Discovery of BMS-986365, a first-in-class dual androgen receptor ligand-directed degrader (AR LDD) and antagonist, for the treatment of advanced prostate cancer.

Purpose: BMS-986365, a heterobifunctional AR LDD, was designed as a potent cereblon-dependent degrader and competitive antagonist of AR to overcome resistance to ARPIs in metastatic prostate cancer (PC).

Experimental Design: In vitro impact of BMS-986365-induced AR degradation on AR activity and PC cell proliferation was evaluated. Intrinsic agonistic and antagonist activities of BMS-987365 were assessed.

Augmented Reality in Airway Management: A Scoping Review.

Augmented reality, which overlays virtual information onto the physical environment, is an emerging technology in health care with promising applications in education, diagnostics, and procedural support. Its use in airway management-an essential aspect of anesthesiology and critical care-remains underexplored. This scoping review evaluates the current literature on augmented reality in airway management, with the aim of identifying its benefits, limitations, and future potential.

Rising nitrogen deposition leads to only a minor increase in CO uptake in Earth system models.

Current frameworks for evaluating biogeochemical climate change feedbacks in Earth System Models lack an explicit consideration of nitrogen cycling in the land and ocean spheres despite its vital role in limiting primary productivity. As coupled carbon-nitrogen cycling becomes the norm, a better understanding of the role of nitrogen cycling is needed. Here we develop a new framework for quantifying carbon-nitrogen feedbacks in Earth System Models and show that rising nitrogen deposition acts as a negative feedback over both land and ocean, enhancing carbon dioxide (CO) fertilisation in a model ensemble.

Human driven climate change increased the likelihood of the 2023 record area burned in Canada.

In 2023, wildfires burned 15 million hectares in Canada, more than doubling the previous record. These wildfires caused a record number of evacuations, unprecedented air quality impacts across Canada and the northeastern United States, and substantial strain on fire management resources. Using climate models, we show that human-induced climate change significantly increased the likelihood of area burned at least as large as in 2023 across most of Canada, with more than two-fold increases in the east and southwest.

Global climate change below 2 °C avoids large end century increases in burned area in Canada.

Wildfire impacts the global carbon cycle, property, harvestable timber, and public health. Canada saw a record fire season in 2023 with 14.9 Mha burned-over seven times the 1986-2022 average of 2.

Cell-free DNA from ascites identifies clinically relevant variants and tumour evolution in patients with advanced ovarian cancer.

The emergence of targeted therapies has transformed ovarian cancer treatment. However, biomarker profiling for precision medicine is limited by access to quality, tumour-enriched tissue samples. The use of cell-free DNA (cfDNA) in ascites presents a potential solution to this challenge.

Analysis of Anxiety, Depression and Fear of Progression at 12 Months Post-Cytoreductive Surgery in the SOCQER-2 (Surgery in Ovarian Cancer-Quality of Life Evaluation Research) Prospective, International, Multicentre Study.

Patients with ovarian cancer (OC) often experience anxiety, depression and fear of progression (FOP); however, it is unclear whether surgical complexity has a role to play. We investigated the prevalence of anxiety, depression and FOP at 12 months post-cytoreductive surgery and investigated associations with surgical complexity, patient (age, ethnicity, performance status, BMI) and tumour (stage, disease load) factors. One hundred and forty-one patients with FIGO Stage III-IV OC, who did not have disease progression at 12 months post-surgery, completed the Hospital Anxiety and Depression Scale and FOP short-form questionnaire.

Endothelial cells are a key target of IFN-g during response to combined PD-1/CTLA-4 ICB treatment in a mouse model of bladder cancer.

To explore mechanisms of response to combined PD-1/CTLA-4 immune checkpoint blockade (ICB) treatment in individual cell types, we generated scRNA-seq using a mouse model of invasive urothelial carcinoma with three conditions: untreated tumor, treated tumor, and tumor treated after CD4 T cell depletion. After classifying tumor cells based on detection of somatic variants and assigning non-tumor cell types using SingleR, we performed differential expression analysis, overrepresentation analysis, and gene set enrichment analysis (GSEA) within each cell type. GSEA revealed that endothelial cells were enriched for upregulated IFN-g response genes when comparing treated cells to both untreated cells and cells treated after CD4 T cell depletion.

