Oral estrogen receptor PROTAC® vepdegestrant (ARV-471) is highly efficacious as monotherapy and in combination with CDK4/6 or PI3K/mTOR pathway inhibitors in preclinical ER+ breast cancer models.

PURPOSE: Estrogen Receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR or PI3K inhibitors is now a central strategy for the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from ESR1 mutation dictates that new therapies are needed. EXPERIMENTAL DESIGN: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, potent small molecule PROteolysis-TArgeting Chimera (PROTAC®) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition. RESULTS: Vepdegestrant induced ≥90% degradation of wild-type (WT) and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in-vitro and achieved significant tumor growth inhibition (TGI) (87-123%) in MCF7 orthotopic xenograft models, better than the ET agent fulvestrant (31-80% TGI). In the hormone-independent ER Y537S patient derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regressions and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib, the mTOR inhibitor everolimus, and the PI3K inhibitors alpelisib and inavolisib. CONCLUSIONS: Vepdegestrant achieved greater ER degradation in-vivo compared to fulvestrant, which correlated with improved tumor growth inhibition, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer.

Social Determinants of Health are Associated with Coping of Informal Caregivers of Adults with Heart Failure.

We explored the influence of social determinants of health (SDH) risk on stress and coping style in heart failure (HF) caregivers. In this cross-sectional study, data from 250 caregivers were analyzed. Multivariable linear regression analyses were performed to determine the extent to which SDH risk (measured using a modified PRAPARE tool (National Association of Community Health Centers), range 0-22) predicted stress (Perceived Stress Scale, 0-56) and coping style (active (0-45), avoidance (0-30), and minimization (0-30)) while accounting for caregiver burden (HF Caregiver Questionnaire (HF-CQ) 0-100). Multivariable regression analysis with backwards elimination variable selection approach was used to identify which SDH risk factors best predicted coping styles. SDH risk was significantly associated with avoidance and minimization coping styles. Each unit increase in SDH risk was associated with an increase of 0.6 ± 0.2 units (p = .0008) in avoidance and 0.7 ± 0.2 units (p < .0001) in minimization coping style. Race and "supporting others" significantly predicted avoidance coping style; scores were 3.3 ± 0.8 units greater for caregivers who were not White (p < .0001) and 1.4 ± 0.5 units greater (p < .01) for each additional person whom they supported. Race significantly predicted minimization coping style; scores were 4.4 ± 0.7 units greater for caregivers who were not White (p < .0001). Caregivers with higher SDH risk may avoid and minimize to cope with caregiving challenges.

Longitudinal White and Gray Matter Response to Precision Medicine-Guided Intervention for Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a debilitating condition that is widely known to adversely affect gray matter (GM) and white matter (WM) tracts within the brain. Recently, precision medicine has shown promise in alleviating the clinical and gross morphological trajectories of patients with AD. However, regional morphological changes have not yet been adequately characterized. OBJECTIVE: Investigate regional morphological responses to a precision medicine-guided intervention with regards to white and gray matter in AD and mild cognitive impairment (MCI). METHODS: Clinical and neuroimaging data were compiled over a 9-month period from 25 individuals who were diagnosed with AD or MCI receiving individualized treatment plans. Structural T1-weighted MRI scans underwent segmentation and volumetric quantifications via Neuroreader. Longitudinal changes were calculated via annualized percent change of WM or GM ratios. RESULTS: Montreal Cognitive Assessment scores (p < 0.001) and various domains of the Computerized Neurocognitive Screening Vital Signs significantly improved from baseline to 9-month follow-up. There was regional variability in WM and GM atrophy or hypertrophy, but none of these observed changes were statistically significant after correction for multiple comparisons.

Precision Medicine Approach to Alzheimer's Disease: Rationale and Implications.

The neurodegenerative disease field has enjoyed extremely limited success in the development of effective therapeutics. One potential reason is the lack of disease models that yield accurate predictions and optimal therapeutic targets. Standard clinical trials have pre-determined a single treatment modality, which may be unrelated to the primary drivers of neurodegeneration. Recent proof-of-concept clinical trials using a precision medicine approach suggest a new model of Alzheimer's disease (AD) as a chronic innate encephalitis that creates a network insufficiency. Identifying and addressing the multiple potential contributors to cognitive decline for each patient may represent a more effective strategy. Here we review the rationale for a precision medicine approach in prevention and treatment of cognitive decline associated with AD. Results and implications from recent proof-of-concept clinical trials are presented. Randomized controlled trials, with much larger patient numbers, are likely to be significant to establishing precision medicine protocols as a standard of care for prevention and treatment of cognitive decline. Furthermore, combining this approach with the pharmaceutical approach offers the potential for enhanced outcomes. However, incorporating precision medicine approaches into everyday evaluation and care, as well as future clinical trials, would require fundamental changes in trial design, IRB considerations, funding considerations, laboratory evaluation, personalized treatment plans, treatment teams, and ultimately in reimbursement guidelines. Nonetheless, precision medicine approaches to AD, based on a novel model of AD pathophysiology, offer promise that has not been realized to date with monotherapeutic approaches.

