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Nicolaou, D.

Publications and source records attributed to Nicolaou, D..

2 recordsLinked to original sources

Cerclage Wire as an Affordable Alternative for Internal Fixation in Murine Critical Sized Defect Models

Critical sized defects (CSDs) are a serious challenge in orthopedics that require the development of more robust and effective treatments to improve quality of life for patients. Current CSD research is limited by the applicable and affordable animal models available. Mice would be the preferred species as they are cheaply housed and have many transgenic variations readily available; however, their small size makes CSD surgeries difficult and expensive. We propose the use of cerclage wires to achieve internal plate fixation. PEEK plates were secured to the right femur of 26 C57BL/6 mice using four cerclage wires to achieve modified double-loop fixation implemented through bicortical holes and defects were created. 10 received 3mm defects and 6 received 4mm defects that were left empty and were taken out to 20 weeks (Group E3, E4). Another 10 received 3mm defects that were filled with a morselized bone graft and were taken out to 8 weeks (Group G3). Blinded longitudinal x-ray grading by orthopedic surgeons was conducted on the empty defects for plate stability and wire fixation. All samples received microCT analysis at their endpoints. There were no significant differences in plate or wire stability between the empty groups and wire scores worsened negligibly over time. MicroCT analysis further supported wire integration as bone growth directly upon the wires was observed in all samples. The efficacy of this model in achieving non-union when left untreated was also confirmed via microCT. Further, only three mice in group G3 achieved union and two of these unions were not optimal. Our study is the first to successfully show that cerclage wire can be used in a murine CSD model to achieve affordability and clinical relevancy.

bioengineering↗

Rational Tuning of CAR Tonic Signaling Yields Superior T-Cell Therapy for Cancer

Chimeric antigen receptors (CARs) are modular proteins capable of redirecting immune cells toward a wide variety of disease-associated antigens. Here, we explore the effects of CAR protein sequence and structure on CAR-T cell function. Based on the empirical observation that CD20 CARs with similar sequences exhibit divergent tonic-signaling and anti-tumor activities, we devised engineering strategies that aimed to improve CAR-T cell function by tuning the intensity of tonic signaling. We found that CARs designed to exhibit low but non-zero levels of tonic signaling show robust effector function upon antigen stimulation while avoiding premature functional exhaustion by CAR-T cells. Through alterations of the CARs ligand-binding domain and overall protein conformation, we generated CD20 CAR variants that outperform the CD19 CAR in mouse models of human lymphoma. We further demonstrate that rational modification of protein confirmation can be generalized to improve GD2 CAR-T cell efficacy against neuroblastoma. These findings point to tonic signaling and basal T-cell activation as informative parameters to guide the rational design of next-generation CARs for cancer therapy.

bioengineering↗