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UNLABELLED: PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities. SIGNIFICANCE: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 227 . This article is featured in Selected Articles from This Issue, p. 201.

Purpose of review: One of the challenges in the diagnosis and management of primary aldosteronism (PA), the most common type of secondary hypertension with curative potential, is the modification of antihypertensive medications. We seek to explore whether these medications can be continued during the diagnostic process of PA to minimize the duration and risks associated with medication adjustments. Recent findings: We searched PubMed for eligible original literature between 1990 and 2024 using the following keywords: (screening) AND (primary aldosteronism); (confirmatory) AND (primary aldosteronism); (adrenal vein sampling) AND primary aldosteronism). Some recent studies support the feasibility of PA-related tests and even adrenal vein sampling (AVS) without the need to discontinue antihypertensive medications in certain cases. Summary: In this review, we propose a management approach that considers the specific effects of antihypertensive medications on the RAAS axis and the patient's disease phenotype. Based on this, we suggest a strategy that enables the diagnosis of PA in certain patients without discontinuing their antihypertensive medications. [ABSTRACT FROM AUTHOR]

Statins have the potential to reduce breast cancer incidence and recurrence as shown in both epidemiologic and laboratory studies. The purpose of this study was to evaluate the effect of a lipophilic statin, atorvastatin, on breast cancer biomarkers of risk [mammographic density (MD) and insulin growth factor 1 (IGF-1)] in high-risk premenopausal women.Premenopausal women at increased risk for breast cancer received either 40 mg of atorvastatin or placebo for 1 year. Biomarker assessment was performed prior to initiation and at completion of study medication. MD was determined using both Breast Imaging Reporting and Data System and the visual analogue scale. Serum IGF-1 was determined by ELISA assay at the end of the study.Sixty-three women were enrolled between December 2005 and May 2010. Sixteen (25%) women withdrew. The mean age of participants was 43 (range, 35-50), 100% were white, and the average body mass index (BMI) was 26.4. The statin group demonstrated a significant decrease in cholesterol and low-density lipoprotein (LDL), suggesting compliance with study medication. After accounting for BMI, there was no difference in change in MD between groups. There was a significant increase in serum IGF-1 in the statin group.In this multi-institutional randomized prospective clinical trial of premenopausal women at increased risk for breast cancer, we did not see an effect of atorvastatin on MD. Further investigation of statins may be warranted; however, design of prior trials and potential mechanism of action of the agent need to be considered in the design of future trials. Cancer Prev Res; 9(5); 379-84. ©2016 AACR.

Introduction: To achieve the "dual carbon" goal, the integrated energy system (IES) needs to take into account both economic and low-carbon requirements while meeting the growing energy demand. Methods: Therefore, an optimal scheduling model for low-carbon economic operation is proposed. Firstly, a more accurate carbon emission model is used to consider the actual carbon emission of gas load, to improve the original carbon emission model. A ladder-type carbon trading mechanism is introduced to further constrain the carbon emission of IES. Then, the demand-side response model is proposed, which uses the time-of-use price and mutual substitution of electricity, heat, and gas loads to curtail, time-shift, and substitute the load. Finally, an optimal scheduling model with minimum energy purchase cost, wind and photovoltaic curtailment cost, demand response cost, and carbon emission cost is constructed, which is solved by the GUROBI solver. Results: Through comparative simulation analysis of 6 cases, the results show that the objective function considers the traditional carbon trading cost to reduce carbon emission by about 19.3% compared with the case without considering. After adopting the ladder-type carbon trading mechanism, the carbon emission of IES can be further limited by about 0.35%, and the appropriate carbon trading base price is explored. In addition, after the demand response, the energy purchase cost, carbon trading cost, and carbon emission of IES are reduced by about 3.4%, 18.5%, and 36.2%, respectively, compared with those before the demand response. The simulation results verify the effectiveness of the proposed model. [ABSTRACT FROM AUTHOR]

Adipose-derived stem cells (ADSCs) can differentiate into vascular lineages and participate in vascular remodeling. Perivascular ADSCs (PV-ADSCs) draw attention because of their unique location. The heterogeneity of subcutaneous (SUB) and abdominal ADSCs were well addressed, but PV-ADSCs' heterogeneity has not been investigated. In this study, we applied single-cell analysis to compare SUB-ADSCs and PV-ADSCs regarding their subpopulations, functions, and cell fates. We uncovered four subpopulations of PV-ADSCs (Dpp4+, Col4a2+/Icam1+, Clec11a+/Cpe+, and Sult1e1+ cells), among which the Clec11a+ subpopulation potentially participated in and regulated PV-ADSC differentiation toward a smooth muscle cell (SMC) phenotype. Distinct characteristics between PV-ADSCs and SUB-ADSCs were revealed. [ABSTRACT FROM AUTHOR]