Dr. Joshua B. Rubin Profile

Dr. Joshua B. Rubin

at Washington Univ in St Louis

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Publications (3)

Proceedings Article | 9 March 2020 Presentation

Functional connectivity predicts behavior deficit in a mouse model of brain tumor growth (Conference Presentation)

Inema Orukari, Nicole Warrington, Adam Bauer, Joshua Rubin, Joseph Culver

Proceedings Volume 11225, 1122506 (2020) https://doi.org/10.1117/12.2556218

KEYWORDS: Tumors, Brain, Mouse models, Magnetic resonance imaging, Neuroimaging, Modulation, Nervous system, Human subjects, Optical imaging, Sensors

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Tumors in the central nervous system (CNS) can produce significant behavior deficits. These deficits significantly reduce the quality of life of long-term brain tumor survivors. Motor deficits can be the main presenting symptoms that brings a brain tumor patient into the hospital. Additionally, motor deficits can either improve or worsen after treatment. Its poorly understood how tumor phenotype (e.g infiltrative or circumscribed) contributes to the development and evolution of motor deficits. Resting state functional connectivity magnetic resonance imaging (rsfc-MRI) could help determine a relationship between brain function and tumor phenotype. rsfc-MRI provides measurements of functional connectivity (FC), which is a measure of brain activity and has been shown to correlate with neurological function (e.g. cognitive and motor deficit) in many disease states. Additional studies are needed before rsfc-MRI can be included in the standard of care for brain tumor patients because it is largely unknown how important clinical factors, such as tumor location and tumor burden (e.g. tumor volume), modulate the association between FC measurements and neurological performance. However, human studies are unlikely to have the statistical power to determine the relationships between FC, clinical factors, and neurological function because it is difficult to enroll many human subjects while controlling for a factor. Fortunately, mice can be used to control for a factor in many genetically identical specimens. Therefore, FC assessments need to be applied to studies in mouse models of brain tumors to assess the interactions be specific clinical factors, FC measurements and neurological function. FC measurements are infrequently obtained in mouse models because it is technically difficult to perform rsfc-MRI on the small mouse brain. Fortunately, functional connectivity optical intrinsic signal imaging (fcOISI) can be used obtain FC measurements in mice. In this study, we investigated how tumor phenotype modulates the relationship between tumor burden measures and motor function. We injected in two groups of mice with human brain tumor cell lines that exhibit different growth phenotypes. We assessed the motor function of the mice by their performance on a battery of sensorimotor tests. We determined tumor burden with bioluminescence and MRI and assessed FC with fcOISI. Lastly, we performed linear regression analysis to determine how these measured factors interact in the prediction of performance on the motor tests.

SPIE Journal Paper | 28 February 2020 Open Access

Intracranial glioma xenograft model rapidly reestablishes blood–brain barrier integrity for longitudinal imaging of tumor progression using fluorescence molecular tomography and contrast agents

LeMoyne Habimana-Griffin, Dezhuang Ye, Julia Carpenter, Julie Prior, Gail Sudlow, Lynne Marsala, Matthew Mixdorf, Joshua Rubin, Hong Chen, Samuel Achilefu

JBO, Vol. 25, Issue 02, 026004, (February 2020) https://doi.org/10.1117/12.10.1117/1.JBO.25.2.026004

KEYWORDS: Tumors, Luminescence, Brain, Blood brain barrier, Neuroimaging, Near infrared, Tissues, Fluorescence tomography, Tomography, Bioluminescence

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Significance: The blood–brain barrier (BBB) is a major obstacle to detecting and treating brain tumors. Overcoming this challenge will facilitate the early and accurate detection of brain lesions and guide surgical resection of tumors. Aim: We generated an orthotopic brain tumor model that simulates the pathophysiology of gliomas at early stages; determine the BBB integrity and breakdown over the time course of tumor progression using generic and cancer-targeted near-infrared (NIR) fluorescent molecular probes. Approach: We developed an intracranial tumor xenograft model that rapidly reestablished BBB integrity and monitored tumor progression by bioluminescence imaging. Sham control mice were injected with phosphate-buffered saline only. Fluorescence molecular tomography (FMT) was used to quantify the uptake of tumor-targeted and passive NIR fluorescent imaging agents in orthotopic glioma (U87-GL-GFP PDE7B H217Q cells) tumor model. Cancer-induced and transient (with focused ultrasound, FUS) disruption of BBB integrity was monitored with NIR fluorescent dyes. Results: Stereotactic injection of 50,000 cells into mouse brain allowed rapid reestablishment of BBB integrity within a week, as determined by the inability of both tumor-targeted and generic NIR imaging agents to extravasate into the brain. Tumor-induced BBB disruption was observed 7 weeks after tumor implantation. FUS achieved a similar effect at any time point after reestablishing BBB integrity. While tumor uptake and retention of the passive NIR dye, indocyanine green, was negligible, both actively tumor-targeting agents exhibited selective accumulation in the tumor region. The tumor-targeting molecular probe that clears rapidly from nontumor brain tissue exhibits higher contrast than the analogous vascular-targeting agent and helps delineate tumors from sham control. Conclusions: We highlight the utility of FMT imaging for longitudinal assessment of brain tumors and the interplay between the stages of BBB disruption and molecular probe retention in tumors, with potential application to other neurological diseases.

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Proceedings Article | 19 April 2017 Presentation

An optical assessment of the effects of glioma growth on resting state networks in mice (Conference Presentation)

Inema Orukari, Adam Bauer, Grant Baxter, Joshua Rubin, Joseph Culver

Proceedings Volume 10051, 100510P (2017) https://doi.org/10.1117/12.2252817

KEYWORDS: Tumors, Current controlled current source, Brain, Optical imaging, Mouse models, Somatosensory cortex, Magnetic resonance imaging, Bioluminescence

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