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.

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.

Should Researchers Offer Results to Family Members of Cancer Biobank Participants? A Mixed-Methods Study of Proband and Family Preferences.

BACKGROUND: Genomic analysis may reveal both primary and secondary findings with direct relevance to the health of probands' biological relatives. Researchers question their obligations to return findings not only to participants but also to family members. Given the social value of privacy protection, should researchers offer a proband's results to family members, including after the proband's death? METHODS: Preferences were elicited using interviews and a survey. Respondents included probands from two pancreatic cancer research resources, plus biological and nonbiological family members. Hypothetical scenarios based on actual research findings from the two cancer research resources were presented; participants were asked return of results preferences and justifications. Interview transcripts were coded and analyzed; survey data were analyzed descriptively. RESULTS: Fifty-one individuals (17 probands, 21 biological relatives, 13 spouses/partners) were interviewed. Subsequently, a mailed survey was returned by 464 probands, 1,040 biological family members, and 399 spouses/partners. This analysis highlights the interviews, augmented by survey findings. Probands and family members attribute great predictive power and lifesaving potential to genomic information. A majority hold that a proband's genomic results relevant to family members' health ought to be offered. While informants endorse each individual's choice whether to learn results, most express a strong moral responsibility to know and to share, particularly with the younger generation. Most have few concerns about sharing genetic information within the family; rather, their concerns focus on the health consequences of not sharing. CONCLUSIONS: Although additional studies in diverse populations are needed, policies governing return of genomic results should consider how families understand genomic data, how they value confidentiality within the family, and whether they endorse an ethics of sharing. A focus on respect for individual privacy-without attention to how the broad social and cultural context shapes preferences within families-cannot be the sole foundation of policy.

Extended SSD VMAT treatment for total body irradiation.

In this work, we develop a total body irradiation technique that utilizes arc delivery, a buildup spoiler, and inverse optimized multileaf collimator (MLC) motion to shield organs at risk. The current treatment beam model is verified to confirm its applicability at extended source-to-surface distance (SSD). The delivery involves 7-8 volumetric modulated arc therapy arcs delivered to the patient in the supine and prone positions. The patient is positioned at a 90° couch angle on a custom bed with a 1 cm acrylic spoiler to increase surface dose. Single-step optimization using a patient CT scan provides enhanced dose homogeneity and limits organ at risk dose. Dosimetric data of 109 TBI patients treated with this technique is presented along with the clinical workflow. Treatment planning system (TPS) verification measurements were performed at an extended SSD of 175 cm. Measurements included: a 4-point absolute depth-dose curve, profiles at 1.5, 5, and 10 cm depth, absolute point-dose measurements of an treatment field, 2D Gafchromic® films at four locations, and measurements of surface dose at multiple locations of a Alderson phantom. The results of the patient DVH parameters were: Body-5 mm D98 95.3 ± 1.5%, Body-5 mm D2 114.0 ± 3.6%, MLD 102.8 ± 2.1%. Differences between measured and calculated absolute depth-dose values were all <2%. Profiles at extended SSD had a maximum point difference of 1.3%. Gamma pass rates of 2D films were greater than 90% at 5%/1 mm. Surface dose measurements with film confirmed surface dose values of >90% of the prescription dose. In conclusion, the inverse optimized delivery method presented in the paper has been used to deliver homogenous dose to over 100 patients. The method provides superior patient comfort utilizing a commercial TPS. In addition, the ability to easily shield organs at risk is available through the use of MLCs.

Cancer Ecology and Evolution: Positive interactions and system vulnerability.

Parallels of cancer with ecology and evolution have provided new insights into the initiation and spread of cancer, and new approaches to therapy. This review describes those parallels while emphasizing some key contrasts. We argue that cancers are less like invasive species than like native species or even crops that have escaped control, and that ecological control and homeo-static control differ fundamentally through both their ends and their means. From our focus on the role of positive interactions in control processes, we introduce a novel mathematical modeling framework that tracks how individual cell lineages arise, and how the many layers of control break down in the emergence of cancer. The next generation of therapies must continue to look beyond cancers as being created by individual renegade cells and address not only the network of interactions those cells inhabit, but the evolutionary logic that created those interactions and their intrinsic vulnerability.

Attitudes Toward Return of Genetic Research Results to Relatives, Including After Death: Comparison of Cancer Probands, Blood Relatives, and Spouse/Partners.

