Filtering by
- All Subjects: Glioblastoma
- All Subjects: Oncology
- Creators: LaBaer, Joshua
![137083-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-05/137083-Thumbnail%20Image.png?versionId=wfwp1XiFhndM_l_D6BlxiGxJKd_iCqnH&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240614/us-west-2/s3/aws4_request&X-Amz-Date=20240614T081554Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=7f1c0534365656ec070d32e6350caa77d0b178b9ed443b5a3019f0da3b259dcb&itok=QEGPPz4v)
![134436-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-05/134436-Thumbnail%20Image.png?versionId=swW3Xn0bKJ4EW0T.lD4z_280502WLCM9&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240614/us-west-2/s3/aws4_request&X-Amz-Date=20240614T175632Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=54c86a86e064d3acc7255d55f65c19422fb2cc126be5a967887bd169607bf09b&itok=ASASboVA)
![168823-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2022-08/168823-Thumbnail%20Image.png?versionId=dB435eJ4GKr81GmPdGY.GWO0eBo4DC_Y&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240614/us-west-2/s3/aws4_request&X-Amz-Date=20240614T175632Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=ba1e40a134e4e54b59a6edcec13974b0c7e83b7a02162bd63567ee40f1cd057f&itok=CTOJ1AkT)
Redox homeostasis is described as the net physiologic balance between inter-convertible oxidized and reduced equivalents within subcellular compartments that remain in a dynamic equilibrium. This equilibrium is impacted by reactive oxygen species (ROS), which are natural by-products of normal cellular activity. Studies have shown that cancer cells have high ROS levels and altered redox homeostasis due to increased basal metabolic activity, mitochondrial dysfunction, peroxisome activity, as well as the enhanced activity of NADPH oxidase, cyclooxygenases, and lipoxygenases. Glioblastoma (GBM) is the most prevalent primary brain tumor in adults with a median survival of 15 months. GBM is characterized by its extreme resistance to therapeutic interventions as well as an elevated metabolic rate that results in the exacerbated production of ROS. Therefore, many agents with either antioxidant or pro-oxidant mechanisms of action have been rigorously employed in preclinical as well as clinical settings for treating GBM by inducing oxidative stress within the tumor. Among those agents are well-known antioxidant vitamin C and small molecular weight SOD mimic BMX-001, both of which are presently in clinical trials on GBM patients. Despite the wealth of investigations, limited data is available on the response of normal brain vs glioblastoma tissue to these therapeutic interventions. Currently, a sensitive and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was established for the quantification of a panel of oxidative stress biomarkers: glutathione (GSH), cysteine (Cys), glutathione disulfide (GSSG), and cysteine disulfide in human-derived brain tumor and mouse brain samples; this method will be enriched with additional oxidative stress biomarkers homocysteine (Hcy), methionine (Met), and cystathionine (Cyst). Using this enriched method, we propose to evaluate the thiol homeostasis and the redox state of both normal brain and GBM in mice after exposure with redox-active therapeutics. Our results showed that, compared to normal brain (in intact mice), GBM tissue has significantly lower GSH/GSSG and Cys/CySS ratios indicating much higher oxidative stress levels. Contralateral “normal” brain tissue collected from the mice with intracranial GBM were also under significant oxidative stress compared to normal brains collected from the intact mice. Importantly, normal brain tissue in both studies retained the ability to restore redox homeostasis after treatment with a redox-active therapeutic within 24 hours while glioblastoma tissue does not. Ultimately, elucidating the differential redox response of normal vs tumor tissue will allow for the development of more redox-active agents with therapeutic benefit.
![157007-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-09/157007-Thumbnail%20Image.png?versionId=LB4VBvUugJOzYoKW0LR7fDBMD91PNQW9&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240614/us-west-2/s3/aws4_request&X-Amz-Date=20240614T175632Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=22625da40e2fb7cf8ac9fedc4e40748580dba87458443525e241de3844be8d39&itok=SDSlGxqz)
![152885-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-09/152885-Thumbnail%20Image.png?versionId=9CxBwr5wyPfxGKFu7DULEGyDvdfGFJcX&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240614/us-west-2/s3/aws4_request&X-Amz-Date=20240614T173514Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=29c66714f93cdfceacce68b946966059318cc7cbf98c2108af180688f2a6b813&itok=RfN2X1YX)
The current study reports that KetoCal® (KC; 4:1 fat:protein/carbohydrates), fed ad libitum, alters hypoxia, angiogenic, and inflammatory pathways in a mouse model of glioma. Tumors from animals maintained on KC showed reduced expression of the hypoxia marker carbonic anhydrase 9 (CA IX), a reduction in hypoxia inducible factor 1-alpha (HIF-1α) and decreased activation of nuclear factor kappa B (NF-κB). Animals maintained on KC also showed a reduction in expression of vascular endothelial growth factor receptor 2 (VEGFR2) and decreased microvasculature in their tumors. Further, peritumoral edema was significantly reduced in animals fed the KC and protein analysis showed significantly altered expression of the tight junction protein zona occludens-1 (ZO-1) and the water channeling protein aquaporin-4 (AQP4), both of which have been implicated in malignant processes in glioma, including the formation of peritumoral edema in patients. Taken together the data suggests that KC alters multiple processes involved in malignant progression of gliomas. A greater understanding of the effects of the ketogenic diet as an adjuvant therapy will allow for a more rational approach to its clinical use.
![155948-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-08/155948-Thumbnail%20Image.png?versionId=r3Y4f_.1uE2CoXt__gdKHoSEhCi8MTkR&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240614/us-west-2/s3/aws4_request&X-Amz-Date=20240614T175632Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=a5420bc48653a876fbefa81a6edf083c6dd4c0afd951dea8ad094ac1aa04bcd2&itok=ku7RG7O9)
onself discrimination. Project 2 develops a bioinformatic and experimental methodology for the identification of CTL-epitopes from low frequency T-cells against tumor antigens and chronic viruses. This methodology is employed in Project 3 to identify novel immunogenic CTL-epitopes from human papillomavirus (HPV)-associated head and neck cancer patients. In Project 3, I further study the mechanisms of HPV-specific T-cell dysfunction, and I demonstrate that combination inhibition of Indoleamine 2, 3-dioxygenase (IDO-1) and programmed cell death protein (PD-1) can be a potential immunotherapy against HPV+ head and neck cancers. Lastly, in Project 4, I develop a single-cell assay for high-throughput identification of antigens targeted by CTLs from whole pathogenome libraries. Thus, this dissertation contributes to fundamental T-cell immunobiology by identifying rules of T-cell immunogenicity and dysfunction, as well as to translational immunology by identifying novel CTL-epitopes, and therapeutic targets for T-cell immunotherapy.
![135769-Thumbnail Image.png](https://d1rbsgppyrdqq4.cloudfront.net/s3fs-public/styles/width_400/public/2021-05/135769-Thumbnail%20Image.png?versionId=MEkLtAY5oWZaJpEewIzl3dn8JSGw6Is_&X-Amz-Content-Sha256=UNSIGNED-PAYLOAD&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIASBVQ3ZQ42ZLA5CUJ/20240614/us-west-2/s3/aws4_request&X-Amz-Date=20240614T175632Z&X-Amz-SignedHeaders=host&X-Amz-Expires=120&X-Amz-Signature=216c99bac2b3b3818e8de634d1d5f99973728e142d0f585d6a78f9a4fb077131&itok=3e2wfOpZ)