Collective behavior in relation with changing environments: Dynamics, modularity, and agency.

Collective behavior operates without central control, using local interactions among participants to adjust to changing conditions. Many natural systems operate collectively, and by specifying what objectives are met by the system, the idea of agency helps to describe how collective behavior is embedded in the conditions it deals with. Ant colonies function collectively, and the enormous diversity of more than 15K species of ants, in different habitats, provides opportunities to look for general ecological patterns in how collective behavior operates. The foraging behavior of harvester ants in the desert regulates activity to manage water loss, while the trail networks of turtle ants in the canopy tropical forest respond to rapidly changing resources and vegetation. These examples illustrate some broad correspondences in natural systems between the dynamics of collective behavior and the dynamics of the surroundings. To outline how interactions among participants, acting in relation with changing surroundings, achieve collective outcomes, I focus on three aspects of collective behavior: the rate at which interactions adjust to conditions, the feedback regime that stimulates and inhibits activity, and the modularity of the network of interactions. To characterize the dynamics of the surroundings, I consider gradients in stability, energy flow, and the distribution of resources and demands. I then propose some hypotheses that link how collective behavior operates with changing environments.

Biological rhythms and task allocation in ant colonies.

Task allocation in ant colonies, mediated by social interactions, regulates which individuals perform which task and when they are active, in response to the current situation. Many tasks are performed in a daily temporal pattern. An ant's biological clock depends on the patterns of gene expression that are regulated using a negative feedback loop which is synchronized to the earth's rotation by external cues. An individual's biological clock can shift in response to social cues, and this plasticity contributes to task switching. Daily rhythms in individual ant behavior combine via interactions within and across task groups to adjust the collective behavior of colonies. Further work is needed to elucidate how the social cues, which lead to task switching, influence the molecular mechanisms that generate clock outputs associated with each task and to investigate the evolution of temporal patterns in task allocation in relation to ecological factors.

Modeling collective cell behavior in cancer: Perspectives from an interdisciplinary conversation.

Collective cell behavior contributes to all stages of cancer progression. Understanding how collective behavior emerges through cell-cell interactions and decision-making will advance our understanding of cancer biology and provide new therapeutic approaches. Here, we summarize an interdisciplinary discussion on multicellular behavior in cancer, draw lessons from other scientific disciplines, and identify future directions.

Distributed algorithms from arboreal ants for the shortest path problem.

Colonies of the arboreal turtle ant create networks of trails that link nests and food sources on the graph formed by branches and vines in the canopy of the tropical forest. Ants put down a volatile pheromone on the edges as they traverse them. At each vertex, the next edge to traverse is chosen using a decision rule based on the current pheromone level. There is a bidirectional flow of ants around the network. In a previous field study, it was observed that the trail networks approximately minimize the number of vertices, thus solving a variant of the popular shortest path problem without any central control and with minimal computational resources. We propose a biologically plausible model, based on a variant of the reinforced random walk on a graph, which explains this observation and suggests surprising algorithms for the shortest path problem and its variants. Through simulations and analysis, we show that when the rate of flow of ants does not change, the dynamics converges to the path with the minimum number of vertices, as observed in the field. The dynamics converges to the shortest path when the rate of flow increases with time, so the colony can solve the shortest path problem merely by increasing the flow rate. We also show that to guarantee convergence to the shortest path, bidirectional flow and a decision rule dividing the flow in proportion to the pheromone level are necessary, but convergence to approximately short paths is possible with other decision rules.

Critical thermal limits and temperature-dependent walking speed may mediate coexistence between the native winter ant (Prenolepis imparis) and the invasive Argentine ant (Linepithemahumile).

Comparing the thermal tolerance and performance of native and invasive species from varying climatic origins may explain why some native and invasive species can coexist. We compared the thermal niches of an invasive and native ant species. The Argentine ant (Linepithema humile) is an invasive species that has spread to Mediterranean climates worldwide, where it is associated with losses in native arthropod biodiversity. In northern California, long-term surveys of ant biodiversity have shown that the winter ant (Prenolepis imparis) is the native species best able to coexist with Argentine ants. Both species tend hemipteran scales for food, and previous research suggests that these species' coexistence may depend on seasonal partitioning: winter ants are active primarily in the colder winter months, while Argentine ants are active primarily in the warmer months in northern California. We investigated the physiological basis of seasonal partitioning in Argentine and winter ants by a) measuring critical thermal limits, and b) comparing how ant walking speed varies with temperature. While both species had similar CTmax values, we found differences between the two species' critical thermal minima that may allow winter ants to remain functional at ecologically relevant temperatures between 0 and 2.5 °C. We also found that winter ants' walking speeds are significantly less temperature-dependent than those of Argentine ants. Winter ants walk faster than Argentine ants at low temperatures, which may allow the winter ants to remain active and forage at lower winter temperatures. These results suggest that partitioning based on differences in temperature tolerance promotes the winter ant's continued occupation of areas invaded by the Argentine ant.

