ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity.

PURPOSE: Tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer (BC), resulting in tumor progression, therapeutic failure and metastatic spread. The transcription factor ONECUT2 (OC2) has been shown to be a master regulator protein of metastatic castration-resistant prostate cancer (mCRPC) tumors that promotes lineage plasticity to a drug-resistant neuroendocrine (NEPC) phenotype. Here, we investigate the role of OC2 in the dynamic conversion between different molecular subtypes in BC. METHODS: We analyze OC2 expression and clinical significance in BC using public databases and immunohistochemical staining. In vitro, we perform RNA-Seq, RT-qPCR and western-blot after OC2 enforced expression. We also assess cellular effects of OC2 silencing and inhibition with a drug-like small molecule in vitro and in vivo. RESULTS: OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and tamoxifen-resistant models, and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. OC2 inhibits ER expression and activity, suppresses a gene expression program associated with luminal differentiation and activates a basal-like state at the gene expression level. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors. CONCLUSIONS: The transcription factor OC2 is a driver of BC heterogeneity and a potential drug target in distinct cell states within the breast tumors.

Analysis of Mercury in Aquifers in Gold Mining Areas in the Ecuadorian Amazon and Its Associated Risk for Human Health.

Gold mining activity is a source of supply in many areas of the world, and especially in developing countries, it is practiced illegally and by applying unsafe techniques. Particularly in Ecuador, artisanal and small-scale gold mining (ASGM) is widespread, and it is based on the use of toxic substances, such as mercury (Hg), in gold recovery. Hg is a heavy metal that is water-insoluble, which, once mobilized, poses a threat to both the environment and human health. This study analyzes Hg concentrations in the six provinces of Napo, Sucumbíos, Orellana, Pastaza, Morona Santiago, and Zamora Chinchipe of the Ecuadorian Amazon region to conduct a human health risk assessment. Significant differences in Hg levels were found between provinces, but concentrations were below MPL imposed by Ecuadorian regulations everywhere. Nevertheless, a worrisome picture emerges, especially with regard to the most vulnerable receptors represented by the child population. There are multiple factors of incidence that may affect the possible future development of the phenomenon, and with reference to the social, economic, and environmental context of the region, it can be concluded that it may be appropriate to plan further investigation to arrive at a more comprehensive assessment. The results of this study can be used by decision makers to plan further investigation and to implement monitoring networks, risk mitigation strategies, and groundwater protection measures.

Actionable Driver Events in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) stands out as the most aggressive form of lung cancer, characterized by an extremely high proliferation rate and a very poor prognosis, with a 5-year survival rate that falls below 7%. Approximately two-thirds of patients receive their diagnosis when the disease has already reached a metastatic or extensive stage, leaving chemotherapy as the remaining first-line treatment option. Other than the recent advances in immunotherapy, which have shown moderate results, SCLC patients cannot yet benefit from any approved targeted therapy, meaning that this cancer remains treated as a uniform entity, disregarding intra- or inter-tumoral heterogeneity. Continuous efforts and technological improvements have enabled the identification of new potential targets that could be used to implement novel therapeutic strategies. In this review, we provide an overview of the most recent approaches for SCLC treatment, providing an extensive compilation of the targeted therapies that are currently under clinical evaluation and inhibitor molecules with promising results in vitro and in vivo.

Muerte por luxación atlantoaxial: presentación de caso / Atlantoaxial luxation luxation death: a case report

Se presenta el caso de una muerte por luxación atlantoaxial resultado de una agresión, en la cual no hubo uso de armas u otro objeto que se pudiera identificar como tal. Se realiza el reporte por lo poco común del caso y la importancia que tiene la prevención de las agresiones físicas en nuestra sociedad (AU)