A multiverse of BRCA vulnerabilities
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Semi-mechanistic efficacy model for PARP + ATR inhibitors—application to rucaparib and talazoparib in combination with gartisertib in breast cancer PDXs
Promising cancer treatments, such as DDR inhibitors, are often challenged by the heterogeneity of responses in clinical trials. The present work aimed to build a computational framework to address those challenges.
Commentary: Why is genetic testing underutilized worldwide? The case for hereditary breast cancer
It is thirty years since the BRCA1 and BRCA2 genes were discovered and genetic testing for BRCA1 and BRCA2 was introduced. Despite increasing awareness of the genetic basis of cancer and our evolving knowledge of effective means of prevention, screening, and treatment for hereditary breast and ovarian cancers, genetic testing is underutilized, and most mutation carriers remain unidentified. In this commentary, we explore possible reasons for why this might be so. Our focus is on factors that may influence or deter a patient from pursuing testing, rather than discussing the implications of receiving a positive test result. Issues of concern include an inadequate number of genetic counselors, restrictive (and conflicting) eligibility criteria for testing, the cost of the test, health insurance coverage, fear of future insurance discrimination, privacy issues, lack of familiarity with the testing process in primary care and gaps in both patient and provider knowledge about the impact and the value of testing. We discuss how these factors may lead to the underutilization of genetic testing in North America and throughout the world and discuss alternative models of genetic healthcare delivery. We have invited leaders in cancer genetic from around the world to tell us what they think are the barriers to testing in their host countries.
Low-carbon ammonia production is essential for resilient and sustainable agriculture
Ammonia-based synthetic nitrogen fertilizers (N fertilizers) are critical for global food security. However, their production, primarily dependent on fossil fuels, is energy- and carbon-intensive and vulnerable to supply chain disruptions, affecting 1.8 billion people reliant on either imported fertilizers or natural gas. Here we examine the global N-fertilizer supply chain and analyse context-specific trade-offs of low-carbon ammonia production pathways. Carbon capture and storage can reduce overall emissions by up to 70%, but still relies on natural gas. Electrolytic and biochemical processes minimize emissions but are 2–3 times more expensive and require 100–300 times more land and water than the business-as-usual production. Decentralized production has the potential to reduce transportation costs, emissions, reliance on imports and price volatility, increasing agricultural productivity in the global south, but requires policy support. Interdisciplinary approaches are essential to understand these trade-offs and find resilient ways to feed a growing population while minimizing climate impacts.
A systematic review and meta-analyses of the temporal stability and convergent validity of risk preference measures
Understanding whether risk preference represents a stable, coherent trait is central to efforts aimed at explaining, predicting and preventing risk-related behaviours. We help characterize the nature of the construct by adopting a systematic review and individual participant data meta-analytic approach to summarize the temporal stability of 358 risk preference measures (33 panels, 57 samples, 579,114 respondents). Our findings reveal noteworthy heterogeneity across and within measure categories (propensity, frequency and behaviour), domains (for example, investment, occupational and alcohol consumption) and sample characteristics (for example, age). Specifically, while self-reported propensity and frequency measures of risk preference show a higher degree of stability than behavioural measures, these patterns are moderated by domain and age. Crucially, an analysis of convergent validity reveals a low agreement across measures, questioning the idea that they capture the same underlying phenomena. Our results raise concerns about the coherence and measurement of the risk preference construct.
PIK3CA mutation fortifies molecular determinants for immune signaling in vascular cancers
Angiosarcomas are a group of vascular cancers that form malignant blood vessels. These malignancies are seemingly inflamed primarily due to their pathognomonic nature, which consists of irregular endothelium and tortuous blood channels. PIK3CA mutations are oncogenic and disrupt the PI3K pathway. In this study, we aimed to define the molecular and functional consequences of oncogenic PIK3CA mutations in angiosarcoma. We first generated two isogenic hemangiosarcoma cell lines harboring the H1047R hotspot mutations in PIK3CA gene using CRISPR/Cas9. We found PIK3CA-mutant cells established distinct molecular signatures in global gene expression and chromatin accessibility, which were associated with enrichment of immune cytokine signaling, including IL-6, IL-8, and MCP-1. These molecular processes were disrupted by the PI3K-α specific inhibitor, alpelisib. We also observed that the molecular distinctions in PIK3CA-mutant cells were linked to metabolic reprogramming in glycolytic activity and mitochondrial respiration. Our multi-omics analysis revealed that activating PIK3CA mutations regulate molecular machinery that contributes to phenotypic alterations and resistance to alpelisib. Furthermore, we identified potential therapeutic vulnerabilities of PIK3CA mutations in response to PI3K-α inhibition mediated by MAPK signaling. In summary, we demonstrate that PIK3CA mutations perpetuate PI3K activation and reinforce immune enrichment to promote drug resistance in vascular cancers.
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