Cottonwoods are foundation riparian species, and hybridization among species is known to produce ecological effects at levels higher than the population, including effects on dependent species, communities and ecosystems. Because these patterns result from increased genetic variation in key cottonwood traits, novel applications of genetic tools (for example, QTL mapping) could be used to place broad-scale ecological research into a genomic perspective. In addition, linkage maps have been produced for numerous species within the genus, and, coupled with the recent publication of the Populus genome sequence, these maps present a unique opportunity for genome comparisons in a model system. Here, we conducted linkage analyses in order to (1) create a platform for QTL and candidate gene studies of ecologically important traits, (2) create a framework for chromosomal-scale perspectives of introgression in a natural population, and (3) enhance genome-wide comparisons using two previously unmapped species. We produced 246 backcross mapping (BC 1 ) progeny by crossing a naturally occurring F 1 hybrid (Populus fremontii  P. angustifolia) to a pure P. angustifolia from the same population. Linkage analysis resulted in a dense linkage map of 541 AFLP and 111 SSR markers distributed across 19 linkage groups. These results compared favorably with other Populus linkage studies, and addition of SSR loci from the poplar genome project provided coarse alignment with the genome sequence. Preliminary applications of the data suggest that our map represents a useful framework for applying genomic research to ecological questions in a well-studied system, and has enhanced genome-wide comparisons in a model tree.

Neural EGFL-like 1 (Nell-1) is a well-studied osteogenic factor that has comparable osteogenic potency with the Food and Drug Administration–approved bone morphogenic protein 2 (BMP-2). In this review, which aims to summarize the advanced Nell-1 research in the past 10 y, we start with the correlation of structural and functional relevance of the Nell-1 protein with the identification of a specific receptor of Nell-1, contactin-associated protein-like 4 (Cntnap4), for osteogenesis. The indispensable role of Nell-1 in normal craniofacial and appendicular skeletal development and growth was also defined by using the newly developed tissue-specific Nell-1 knockout mouse lines in addition to the existing transgenic mouse models. With the achievements on Nell-1’s osteogenic therapeutic evaluations from multiple preclinical animal models for local and systemic bone regeneration, the synergistic effect of Nell-1 with BMP-2 on osteogenesis, as well as the advantages of Nell-1 as an osteogenic protein with antiadipogenic, anti-inflammatory, and provascularized characteristics over BMP-2 in bone tissue engineering, is highlighted, which lays the groundwork for the clinical trial approval of Nell-1. At the molecular level, besides the mitogen-activated protein kinase (MAPK) signaling pathway, we emphasize the significant involvement of the Wnt/β-catenin pathway as well as the key regulatory molecules Runt-related transcription factor 2 (Runx2) in Nell-1-induced osteogenesis. In addition, the involvement of Nell-1 in chondrogenesis and its relevant pathologies have been revealed with the participation of the nuclear factor of activated T cells 1 (Nfatc1), Runx3, and Indian hedgehog (Ihh) signaling pathways, although the mechanistic insights of Nell-1’s osteochondrogenic property will be continuously evolving. With this perspective, we elucidate some emerging and novel functional properties of Nell-1 in oral-dental and neural tissues that will be the frontiers of future Nell-1 studies beyond the context of bone and cartilage. As such, the therapeutic potential of Nell-1 continues to evolve and grow with continuous pursuit.

Background: Cancer immunotherapy (CIT) has significantly improved overall survival across multiple tumor types, but only subsets of patients experience durable response with single-agent CIT. Combinations of CIT with targeted therapy or chemotherapy may be needed in order to target multiple cancer immune escape mechanisms simultaneously, thus providing personalized treatment options that extend clinical benefit to more patients. The MORPHEUS platform includes multiple phase Ib/II trials designed to identify early signals of safety and activity of CIT combinations. Using a randomized trial design, multiple CIT combination arms are compared with a single standard-of-care control arm. These trials have the flexibility to open new treatment arms with novel CIT combinations as they become available and to close arms that show minimal activity or unacceptable toxicity. Here we describe MORPHEUS trials in patients with metastatic or unresectable locally advanced hormone receptor–positive (HR+BC) or triple-negative breast cancer (TNBC), 2 patient populations in need of more treatment options. Trial design: MORPHEUS-HR+BC (NCT03280563) will enroll patients with metastatic or unresectable locally advanced HR+BC who have progressed during or after first-line treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor and whose tumors do not express human epidermal growth factor 2 (HER2). MORPHEUS-TNBC (NCT03424005) will enroll patients with metastatic or unresectable locally advanced TNBC who have progressed during or after first-line treatment with chemotherapy. For both studies, key inclusion criteria include Eastern Cooperative Oncology Group performance status of 0-1 (stage 1) or 0-2 (stage 2) and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Key exclusion criteria include prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies, and symptomatic, untreated, or actively progressing central nervous system metastases. Patients in both trials will be randomized to one of the CIT atezolizumab combination arms or a control arm (up to 5 arms in HR+BC and up to 6 arms in TNBC). Patients experiencing loss of clinical benefit or unacceptable toxicity in stage 1 may be eligible to switch to a different CIT atezolizumab combination arm in stage 2. Primary endpoints are safety measures and investigator-assessed objective response rate per RECIST v1.1. Progression-free survival, overall survival, duration of response, clinical benefit rate (HR+BC) or disease control rate (TNBC) are among the secondary endpoints. Exploratory biomarkers will also be examined. Citation Format: Yardley DA, Abu-Khalaf M, Boni V, Brufsky A, Emens LA, Gutierrez M, Hurvitz S, Im S-A, Loi S, McCune SL, Schmid P, O'Hear C, Zhang X, Vidal GA. MORPHEUS: A phase Ib/II trial platform evaluating the safety and efficacy of multiple cancer immunotherapy combinations in patients with hormone receptor–positive and triple-negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-06-04.