Understanding variability in petroleum jet fuel life cycle greenhouse gas emissions to inform aviation decarbonization.

A pressing challenge facing the aviation industry is to aggressively reduce greenhouse gas emissions in the face of increasing demand for aviation fuels. Climate goals such as carbon-neutral growth from 2020 onwards require continuous improvements in technology, operations, infrastructure, and most importantly, reductions in aviation fuel life cycle emissions. The Carbon Offsetting Scheme for International Aviation of the International Civil Aviation Organization provides a global market-based measure to group all possible emissions reduction measures into a joint program. Using a bottom-up, engineering-based modeling approach, this study provides the first estimates of life cycle greenhouse gas emissions from petroleum jet fuel on regional and global scales. Here we show that not all petroleum jet fuels are the same as the country-level life cycle emissions of petroleum jet fuels range from 81.1 to 94.8 gCO2e MJ-1, with a global volume-weighted average of 88.7 gCO2e MJ-1. These findings provide a high-resolution baseline against which sustainable aviation fuel and other emissions reduction opportunities can be prioritized to achieve greater emissions reductions faster.

Tackling unlit and inefficient gas flaring.

Emissions from flaring threaten the global climate and the health of local communities.

"If relatives inherited the gene, they should inherit the data." Bringing the family into the room where bioethics happens.

Biological kin share up to half of their genetic material, including predisposition to disease. Thus, variants of clinical significance identified in each individual's genome can implicate an exponential number of relatives at potential risk. This has renewed the dilemma over family access to research participant's genetic results, since prevailing U.S. practices treat these as private, controlled by the individual. These individual-based ethics contrast with the family-based ethics- in which genetic information, privacy, and autonomy are considered to be familial- endorsed in UK genomic medicine and by participants in a multi-method study of U.S. research participants presented here. The dilemma reflects a conflict between U.S. legal and ethical frameworks that privilege "the individual" and exclude "the family" versus actual human genetics that are simultaneously individual and familial. Can human genetics succeed in challenging bioethics' hegemonic individualism to recognize and place the family at the center of the room where bioethics happens?

Precision Medicine Approach to Alzheimer's Disease: Successful Pilot Project.

BACKGROUND: Effective therapeutics for Alzheimer's disease are needed. However, previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of the neurodegenerative process. Therefore, increasing data set size to include the potential contributors to cognitive decline for each patient, and addressing the identified potential contributors, may represent a more effective strategy. OBJECTIVE: To determine whether a precision medicine approach to Alzheimer's disease and mild cognitive impairment is effective enough in a proof-of-concept trial to warrant a larger, randomized, controlled clinical trial. METHODS: Twenty-five patients with dementia or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Patients were treated for nine months with a personalized, precision medicine protocol, and cognition was assessed at t = 0, 3, 6, and 9 months. RESULTS: All outcome measures revealed improvement: statistically significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and Alzheimer's Questionnaire Change score were documented. No serious adverse events were recorded. MRI volumetrics also improved. CONCLUSION: Based on the cognitive improvements observed in this study, a larger, randomized, controlled trial of the precision medicine therapeutic approach described herein is warranted.

Leveraging Shared Governance to Build a Healthier Work Environment in a NICU.

PURPOSE: A unit-shared governance model was established in the NICU at Tampa General Hospital to enhance nursing autonomy and improve job satisfaction, teamwork, and patient outcomes. SIGNIFICANCE: Shared governance models have been introduced within health systems to shape healthy work environments. STRATEGY AND IMPLEMENTATION: The NICU experienced an extended hiring freeze that led to a significant nursing shortage and staff dissatisfaction. A unit-shared governance model was established to address key areas of concern. This led to the development of the new employee orientation committee. Their goal was to make significant changes in the onboarding and precepting process, including: (1) revising the Registered Nurse Competency-Based Orientation tool to align with a 3-phased orientation process, (2) incorporating a systems approach throughout the orientation period, (3) embedding references to best practices and policies, (4) creating a reference list of recommended reading materials, and (5) developing a skills checklist to guide in selection of patient assignments. The final step was developing a NICU preceptor course to increase consistency between preceptors and standardize orientation. OUTCOMES: Recent engagement survey results revealed significant improvements in employee satisfaction, validating key improvements made in the onboarding process.

Better tired than lost: Turtle ant trail networks favor coherence over short edges.

