ERα dysfunction caused by ESR1 mutations and therapeutic pressure promotes lineage plasticity in ER breast cancer.

Multiple next-generation molecules targeting estrogen receptor α (ERα) are being investigated in breast cancer clinical trials, encompassing thousands of women globally. Development of these molecules was partly motivated by the discovery of resistance-associated mutations in ESR1 (encodes ERα). Here, we studied the impact of ERα antagonist/degraders against Esr1 mutations expressed in mouse mammary glands.

Transformer-based modeling of Clonal Selection and Expression Dynamics reveals resistance mechanisms in breast cancer.

Understanding transcriptional heterogeneity in cancer cells and its implication for treatment response is critical to identify how resistance occurs and may be targeted. Such heterogeneity can be captured by in vitro studies through clonal barcoding methods. We present TraCSED (Transformer-based modeling of Clonal Selection and Expression Dynamics), a dynamic deep learning approach for modeling clonal selection.

Protection against Clostridioides difficile disease by a naturally avirulent strain.

Clostridioides difficile is a leading cause of healthcare infections. Gut dysbiosis promotes C. difficile infection (CDI) and CDIs promote gut dysbiosis, leading to frequent CDI recurrence.

Effectiveness and cost-effectiveness of guided self-help for depression for autistic adults: the Autism Depression Trial (ADEPT-2) - protocol for a multicentre, randomised controlled trial of a remotely delivered low-intensity intervention.

Introduction: Depression is three to four times more prevalent in autistic people and is related to reduced quality of life. There is a need for empirically supported psychological interventions for depression specifically adapted to meet the needs of autistic adults. ADEPT-2 aims to establish the clinical and cost-effectiveness of an adapted low-intensity psychological intervention (guided self-help) for depression in autistic adults.

Inhibition of GPX4 enhances CDK4/6 inhibitor and endocrine therapy activity in breast cancer.

CDK4/6 inhibition in combination with endocrine therapy is the standard of care for estrogen receptor (ER+) breast cancer, and although cytostasis is frequently observed, new treatment strategies that enhance efficacy are required. Here, we perform two independent genome-wide CRISPR screens to identify genetic determinants of CDK4/6 and endocrine therapy sensitivity. Genes involved in oxidative stress and ferroptosis modulate sensitivity, with GPX4 as the top sensitiser in both screens.