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Models of bottom-up visual attention such as the "saliency map" predict overt gaze under laboratory conditions while subjects view static images or videos while seated. Here, we show that the saliency map model predicts gaze at similar rates even when applied to video from a head-camera as part of a wearable eye-tracking system (Tobii Pro Glasses 2) while subjects drive an automobile or are passively driven while sitting in the front passenger-side seat. The ability of saliency to predict gaze varies depending on the driving task (saliency better predicts passenger gaze) and external conditions (saliency better predicts gaze at night). We further demonstrate that predictive performance is improved when the head-camera video is transformed to retinal coordinates before feeding it to the saliency model.

The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we perform haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identify distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss. While abnormal mitosis, including whole-genome duplication, underlies chromosomal copy-number changes, segmental alterations display signatures of successive breakage-fusion-bridge cycles and chromothripsis of unstable dicentric chromosomes. Our analysis elucidates how multigenerational chromosomal instability generates copy-number variation in BE cells, precipitates complex alterations including DNA amplifications, and promotes their independent clonal expansion and transformation. In particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability that precedes copy-number complexity. These findings suggest copy-number heterogeneity in advanced cancers originates from chromosomal instability in precancerous cells and such instability may be identified from the presence of sloping copy-number variation in bulk sequencing data.

Spatial perspective-taking is predicted to include two crucial processes: the detachment of representational self and the self-representation movement. This study shows the features of these processes in three age groups: 36 children aged 5–6 years (13 girls), 29 students aged 19–24 years (20 women), and 33 adults aged 60–84 years (14 women). Participants performed a video game task of spatial perspective-taking. Their response times and eye movements were measured. Reaction latency (RL) data were gathered from the stimulus presentation to the beginning of the gaze movement as the detachment. The remaining time (RT) calculated from the perspective of operation time minus RL was measured as the self-representation movement. A two-way mixed-design analysis of variance (ANOVA) was conducted on the RTs. Significant main effects of age group in RTs revealed that the child group was significantly slower than the students’ and older adults’ groups. Older adults were significantly slower than students. In a two-way mixed design ANOVA conducted on the RLs, a significant main effect of age group in RLs revealed that the child group was significantly slower than the students’ and older adults’ groups. The results suggest that the core of spatial perspective-taking comprises the anticipated processes.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy.

Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such therapies is that genomic profiling 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, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed significant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifications not detected in PT sampling. Lastly, we profiled 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 profiling 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 profiling 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 profiling of metastatic lesions and/or cfDNA should be systematically evaluated. Cancer Discov; 8(1); 37-48. ©2017 AACR.See related commentary by Sundar and Tan, p. 14See related article by Janjigian et al., p. 49This article is highlighted in the In This Issue feature, p. 1.

Simple Summary: Interstitial pneumonia (IP) represents a significant prognostic comorbidity in patients diagnosed with non-small-cell lung cancer (NSCLC). Even if treatment for lung cancer proves effective, the occurrence of an acute exacerbation in pre-existing IP can pose a substantial risk to patient survival. Consequently, it is crucial to opt for a therapy that minimizes the likelihood of triggering an acute IP exacerbation. Evidence is limited regarding pharmacotherapy for advanced NSCLC with a low risk of triggering the exacerbation of pre-existing IP, but KRASG12C inhibitors may be a potential treatment option for NSCLC with comorbid IP. In this review article, we discuss the promise and prospects of molecular-targeted therapy, particularly KRASG12C inhibitors, which gained little attention as a treatment for NSCLC with comorbid IP. Non-small-cell lung cancer (NSCLC) with comorbid interstitial pneumonia (IP) is a population with limited treatment options and a poor prognosis. Patients with comorbid IP are at high risk of developing fatal drug-induced pneumonitis, and data on the safety and efficacy of molecularly targeted therapies are lacking. KRAS mutations have been frequently detected in patients with NSCLC with comorbid IP. However, the low detection rate of common driver gene mutations, such as epidermal growth factor receptor and anaplastic lymphoma kinase, in patients with comorbid IP frequently results in inadequate screening for driver mutations, and KRAS mutations may be overlooked. Recently, sotorasib and adagrasib were approved as treatment options for advanced NSCLC with KRASG12C mutations. Although patients with comorbid IP were not excluded from clinical trials of these KRASG12C inhibitors, the incidence of drug-induced pneumonitis was low. Therefore, KRASG12C inhibitors may be a safe and effective treatment option for NSCLC with comorbid IP. This review article discusses the promise and prospects of molecular-targeted therapies, especially KRASG12C inhibitors, for NSCLC with comorbid IP, along with our own clinical experience. [ABSTRACT FROM AUTHOR]