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Background: The Androgen Receptor (AR) pathway is crucial in driving the progression of prostate cancer (PCa) to an advanced state. Despite the introduction of second-generation AR antagonists, such as enzalutamide, majority of patients develop resistance. Several mechanisms of resistance have been identified, including the constitutive activation of the AR pathway, the emergence of AR spliced variants, and the influence of other signalling pathways. The Serum Response Factor (SRF) was previously identified as a possible player of resistance involved in a crosstalk with the AR signalling pathway. Elevated SRF levels in PCa patients were associated with disease progression and resistance to enzalutamide. However, the molecular mediators of the crosstalk between SRF and AR still need to be elucidated. The objective of this study was to identify common interactors of the AR/SRF crosstalk as therapeutic targets., Methods: Here we used affinity purification mass spectrometry (MS) following immunoprecipitation of SRF and AR, to identify proteins that interact with both SRF and AR. The list of common interactors was expanded using STRING. Four common interactors were functionally validated using MTT assays., Results: Seven common interactors were identified, including HSP70, HSP0AA1, HSP90AB1, HSAP5, PRDX1 and GAPDH. Pathway analysis revealed that the PI3k/AKT pathway was the most enriched in the AR/SRF network. Moreover, pharmacological inhibition of several proteins in this network, including HSP70, HSP90, PI3k and AKT, significantly decreased cellular viability of PCa cells., Conclusions: This study identified a list of AR/SRF common interactors that represent a pipeline of druggable targets for the treatment of PCa., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Azam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Ethnopharmacological Relevance: The use of medicinal plants for central nervous system (CNS)-related ailments, such as epilepsy and anxiety, is prevalent in South Africa. Plants from the Lamiaceae family are commonly used for their therapeutic benefits. Leonotis leonurus (L.) R.Br. has been reported in ethnobotanical literature to have anticonvulsant and anxiolytic effects through the inhalation of pyrolysis products obtained by combustion of the aerial parts., Aim and Objectives: To explore the chemical profiles and CNS activity of the smoke extract and isolated constituents of L. leonurus in zebrafish larvae, through anticonvulsive and anxiolytic activity assays., Materials and Methods: The smoke extract of L. leonurus was obtained through the combustion of the aerial parts of the plant using a custom-built smoke recovery apparatus. The chemical profile of the smoke constituents was determined using Ultra-Performance Liquid Chromatography coupled with Mass Spectrometry (UPLC-MS). Targeted compounds were subjected to preparative High-Performance Liquid Chromatography for separation before structure elucidation using Nuclear Magnetic Resonance (NMR). The maximum tolerated concentrations, as well as the anxiolytic activity of the smoke extract were determined in five days post fertilisation zebrafish larvae. Reverse-thigmotaxis and locomotor activity of larvae in the light/dark transition assay were used to determine anxiolytic activity. Zebrafish larvae at six days post fertilisation (dpf) were subjected to several concentrations of the smoke constituents of L. leonurus. The baseline locomotor activity of the larvae was tracked for 30 min, prior to addition of pentylenetetrazole (PTZ) to induce seizure-like behaviour in the larvae, after which the locomotor activity of the larvae was once again tracked for an additional 30 min., Results: The UPLC-MS profiles of the smoke extract revealed the presence of two main compounds, leoleorin A and leoleorin B, which were targeted and isolated. Upon subjection to NMR spectroscopy for structure elucidation, the compounds were confirmed to be labdane diterpenoids. Both leoleorin A and leoleorin B, and the smoke extract displayed suppression of the PTZ induced seizure-like behaviour in zebrafish larvae. Under light and dark conditions, the smoke extract and compounds displayed potential anxiolytic activity at different concentrations., Conclusion: Our results suggest that the smoke constituents of L. leonurus may exert anticonvulsant and anxiolytic effects which align with the traditional indications and the mode of administration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. No conflicts to declare. A Viljoen has declared his role as Editor-in-Chief of JEP and the submission will obviously be handled completely by one of the associate editors., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Accelerated partial breast irradiation (APBI) is an attractive treatment modality for eligible patients as it has been shown to result in similar local control and improved cosmetic outcomes compared with whole breast radiation therapy. The use of online adaptive radiation therapy (OART) for APBI is promising as it allows for a reduction of planning target volume margins because breast motion and lumpectomy