A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / The Warburg effect is defined as the propensity for cancer cells to favor glycolysis over oxidative phosphorylation under aerobic conditions. Finding a way to reverse this effect would likely be very beneficial for cancer therapy. The PI3K/Akt pathway has been suggested to be responsible for the Warburg effect, and estrogen is a known regulator of this pathway. Estrogen, specifically 17 β-estradiol, has been shown to be protective at the level of the mitochondria. The purpose of this study was to try to use 17 β-estradiol to reverse aspects of the Warburg effect in two cancer lines. Various concentrations of 17 β-estradiol were added to the samples (0, 10nm, 100nm, 1μm) for various amounts of time (16-96h). Western blots probes for select subunits of the electron transport chain (ETC) showed no differences in cells with and without 17 β-estradiol across various times. Due to technical difficulties with cell lines, considerable troubleshooting was required, consuming the time available for further analysis. The available results do not suggest that 17 β-estradiol alone is able to reverse the Warburg effect.

Universiẗat-Gesamthochsch., Diss.--Kassel, 2001.

Jena, Universiẗat, Diss., 1998.

Proefschrift--Rijksuniversiteit te Leiden, 1992. / Résumé en anglais.

Thesis advisor: Thomas N. Seyfried / Mycoplasmas are the smallest, self-replicating free-living prokaryotes, and have been associated with carcinogenesis. Mycoplasmas can be detected in a high percentage of a wide variety of primary human cancers. Some mycoplasma species such as M. fermentans and M. hyorhinis can transform normal murine and human cell lines into tumorigenic cells. Mycoplasma infection can activate oncogenes as well as inactivate tumor suppressor genes. These observations suggest that mycoplasmas can be both carcinogenic and or onco-modulatory. I found that the metastatic macrophage VM-M3 cell line (referred to as M3+) was infected with mycoplasmas. Mycoplasmal16S rDNA sequencing showed M3+ cells were infected by the mycoplasma species M. arginini. Antibiotic was used to eradicate M. arginini from M3+ cells (referred to as M3- cells). The energetics of the infected M3+ cells and the non-infected M3- cells was studied by measuring respiration (oxygen consumption) and fermentation (lactate production). Respiration was enhanced and fermentation was reduced in the M3- cells compared to the M3+ cells. Glucose enhanced the fermentation and reduced the respiration of both the M3+ and the M3- cells. The M3+ cells produced higher quantities of metabolites indicative of immunological activation (itaconic acid, succinate, and citrulline) compared to M3- cells. In addition, in-vitro proliferation was higher in the M3+ cells than in the M3- cells at high cell densities. Primary subcutaneous tumor growth and metastasis was less in mice inoculated with the M3- cells than with the M3+ cells. The survival of a VM mouse was longer when inoculated with the M3- cells compared to the M3+ cells. Altogether these data indicates that M. arginini is an onco-modulator associated with activation, deregulated energetics and enhanced tumor progression of VM-M3 metastatic macrophage cells. / Thesis (MS) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

Thesis advisor: Thomas N. Seyfried / Two major metabolic phenomena observed in cancer cells include the Warburg effect and Crabtree effect. The Crabtree effect is the in vitro inhibition of respiration by glucose. The influence of glucose on the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of tumorigenic RAW264.7 and VM-M3 macrophage cells, as well as non-tumorigenic BV-2 microglia cells, was studied using the Seahorse XF96 extracellular flux analyzer. RAW264.7, VM-M3, and BV-2 cells incubated in glucose medium displayed a significantly lower OCR and higher ECAR compared to cells incubated in no glucose medium. Furthermore, when glucose medium was added to the RAW264.7 and BV-2 cells in real-time using the Seahorse XF96 injection ports, a rapid decrease in OCR and increase and ECAR was observed. Therefore, RAW264.7, VM-M3, and BV-2 cells display a robust Crabtree effect in vitro, as assessed by OCR and ECAR. Additionally, it is important to consider the Crabtree effect when studying in vitro energy metabolism of all cell and tissue types. It was also found that the elimination of the Crabtree effect through glucose deprivation resulted in dynamic cardiolipin (CL) fatty acid changes in VM-M3 cells. VM-M3 cells incubated in 10 mM glucose medium for four hours displayed a short-chain, saturated (immature) CL fatty acid composition, while VM-M3 cells incubated in no glucose media for four hours displayed long-chain, unsaturated (mature) CL fatty acid composition. Cardiolipin (CL) is a phospholipid highly enriched in the inner mitochondrial membrane. Mature, long-chain, unsaturated CL molecular species are involved in maintaining mitochondrial function and membrane integrity. Overall, these data suggest that CL fatty acid composition may function as a structural component of the Crabtree effect in vitro. The Warburg effect, or aerobic glycolysis, is the observation that tumor cells consume less oxygen and more glucose than normal, untransformed cells in the presence of oxygen. It has been shown that immune cells display a Warburg effect upon activation by changing their core metabolism from oxidative phosphorylation to glycolysis. In this study, it was observed that both RAW264.7 macrophage cells and BV-2 microglia cells display a significantly lower OCR and higher ECAR following LPS-activation. However, this observation is dependent on the concentration of LPS. Therefore, these data suggest that both RAW264.7 and BV-2 cells display a LPS concentration-dependent change in metabolism from oxidative phosphorylation to glycolysis upon LPS-activation in vitro. The in vitro lipid profiles that resulted from the Crabtree effect and the LPS-activated Warburg effect were also studied in the RAW264.7 cell line. The lipids phosphatidylserine (PS) and cardiolipin (CL) displayed the most robust changes in the RAW264.7 cells. Both PS and CL have been shown to be associated with cellular respiration. / Thesis (MS) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

