Synthetic biology approaches to improve cell-based cancer immunotherapy

Adoptive T cell immunotherapy is a promising anti-cancer therapy that has the potential to become the ultimate therapeutic agents to treat a variety of diseases. Recently, chimeric antigen receptor (CAR) expressing T cells has demonstrated to be a very effective approach to treat B cell cancer patients. Despite optimistic results, there are several improvements that need to be made to enhance the safety and efficacy of current CAR T cell therapy. Fortunately, different synthetic biology tools can be implemented to overcome many of the current deficiencies of CAR T cell therapy. Here, we develop anti-Axl CAR and synNotch receptors to target Axl which is a tyrosine kinase receptor that is commonly overexpressed in many cancers and considered as one of important cancer therapeutic targets. Next, we develop a split, universal, and programmable (SUPRA) CAR system that can be used to switch targets without re-engineering T cells, fine-tune T cell activation level, and sense and logically respond to multiple antigens. These multiple features are useful in mitigating tumor relapse, limiting CAR-T induced toxicities, and enhancing tumor specificity. Orthogonal SUPRA CARs are also used to control different cell types and signaling domains, enabling diverse immune responses from SUPRA CAR T cells. Lastly, we demonstrate that SUPRA CAR can redirect the activity of both innate and adaptive immune cell types. We also expand the logic capabilities of SUPRA CAR T cells by integrating three inputs in a single immune cell. We also show intercellular logic gate by engineering immune cell-cell interaction. We further demonstrate controlling endogenous immune cell polarization using SUPRA CAR T cells. These wide-ranges of SUPRA CAR applications imply its versatility as a platform for engineering cell-cell interactions with advanced logic functions to enhance efficacy and safety of cell-based cancer immunotherapy

Improving Statistical Image Reconstruction for Cardiac X-ray Computed Tomography.

Technological advances in CT imaging pose new challenges such as increased X-ray radiation dose and complexity of image reconstruction. Statistical image reconstruction methods use realistic models that incorporate the physics of the measurements and the statistical properties of the measurement noise, and they have potential to provide better image quality and dose reduction compared to the conventional filtered back-projection (FBP) method. However, statistical methods face several challenges that should be addressed before they can replace the FBP method universally. In this thesis, we develop various methods to overcome these challenges of statistical image reconstruction methods. Rigorous regularization design methods in Fourier domain were proposed to achieve more isotropic and uniform spatial resolution or noise properties. The design framework is general so that users can control the spatial resolution and the noise characteristics of the estimator. In addition, a regularization design method based on the hypothetical geometry concept was introduced to improve resolution or noise uniformity. Proposed designs using the new concept effectively improved the spatial resolution or noise uniformity in the reconstructed image. The hypothetical geometry idea is general enough to be applied to other scan geometries. Statistical weighting modification, based on how much each detector element affects insufficiently sampled region, was proposed to reduce the artifacts without degrading the temporal resolution within the region-of-interest (ROI). Another approach using an additional regularization term, that exploits information from the prior image, was investigated. Both methods effectively removed short-scan artifacts in the reconstructed image. We accelerated the family of ordered-subsets algorithms by introducing a double surrogate so that faster convergence speed can be achieved. Furthermore, we present a variable splitting based algorithm for motion-compensated image reconstruction (MCIR) problem that provides faster convergence compared to the conjugate gradient (CG) method. A sinogram-based motion estimation method that does not require any additional measurements other than the short-scan amount of data was introduced to provide decent initial estimates for the joint estimation. Proposed methods were evaluated using simulation and real patient data, and showed promising results for solving each challenge. Some of these methods can be combined to generate more complete solutions for CT imaging.PhDElectrical Engineering: SystemsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/110319/1/janghcho_1.pd

