Development of a gigawatt repetitive pulse modulator and high-pressure switch test stand and results from high-pressure switch tests

The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.Title from title screen of research.pdf file (viewed on April 22, 2009)Includes bibliographical references.Thesis (M.S.) University of Missouri-Columbia 2006.Dissertations, Academic -- University of Missouri--Columbia -- Electrical engineering.The research described in this thesis documents the efforts in developing repetitively pulsed, high-pressure oil switch technology. A high-pressure oil switch has been designed and optimized for lifetime operation to more than 10⁷ shots at the 250 J-level under repetitive pulsed conditions. The switch delivers pulses that are - 125 [kappa]V and 25 [kappa]A in amplitude, and 70 ns in duration, providing peak power up to 3.25 GW into a matched impedance load. A pulsed modulator and pulse generating system has been developed to test the high-pressure oil switch to repetition rates of 22 pulses per second for sustained bursts at least 1,000 shots long. Experiments were conducted under both single-shot and rep-rate conditions. The experiments identified both the mean breakdown voltage as well as the deviation of the breakdown voltages as functions of oil pressure and oil flow rate. The experiments found the breakdown voltage magnitude tracked the oil pressure. The experiments were inconclusive with respect to oil flow rate and breakdown performance. The experiments indicated that electrode erosion at 1,000,000 shots was relatively insignificant and thus all of the program goals (long life, high performance) have been met

Critical changes in hypothalamic gene networks in response to pancreatic cancer as found by single-cell RNA sequencing

OBJECTIVE: Cancer cachexia is a devastating chronic condition characterized by involuntary weight loss, muscle wasting, abnormal fat metabolism, anorexia, and fatigue. However, the molecular mechanisms underlying this syndrome remain poorly understood. In particular, the hypothalamus may play a central role in cachexia, given that it has direct access to peripheral signals because of its anatomical location and attenuated blood–brain barrier. Furthermore, this region has a critical role in regulating appetite and metabolism. METHODS: To provide a detailed analysis of the hypothalamic response to cachexia, we performed single-cell RNA-seq combined with RNA-seq of the medial basal hypothalamus (MBH) in a mouse model for pancreatic cancer. RESULTS: We found many cell type-specific changes, such as inflamed endothelial cells, stressed oligodendrocyes and both inflammatory and moderating microglia. Lcn2, a newly discovered hunger suppressing hormone, was the highest induced gene. Interestingly, cerebral treatment with LCN2 not only induced many of the observed molecular changes in cachexia but also affected gene expression in food-intake decreasing POMC neurons. In addition, we found that many of the cachexia-induced molecular changes found in the hypothalamus mimic those at the primary tumor site. CONCLUSION: Our data reveal that multiple cell types in the MBH are affected by tumor-derived factors or host factors that are induced by tumor growth, leading to a marked change in the microenvironment of neurons critical for behavioral, metabolic, and neuroendocrine outputs dysregulated during cachexia. The mechanistic insights provided in this study explain many of the clinical features of cachexia and will be useful for future therapeutic development

RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitis-associated carcinogenesis

Patients with inflammatory bowel diseases are at increased risk for colorectal cancer, but the molecular mechanisms linking inflammation and cancer are not well defined. We earlier showed that carboxylated N-glycans expressed on receptor for advanced glycation end products (RAGE) and other glycoproteins mediate colitis through activation of nuclear factor kappa B (NF-κB). Because NF-κB signaling plays a critical role in the molecular pathogenesis of colitis-associated cancer (CAC), we reasoned that carboxylated glycans, RAGE and its ligands might promote CAC. Carboxylated glycans are expressed on a subpopulation of RAGE on colon cancer cells and mediate S100A8/A9 binding to RAGE. Colon tumor cells express binding sites for S100A8/A9 and binding leads to activation of NF-κB and tumor cell proliferation. Binding, downstream signaling and tumor cell proliferation are blocked by mAbGB3.1, an anti-carboxylate glycan antibody, and by anti-RAGE. In human colon tumor tissues and in a mouse model of CAC, we found that myeloid progenitors expressing S100A8 and S100A9 infiltrate regions of dysplasia and adenoma. mAbGB3.1 administration markedly reduces chronic inflammation and tumorigenesis in the mouse model of CAC and RAGE-deficient mice are resistant to the onset of CAC. These findings show that RAGE, carboxylated glycans and S100A8/A9 play essential roles in tumor–stromal interactions, leading to inflammation-associated colon carcinogenesis

Physiologic and molecular characterization of a novel murine model of metastatic head and neck cancer cachexia

Abstract Background Cancer cachexia is a metabolic disorder characterized by the progressive loss of fat and lean mass that results in significant wasting, ultimately leading to reduced quality of life and increased mortality. Effective therapies for cachexia are lacking, potentially owing to the mismatch in clinically relevant models of cachexia. Specifically, cachexia observed in a clinical setting is commonly associated with advanced or late‐stage cancers that are metastatic, yet pre‐clinical metastatic models of cachexia are limited. Furthermore, the prevalence of cachexia in head and neck cancer patients is high, yet few pre‐clinical models of head and neck cancer cachexia exist. In addition to these shortcomings, cachexia is also heterogeneous among any given cancer, whereas patients with similar disease burden may experience significantly different degrees of cachexia symptoms. In order to address these issues, we characterize a metastatic model of human papilloma virus (HPV) positive head and neck squamous cell carcinoma that recapitulates the cardinal clinical and molecular features of cancer cachexia. Methods Male and female C57BL/6 mice were implanted subcutaneously with oropharyngeal squamous cell carcinoma cells stably transformed with HPV16 E6 and E7 together with hRas and luciferase (mEERL) that metastasizes to the lungs (MLM). We then robustly characterize the physiologic, behavioural, and molecular signatures during tumour development in two MLM subclones. Results Mice injected with MLM tumour cells rapidly developed primary tumours and eventual metastatic lesions to the lungs. MLM3, but not MLM5, engrafted mice progressively lost fat and lean mass during tumour development despite the absence of anorexia (P < 0.05). Behaviourally, MLM3‐implanted mice displayed decreased locomotor behaviours and impaired nest building (P < 0.05). Muscle catabolism programmes associated with cachexia, including E3 ubiquitin ligase and autophagy up‐regulation, along with progressive adipose wasting and accompanying browning gene signatures, were observed. Tumour progression also corresponded with hypothalamic and peripheral organ inflammation, as well as an elevation in neutrophil‐to‐lymphocyte ratio (P < 0.05). Finally, we characterize the fat and lean mass sparing effects of voluntary wheel running on MLM3 cachexia (P < 0.05). Conclusions This syngeneic MLM3 allograft model of metastatic cancer cachexia is reliable, consistent, and readily recapitulates key clinical and molecular features and heterogeneity of cancer cachexia. Because few metastatic models of cachexia exist—even though cachexia often accompanies metastatic progression—we believe this model more accurately captures cancer cachexia observed in a clinical setting and thus is well suited for future mechanistic studies and pre‐clinical therapy development for this crippling metabolic disorder