Introduction: Cancer associated thrombosis is a well-recognized phenomenon that results in considerable patient morbidity and mortality. Malignancy conveys an increased risk for thrombosis and chemotherapy further elevates this risk. The pathophysiological mechanisms underlying this process remain poorly defined. Materials and Methods: A human acute monocytic leukemia cell line (THP-1) was treated with commonly used anthracycline chemotherapeutics at concentrations similar to those found in the plasma of cancer patients. Cells were analyzed for tissue factor (TF) mRNA, protein, and activity. Microparticle (MP) TF activity was also measured. Phosphatidylserine (PS) exposure on cells and MPs was analyzed by flow cytometry. PS levels on MPs was also evaluated in an annexin V capture assay. Results: Anthracycline treatment of THP-1 cells resulted in a concentration-dependent increase in cellular TF activity without a change in TF protein, which was associated with increased PS exposure on the cell surface and apoptosis. The increase in TF activity was abolished by annexin V or lactadherin indicating that PS exposure was required. Anthracycline treatment of THP-1 cells also increased the number of TF-positive MPs. Conclusion: Treatment of THP-1 cells with anthracyclines induces apoptosis and increases cellular TF activity. The increased activity required an increase in exposure of PS. Additionally, anthracyclines increase the release of TF-positive MPs from THP-1 cells. We propose that the increase in cellular TF activity in circulating leukemic cells, combined with increased numbers of TF-positive MPs, may contribute to thrombosis in cancer patients receiving chemotherapy.

Introduction The problem at hand is understanding if pediatric acute lymphoblastic leukemia (ALL) treatment affects neurocognitive function or development. As the children battle ALL and are given treatments such as cranial radiation therapy and chemotherapy, they are having issues later on in life because the treatment regimens are very strong and are given during a crucial period of development. Purpose Statement and Question Does one pediatric treatment option affect neurocognitive development more than another later in life? Literature Review Research was conducted online via Google Scholar and East Tennessee State University Library database. Key terms used were pediatric ALL and neurocognitive effects of chemotherapy and radiation. Five studies were collected all pertaining to the question at hand. Findings The findings from the research collected was that certain demographics have a stronger effect on the development of a child post-ALL treatment. The treatment regimen and the strength of the treatment affect cognitive development. Cognitive impairment related to attention occurs with all children treated for ALL. Conclusion Nurses see first-hand the effects treatment have on children as the grow. We have to provide resources to help with attention deficits among other cognitive issues that result from treatment. The literature gave a great insight to what effects are to be expected post-treatment.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19363号 / 医博第4040号 / 新制||医||1011(附属図書館) / 32377 / 新制||医||1011 / 京都大学大学院医学研究科医学専攻 / (主査)教授 小柳 義夫, 教授 河本 宏, 教授 松岡 雅雄 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20072号 / 医博第4165号 / 新制||医||1018(附属図書館) / 33188 / 京都大学大学院医学研究科医学専攻 / (主査)教授 前川 平, 教授 小川 誠司, 教授 小柳 義夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Indiana University-Purdue University Indianapolis (IUPUI) / Cancer cells display increased metabolic demands to support their proliferation and biosynthetic needs. It has been extensively shown in cancers, that amino acids have functions beyond the role of mRNA translation. The breadth of functions makes amino acid restriction an effective strategy for cancer therapy; hence an important line of research involves targeting amino acid acquisition and metabolism therapeutically. Currently, asparagine depletion via L-Asparaginase in acute lymphoblastic leukemia (ALL) remains the only clinically approved therapy to date. In the first project, we showed that ALL cells are auxotrophic for asparagine and rely on exogenous sources for this non-essential amino acid. However, sensitivity to L-Asparaginase therapy is mitigated by the expression of the enzyme asparagine synthetase (ASNS), involved in de novo asparagine biosynthesis. We showed that this adaptive response requires two essential steps; demethylation of the ASNS promoter and recruitment of activating transcription factor 4 (ATF4) to the promoter to drive ASNS transcription. Our follow-up study in ALL cells showed that asparagine bioavailability (through de novo biosynthesis or exogenous sources) is essential to maintain the expression of the critical oncogene c-MYC. c-MYC is a potent transcription factor and is dysregulated in over 60% of cancers, including hematopoietic malignancies. We showed that this regulation by asparagine is primarily at the translation level and c-MYC expression is rescued only when exogenous asparagine is available or when cells can undertake de novo biosynthesis. At the biochemical level, asparagine depletion also causes an induction of ATF4 mediated stress response and suppression of global translation mediated by decreased mammalian target of rapamycin complex 1 (mTORC1) activity. However, we found that neither inhibition of the stress response or rescuing global translation rescued c-MYC protein expression. We also extended this observation to c-MYC-driven lymphomas using cell lines and orthotopic in vivo models. We showed that genetic inhibition of ASNS or pharmacological inhibition of asparagine production can significantly limit c-MYC protein and tumor growth when environmental asparagine is limiting. Overall, our work shows an essential role for asparagine in lymphoid cancers and has expanded on the usage of L-Asparaginase to resistant leukemias and lymphomas.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13534号 / 論医博第2274号 / 新制||医||1065(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 滝田 順子, 教授 伊藤 貴浩, 教授 江藤 浩之 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