Creating a routing backbone is a fundamental problem in both biology and engineering. The routing backbone of the trail networks of arboreal turtle ants (Cephalotes goniodontus) connects many nests and food sources using trail pheromone deposited by ants as they walk. Unlike species that forage on the ground, the trail networks of arboreal ants are constrained by the vegetation. We examined what objectives the trail networks meet by comparing the observed ant trail networks with networks of random, hypothetical trail networks in the same surrounding vegetation and with trails optimized for four objectives: minimizing path length, minimizing average edge length, minimizing number of nodes, and minimizing opportunities to get lost. The ants' trails minimized path length by minimizing the number of nodes traversed rather than choosing short edges. In addition, the ants' trails reduced the opportunity for ants to get lost at each node, favoring nodes with 3D configurations most likely to be reinforced by pheromone. Thus, rather than finding the shortest edges, turtle ant trail networks take advantage of natural variation in the environment to favor coherence, keeping the ants together on the trails.

Movement, Encounter Rate, and Collective Behavior in Ant Colonies.

Spatial patterns of movement regulate many aspects of social insect behavior, because how workers move around, and how many are there, determines how often they meet and interact. Interactions are usually olfactory; for example, in ants, by means of antennal contact in which one worker assesses the cuticular hydrocarbons of another. Encounter rates may be a simple outcome of local density: a worker experiences more encounters, the more other workers there are around it. This means that encounter rate can be used as a cue for overall density even though no individual can assess global density. Encounter rate as a cue for local density regulates many aspects of social insect behavior, including collective search, task allocation, nest choice, and traffic flow. As colonies grow older and larger, encounter rates change, which leads to changes in task allocation. Nest size affects local density and movement patterns, which influences encounter rate, so that nest size and connectivity influence colony behavior. However, encounter rate is not a simple function of local density when individuals change their movement in response to encounters, thus influencing further encounter rates. Natural selection on the regulation of collective behavior can draw on variation within and among colonies in the relation of movement patterns, encounter rate, and response to encounters.

Multiyear drought exacerbates long-term effects of climate on an invasive ant species.

Invasive species threaten biodiversity, ecosystem function, and human health, but the long-term drivers of invasion dynamics remain poorly understood. We use data from a 28-yr ongoing survey of a Northern California ant community invaded by the Argentine ant (Linepithema humile) to investigate the influence of abiotic and biotic factors on invasion dynamics. We found that the distribution of L. humile retracted following an extreme drought that occurred in the region from 2012 to 2015. The distribution of several native ant species also contracted, but overall native ant diversity was higher after the drought and for some native ant species, distributions expanded over the 28-yr survey period. Using structural equation models, we found the strongest impact on the distribution of L. humile was from direct effects of climate, namely, cumulative precipitation and summer maximum temperatures, with only a negligible role for biotic resistance and indirect effects of climate mediated by native ants. The increasing drought and high temperature extremes projected for northern California because of anthropogenic-driven climate change may limit the spread, and possibly the impact, of L. humile in invaded regions. The outcome will depend on the response of native ant communities to these climatic stressors.

Measuring collective behavior: an ecological approach.

Collective behavior is ubiquitous throughout nature. Many systems, from brains to ant colonies, work without central control. Collective behavior is regulated by interactions among the individual participants such as neurons or ants. Interactions create feedback that produce the outcome, the behavior that we observe: Brains think and remember, ant colonies collect food or move nests, flocks of birds turn, human societies develop new forms of social organization. But the processes by which interactions produce outcomes are as diverse as the behavior itself. Just as convergent evolution has led to organs, such as the eye, that are similar in function but are based on different physiological processes, so it has led to forms of collective behavior that appear similar but arise from different social processes. An ecological perspective can help us to understand the dynamics of collective behavior and how it works.

Health Care Consumer Shopping Behaviors and Sentiment: Qualitative Study.

BACKGROUND: Although some health care market reforms seek to better engage consumers in purchasing health care services, health consumer behavior remains poorly understood. OBJECTIVE: This study aimed to characterize the behaviors and sentiment of consumers who attempt to shop for health care services. METHODS: We used a semistructured interview guide based on grounded theory and standard qualitative research methods to examine components of a typical shopping process in a sample size of 54 insured adults. All interviews were systematically coded to capture consumer behaviors, barriers to shopping behavior, and sentiments associated with these experiences. RESULTS: Participants most commonly described determining and evaluating options, seeking value, and assessing or evaluating value. In total, 83% (45/54) of participants described engaging in negotiations regarding health care purchasing. The degree of positive sentiment expressed in the interview was positively correlated with identifying and determining the health plan, provider, or treatment options; making the decision to purchase; and evaluating the decision to purchase. Conversely, negative sentiment was correlated with seeking value and making the decision to buy. CONCLUSIONS: Consumer shopping behaviors are prevalent in health care purchasing and can be mapped to established consumer behavior models.