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The majority of adult patients with acute lymphoblastic leukemia (ALL) suffer relapse, and in patients with central nervous system (CNS) metastasis, prognosis is particularly poor. We recently demonstrated a novel route of ALL CNS metastasis dependent on PI3Kδ regulation of the laminin receptor integrin α6. B-ALL cells did not, however, rely on PI3Kδ signaling for growth. Here we show that broad targeting of PI3K isoforms can induce growth arrest in B-ALL, reducing systemic disease burden in mice treated with a single agent pan-PI3Ki, copanlisib. Moreover, we show that cellular stress activates PI3K/Akt-dependent survival pathways in B-ALL, exposing their vulnerability to PI3Kδ and pan-PI3Ki. The addition of a brief course of copanlisib to chemotherapy delivered the combined benefits of increased survival, decreased systemic disease, and reduced CNS metastasis. These data suggest the promising, multifaceted potential of pan-PI3Ki for B-ALL CNS prophylaxis, systemic disease control, and chemosensitization.

Multinational surveillance programmes for methicillin-resistant Staphylococcus aureus (MRSA) are dependent on national structures for data collection. This study aimed to capture the diversity of national MRSA surveillance programmes and to propose a framework for harmonisation of MRSA surveillance. The International Society of Antimicrobial Chemotherapy (ISAC) MRSA Working Group conducted a structured survey on MRSA surveillance programmes and organised a webinar to discuss the programmes' strengths and challenges as well as guidelines for harmonisation. Completed surveys represented 24 MRSA surveillance programmes in 16 countries. Several countries reported separate epidemiological and microbiological surveillance. Informing clinicians and national policy-makers were the most common purposes of surveillance. Surveillance of bloodstream infections (BSIs) was present in all programmes. Other invasive infections were often included. Three countries reported active surveillance of MRSA carriage. Methodology and reporting of antimicrobial susceptibility, virulence factors, molecular genotyping and epidemiological metadata varied greatly. Current MRSA surveillance programmes rely upon heterogeneous data collection systems, which hampers international epidemiological monitoring and research. To harmonise MRSA surveillance, we suggest improving the integration of microbiological and epidemiological data, implementation of central biobanks for MRSA isolate collection, and inclusion of a representative sample of skin and soft-tissue infection cases in addition to all BSI cases.

Breast cancer cell (BCC) metastasis to the leptomeninges (LM) is an increasingly common disease complication with a grim prognosis of weeks to months. There are currently few therapeutic options to prevent or treat leptomeningeal disease (LMD), in part due to our limited knowledge of the molecular pathways involved in tumor invasion and survival within this unique niche. Here we show that BCCs in mice can bypass the restrictive blood-brain barrier and invade the LM by migrating along the abluminal surface of emissary vessels that connect the vertebral/calvarial bone marrow and meninges. This is mediated by tumor cell integrin α6 engaging extracellular matrix laminin on the vascular basement membrane. Upon invasion of the LM, BCCs co-localize with CSF1R+ meningeal macrophages/microglia in the perivascular space. We demonstrate that ablation of these myeloid cells by CSF1R inhibition leads to prolonged disease-free survival due to decreased LMD burden. Importantly, we show that CSF1R+ cell depletion does not prevent tumor cell LM colonization, but instead limits disease expansion within the LM, highlighting the pro-tumor phenotype of these meningeal macrophages/microglia. Our data suggest that meningeal macrophages/microglia support BCC proliferation/survival by up-regulating glial cell line-derived neurotrophic factor (GDNF), a key neurotrophic factor released by macrophages/microglia in response to neuronal injury. In vitro, GDNF protects BCCs from cell death induced by glucose deprivation, suggesting that tumor cells may hijack a macrophage neuronal injury response program to thrive within the nutrient-poor LM niche. Unexpectedly, we found that integrin α6 deletion or antibody blockade eliminates the protective role of GDNF by modulating GDNF/NCAM receptor signaling in BCCs. Taken together, our data suggest that BCCs co-opt neuronal pathfinding mechanisms and resident macrophages/glia to efficiently invade and thrive within the LM niche. Integrin α6 appears to be a master regulator of this neuronal mimicry through its ability to promote abluminal vessel trafficking and mediate responsiveness to GDNF. Finally, a case-control study of bone-metastatic breast cancer patients reveals a significant correlation between integrin α6 expression and incidence of dural-based meningeal metastasis, suggesting the clinical relevance of this pathway and potential role of α6 integrin as a biomarker of LMD risk and therapeutic target. Citation Format: Andrew E. Whiteley, Trevor T. Price, Brennan G. Simon, Katie R. Xu, Dorothy A. Sipkins. Neuronal mimicry promotes breast cancer leptomeningeal metastasis from bone marrow [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3848.