Non-Iterative Tone Mapping With High Efficiency and Robustness

This paper proposes an efficient approach for tone mapping, which provides a high perceptual image quality for diverse scenes. Most existing methods, optimizing images for the perceptual model, use an iterative process and this process is time consuming. To solve this problem, we proposed a new layer-based non-iterative approach to finding an optimal detail layer for generating a tone-mapped image. The proposed method consists of the following three steps. First, an image is decomposed into a base layer and a detail layer to separate the illumination and detail components. Next, the base layer is globally compressed by applying the statistical naturalness model based on the statistics of the luminance and contrast in the natural scenes. The detail layer is locally optimized based on the structure fidelity measure, representing the degree of local structural detail preservation. Finally, the proposed method constructs the final tone-mapped image by combining the resultant layers. The performance evaluation reveals that the proposed method outperforms the benchmarking methods for almost all the benchmarking test images. Specifically, the proposed method improves an average tone mapping quality index-II (TMQI-II), a feature similarity index for tone-mapped images (FSITM), and a high-dynamic range-visible difference predictor (HDR-VDP)-2.2 by up to 0.651 (223.4%), 0.088 (11.5%), and 10.371 (25.2%), respectively, compared with the benchmarking methods, whereas it improves the processing speed by over 2611 times. Furthermore, the proposed method decreases the standard deviations of TMQI-II, FSITM, and HDR-VDP-2.2, and processing time by up to 81.4%, 18.9%, 12.6%, and 99.9%, respectively, when compared with the benchmarking methods.11Ysciescopu

Synovial Sarcoma of the Thyroid Gland

Primary synovial sarcoma of the thyroid is an extremely rare condition which has only been reported twice in the literature. We herein report a case of highly aggressive and rapidly lethal primary synovial sarcoma of the thyroid. A 72-year-old woman presented with extensive local invasion, rapid progression, and early distant metastasis secondary to primary thyroid synovial sarcoma. The tumor exhibited an atypical histologic and immunohistochemical staining pattern. Detection of SYT/SSX fusion transcript confirmed the diagnosis of synovial sarcoma. Due to the aggressive nature of primary synovial sarcoma of the thyroid gland, early diagnosis and comprehensive treatment including wide resection and postoperative chemoradiation is required

Effects of Berberine and Hwangryunhaedok-Tang on Oral Bioavailability and Pharmacokinetics of Ciprofloxacin in Rats

Hwangryunhaedok-Tang (HR) and berberine-containing single herbs are used to treat bacterial infection and inflammatory diseases in eastern Asia. The combination of berberine-containing herbal medicines and ciprofloxacin can be an excellent antibacterial chemotherapy against multidrug resistance bacteria. To evaluate the pretreatment effect of berberine and HR, vehicle, berberine (25 and 50 mg/kg/day), and HR (1.4 g/kg/day) were daily administered to rats for five consecutive days. On day 6, ciprofloxacin was administered (10 mg/kg, i.v. and 20 mg/kg, p.o.) to rats. To assess cotreatment effect of berberine and ciprofloxacin, berberine (50 mg/kg) and ciprofloxacin (20 mg/kg) were coadministered by single oral gavage. Pharmacokinetic data were estimated by noncompartmental model. Compared with ciprofloxacin alone (control group), coadministration of berberine (50 mg/kg) and ciprofloxacin significantly decreased Cmax of ciprofloxacin (P<0.05). In addition, the pretreatment of berberine (50 mg/kg/day) and HR (1.4 g/kg/day) significantly decreased Cmax and AUC0→∞, compared with control group (P<0.05). The oral bioavailability of ciprofloxacin was reduced by cotreatment of berberine and pretreatment of berberine and HR. Our results suggest that the expression of P-glycoprotein and organic anion and/or organic cation transporters (OAT/OCT) could take a role in reduced oral bioavailability of ciprofloxacin by berberine and HR

Fabrication of AlGaN/GaN Fin-Type HEMT Using a Novel T-Gate Process for Improved Radio-Frequency Performance

To increase the radio-frequency (RF) performance of AlGaN/GaN-based fin-type high electron mobility transistors (HEMTs), a novel T-gate process was developed and applied to fabricate a device with high RF performance. In a single lithography process, the applied T-gate process shows a technique for forming a T-gate using the reactivity difference of several photoresists. The fabricated device has a steep fin width (W-fin) of 130 nm, a fin height (H-fin) of 250 nm, and a gate length (L-G) of 190 nm. The device exhibits a low leakage current (I-off) of 6.6 x 10(-10) A/mm and a high I-on/I-off current ratio of 4.7 x 10(8). Moreover, the fabricated device achieved a high cut-off frequency (f(T)) of 9.7 GHz and a very high maximum oscillation frequency (f(max)) of 27.8 GHz. The f(max) value of the proposed device is 138% higher than that of GaN-based fin-type HEMTs without T-gate.1

Lipotoxicity induces hepatic protein inclusions through TANK binding kinase 1â mediated p62/sequestosome 1 phosphorylation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146331/1/hep29742.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146331/2/hep29742_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146331/3/hep29742-sup-0011-suppinfo.pd