Cancer cells exhibit an abnormal metabolic phenotype characterized by glycolysis and lactate fermentation in the presence of oxygen, a phenomenon known as the Warburg effect. This dysregulated metabolism plays an important role in every aspect of cancer progression, from tumorigenesis to invasion and metastasis. The Warburg effect is a common phenotype shared by most, if not all, cancer types. It is especially prominent in metastatic tumors, which are notoriously resistant to treatment and responsible for the majority of cancer-related deaths. Thus, metabolic therapies which target the Warburg effect could offer novel therapeutic options for most cancer patients, including those with aggressive or late-stage cancers. The ketogenic diet is a high fat, low carbohydrate diet that induces a physiological state of nutritional ketosis - decreased blood glucose and elevated blood ketones. It has been investigated as a cancer therapy for its potential to exploit the Warburg effect by restricting glucose availability to glycolysis-dependent tumors, and has been reported to slow cancer progression in some animal models as well as in anecdotal reports and small clinical studies in humans. Interestingly, there is some evidence that the elevation in blood ketones induced by the ketogenic diet contributes to its anti-cancer effects, suggesting that ketone supplementation could possibly inhibit cancer progression on its own. Rapid growth outstrips a tumor's ability to adequately perfuse its tissue, creating regions of tumor hypoxia which exacerbate the Warburg effect and promote a malignant phenotype. Hyperbaric oxygen therapy is the administration of 100% oxygen at elevated barometric pressure. It supersaturates the blood with oxygen, increasing its diffusion distance into the tissues, and can therefore be used to increase intratumoral pO2 and reverse tumor hypoxia. Here we present evidence that the ketogenic diet, ketone supplementation, and hyperbaric oxygen therapy work individually and in combination to slow progression and extend survival in the VM-M3 model of metastatic cancer. This study strongly suggests that these cost effective, non-toxic metabolic therapies should be further evaluated in animal and human studies to determine their potential clinical use.

Thesis (Ph. D.)--Munster, 1908. / Lebenslauf. Published also as 13. hft. [3. bd.] of Beitrage fur die geschichte Niedersachsens und Westfalens.

Thesis (doctoral)--University of Jyväskylä, 1997. / Includes bibliographical references (p. 192-200).

This study aims to explore the visual knowledge organization of Aby Warburg’s Bilderatlas Mnemosyne by tracing some of the essential lines in his thinking and relating these to the conceptualization and realization of the atlas project. The image atlas – which at the time of Warburg’s death in 1929 remained unfinished – can be described as a synoptical and experimental didactic instrument, a monumental work in progress conceived to guide art historical thought, which in Warburg’s research expands into a pluridisciplinary field of ”kulturwissenschaftlicher Bildgeschichte”. Within its historical context the Mnemosyne atlas can be seen as an object of critical knowledge that, in presenting art history as an open and mobile visual structure, evades the universalistic aims of encyclopaedic projects. Drawing upon Foucault’s archaeological examination of the humanities in The Order of Things and Agamben’s reflection on method – and specifically on the notion of the paradigm – in The Signature of All Things, I argue that the Mnemosyne atlas with its non-linear arrangement and associative technique should be read in its relation to a pre-encyclopaedic knowledge culture where similarity, kinship and analogy, rather than division, taxonomy and binarity, rule the organization of the world and its objects. This allows us to better understand the scientific foundations of the atlas and to perceive its ongoing compilation of documents as a systematic procedure. Lastly, the study also emphazises the vicinity between Warburg’s image atlas and his library, both in the physical space of his research institute in Hamburg and as a mode of thought.