Biology subjects

Edwards, W. B.

Publications and source records attributed to Edwards, W. B..

6 recordsLinked to original sources

bioRxiv2026

Groucho running reveals disparate results between ground reaction force and tibia-fibula bone strain in runners

The relationship between external forces and bone strain in running is often complex and nonintuitive. We used Groucho running (i.e., running with exaggerated knee flexion) as a model to dramatically reduce the vertical ground reaction force (VGRF) and examined the relationship between peak VGRF and finite element (FE)-predicted tibia-fibula bone strain. Nine physically active males ran on an instrumented treadmill at 2.8 m/s with their preferred running technique, increased knee flexion (Groucho), and exaggerated knee flexion (Ex Groucho) in a randomized order. Strains at the tibia-fibula midshaft were calculated using computed-tomography-based FE modeling with loads and boundary conditions calculated from an inverse-dynamics based musculoskeletal model. Pressure-modified von Mises strain was used to quantify the peak strain (90th percentile strain) and strained volume (volume of bone experiencing strains above 3000 micro strains). We further explored the relationship between peak VGRF, lower leg angle, and FE-predicted strain variables. The results showed that a 15.8% and 22.9% reduction in VGRF during Groucho and Ex Groucho, respectively, had no significant effect on FE-predicted peak strain (p > 0.304) and strained volume (p>0.053). Changes in peak VGRF did not correlate with FE-predicted strain variables (p>0.54) while changes in lower leg angle in the sagittal plane were moderately correlated (r>0.65; p<0.047). Our findings suggest that reductions in peak external forces do not always coincide with reductions in bone strain, especially in cases where running kinematics are dramatically altered. This work has important implications for designing gait retraining interventions based on reductions in external force measures.

bioengineering↗

bioRxiv2024

CD200 depletion in glioma enhances antitumor immunity and induces tumor rejection

High-grade gliomas are a major health challenge with poor prognosis and high morbidity. Immune-checkpoint inhibitors (ICI) have emerged as promising therapeutic options for several malignancies yet show little efficacy against central nervous system (CNS) tumors. CD200 is a newly recognized immune checkpoint that modulates immune homeostasis. CD200 protein is expressed by a variety of cells, including immune cells and stromal cells, and is overexpressed by many tumors. The shedding of CD200 from tumor cells can create an immunosuppressive environment that dampens anti-tumor immunity by modulating cytolytic activity and cytokine expression both within and outside the tumor microenvironment (TME). While it is well-accepted that CD200 induces a pro-tumorigenic environment through its ability to suppress the immune response, we sought to determine the role of glioma-specific expression of CD200. We show that CD200 is expressed across glioma types, is shed from tumor cells, and increases over time in the serum of patients undergoing immunotherapy. Using CD200 knockout (KO) glioma models, we demonstrated that glioma cell-derived CD200 promotes tumor growth in vivo and in vitro. Notably, CD200 KO gliomas are spontaneously rejected by their host, a process that required a fully functional immune system, including NK and T-cells. Moreover, we report that glioma-derived or brain-injected soluble CD200 contributes to the suppression of antigen-specific CD8 T-cells in the draining lymph nodes (dLNs). Our work provides new mechanistic insights regarding CD200-mediated immunosuppression by gliomas. Statement of significanceWe demonstrate mechanisms of the druggable glioma-derived CD200 checkpoint on tumor growth and immune suppression.

immunology↗

bioRxiv2023

Novel orthotopic model of neuroblastoma in RNU homozygous rats

Neuroblastoma, the most common extracranial solid malignancy in children, accounts for 15% of pediatric cancer deaths despite multimodal therapy including surgical resection. Unfortunately, complete surgical resection remains challenging due to encasement of major neurovascular structures, unclear tumor margins, and remote nodal disease. While mouse models of neuroblastoma are extremely valuable for studying tumor biology and medical treatments, the small size renders the mouse model insufficient to evaluate novel surgical therapy. Here, we have developed a novel rat model of neuroblastoma to facilitate further development of surgical treatment. Human neuroblastoma cells (SK-N-BE(2)) were injected into the adrenal gland of RNU nude rats. They developed 2 cm xenograft tumors at 5 weeks which were easily identifiable on MRI imaging and on visual inspection. The rats began losing weight and neared end stage at 7 weeks, at which point surgical resection was attempted. While surgical resection was technically feasible, the rats were too frail to survive surgery at the late stage. The pathology of the tumors was consistent with neuroblastoma: small round blue cells with strong PHOX2B staining. Thus, we present a novel rat neuroblastoma model that can be used for development of surgical techniques, such as the use of intraoperative contrast agents.

cancer biology↗

bioRxiv2021

High spatial resolution analysis using indentation mapping differentiates biomechanical properties of normal vs. degenerated mouse articular cartilage