The human bone marrow (BM) is one of the most complex and critical tissues in the adult, functioning as the site for blood and immune cell production in homeostasis, injury, and disease. The marrow acts as an incredibly diverse stem cell niche, containing stromal and blood cells that help support the maintenance and differentiation capacity of hematopoietic stem and progenitor cells (HSPCs). The cell-cell and cell-matrix interactions within the niche help alter the marrow to trigger blood cell production in response to injury, as well as harbor downstream changes that may persist in the hematopoietic system during disease, such as in cancer metastasis or leukemias of the BM. As the development of engineered human tissue models including organs-on-a-chip (OoC) have emerged over the past decade, there has been an increased relevance of using human BM models to study human- and patient-specific immune interactions in vitro. In this dissertation, we have developed patient-specific bioengineering technologies to model the BM, as well as those to study multi-organ interactions, for a host of translational applications of injury and disease. In Chapters 1 and 2, we introduce a number of concepts in bioengineering and stem cell biology for studying human organ functions outside of the body. In Chapter 3, we describe the tools that are critical for modeling individual organ functions (healthy human BM) and immune cells, as well as when combining multiple OoC systems together. In Chapter 4, we apply these tools for disease modeling, in studying the complex interactions in either acute leukemia development or metastatic colonization of the BM. In Chapter 5, we use our human-specific engineered models for studies of acute and systemic injury, including the effects of cosmic radiation on human tissue function. To tie together the tissue engineered tools developed in this thesis, we described in Chapter 6 the utility of scientific outreach and social media in the widespread dissemination of tissue engineering and stem cell principles to the broader scientific community and general public. Collectively, this dissertation provides a unique look at the use of engineered human tissue systems to model human blood and immune interactions using bioengineering tools, with applications in disease modeling of primary and metastatic cancers, as well as in acute and systemic injuries.

Systemic mastocytosis refers to a heterogeneous group of clinical disorders characterized by excessive mast cell accumulation in one or multiple organs. Mastocytosis is now considered as a separate disease category in the 2016 WHO classification of myeloid neoplasm and acute leukemia. It is no longer considered as a subgroup of meyloproliferate neoplasms. The clinical presentation of mastocytosis is heterogeneous ranging from skin-limited disease (cutaneous mastocytosis) to a more aggressive form with extra cutaneous presentation (systemic mastocytosis) with or without skin involvement. We are presenting a case of systemic mastocytosis that aroused in a patient who carried diagnosis of CMML for almost 2 years. The worsening B symptoms along with worsening splenomegaly were the driving factor for further investigations including Bone Marrow biopsy which revealed the diagnosis. A 74 year old Caucasian male with past oncology history of Chronic myelomoncytic leukemia diagnosed after persistant monocytosis on complete blood count . Patient presented with gradual onset of low grade fever , weight loss and night sweating , CT abdomen showed hepatosplenomegaly. core biopsy of the liver showed portal and lobular infiltrate consistent with involvement by mastocytes and extra medullary hematopoiesis. The infiltrate was positive for CD117, CD33, CD68, myeloperoxidase and CD163. Patient had bone marrow biopsy which showed increased CD117 positive cells consistent with involvement by systemic mastocytosis. The core biopsy showed multifocal nodules of spindle cells with fibrosis which was morphologically consistent with abnormal mast cells. Immunohistochemistry for CD117 was strongly positive in the spindle cell nodules and scattered polygonal cell nodules. KIT D816V mutation was detected. Patient met criteria for diagnosis of systemic mastocytosis with presence of previous diagnosis of CMML and classified as Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN). Due to patient multiple comorbiditeis , he was not a candidate for Allo HCT. In an attempt to control his disease , patient was started on dose reduced Dacogen, but his functional status continued to delined and eventually dacogen was discontinued and patient was placed on best supportive car Conclusion Systemic mastocytosis is a rare entity with heterogeneous clinical presentation, highly variable disease course and consequently survival rates.Though recent advances in understanding genetic and molecular basis of disease, bone marrow transplantation remains the only treatment with possible curative potential in patients with advanced form of mastocytosis though carrying substantial mortality risk .Further understanding of Kit mutation might be able to offer a highly effective medication with durable response in a fashion similar to the success story of gleevac with CML treatment .