The management of metastatic castration-resistant prostate cancer (mCRPC) is continuously challenged by the emergence of therapeutic resistance. Under the selective pressure of profound androgen inhibition, a significant proportion of tumors undergo lineage plasticity, evolving into double-negative prostate cancer (DNPC). Defined by the concomitant loss of androgen receptor (AR) dependence and the absence of classic neuroendocrine markers, DNPC represents a highly aggressive, independent evolutionary steady state. The fundamental drivers of this phenotypic transition include the concurrent functional loss of TP53 and RB1, coupled with pervasive epigenetic reprogramming. These genetic and epigenetic events profoundly rewire core transcriptional networks, activate alternative kinase pathways, and establish an immunosuppressive microenvironment. Because the downregulation of conventional targets renders standard diagnostic and therapeutic interventions ineffective, a paradigm shift in clinical strategy is imperative. This review delineates the molecular ontogeny of DNPC. We further explore mechanistically grounded therapeutic modalities, including epigenetic modulation, synthetic lethality, and precision delivery systems. Ultimately, we advocate for the concept of "evolutionary interception," providing a strategic roadmap to dismantle the survival networks of advanced DNPC.
Lei Fan, Jiawei Li, Chunhao Mo et al.· Critical reviews in oncology...· 0 citations
Rapid urbanization and intensifying climate extremes are increasing pressure on conventional urban drainage systems, accelerating interest in digital transformation. Yet how such transformation unfolds in practice, particularly in medium-sized cities, remains poorly understood. Using Lianyungang City, China, as an illustrative case, this study examines stakeholder perceptions of the socio-technical conditions associated with its digital drainage transformation. Drawing on a structured questionnaire survey of drainage professionals, the analysis assesses stakeholder perceptions of system performance, awareness and expectations of digital technologies, governance readiness, and stage-specific barriers. The results reveal strong support for digitalization but persistent constraints. At the initiation stage, progress is limited by aging infrastructure, shortages of interdisciplinary expertise, and financial constraints. During implementation, socio-technical misalignment, legacy-system incompatibility, fragmented data governance, and weak operation and maintenance capacity dominate. Governance limitations are a perceived limiting factor on scaling digital initiatives, while transparency and public participation remain underprioritized. The study advances a capacity-oriented understanding of digital drainage transformation and offers policy insights for medium-sized cities.
Lei Fan, Bowen Tan· Discover Civil Engineering· 0 citations