cavity volume changes are accounted for in daily imaging. Here we present a retrospective, single-institution evaluation on the adequacy of kV-cone beam computed tomography (CBCT) OART for APBI treatments., Methods and Materials: Nineteen patients (21 treatment sites) were treated to 30 Gy in 5 fractions between January of 2022 and May of 2023. Time between simulation and treatment, change in gross tumor (ie, lumpectomy cavity) volume, and differences in dose volume histogram metrics with adaption were analyzed. The Wilcoxon paired, nonparametric test was used to test for dose volume histogram metric differences between the scheduled plans (initial plans recalculated on daily CBCT anatomy) and delivered plans, either the scheduled or adapted plan, which was reoptimized using daily anatomy., Results: Median (interquartile range) time from simulation to first treatment was 26 days (21-32 days). During this same time, median gross tumor volume reduction was 16.0% (7.3%-23.9%) relative to simulation volume. Adaptive treatments took 31.3 minutes (27.4-36.6 minutes) from start of CBCT to treatment session end. At treatment, the adaptive plan was selected for 86% (89/103) of evaluable fractions. In evaluating plan quality, 78% of delivered plans met all target, organs at risk, and conformity metrics evaluated, compared with 34% of scheduled plans., Conclusions: Use of OART for stereotactic linac-based APBI allowed for safe, high-quality treatments in this cohort of 21 treatment courses. Although treatment delivery times were longer than traditional stereotactic body treatments, there were notable improvements in plan quality for APBI using OART., Competing Interests: Richard A. Popple's institution, University of Alabama at Birmingham, has product evaluation agreements and research grants with Varian Medical Systems. He has a patent licensed by UAB Research Foundation to Varian Medical Systems. He has received honoraria for presentations on behalf of Varian Medical Systems. He has received a stipend to speak at Sun Nuclear meetings. Varian Medical Systems provides equipment to UAB as a part of a product evaluation agreement. Dennis N. Stanley and his institution, University of Alabama at Birmingham, have received payment and consulting fees from Varian Medical Systems., (© 2023 The Author(s).)

Purpose: Currently, there is insufficient guidance for standard fractionation lung planning using the Varian Ethos adaptive treatment planning system and its unique intelligent optimization engine. Here, we address this gap in knowledge by developing a methodology to automatically generate high-quality Ethos treatment plans for locally advanced lung cancer., Methods and Materials: Fifty patients previously treated with manually generated Eclipse plans for inoperable stage IIIA-IIIC non-small cell lung cancer were included in this institutional review board-approved retrospective study. Fifteen patient plans were used to iteratively optimize a planning template for the Daily Adaptive vs Non-Adaptive External Beam Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Prospective Randomized Trial of an Individualized Approach for Toxicity Reduction (ARTIA-Lung); the remaining 35 patients were automatically replanned without intervention. Ethos plan quality was benchmarked against clinical plans and reoptimized knowledge-based RapidPlan (RP) plans, then judged using standard dose-volume histogram metrics, adherence to clinical trial objectives, and qualitative review., Results: Given equal prescription target coverage, Ethos-generated plans showed improved primary and nodal planning target volume V95% coverage ( P < .001) and reduced lung gross tumor volume V5 Gy and esophagus D0.03 cc metrics ( P ≤ .003) but increased mean esophagus and brachial plexus D0.03 cc metrics ( P < .001) compared with RP plans. Eighty percent, 49%, and 51% of Ethos, clinical, and RP plans, respectively, were "per protocol" or met "variation acceptable" ARTIA-Lung planning metrics. Three radiation oncologists qualitatively scored Ethos plans, and 78% of plans were clinically acceptable to all reviewing physicians, with no plans receiving scores requiring major changes., Conclusions: A standard Ethos template produced lung radiation therapy plans with similar quality to RP plans, elucidating a viable approach for automated plan generation in the Ethos adaptive workspace., Competing Interests: Richard Popple reports that his institution, University of Alabama at Birmingham, has product evaluation agreements and research grants with Varian Medical Systems. He also reports that he has a patent licensed by UAB Research Foundation to Varian Medical Systems, has received honoraria for presentations on behalf of Varian Medical Systems, has received a stipend to speak at Sun Nuclear meetings, and that Varian Medical Systems provides equipment to UAB as a part of a product evaluation agreement. Andrew McDonald and his institution, University of Alabama at Birmingham, have received payment from Varian Medical Systems. Dennis N. Stanley and his institution, University of Alabama at Birmingham, have received payment from Varian Medical Systems., (© 2023 The Author(s).)