Since its invention, general anesthesia has been an indispensable component of modern surgery. While traditionally considered safe and beneficial in many pathological settings, hundreds of preclinical studies in various animal species have raised concerns about the detrimental and long-lasting consequences that general anesthetics may cause to the developing brain. Clinical evidence of anesthetic neurotoxicity in humans continues to mount as we continue to contemplate how to move forward. Notwithstanding the alarming evidence, millions of children are being anesthetized each year, setting the stage for substantial healthcare burdens in the future. Hence, furthering our knowledge of the molecular underpinnings of anesthesia-induced developmental neurotoxicity is crucially important and should enable us to develop protective strategies so that currently available general anesthetics could be safely used during critical stages of brain development. In this mini-review, we provide a summary of select strategies with primary focus on the mechanisms of neuroprotection and potential for clinical applicability. First, we summarize a diverse group of chemicals with the emphasis on intracellular targets and signal-transduction pathways. We then discuss epigenetic and transgenerational effects of general anesthetics and potential remedies, and also anesthesia-sparing or anesthesia-delaying approaches. Finally, we present evidence of a novel class of anesthetics with a distinct mechanism of action and a promising safety profile.

Bone metastasis (BM) is a leading cause of morbidity and mortality in patients with prostate and renal cancer. The complex and dynamic biological processes driving its progression present significant challenges for both understanding and treating this disease. Although current in vivo research provides valuable insights, it is often limited by the inability to fully capture the intricate and multifactorial nature of BM. Thus, complementing existing in vivo models with multiscale computational approaches is crucial for dissecting the complex interactions between tumor cells and the bone microenvironment to advance our understanding of the metastatic process and therapy response. Accordingly, we developed a series of in vivo-inspired, spatially explicit, multicellular agent-based models of BM that effectively recapitulate key aspects of tumor progression, including angiogenesis and bone resorption. The digital twins were rigorously calibrated using in vivo data from prostate and kidney tumors. The models have utility for evaluating therapy response, as verified by the simulation of both the antiangiogenic effects of cabozantinib and the antiresorptive effects of zoledronic acid. These results highlight the predictive character of the agent-based models of BM in anticipating therapeutic outcomes and increasing our understanding of the complex dynamics of BM. Significance: The model offers a transformative tool for evaluating treatment strategies, including combination therapies, with the potential to accelerate the development of highly effective, targeted interventions for bone metastatic cancers. This article is part of a special series: Driving Cancer Discoveries with Computational Research, Data Science, and Machine Learning/AI .

Over the past three decades, we have been grappling with rapidly accumulating evidence that general anesthetics (GAs) may not be as innocuous for the young brain as we previously believed. The growing realization comes from hundreds of animal studies in numerous species, from nematodes to higher mammals. These studies argue that early exposure to commonly used GAs causes widespread apoptotic neurodegeneration in brain regions critical to cognition and socio-emotional development, kills a substantial number of neurons in the young brain, and, importantly, results in lasting disturbances in neuronal synaptic communication within the remaining neuronal networks. Notably, these outcomes are often associated with long-term impairments in multiple cognitive-affective domains. Not only do preclinical studies clearly demonstrate GA-induced neurotoxicity when the exposures occur in early life, but there is a growing body of clinical literature reporting similar cognitive-affective abnormalities in young children who require GAs. The need to consider alternative GAs led us to focus on synthetic neuroactive steroid analogues that have emerged as effective hypnotics, and analgesics that are apparently devoid of neurotoxic effects and long-term cognitive impairments. This would suggest that certain steroid analogues with different cellular targets and mechanisms of action may be safe alternatives to currently used GAs. Herein we summarize our current knowledge of neuroactive steroids as promising novel GAs.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney neoplasm; bone metastasis (BM) develops in 35% to 40% of metastatic patients and results in substantial morbidity and mortality, as well as medical costs. A key feature of ccRCC is the loss of function of the von Hippel–Lindau protein, which enhances angiogenesis via vascular endothelial growth factor release. Consequently, antiangiogenic tyrosine kinase inhibitors (TKI) emerged as a treatment for ccRCC. However, limited data about their efficacy in BM is available, and no systematic comparisons have been performed. We developed mouse models of bone and lung ccRCC tumors and compared their anticancer efficacy, impact on mouse survival, and mechanisms of action, including effects on tumor cells and both immune and nonimmune (blood vessels and osteoclasts) bone stromal components. This approach elucidates the efficacy of TKIs in ccRCC bone tumors to support rational interrogation and development of therapies. Significance: TKIs showed different efficacy in synchronous bone and lung metastases and did not eradicate tumors as single agents but induced extensive reprogramming of the BM microenvironment. This resulted in a significant decrease in neoangiogenic blood vessels, bone remodeling, and immune cell infiltration (including CD8 T cells) with altered spatial distribution.

In vivo efficacy of TKIs in VHL- RENCA model over 20 days. A, B) Response to TKIs in bone (A) and lung (B) tumors detected by bioluminescence, mean + SEM, n = 8 to 16/group.

Blood vessel marker expression in bone marrow and tumors. A, B) Detection of bone marrow (A) and tumor (B) blood vessels by confocal acquisition; blue, DAPI; yellow, endomucin; red, laminin; green, tumor GFP; white boxes, magnifications reported on right panels; arrowhead, lack of physical overlap between markers; C) Immunofluorescence detection of blood vessels in VHL- RENCA bone tumors by confocal microscopy; blue, DAPI; yellow, endomucin; red, laminin; green, tumor GFP; D) Quantification of blood vessel area inside and outside tumor area based on laminin (red) and endomucin (yellow) signal, mean + SEM, n=3-4/group; blue, DAPI; green, GFP; arrowhead, blood vessels with only one marker expressed. Bar, 10 µm. Endo-endomucin; Lam-laminin; IN T-inside tumor; OUT T-outside tumor.