Objective: Challenging differential diagnosis Background: B cell lymphoma constitutes 80-85% of cases of Non Hodgkin's lymphoma in the Untied States. Metabolic complications may arise from the disease itself or through its end organ involvement. Case Report: We describe a case of a diffuse large B cell lymphoma diagnosed by abdominal computed tomography after it initially presented as hypoglycemia not correctable by dextrose infusion that instead resulted in increased anion gap metabolic acidosis with elevated lactate levels. Conclusions: The case illustrates how lymphomas can present unusually with hypoglycemia and lactic acidosis, the latter being an ominous sign that can occur without liver involvement. In this regard, the case demonstrates the metabolic sequelae of lymphoma that should raise suspicion for an underlying process. This has implications for diagnosis, treatment, and patient survival. Attention should be paid especially in the primary care setting in order to minimize delays in diagnosis.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19591号 / 医博第4098号 / 新制||医||1014(附属図書館) / 32627 / 京都大学大学院医学研究科医学専攻 / (主査)教授 野田 亮, 教授 武田 俊一, 教授 小川 修 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

Background: Tumor cells are highly dependent on glucose even in the presence of oxygen. This concept called the Warburg effect is a hallmark of cancer and strategies are considered to therapeutically exploit the phenomenon such as ketogenic diets. The success of such strategies is dependent on a profound understanding of tumor cell metabolism. With new techniques it is now possible to thoroughly analyze the metabolic responses to the withdrawal of substrates and their substitution by others. In the present study we used gas chromatography coupled to mass spectrometry (GC-MS) to analyze how glioblastoma brain tumor cells respond metabolically when glucose is withdrawn and substituted by pyruvate. Methods: Glioblastoma brain tumor cells were cultivated in medium with high (25 mM), medium (11 mM) or low (5.5 mM) glucose concentration or with pyruvate (5 mM). After 24 h GC-MS metabolite profiling was performed. Results: The abundances of most metabolites were dependent on the supply of glucose in tendency but not in a linear manner indicating saturation at high glucose. Noteworthy, a high level of sorbitol production and release was observed at high concentrations of glucose and high release of alanine, aspartate and citrate were observed when glucose was substituted by pyruvate. Intermediates of the TCA cycle were present under all nutritional conditions and evidence was found that cells may perform gluconeogenesis from pyruvate. Conclusions: Our experiments reveal a high plasticity of glioblastoma cells to changes in nutritional supply which has to be taken into account in clinical trials in which specific diets are considered for therapy.

Lactate Dehydrogenase-A (LDH-A) is up-regulated in a broad array of cancers and is associated with poor prognosis. Involved in the hypoxic response, LDH-A is a HIF-1 target and is responsible for the enzymatic reduction of pyruvate to lactate. This is important for several reasons, chiefly (1) the regeneration of NAD+ which feeds back into earlier glycolytic stages and (2) the depletion of intracellular pyruvate concentrations. High intracellular pyruvate is known to inhibit HDACs and is associated with increased apoptosis. LDH-A is also known to be controlled by oncogenes such as c-Myc suggesting an oncogenic role. Studies have shown that the knock-out of LDH-A reduces proliferation and tumourgenicity, and stimulates the mitochondria. This thesis therefore had three aims: firstly, to validate LDH-A inhibition and elucidate its full nature in terms of the implications for tumour survival; secondly, to ascertain the role of LDH-B in order to determine whether selectivity towards LDH-A would be a necessary feature of any small molecule; lastly, to recapitulate siRNA mediated LDH-A inhibition with small molecule inhibitors that had the potential for clinical application. The thesis examined both clinical data and a broad panel of cultured cancer cell types in order to select appropriate model in which to validate siRNA mediated inhibition of LDH-A and LDH-B. After it was demonstrated that LDH-A inhibition reduced the growth of cultured cells, a range of techniques were used to quantify this reduced growth in terms of cell death and changes in metabolism. Further to this, literature studies had proposed a role for LDH-B in maintaining lactate fuelled tumour growth; however, this thesis shows that in the cell lines studied, lactate-fuelled tumour growth was an LDH-A dependent phenomenon. Finally, a high throughput assay system was designed and validated and a library of small molecules was selected, synthesized, and screened in order to identify selective inhibitors of LDH-A.