Biology subjects

Costanzo, F.

Publications and source records attributed to Costanzo, F..

8 recordsLinked to original sources

bioRxiv2025

Targeting FOXA1 and FOXA2 Disrupts the Lineage-Specific Oncogenic Output Program in Prostate Cancer

Activation of the androgen receptor (AR) is the key lineage-specific oncogenic pathway and the primary therapeutic target in prostate cancer. While AR signaling is enabled by the pioneer transcription factor FOXA1, its homolog FOXA2 is specifically expressed in advanced lineage plasticity prostate cancers that have lost the AR signaling axis. However, their roles and utility as drug targets remain incompletely characterized. Here, we show an unexpected collaboration of FOXA1 and FOXA2 in mediating AR-independent cell proliferation in different lineage plasticity cancer subtypes. Conversely, joint loss-of-function or pharmacologic disruption of FOXA1 and FOXA2 leads to the collapse of lineage-specific oncogenic transcription factors followed by cell cycle arrest. In summary, our findings uncover a druggable dependency for AR-positive and - negative prostate cancers.

cancer biology↗

bioRxiv2025

Gut-Brain Hydraulics: Brain motion and CSF circulation is driven by mechanical coupling with the abdomen

The brain moves within the skull, but the drivers and function of this motion are not understood. We visualized brain motion relative to the skull in awake head-fixed mice using high-speed, multi-plane two-photon microscopy. Brain motion was primarily rostrally and laterally directed, and was tightly correlated with locomotion, but not with respiration or the cardiac cycle. Electromyography recordings in abdominal muscles and microCT reconstructions of the trunk and spinal vasculature showed that brain motion was driven by abdominal muscle contractions that activate a hydraulic-like vascular connection between the nervous system and the abdominal cavity. Externally-applied abdominal pressure generated brain motion similar to those seen during abdominal muscle contractions. Simulations showed that brain motion drives substantial volumes of interstitial fluid through and out of the brain (at volumetric rates several times higher than production) into the subarachnoid space, in the opposite direction of fluid flow seen during sleep. The brain is hydraulically linked to the abdominal compartment, and fluid flow in the brain is coupled to body movements, providing a mechanism by which the mechanics of the viscera directly impact brain health.

neuroscience↗

bioRxiv2023

Modeling Flow in an In Vitro Anatomical Cerebrovascular Model with Experimental Validation

Acute ischemic stroke (AIS) is a leading cause of mortality that occurs when an embolus becomes lodged in the cerebral vasculature and obstructs blood flow in the brain. The severity of AIS is determined by the location and how extensively emboli become lodged, which are dictated in large part by the cerebral flow and the dynamics of embolus migration which are difficult to measure in vivo in AIS patients. Computational fluid dynamics (CFD) can be used to predict the patient-specific hemodynamics and embolus migration and lodging in the cerebral vasculature to better understand the underlying mechanics of AIS. To be relied upon, however, the computational simulations must be verified and validated. In this study, a realistic in vitro experimental model and a corresponding computational model of the cerebral vasculature are established that can be used to investigate flow and embolus migration and lodging in the brain. First, the in vitro anatomical model is described, including how the flow distribution in the model is tuned to match physiological measurements from the literature. Measurements of pressure and flow rate for both normal and stroke conditions were acquired and corresponding CFD simulations were performed and compared with the experiments to validate the flow predictions. Overall, the CFD simulations were in relatively close agreement with the experiments, to within {+/-}7% of the mean experimental data with many of the CFD predictions within the uncertainty of the experimental measurement. This work provides an in vitro benchmark data set for flow in a realistic cerebrovascular model and is a first step towards validating a computational model of AIS.

bioengineering↗

bioRxiv2022

Computational Analysis of Effects of Clot Length on Acute Ischemic Stroke Recanalization under Different Cyclic Aspiration Loading Conditions

Acute ischemic stroke, the second leading cause of death worldwide, results from occlusion of a cerebral artery by a blood clot. Application of cyclic aspiration using an aspiration catheter is a current therapy for the removal of lodged clots. In this study, we perform finite element simulations to analyze deformation of long clots, having length to radius ratio of 2 to 10, which corresponds to clot-length of 2.85-14.25 mm, under peak-to-peak cyclic aspiration pressures of 10 to 50mmmHg, and frequencies of 0.5, 1 and 2 Hz. Our computational system comprises of a nonlinear viscoelastic solid clot, a hyperelastic artery, and a nonlinear viscoelastic cohesive zone, the latter modeling the clot-artery interface. We observe that clots having length-to-radius ratio approximately greater than two separate from the inner arterial surface somewhere between the axial and distal ends, irrespective of the cyclic aspiration loading conditions. The stress distribution within the clot shows large tensile stresses in the clot interior, indicating the possibility of simultaneous fragmentation of the clot. Thus, this study shows us the various failure mechanisms simultaneously present in the clot during cyclic aspiration. Similarly, the stress distribution within the artery implies a possibility of endothelial damage to the arterial wall near the end where the aspiration pressure is applied. This framework provides a foundation for further investigation to clot fracture and adhesion characterization.

