Objective Metrics of diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) can detect diffuse axonal injury in traumatic brain injury (TBI). The relationship between the changes of these imaging measures and the underlying pathologies is still relatively unknown. This study investigated the radiological-pathological correlation between these imaging techniques and immunohistochemistry using a closed head rat model of TBI. Methods TBI was performed on female rats followed longitudinally by MRI out to 30 days post-injury, with a subset of animals selected for histopathological analyses. A MRI-based finite element analysis was generated to characterize the pattern of the mechanical insult and estimate the extent of brain injury to direct the pathological correlation with imaging findings. Results DTI axial diffusivity and fractional anisotropy (FA) were sensitive to axonal integrity, while radial diffusivity showed significant correlation to the myelin compactness. FA was correlated to astrogliosis in the gray matter while mean diffusivity was correlated to increased cellularity. Secondary inflammatory responses also partly affected the changes of these DTI metrics. The magnetization transfer ratio (MTR) at 3.5 ppm demonstrated a strong correlation with both axon and myelin integrity. Decrease in MTR at 20 ppm correlated with the extent of astrogliosis in both gray and white matter. Interpretation While conventional T2-weighted MRI did not detect abnormalities following TBI, DTI and MTI afforded complementary insight into the underlying pathologies reflecting varying injury states over time, thus may substitute for histology to reveal DAI pathologies in vivo. This correlation of MRI and histology furthers understanding of the microscopic pathology underlying DTI and MTI changes in TBI.

CD133 marks self-renewing cancer stem cells (CSCs) in a variety of solid tumors, and CD133+ tumor-initiating cells are known markers of chemo-and radio-resistance in multiple aggressive cancers, including glioblastoma (GBM), that may drive intra-tumoral heterogeneity. Here, we report three immunotherapeutic modalities based on a human anti-CD133 antibody fragment that targets a unique epitope present in glycosylated and non-glycosylated CD133 and studied their effects on targeting CD133+ cells in patient-derived models of GBM. We generated an immunoglobulin G (IgG) (RW03-IgG), a dual-antigen T cell engager (DATE), and a CD133-specific chimeric antigen receptor T cell (CAR-T): CART133. All three showed activity against patient-derived CD133+ GBM cells, and CART133 cells demonstrated superior efficacy in patient-derived GBM xenograft models without causing adverse effects on normal CD133+ hematopoietic stem cells in humanized CD34+ mice. Thus, CART133 cells may be a therapeutically tractable strategy to target CD133+ CSCs in human GBM or other treatment-resistant primary cancers.ll Clinical and Translational Report

Background: Cell surface recognition of the AC133 epitope on CD133 marks many stem cell and cancer stem cell types. Results: A large scale RNA interference screen identifies genes involved in N-glycosylation that regulate cell surface AC133 recognition. Conclusion: CD133 N-glycosylation and its processing contribute to cell surface AC133 recognition. Significance: Glycobiological differences between primitive and differentiated cells may be responsible for regulating cell surface AC133.

Maximal homing of infused stem cells to diseased tissue is critical for regenerative medicine. Pulsed focused ultrasound (pFUS) is a clinically relevant platform to direct stem cell migration. Through mechanotransduction, pFUS establishes local gradients of cytokines, chemokines, trophic factors (CCTF) and cell adhesion molecules (CAM) in treated skeletal muscle that subsequently infused mesenchymal stromal cells (MSC) can capitalize to migrate into the parenchyma. Characterizing molecular responses to mechanical pFUS effects revealed tumor necrosis factor-alpha (TNFα) drives cyclooxygenase-2 (COX2) signaling to locally increase CCTF/CAM that are necessary for MSC homing. pFUS failed to increase chemoattractants and induce MSC homing to treated muscle in mice pretreated with ibuprofen (non-specific COX inhibitor) or etanercept (TNFα inhibitor). pFUS-induced MSC homing was also suppressed in COX2-knockout mice, demonstrating ibuprofen blocked the mechanically-induced CCTF/CAM by acting on COX2. Anti-inflammatory drugs, including ibuprofen, are administered to muscular dystrophy (MD) patients and ibuprofen also suppressed pFUS-induced homing to muscle in a mouse model of MD. Drug interactions with cell therapies remain unexplored and are not controlled for during clinical cell therapy trials. This study highlights potentially negative drug-host interactions that suppress stem cell homing and could undermine cell-based approaches for regenerative medicine.

Wistar rats are widely used in biomedical research and commonly serve as a model organism in neuroscience studies. In most cases when noninvasive imaging is not utilized, studies assume a consistent baseline condition in rats that lack visible differences. While performing a series of traumatic brain injury studies, we discovered mild spontaneous ventriculomegaly in 70/162 (43.2%) of Wistar rats that had been obtained from 2 different vendors. Advanced magnetic resonance (MR) imaging techniques, including MR angiography and diffusion tensor imaging, were utilized to evaluate the rats. Multiple neuropathologic abnormalities, including presumed arteriovenous malformations, aneurysms, cysts, white matter lesion and astrogliosis were found in association with ventriculomegaly. Postmortem micro-CT and immunohistochemical staining confirmed the presence of aneurysms and arteriovenous malformations. Diffusion tensor imaging significant decreases in fractional anisotropy and increases in mean diffusivity, axial diffusivity, and radial diffusivity in multiple white matter tracts (p < 0.05). These results could impact the interpretation, e.g. of a pseudo-increase of axon integrity and a pseudo-decrease of myelin integrity, based on characteristics intrinsic to rats with ventriculomegaly. We suggest the use of baseline imaging to prevent the inadvertent introduction of a high degree of variability in preclinical studies of neurological disease or injury in the Wistar rats.