8], medulloblastoma [1] and eight kidney cancer lines (six Wilms tumors, two rhabdoid). ABT-751 was administered at 100 mg/kg P.O. on a schedule of 5 days on, 5 days off, 5 days on, repeating the cycle at 21 days. Tumor diameters were measured at 7 day intervals for a period of 12 weeks. Three measures of antitumor activity were used: (1) clinical response criteria [e.g., partial response (PR), complete response (CR), etc.]; (2) treated to control (T/C) tumor volume at day 21; and (3) a time to event measure based on the median event free survival (EFS) of treated and control lines. ABT-751 induced regression in 4 of 25 models (16%) including models of neuroblastoma that are refractory to vincristine and paclitaxel. Other regressions occurred in rhabdomyosarcoma and Wilms tumor models. ABT-751 significantly increased event free survival (EFS > 2.0) in eight models (33%) in addition to those with objective responses. ABT-751 demonstrated intermediate activity against this tumor panel. Neuroblastoma models appear somewhat more sensitive to this agent, with objective regressions also in rhabdomyosarcoma and Wilms tumor. ABT-751 was also active in several tumor lines intrinsically refractory to vincristine or paclitaxel.

Pediatric high-grade glioma (pHGG) is a major contributor to cancer-related death in children. In vitro and in vivo disease models reflecting the intimate connection between developmental context and pathogenesis of pHGG are essential to advance understanding and identify therapeutic vulnerabilities. Here we report establishment of 21 patient-derived pHGG orthotopic xenograft (PDOX) models and eight matched cell lines from diverse groups of pHGG. These models recapitulate histopathology, DNA methylation signatures, mutations and gene expression patterns of the patient tumors from which they were derived, and include rare subgroups not well-represented by existing models. We deploy 16 new and existing cell lines for high-throughput screening (HTS). In vitro HTS results predict variable in vivo response to PI3K/mTOR and MEK pathway inhibitors. These unique new models and an online interactive data portal for exploration of associated detailed molecular characterization and HTS chemical sensitivity data provide a rich resource for pediatric brain tumor research. Patient-derived xenografts provide a resource for basic and translational cancer research. Here, the authors generate multiple pediatric high-grade glioma xenografts, use omics technologies to show that they are representative of primary tumours and use them to assess therapeutic response.

Abstract Pediatric high-grade glioma (pHGG) is a major contributor to cancer-related death in children. In vitro and in vivo disease models reflecting the intimate connection between developmental context and pathogenesis of pHGG are essential to advance understanding and identify therapeutic vulnerabilities. We established 21 patient-derived pHGG orthotopic xenograft (PDOX) models and eight matched cell lines from diverse groups of pHGG. These models recapitulated histopathology, DNA methylation signatures, mutations and gene expression patterns of the patient tumors from which they were derived, and included rare subgroups not well-represented by existing models. We deployed 16 new and existing cell lines for high-throughput screening (HTS). In vitro HTS results predicted variable in vivo response to inhibitors of PI3K/mTOR and MEK signaling pathways. These unique new models and an online interactive data portal to enable exploration of associated detailed molecular characterization and HTS chemical sensitivity data provide a rich resource for pediatric brain tumor research. Competing Interest Statement The authors have declared no competing interest. Footnotes * https://pbtp.stjude.cloud

Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP–PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAP1 ) and PAC1 (encoded by ADCYAP1R1 ) genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen replacement in rodent models. These data suggest that perturbations in the PACAP–PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via oestrogen regulation of ADCYAP1R1 . PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD. A biomarker for stress disorders In many species, pituitary adenylate cyclase-activating polypeptide (PACAP) is implicated in physiological responses to stress. A study of a sample of highly traumatized human females now shows that PACAP blood levels correlate with a diagnosis of post-traumatic stress disorder and with the degree of fear conditioning responses. One particular single-nucleotide polymorphism in the oestrogen response element of the receptor gene is closely associated with the condition, as is increased methylation of the receptor gene. Experiments in mice subjected to fear conditioning revealed increased transcription of both PACAP and receptor genes in the amygdala. These findings may set the stage for a novel biomarker for stress disorders and for explaining known sex differences in the occurrence of such conditions.

Tropical cyclone (TC) track forecasts have improved in recent decades while intensity forecasts, particularly predictions of rapid intensification (RI), continue to show low skill. Many statistical methods have shown promise in predicting RI using environmental fields, although these methods rely heavily upon supervised learning techniques such as classification. Advances in unsupervised learning techniques, particularly those that integrate nonlinearity into the class separation problem, can improve discrimination ability for difficult tasks such as RI prediction. This study quantifies separability between RI and non-RI environments for 2004–16 Atlantic Ocean TCs using an unsupervised learning method that blends principal component analysis with k-means cluster analysis. Input fields consisted of TC-centered 1° Global Forecast System analysis (GFSA) grids (170 different variables and isobaric levels) for 3605 TC samples and five domain sizes. Results are directly compared with separability offered by operational RI forecast predictors for eight RI definitions. The unsupervised learning procedure produced improved separability over operational predictors for all eight RI definitions, five of which showed statistically significant improvement. Composites from these best-separating GFSA fields highlighted the importance of mid- and upper-level relative humidity in identifying the onset of short-term RI, whereas long-term, higher-magnitude RI was generally associated with weaker absolute vorticity. Other useful predictors included optimal thermodynamic RI ingredients along the mean trajectory of the TC. The results suggest that the orientation of a more favorable thermodynamic environment relative to the TC and midlevel vorticity magnitudes could be useful predictors for RI.