Characterizing the biomechanical properties of articular cartilage is crucial to understanding processes of tissue homeostasis vs. degeneration. In mouse models, however, limitations are imposed by their small joint size and thin cartilage surfaces. Here we present a 3D automated surface mapping system and methodology that allows for mechanical characterization of mouse cartilage with high spatial resolution. We performed repeated indentation mappings, followed by cartilage thickness measurement via needle probing, at 31 predefined positions distributed over the medial and lateral femoral condyles of healthy mice. High-resolution 3D x-ray microscopy (XRM) imaging was used to validate tissue thickness measurements. The automated indentation mapping was reproducible, and needle probing yielded cartilage thicknesses comparable to XRM imaging. When comparing healthy vs. degenerated cartilage, topographical variations in biomechanics were identified, with altered thickness and stiffness (instantaneous modulus) across condyles and within anteroposterior sub-regions. This quantitative technique comprehensively characterized cartilage function in mice femoral condyle cartilage. Hence, it has the potential to improve our understanding of tissue structure-function interplay in mouse models of repair and disease.

bioengineering↗

bioRxiv2021

Predicting continuous ground reaction forces from accelerometers during uphill and downhill running: A recurrent neural network solution

Ground reaction forces (GRFs) are important for understanding human movement, but their measurement is generally limited to a laboratory. Previous studies used neural networks to predict GRF waveforms during running from wearable device data, but these predictions are limited to the stance phase of level-ground running. We sought to develop a recurrent neural network capable of predicting continuous normal (perpendicular to surface) GRFs across a range of running speeds and slopes from accelerometer data. 19 subjects ran on a force-measuring treadmill at five slopes (0{degrees}, {+/-}5{degrees}, {+/-}10{degrees}) and three speeds (2.5, 3.33, 4.17 m/s) per slope with sacral- and shoe-mounted accelerometers. We then trained a recurrent neural network to predict normal GRF waveforms frame-by-frame. The predicted versus measured GRF waveforms had an average {+/-} SD RMSE of 0.16 {+/-} 0.04 BW and relative RMSE of 6.4 {+/-} 1.5% across all conditions and subjects. The recurrent neural network predicted continuous normal GRF waveforms across a range of running speeds and slopes with greater accuracy than neural networks implemented in previous studies. This approach may facilitate predictions of biomechanical variables outside the laboratory in near real-time and improves the accurately of quantifying and monitoring external loads experienced by the body when running.

bioengineering↗

bioRxiv2019

Preclinical immunoPET imaging of glioblastoma-infiltrating myeloid cells using Zirconium-89-labeled anti-CD11b antibody

PurposeGlioblastoma is a lethal brain tumor, heavily infiltrated by tumor-associated myeloid cells (TAMCs). TAMCs are emerging as a promising therapeutic target as they suppress antitumor immune responses and promote tumor cell growth. Quantifying TAMCs using non-invasive immunoPET could facilitate patient stratification for TAMC-targeted treatments and monitoring of treatment efficacy. As TAMCs uniformly express the cell surface marker, integrin CD11b, we evaluated a 89Zr-labeled anti-CD11b antibody for non-invasive imaging of TAMCs in a syngeneic orthotopic mouse glioma model.\n\nProceduresA human/mouse cross-reactive anti-CD11b antibody (clone M1/70) was conjugated to a DFO chelator and radiolabeled with Zr-89. PET/CT and biodistribution with or without a blocking dose of anti-CD11b Ab were performed 72 hours post-injection of 89Zr-anti-CD11b Ab in mice bearing established orthotopic syngeneic GL261 gliomas. Flow cytometry and immunohistochemistry of dissected GL261 tumors were conducted to confirm the presence of CD11b+ TAMCs.\n\nResultsSignificant uptake of 89Zr-anti-CD11b Ab was detected at the tumor site (SUVmean = 2.60 {+/-} 0.24) compared with the contralateral hemisphere (SUVmean = 0.6 {+/-} 0.11). Blocking with a 10-fold lower specific activity of 89Zr-anti-CD11b Ab markedly reduced the SUV in the right brain (SUVmean = 0.11 {+/-} 0.06), demonstrating specificity. Spleen and lymph nodes (myeloid cell rich organs) also showed high uptake of the tracer, and biodistribution analysis correlated with the imaging results. CD11b expression within the tumor was validated using flow cytometry and immunohistochemistry, which showed high CD11b expression primarily in the tumoral hemisphere compared to the contralateral hemisphere.\n\nConclusionThese data establish that 89Zr-anti-CD11b Ab immunoPET targets CD11b+ cells (TAMCs) with high specificity in a mouse model of GBM, demonstrating the potential for non-invasive quantification of tumor infiltrating CD11b+ immune cells during disease progression and immunotherapy in patients with GBM.

immunology↗