Genetic research generates results with implications for relatives. Recommendations addressing relatives' access to a participant's genetic research findings include eliciting participant preferences about access and choosing a representative to make decisions about access upon participant incapacity/death. Representatives are likely to be blood relatives or spouse/partners (who may share genetically related children). This raises the question of whether relatives hold similar attitudes about access or divergent attitudes that may yield conflict. We surveyed pancreatic cancer biobank participants (probands) and relatives in a family registry (blood relatives and spouse/partners of probands); 1,903 (>55%) surveys were returned. Results revealed few attitudinal differences between the groups. A slightly higher proportion of blood relatives agreed with statements reflecting proband privacy. In conclusion, probands' decisions on access are likely to be accepted by relatives; in choosing a representative, probands may not face major differences in attitudes about privacy/sharing between a blood relative and a spouse/partner.

Local Regulation of Trail Networks of the Arboreal Turtle Ant, Cephalotes goniodontus.

This study examines how an arboreal ant colony maintains, extends, and repairs its network of foraging trails and nests, built on a network of vegetation. Nodes are junctions where a branch forks off from another or where a branch of one plant touching another provides a new edge on which ants could travel. The ants' choice of edge at a node appears to be reinforced by trail pheromone. Ongoing pruning of the network tends to eliminate cycles and minimize the number of nodes and thus decision points, but not the distance traveled. At junctions, trails tend to stay on the same plant. In combination with the long internode lengths of the branches of vines in the tropical dry forest, this facilitates travel to food sources at the canopy edge. Exploration, when ants leave the trail on an edge that is not being used, makes both search and repair possible. The fewer the junctions between a location and the main trail, the more likely the ants are to arrive there. Ruptured trails are rapidly repaired with a new path, apparently using breadth-first search. The regulation of the network promotes its resilience and continuity.

PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer.

Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extra-terminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. Here, we demonstrate that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is, to our knowledge, the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC.

Energy Return on Investment (EROI) for Forty Global Oilfields Using a Detailed Engineering-Based Model of Oil Production.

Studies of the energy return on investment (EROI) for oil production generally rely on aggregated statistics for large regions or countries. In order to better understand the drivers of the energy productivity of oil production, we use a novel approach that applies a detailed field-level engineering model of oil and gas production to estimate energy requirements of drilling, producing, processing, and transporting crude oil. We examine 40 global oilfields, utilizing detailed data for each field from hundreds of technical and scientific data sources. Resulting net energy return (NER) ratios for studied oil fields range from ≈2 to ≈100 MJ crude oil produced per MJ of total fuels consumed. External energy return (EER) ratios, which compare energy produced to energy consumed from external sources, exceed 1000:1 for fields that are largely self-sufficient. The lowest energy returns are found to come from thermally-enhanced oil recovery technologies. Results are generally insensitive to reasonable ranges of assumptions explored in sensitivity analysis. Fields with very large associated gas production are sensitive to assumptions about surface fluids processing due to the shifts in energy consumed under different gas treatment configurations. This model does not currently include energy invested in building oilfield capital equipment (e.g., drilling rigs), nor does it include other indirect energy uses such as labor or services.

Preferences Regarding Return of Genomic Results to Relatives of Research Participants, Including after Participant Death: Empirical Results from a Cancer Biobank.

Data are lacking with regard to participants' perspectives on return of genetic research results to relatives, including after the participant's death. This paper reports descriptive results from 3,630 survey respondents: 464 participants in a pancreatic cancer biobank, 1,439 family registry participants, and 1,727 healthy individuals. Our findings indicate that most participants would feel obligated to share their results with blood relatives while alive and would want results to be shared with relatives after their death.

Catalytic in vivo protein knockdown by small-molecule PROTACs.

The current predominant therapeutic paradigm is based on maximizing drug-receptor occupancy to achieve clinical benefit. This strategy, however, generally requires excessive drug concentrations to ensure sufficient occupancy, often leading to adverse side effects. Here, we describe major improvements to the proteolysis targeting chimeras (PROTACs) method, a chemical knockdown strategy in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the target's ubiquitination and degradation. These compounds behave catalytically in their ability to induce the ubiquitination of super-stoichiometric quantities of proteins, providing efficacy that is not limited by equilibrium occupancy. We present two PROTACs that are capable of specifically reducing protein levels by >90% at nanomolar concentrations. In addition, mouse studies indicate that they provide broad tissue distribution and knockdown of the targeted protein in tumor xenografts. Together, these data demonstrate a protein knockdown system combining many of the favorable properties of small-molecule agents with the potent protein knockdown of RNAi and CRISPR.

Discovery and synthesis of novel 4-aminopyrrolopyrimidine Tie-2 kinase inhibitors for the treatment of solid tumors.

The synthesis and biological evaluation of novel Tie-2 kinase inhibitors are presented. Based on the pyrrolopyrimidine chemotype, several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-position of the 4-amino-pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with improved physicochemical properties, demonstrated favorable in vitro attributes as well as dose responsive and robust oral tumor growth inhibition in animal models.

Design of selective, ATP-competitive inhibitors of Akt.

This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.