Biology subjects

Caskey, C. F.

Publications and source records attributed to Caskey, C. F..

5 recordsLinked to original sources

bioRxiv2023

Ultrasound Imaging Enables Longitudinal Tracking of Vascular Changes that Correlate with Immune Cell Infiltration After Radiotherapy

BackgroundWhile immunotherapy shows great promise in patients with triple negative breast cancer, many will not respond to treatment. Radiotherapy has the potential to prime the tumor-immune microenvironment for immunotherapy. However, predicting response is difficult due to tumor heterogeneity across patients, which necessitates personalized medicine strategies that incorporate tumor tracking into the therapeutic approach. Here, we investigated the use of ultrasound (US) imaging of the tumor vasculature to monitor the tumor response to treatment. MethodsWe utilized ultrafast power doppler US to track the vascular response to radiotherapy over time. We used 4T1 (metastatic) and 67NR (non-metastatic) breast cancer models to determine if US measurements corroborate conventional immunostaining analysis of the tumor vasculature. To evaluate the effects of radiation, tumor volume and vascular index were calculated using US, and the correlation between vascular changes and immune cell infiltration was determined. ResultsUS tumor measurements and the quantified vascular response to radiation were confirmed with caliper measurements and immunostaining, respectively, demonstrating a proof-of-principle method for non-invasive vascular monitoring. Additionally, we found significant infiltration of CD8+ T cells into irradiated tumors 10 days after radiation, which followed a sustained decline in vascular index and an increase in splenic CD8+ T cells that was first observed 1 day post-radiation. ConclusionsOur findings reveal that ultrafast power doppler US can evaluate changes in tumor vasculature that are indicative of shifts in the tumor-immune microenvironment. This work may lead to improved patient outcomes through observing and predicting response to therapy.

cancer biology↗

bioRxiv2023

Growth factor-free, peptide-functionalized gelatin hydrogel promotes arteriogenesis and attenuates tissue damage in a murine model of critical limb ischemia

Critical limb ischemia (CLI) occurs when blood flow is restricted through the arteries, resulting in ulcers, necrosis, and chronic wounds in the downstream extremities. The development of collateral arterioles (i.e. arteriogenesis), either by remodeling of pre-existing vascular networks or de novo growth of new vessels, can prevent or reverse ischemic damage, but it remains challenging to stimulate collateral arteriole development in a therapeutic context. Here, we show that a gelatin-based hydrogel, devoid of growth factors or encapsulated cells, promotes arteriogenesis and attenuates tissue damage in a murine CLI model. The gelatin hydrogel is functionalized with a peptide derived from the extracellular epitope of Type 1 cadherins. Mechanistically, these "GelCad" hydrogels promote arteriogenesis by recruiting smooth muscle cells to vessel structures in both ex vivo and in vivo assays. In a murine femoral artery ligation model of CLI, delivery of in situ crosslinking GelCad hydrogels was sufficient to restore limb perfusion and maintain tissue health for 14 days, whereas mice treated with gelatin hydrogels had extensive necrosis and autoamputated within 7 days. A small cohort of mice receiving the GelCad hydrogels were aged out to 5 months and exhibited no decline in tissue quality, indicating durability of the collateral arteriole networks. Overall, given the simplicity and off-the-shelf format of the GelCad hydrogel platform, we suggest it could have utility for CLI treatment and potentially other indications that would benefit from arteriole development.

bioengineering↗

bioRxiv2023

Small volume blood-brain barrier opening in macaques with a 1 MHz ultrasound phased array

Focused ultrasound blood-brain barrier (BBB) opening is a promising tool for targeted delivery of therapeutic agents into the brain. The volume of opening determines the extent of therapeutic administration and sets a lower bound on the size of targets which can be selectively treated. We tested a custom 1 MHz array transducer optimized for cortical regions in the macaque brain with the goal of achieving small volume openings. We integrated this device into a magnetic resonance image guided focused ultrasound system and demonstrated twelve instances of small volume BBB opening with average opening volumes of 59 {+/-} 37 mm3 and 184 {+/-} 2 mm3 in cortical and subcortical targets, respectively. We developed real-time cavitation monitoring using a passive cavitation detector embedded in the array and characterized its performance on a bench-top flow phantom mimicking transcranial BBB opening procedures. We monitored cavitation during in-vivo procedures and compared cavitation metrics against opening volumes and safety outcomes measured with FLAIR and susceptibility weighted MR imaging. Our findings show small BBB opening at cortical targets in macaques and characterize the safe pressure range for 1 MHz BBB opening. Additionally, we used subject-specific simulations to investigate variance in measured opening volumes and found high correlation (R2 = 0.8577) between simulation predictions and observed measurements. Simulations suggest the threshold for 1 MHz BBB opening was 0.53 MPa. This system enables BBB opening for drug delivery and gene therapy to be targeted to more specific brain regions.

bioengineering↗

bioRxiv2021

Transcranial Ultrasound Stimulation in Anterior Cingulate Cortex Impairs Information Sampling and Learning in Loss Contexts

Neuronal subgroups in anterior cingulate cortex (ACC) and the anterior striatum (STR) encode the reward structure of a given environment. But whether or how this reward information is used to guide information sampling, optimize decision making, or motivate behavior in cognitively challenging situations has remained elusive. Here, we causally tested these scenarios by transiently disrupting ACC and STR of rhesus monkeys with transcranial ultrasound with a learning task that independently varied cognitive and motivational demands. We found that disrupting the ACC, but not the STR, prolonged information sampling and reduced learning efficiency whenever the motivational payoff was low. These impairments were most pronounced at high cognitive demands and based on an inability to use loss experiences to improve performance. These results provide causal evidence that the ACC is necessary for motivation, to overcome anticipated costs from negative (loss) outcomes, and for cognition, to enhance visual information sampling during adaptive behavior. HIGHLIGHTSO_LITranscranial ultrasound stimulation of the anterior cingulate cortex disrupts learning after loss experience. C_LIO_LIThe ultrasound-induced learning deficit is exacerbated at high cognitive load. C_LIO_LIThe ultrasound-induced learning deficit is accompanied by inefficient fixational information sampling. C_LIO_LIAnterior cingulate cortex causally supports credit assignment of aversive outcomes to visual features. C_LI

neuroscience↗

bioRxiv2020

Rapid quantitative imaging of high intensity ultrasonic pressure fields

High-intensity focused ultrasound (FUS) is a noninvasive technique for thermal or mechanical treatment of tissues that can lie deep within the body, with a growing body of FDA-approved indications. There is a pressing need for methods to rapidly and quantitatively map FUS beams for quality assurance in the clinic, and to accelerate research and development of new FUS systems and techniques. However, conventional ultrasound pressure beam mapping instruments including hydrophones and optical techniques are slow, not portable, and expensive, and most cannot map beams at actual therapeutic pressure levels. Here, we report a rapid projection imaging method to quantitatively map FUS pressure beams based on continuous-wave background-oriented schlieren (CW-BOS) imaging. The method requires only a water tank, a background pattern and a camera, and uses a multi-layer deep neural network to reconstruct beam maps. Results at two FUS frequencies show that CW-BOS imaging can produce high-resolution quantitative projected FUS pressure maps in under ten seconds, that the technique is linear and robust to beam rotations and translations, and that it can accurately map aberrated beams.

bioengineering↗