In the United States, a public debate remains about the existence and effects of anthropogenic climate change. This skepticism is present in the agricultural sector, rendering climate science communication challenging. Due to the polarization of climate change issues and the concurrent need for agricultural adaptation, we sought to examine how scientists communicate in this sector. A survey, administered to climate scientists and pertinent U.S. federal agency staff (response rate = 43%), was conducted to examine perspectives on communicating with five agricultural stakeholder groups: agribusinesses, crop advisors, general public, producers, and policymakers. We focused on three aspects of the communication process with these stakeholders to evaluate if scientists, as messengers, were following best practices–communicator training, knowledge of stakeholder, and terminology use. We found scientists valued communication training; however, the majority had not attended formal training. Scientists had different views on climate change than producers and crop advisors but understood their perspective and were deliberate with their communication with different audiences. This suggests stakeholder knowledge and terminology use do not hinder communication between scientist and stakeholder. We also highlight three communication challenges present across stakeholder groups–stakeholder knowledge, timescale, and scientific uncertainty–and others that were specific to each stakeholder group. Future research should support scientists by identifying and resolving barriers to training and effective communication strategies for each stakeholder group that addresses these challenges.

Human disturbance to birds is a subject of concern for bird conservation. Bird recreationalists, such as birders and bird photographers, who actively seek out birds, are identified as a broad group of people that contribute to bird disturbance. There are few studies on birders’ and bird photographers’ perceptions and behaviors related to bird disturbance, and these studies have conflicting results. Furthermore, little research identifies why bird recreationalists engage in behavior that disturbs birds. Understanding perceptions and behavior related to bird disturbance and the context behind engaging in this behavior is important for creating comprehensive solutions for preventing disturbance to birds. The purpose of this thesis is to create a typology of bird recreationalists, based on whether they engage in birding or bird photography as primary activities; identify the socio-demographic characteristics among bird recreationalists that are connected to an increased likelihood to engage in behavior that disturbs birds; assess perceptions of blame for disturbance to birds; and identify how motivations, barriers, challenges and trade-offs are associated with following ethical birding and bird photography guidelines. The thesis used an online survey and in-person interviews of birders and bird photographers in two Midwestern states in the U.S., Illinois and Indiana, to achieve these objectives. Three sub-groups of bird recreationalists were identified through the online survey: individuals who only engage in birding; individuals who primarily engage in birding and secondarily, bird photography; and individuals who primarily engage in bird photography and secondarily, birding. Our findings indicate that individuals who 1) are male, 2) only engage in birding, 3) maintain life lists, 4) have more birds on their life lists, 5) can identify more birds by sight, 6) have more years of experience or 7) have a higher level of achievement-oriented motivation are more likely to engage in potentially harmful behaviors to birds. Additionally, quantitative findings suggest that birders and bird photographers may not perceive themselves as main contributors to bird disturbance. The qualitative portion of the research identifies multiple ethical birding and bird photography guidelines that recreationalists found challenging to follow that had both ecological (e.g., maintaining distance) and social (e.g., respectfully educating others) implications. Recreationalists identified listing, photographing and seeing birds as key motivations to breaking ethical guidelines. Barriers to following guidelines included apathy, ignorance and improper technology. Finally, recreationalists identified bad photography and missed experiences as major trade-offs associated with following ethical guidelines. he concepts explored in this thesis research provide important management implications for natural resource managers and stakeholders in bird conservation and suggest a further need for examining bird recreationalists’ decision-making around bird disturbance.