Endothelial cells are a key target of IFN-g during response to combined PD-1/CTLA-4 ICB treatment in a mouse model of bladder cancer.

To explore mechanisms of response to combined PD-1/CTLA-4 immune checkpoint blockade (ICB) treatment in individual cell types, we generated scRNA-seq using a mouse model of invasive urothelial carcinoma with three conditions: untreated tumor, treated tumor, and tumor treated after CD4+ T cell depletion. After classifying tumor cells based on detection of somatic variants and assigning non-tumor cell types using SingleR, we performed differential expression analysis, overrepresentation analysis, and gene set enrichment analysis (GSEA) within each cell type. GSEA revealed that endothelial cells were enriched for upregulated IFN-g response genes when comparing treated cells to both untreated cells and cells treated after CD4+ T cell depletion.

Diagnosing destabilization risk in global land carbon sinks.

Global net land carbon uptake or net biome production (NBP) has increased during recent decades. Whether its temporal variability and autocorrelation have changed during this period, however, remains elusive, even though an increase in both could indicate an increased potential for a destabilized carbon sink. Here, we investigate the trends and controls of net terrestrial carbon uptake and its temporal variability and autocorrelation from 1981 to 2018 using two atmospheric-inversion models, the amplitude of the seasonal cycle of atmospheric CO concentration derived from nine monitoring stations distributed across the Pacific Ocean and dynamic global vegetation models.

KDM6A Loss Triggers an Epigenetic Switch That Disrupts Urothelial Differentiation and Drives Cell Proliferation in Bladder Cancer.

Unlabelled: Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. Insights into how KDM6A mutations affect the epigenetic landscape to promote carcinogenesis could help reveal potential new treatment approaches. Here, we demonstrated that KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and induces a neoplastic state characterized by increased cell proliferation.

Postanesthesia Recovery Unit Optimization for Patients With Postictal Agitation Secondary to Electroconvulsive Therapy.

Objectives: The occurrence of postictal agitation (PIA) can rapidly alter and intensify the level of care that electroconvulsive therapy (ECT) patients require during their recovery in the postanesthesia care unit (PACU). This operational analysis was undertaken to determine the impact PIA has on phase 1 PACU resources.

Methods: This operational analysis was undertaken at the Seattle Division of the US Department of Veterans Affairs Puget Sound Health Care System.

RBM47 is a Critical Regulator of Mouse Embryonic Stem Cell Differentiation.

RNA-binding proteins (RBPs) are pivotal for regulating gene expression as they are involved in each step of RNA metabolism. Several RBPs are essential for viable growth and development in mammals. RNA-binding motif 47 (RBM47) is an RRM-containing RBP whose role in mammalian embryonic development is poorly understood yet deemed to be essential since its loss in mouse embryos leads to perinatal lethality.

Process-oriented analysis of dominant sources of uncertainty in the land carbon sink.

The observed global net land carbon sink is captured by current land models. All models agree that atmospheric CO and nitrogen deposition driven gains in carbon stocks are partially offset by climate and land-use and land-cover change (LULCC) losses. However, there is a lack of consensus in the partitioning of the sink between vegetation and soil, where models do not even agree on the direction of change in carbon stocks over the past 60 years.

Association Between Local Radiation Therapy to the Primary Bladder Tumor and Overall Survival for Patients with Metastatic Urothelial Cancer Receiving Systemic Chemotherapy.

There are limited data on the role of local therapy for metastatic urothelial carcinoma of the bladder (mUC). In this retrospective cohort analysis, we queried the National Cancer Data Base for patients with newly diagnosed mUC (cT1-4 N0-3 M1). Overall survival (OS) was compared between treatment with chemotherapy (CT) alone (n = 4122) and CT plus bladder-directed radiation therapy (CT + RT; n = 337).

Correction: Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.

Quality of life from cytoreductive surgery in advanced ovarian cancer: Investigating the association between disease burden and surgical complexity in the international, prospective, SOCQER-2 cohort study.

Objective: To investigate quality of life (QoL) and association with surgical complexity and disease burden after surgical resection for advanced ovarian cancer in centres with variation in surgical approach.

Design: Prospective multicentre observational study.

Setting: Gynaecological cancer surgery centres in the UK, Kolkata, India, and Melbourne, Australia.

Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study.

Background: The standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis.