The FDA convened an expert panel on July 17, 2025, to review evidence on the benefits and risks of menopausal hormone therapy. Members of The Menopause Society who served on the expert panel summarize the meeting, including panelists' presentations and future directions. The FDA selected a multidisciplinary group of researchers and clinicians based on their expertise, clinical and academic credibility, leadership, and advocacy in caring for menopausal women's health. The panel emphasized the differences between systemic and local vaginal estrogen and the adverse effects of class labeling and the boxed warning, especially for local vaginal estrogen. The panel discussed differences in risk profiles between estrogen alone and estrogen combined with different types of progestogens, and the importance of formulation, route of administration, dosing, and timing of initiation. Following this discussion, a 60-day public commentary period, and an independent review of the literature, on November 10, 2025, the FDA recommended removing boxed warnings from estrogen therapies, with specific, nuanced considerations.

Metastatic cancer cell dormancy, wherein disseminated cancer cells (DCCs) persist in a quiescent state before reactivating to fuel metastasis, has emerged as a critical determinant of cancer relapse. In this Review, we synthesize recent advances in understanding the microenvironmental drivers of dormancy, including the role of niche-derived signals and extracellular matrix composition in maintaining DCC quiescence, as well as the epigenetic and transcriptional programmes, and chromatin remodelling that enforce and sustain dormancy. We also cover the mechanisms by which dormant DCCs evade immune surveillance, highlighting both innate and adaptive immune interactions, and the strategies tumours use to escape immune-mediated clearance. Although most data come from solid cancers, we also examine the biology of residual cells in haematologic malignancies that share key dormancy and relapse mechanisms with solid tumours. We also discuss how, despite these mechanistic insights, clinical translation remains limited, as available biomarkers or therapies targeting dormancy have yet to be effectively implemented. We conclude that by outlining the challenges and opportunities for leveraging dormancy biology, we may be able to prevent metastatic recurrence and improve patient outcomes.

[177]Lu-PSMA-617 represents a transformative treatment for metastatic castration-resistant prostate cancer (mCRPC), yet biomarkers of benefit beyond prostate-specific membrane antigen positron emission tomography (PSMA-PET) imaging remain lacking. Here, we present findings from a prospective study of 100 mCRPC patients receiving [177]Lu-PSMA-617, using shotgun proteomics to profile plasma-derived extracellular vesicle (EV) proteins alongside PSMA-positive circulating tumor cell (CTC) enumeration. We identify 5,137 EV-derived proteins, including the cell-surface targets PSMA, B7-H3, Trop-2, and STEAP1, with high levels of these proteins associating with worse overall survival (OS). All four EV proteins positively correlate with molecular tumor volume on PSMA-PET imaging, serum PSA, and serum alkaline phosphatase. CTC subpopulations, including PSMA+/EpCAM+ and PSMA-/EpCAM+ cells, associate with worse progression-free survival (PFS) and OS. Pathway analysis reveals that p53 upregulation associates with poor PFS and OS, while an activated E2F pathway unexpectedly portends better PFS and OS. These findings support the integration of liquid biopsy proteomics into biomarker-driven mCRPC trials to improve patient stratification.

Homozygous loss of the 9p21 locus encompassing CDKN2A, CDKN2B, and MTAP is the most frequent copy number alteration across tumor types, making it a promising target for precision medicine strategies. To explore drug vulnerabilities exposed by this loss, we generated 9p21 locus isogenic bladder cancer (BLCA) cell models to perform a multiparametric drug screen, testing 2,349 compounds. We identified cytarabine and methotrexate as significantly more effective in the 9p21 compromised BLCA cells. Analysis of morphological alterations further supported a genotype-specific activity of nucleoside analogs, nominating gemcitabine as a drug with greater efficacy in this context. To further exploit MTAP loss, we explored drug combinations targeting MTAP synthetic lethal partners, PRMT5 and MAT2A. Synergy between cytarabine and inhibitors of PRMT5 (MRTX1719) and MAT2A (AG-270) was mediated by a differential activation of DNA damage and replication stress markers, suggesting an exploitable vulnerability. In fact, rational drug combinations with ATR/CHK1 pathway inhibitors increased efficacy while maintaining 9p21-specificity. Finally, we confirmed the effectiveness of these combinations in cell models of pancreatic adenocarcinoma and pleural mesothelioma, two tumor types with high prevalence of MTAP loss and, most notably, in bladder cancer patient-derived organoids, underscoring the strong translational potential of our findings.

Circulating tumor cells (CTCs) are cancer cells found in the bloodstream that serve as biomarkers for early cancer detection, prognostication, and disease monitoring. However, CTC detection remains challenging due to low cell abundance and heterogeneity. Digital holographic microscopy (DHM) offers a promising, label-free method for high-throughput CTC identification by capturing superior morphological information compared to traditional imaging methods, while remaining compatible with in-flow data acquisition. We present a streamlined DHM-based system that integrates microfluidic enrichment with deep learning-driven image analysis, supplemented by immunofluorescent profiling, to improve sensitivity and specificity of CTC enumeration. Specifically, our platform combines inertial microfluidic preprocessing with dual-modality imaging, integrating holography with fluorescence sensing of up to two markers. A deep learning model, trained on a diverse set of healthy blood samples and cancer cell lines, and executed in real-time, provides a morphological confidence on a cell-by-cell basis that may then be combined with immunofluorescence criteria for enumeration. In a pilot study, we demonstrate higher CTC counts in patients with late-stage prostate cancer (n = 13) compared to healthy controls (n = 8), with a patient-level false positive rate of 1 cell/mL. Notably, nearly two-thirds of identified CTCs were EpCAM-negative but PSMA positive (a prostate specific epithelial marker), suggesting that traditional use of EpCAM as an epithelial marker for CTCs may lead to false negatives. These findings highlight the potential of DHM for applications including but not limited to screening, diagnostics, and precision oncology.

Copyright: © 2026 Makovec et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Prostate gland cells can be transcriptionally and morphologically characterized as basal and luminal. About 30–40% of advanced prostate cancers (PC) harbor basal-like transcription programs. In castration-resistant PC (CRPC), studies indicate that basal and stem cell-like (SCL) tumors are major resistance mechanisms to androgen receptor (AR)-targeted therapies. SCL tumors have reduced AR activity and increased stem-cell activity that promotes tumor formation, which contributes to poor clinical outcomes. We determined that CREB5 is a key regulator of basal and SCL transcriptional programs and tumor-forming phenotypes in PC. Through in silico modeling of PC transcriptomes and several pre-defined PC signaling programs, CREB5 expression was best associated with basal-like gene signatures and SCL-associated genes in primary PC and CRPCs (n = 493 and 208). This included associations with FOSL1 and other AP-1 transcription factors. We further found that CREB5 interacted with AP-1 proteins and bound to the regulatory elements of AP-1 genes, suggesting a mechanistic role in regulating the activity of AP-1 genes. In AR-positive cells, CREB5 overexpression promoted cell colony growth with tumorigenic properties and increased tumor size in vivo. These findings implicate CREB5 as a driver of the transcriptional programs underlying AR-independent basal and SCL CRPC subtypes, and this activity is detectable in primary PC.

Polar chromosomes, which initially attach to the mitotic spindle behind the pole, are prone to missegregation and micronuclear entrapment, contributing to chromosomal instability in cancer. Yet, the mechanisms ensuring their faithful segregation remain unclear. Here, we show that polar chromosomes require a unique step involving spindle elongation, which repositions chromosome-bound astral microtubules by pivoting them around the centrosome toward the spindle surface. By modulating Eg5/KIF11 activity, we demonstrate that spindle elongation determines the direction and extent of pivoting, with microtubules from the opposite spindle half facilitating final movement. Kinetochores on polar chromosomes form mono-lateral attachments, recruiting corona components and partially Mad2, but lacking Astrin. In cancer cell lines, limited spindle elongation delays polar chromosome resolution, whereas enhanced elongation accelerates it. These findings highlight the role of spindle elongation in the timely rescue of chromosomes from the "danger zone" behind the pole, providing mechanistic insight into chromosome congression errors in cancer.

Bladder cancer (BLCA) is a common malignant tumor of the urinary system. Kinetochore-localized astrin-binding protein (KNSTRN) has been implicated in the initiation and progression of multiple cancers. Furthermore, abnormal autophagy levels have been shown to significantly impact tumor development. However, the mechanism by which KNSTRN regulates autophagy in BLCA remains unclear. This study reveals that KNSTRN knockdown inhibits autophagy flux in BLCA. The mechanism involves ROS-dependent disruption of lysosomal function upon KNSTRN knockdown, thereby impeding autophagosome-lysosome fusion. Clioquinol restores lysosomal activity by regulating lysosomal pH, subsequently reestablishing autophagy flux. The ROS scavenger N-acetylcysteine (NAC) reverses lysosomal dysfunction and reactivates the autophagic flux. Furthermore, the autophagy activator rapamycin (Rapa) effectively counteracts KNSTRN knockdown-induced cell death in both in vitro and in vivo experiments. Collectively, we demonstrate that KNSTRN knockdown induces intracellular ROS accumulation and lysosomal dysfunction, thereby disrupting autophagic flux and inhibiting BLCA progression.

Faithful chromosome segregation requires the spatial and temporal remodeling of cell structures driven largely by cyclin-dependent kinase (Cdk) activity. In some experimental systems the timely elevation of one cyclin isoform is sufficient to support mitotic entry and progression. In human somatic cells, however, three cyclins - Cyclin A2, Cyclin B1, and Cyclin B2 - are present at mitotic entry, and their distinct contributions during mitosis remain largely unclear. We demonstrate that Cyclin A2 promotes the kinetochore localization of Cyclin B1, Cyclin B2 and the fibrous corona component CENPF, while suppressing recruitment of the kinetochore-microtubule (k-MT) stabilizer Astrin. Extending Cyclin A2 into metaphase by expressing a non-degradable mutant causes persistent kinetochore localization of Cyclin B1, Cyclin B2, and CENPF. Conversely, Cyclin B1 limits kinetochore localization of Cyclin B2 and CENPF, promotes Astrin recruitment, and stabilizes k-MT attachments and Cyclin B1 overexpression further reduces kinetochore localization of CENPF during prometaphase. These findings reveal an interdependence among mitotic cyclins in early mitosis and the countervailing activities of Cyclin A2 versus Cyclin B1/B2 in regulating key mitotic events. We propose that this circuitry enforces a switch-like transition from prometaphase - marked by corona assembly and high k-MT turnover - to metaphase - marked by corona disassembly, stabilization of end-on k-MT attachments, and eventual spindle assembly checkpoint satisfaction - to choreograph the structural changes required to ensure faithful chromosome segregation.

The Earth BioGenome Project (EBP) aims to "sequence life for the future of life" by generating high-quality reference genome sequences for all recognized eukaryotic species, thereby building a rich knowledge base to inform conservation, inspire bioindustry, ensure food security, advance medicine, and establish a deeper understanding of biodiversity. As the EBP works toward completing the original Phase I goal-a reference genome for each of the approximately 10,000 taxonomic families of eukaryotes-milestone publications have demonstrated the transformative potential of the project. The EBP has promoted global collaboration and established core methods and standards. By the end of 2024, EBP-affiliated projects had publicly released 2,000 high-quality genome assemblies, representing more than 500 eukaryotic families. In this article, we present a revised set of goals for Phases I and II of the EBP. For Phase II, we propose generating reference genomes for 150,000 species over 4 years, including representative genomes for at least 50% of all accepted genera and for additional species of biological and economic importance. To deliver Phase II, EBP-affiliated projects will have to release over 3,000 new genomes per month. We review the magnitude of the tasks in sourcing, sequencing, assembling, annotating, and analyzing genomes at this scale, and explore the scientific, technical, social, legal, ethical, and funding challenges associated with them. Success in Phase II will set the stage for sequencing the remaining ~1.5 million named species of Eukaryota and establishing the knowledge platforms necessary for understanding, preserving, and utilizing Earth's biodiversity in an era of rapid environmental change.

Curated electronic health records offer valuable insights into real-world outcomes for patients with advanced tumors. We described real-world treatment effectiveness among patients with HR+/HER2- metastatic breast cancer (mBC) and metastatic triple-negative breast cancer (mTNBC) using ConcertAI Patient360™ Breast Cancer dataset. Patients initiating therapies selected based on literature review and data availability in the metastatic setting between January 1, 2016, and November 30, 2021, were included. Real-world response rate (rwRR), progression-free survival (rwPFS), overall survival (rwOS), time-to-next treatment (rwTTNT), and time-to-discontinuation (rwTTD) were assessed. Three HR+/HER2- mBC cohorts included 292 patients treated with palbociclib + fulvestrant, 274 patients treated with fulvestrant monotherapy, and 381 patients treated with paclitaxel-based therapy; the mTNBC cohort included 247 chemotherapy-treated patients. Median rwOS in three HR+/HER2- cohorts ranged from 15.6 to 32.3 months and was 13 months in mTNBC; median rwPFS ranged from 5.6 to 8.6 months, and 4.4 months, respectively. The alignment between several real-world and clinical trial endpoints is encouraging and supports the utility of real-world data in contextualizing outcomes, though interpretation may be influenced by data completeness and variability in clinical documentation. These insights are particularly relevant for populations with persistent unmet clinical needs.

High-quality reference genome assemblies have become essential for deepening our understanding of biodiversity, yet obtaining them for many species remains surprisingly challenging. Drawing on experiences from the European Reference Genome Atlas (ERGA) community, we focus on permit and sample-handling procedures leading up to nucleic acid sequencing, covering tasks such as ensuring ethical and legal compliance, verifying accurate species identification, maintaining sample integrity during transport, and isolating high-quality DNA or nuclei. While many of the challenges and solutions we discuss are broadly relevant, our regulatory and logistical examples are primarily from Europe. By synthesising practical guidance, we highlight the crucial importance of taxonomic expertise, proper vouchering and biobanking, rigorous cold-chain management or alternative preservation methods, and emphasise adherence to packaging and shipping requirements for biological materials. We showcase examples spanning diverse regions, taxa and source materials, which underscore the importance of context-specific strategies and internationally harmonised protocols, particularly for metadata reporting. Our recommendations aim to support both small-scale projects and large initiatives, directing collective efforts to facilitate efficient sampling, vouchering and sample processing for future genomic studies.