bioengineering↗

bioRxiv2021

Arterial vasodilation drives convective fluid flow in the brain: a poroelastic model

The movement of fluid into, through, and out of the brain plays an important role in clearing metabolic waste. However, there is controversy regarding the mechanisms driving fluid movement, and whether the movement metabolic waste is primarily driven by diffusion or convection. The dilation of penetrating arterioles in the brain in response to increases in neural activity (neurovascular coupling) is an attractive candidate for driving fluid circulation, as it drives deformation of the brain tissue and of the paravascular space around arteries, resulting in fluid movement. We simulated the effects of vasodilation on fluid movement into and out of the brain using a novel poroelastic model of brain tissue. We found that arteriolar dilations could drive convective flow through the brain radially outward from the arteriole, and that this flow is sensitive to the dynamics of the dilation. Simulations of sleep-like conditions, with larger vasodilations and increased extracellular volume in the brain showed enhanced movement of fluid from the paravascular space into the brain. Our simulations suggest that both sensory-evoked and sleep-related arteriolar dilations can drive convective flow of cerebrospinal fluid from the paravascular space into the brain tissue around arterioles.

neuroscience↗

bioRxiv2020

Aspiration-assisted Freeform Bioprinting of Tissue Spheroids in a Yield-stress Gel

Bioprinting of cellular aggregates, such as tissue spheroids or organoids, in complex three-dimensional (3D) arrangements has been a major obstacle for scaffold-free fabrication of tissues and organs. In this research, we unveiled a new approach to the bioprinting of tissue spheroids in a yield stress granular gel, which exhibited unprecedented capabilities in freeform positioning of spheroids in 3D. Due to its Herschel-Bulkley and self-healing properties as well as its biological inertness, the granular gel supported both the positioning and self-assembly of tissue spheroids. We studied the underlying physical mechanism of the approach to elucidate the interactions between the aspirated spheroids and the gels yield-stress during the transfer of spheroids from cell media to the gel. We demonstrate the application of the proposed approach in the realization of various freeform shapes and self-assembly of human mesenchymal stem cell spheroids for the construction of cartilage and bone tissues.

bioengineering↗

bioRxiv2020

Arterial pulsations drive oscillatory flow of CSF but not directional pumping

The brain lacks a traditional lymphatic system for metabolite clearance. The existence a "glymphatic system" where metabolites are removed from the brains extracellular space by convective exchange between interstitial fluid (ISF) and cerebrospinal fluid (CSF) along the paravascular spaces (PVS) around cerebral blood vessels has been controversial for nearly a decade. While recent work has shown clear evidence of directional flow of CSF in the PVS in anesthetized mice, the driving force for the observed fluid flow remains elusive. The heartbeat-driven peristaltic pulsation of arteries has been proposed as a probable driver of directed CSF flow. In this study, we use rigorous fluid dynamic simulations to provide a physical interpretation for peristaltic pumping of fluids. Our simulations match the experimental results and show that arterial pulsations only drive oscillatory motion of CSF in the PVS. The observed directional CSF flow can be explained by naturally occurring and/or experimenter-generated pressure differences.

neuroscience↗

bioRxiv2019

Functional hyperemia drives fluid exchange in the paravascular space

Maintaining the ionic and chemical composition of the extracellular spaces in the brain is extremely important for its health and function. However, the brain lacks a conventional lymphatic system to remove metabolic waste. It has been proposed that the fluid movement through the paravascular space (PVS) surrounding penetrating arteries can help remove metabolites from the brain. The dynamics of fluid movement in the PVS and its interaction with arterial dilation and brain mechanics are not well understood. Here, we performed simulations to understand how arterial pulsations and dilations interact with brain deformability to drive fluid flow in the PVS. In simulations with compliant brain tissue, arterial pulsations did not drive appreciable flows in the PVS. In contrast, when the artery dilated with dynamics like those seen during functional hyperemia, there was a marked movement of fluid through the PVS. Our simulations suggest that in addition to its other purposes, functional hyperemia may serve to increase fluid exchange between the PVS and the subarachnoid space, improving the clearance of metabolic waste. We measured displacement of the blood vessels and the brain tissue simultaneously in awake, head-fixed mice using two-photon microscopy. Our measurements show that brain tissue can deform in response to fluid movement in the PVS, as predicted by simulations. The results from our simulations and experiments show that the deformability of the soft brain tissue needs to be accounted for when studying fluid flow and metabolite transport in the brain.

neuroscience↗