Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited effi cacy. A potential reason for the failure of such therapies is that genomic profi ling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, fi nding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed signifi cant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplifi cation profi les commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifi cations not detected in PT sampling. Lastly, we profi led paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profi ling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profi ling to enhance selection of therapy. SIGNIFICANCE:We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profi ling of metastatic lesions and/or cfDNA should be systematically evaluated. Cancer Discov; 8(1);[37][38][39][40][41][42][43][44][45][46][47][48]

Three-dimensional (3D) cell culture technologies, such as organoids, are physiologically relevant models for basic and clinical applications. Automated microfluidics offers advantages in high-throughput and precision analysis of cells but is not yet compatible with organoids. Here, we present an automated, high-throughput, microfluidic 3D organoid culture and analysis system to facilitate preclinical research and personalized therapies. Our system provides combinatorial and dynamic drug treatments to hundreds of cultures and enables real-time analysis of organoids. We validate our system by performing individual, combinatorial, and sequential drug screens on human-derived pancreatic tumor organoids. We observe significant differences in the response of individual patient-based organoids to drug treatments and find that temporally-modified drug treatments can be more effective than constant-dose monotherapy or combination therapy in vitro. This integrated platform advances organoids models to screen and mirror real patient treatment courses with potential to facilitate treatment decisions for personalized therapy.

According to moral foundations theory (Haidt & Joseph, 2004), five foundations are central to moral intuition. The two individualizing foundations—harm/care and fairness/reciprocity—hinge on the rights of the individual, whereas the three binding foundations—in‐group/loyalty, authority/respect, and purity/sanctity—focus on communal bonds. Recent work suggests that reliance on the various foundations varies as a function of sociopolitical orientation: liberals consistently rely on the individualizing foundations, whereas conservatives rely on both the individualizing and binding foundations. In an effort to further explore the relationship between sociopolitical orientation and morality, we argue that only certain types of sociopolitical attitudes and beliefs should relate to each cluster of foundations. Drawing on dual‐process models of social and political attitudes, we demonstrate that the individualizing foundations are aligned with attitudes and beliefs relevant to preferences for equality versus inequality (i.e., SDO and competitive‐jungle beliefs), whereas the binding foundations are aligned with attitudes and beliefs relevant to preferences for openness versus social conformity (i.e., RWA and dangerous‐world beliefs). We conclude by discussing the consequences of these findings for our understanding of the relationship between sociopolitical and moral orientations.

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We examine whether two general dimensions of sociopolitical belief-right-wing authoritarianism (RWA) and social dominance orientation (SDO)-are rooted in insecure psychological attachment. Based on an undergraduate sample (N = 255), we model the relations among attachment styles, general worldviews, RWA, and SDO. A structural equation model indicated that anxious attachment led to RWA but not SDO and that this effect was mediated by the belief that the world is a dangerous place. In contrast, avoidant attachment led to SDO but not RWA, and this effect was mediated by the belief that the world is an uncaring, competitive jungle in which people are motivated to maximize personal utility. We discuss the implications of these findings for the nature and origins of political conservatism.