Involving youth in developing and implementing prevention programs to reduce sexual violence (SV) has the potential to improve prevention outcomes. However, there has been little focus on youth-led SV prevention programs, and limited evaluation research to help guide efforts. The current study examined the effectiveness of Youth Voices in Prevention (Youth VIP) leadership retreats on SV victimization and perpetration, forms of violence related to SV (e.g., bullying), SV bystander behaviors and readiness, and perceptions of norms related to SV prevention. Results identified mixed findings for program impact, with variations in outcomes that can help guide future youth-led prevention program initiatives. Youth attending a large “kick-off” leadership retreat (that was less youth-led that subsequent smaller retreats) later reported more bystander behaviors, but also reported increased perpetration and victimization, compared to non-attending youth. However, youth attending smaller, more focused leadership retreats held during the school year, reported reductions in sexual harassment perpetration and improved bystander behaviors and attitudes compared to non-attending youth. Evaluation of moderator variables suggests that program impact was generally stronger for younger participants, sexual minority youth, and non-White youth (which were largely Native American youth in this sample). Findings suggest promise for youth-led prevention work but also highlight the need for testing the impact of different training structures and modalities. Clinical trials number: NCT03207386.

Sources of fisheries information outside of fishery-independent surveys (e.g. fishery-dependent data) are especially valuable for species that support productive fisheries and lack reliable biological information, such as the northern shortfin squid ( Illex illecebrosus ). Fishery-dependent data streams are available for most species, however collaboration with industry members is critical to ensure that these fishery-dependent data are collected, applied, and interpreted correctly. Despite the need for collaboration and the frequency that fishery data are used in scientific research, there is limited literature on the structure of interactions and knowledge sharing that inform the analysis and application of fishery data. Between 2019 and 2022, a group of researchers collaborated with members of the northern shortfin squid fishing industry to bring together research data sets and knowledge from harvesters and processors to better describe the fishery dynamics, distribution, life history, and oceanographic drivers of the species. The collaboration focused on developing custom standardized fishery catch per unit effort (CPUE) indices to provide indicators of population trends that accounted for the impacts of technical and economic aspects of harvesting, processing and marketing on fishing effort, selectivity and landings of northern shortfin squid. We describe the methods used to inform and interpret the CPUE analyses, focusing on novel structure of interactions we had with industry members, and suggest best practices for integrating industry knowledge into CPUE standardization. The information shared and research products produced through this science-industry research collaboration advanced understanding of northern shortfin squid population and fishery dynamics, and contributed directly to the 2022 stock assessment and management process. Given the complex and stochastic nature of the northern shortfin squid population and fishery, we found it critical to maintain open communication and trust with processors and harvesters, who have unique insight into the factors that may be driving changes in catch, landings, and productivity of the valuable resource species.

Chlorpyrifos is an organophosphate pesticide used around the world to protect food crops against insects and mites. Despite guidelines for chlorpyrifos usage, including precautions to protect beneficial insects, such as honeybees from spray drift, this pesticide has been detected in bees in various countries, indicating that exposure still occurs. Here, we examined chlorpyrifos levels in bees collected from 17 locations in Otago, New Zealand, and compared doses of this pesticide that cause sub-lethal effects on learning performance under laboratory conditions with amounts of chlorpyrifos detected in the bees in the field. The pesticide was detected at 17 % of the sites sampled and in 12 % of the colonies examined. Amounts detected ranged from 35 to 286 pg.bee −1 , far below the LD 50 of ~100 ng.bee −1 . We detected no adverse effect of chlorpyrifos on aversive learning, but the formation and retrieval of appetitive olfactory memories was severely affected. Chlorpyrifos fed to bees in amounts several orders of magnitude lower than the LD 50 , and also lower than levels detected in bees, was found to slow appetitive learning and reduce the specificity of memory recall. As learning and memory play a central role in the behavioral ecology and communication of foraging bees, chlorpyrifos, even in sublethal doses, may threaten the success and survival of this important insect pollinator.

Existential theory and previous qualitative research have suggested that a lack of life meaning and purpose causes boredom, as well as other types of negative affect such as depression or anxiety. Although these variables have been shown to be correlated at one point in time, the relationships among these constructs have not been investigated using a controlled, quantitative research design. In Study 1a (N = 131), boredom was shown to be related to, yet psychometrically distinct from, life meaning, depression, and anxiety. In Study 1b (N = 88), life meaning significantly predicted changes in boredom across time while depression and anxiety did not. In addition, boredom was a significant predictor of changes in life meaning across time, while depression and anxiety were not. Finally, in Study 2 (N = 102), manipulating perceptions of life meaning significantly changed boredom, while a manipulation of mood did not. The nature of the relationship between life meaning and boredom, as well as some clinical implications, are discussed. [PUBLICATION ABSTRACT]