Study of novel natural compounds as potential drugs in the treatment of acute leukemias

Introduction: Among all cancer types leukemia represents the leading cause of cancer death in man younger than 40 years. Single-target drug therapy has generally been highly ineffective in treating complex diseases such as cancer. A growing interest has been directed toward multi-target drugs able to hit multiple targets. In this context, plant products, based on their intrinsic complexity, could represent an interesting and promising approach. Aim of the research followed during my PhD was to indentify and study novel natural compounds for the treatment of acute leukemias. Two potential multi-target drugs were identified in Hemidesmus indicus and piperlongumine. Methodology/Principal Findings: A variety of cellular assays and flow cytometry were performed on different cell lines. We demonstrated that Hemidesmus modulates many components of intracellular signaling pathways involved in cell viability and proliferation and alters gene and protein expression, eventually leading to tumor cell death, mediated by a loss of mitochondrial transmembrane potential, raise of [Ca2+]i, inhibition of Mcl-1, increasing Bax/Bcl-2 ratio, and ROS formation. Moreover, we proved that the decoction causes differentiation of HL-60 and regulates angiogenesis of HUVECs in hypoxia and normoxia, by the inhibition of new vessel formation and the processes of migration/invasion. Clinically relevant observations are that its cytotoxic activity was also recorded in primary cells from acute myeloid leukemia (AML) patients. Moreover, both Hemidesmus and piperlongumine showed a selective action toward leukemic stem cell (LSC). Conclusions: Our results indicate the molecular basis of the anti-leukemic effects of Hemidesmus indicus and indentify the mitochondrial pathways, [Ca2+]i, cytodifferentiation and angiogenesis inhibition as crucial actors in its anticancer activity. The ability to selectively hit LSC showed by Hemidesmus and piperlongumine enriched the knowledge of their anti-leukemic activity. On these bases, we conclude that Hemidesmus and piperlongumine can represent a valuable strategy in the anticancer pharmacology.

Essays on Atypicality: A narrative perspective to illuminate how atypical actors can counter the disciplining effect of categories

Using Big Data and Natural Language Processing (NLP) tools, this dissertation investigates the narrative strategies that atypical actors can leverage to deal with the adverse reactions they often elicit. Extensive research shows that atypical actors, those who fail to abide by established contextual standards and norms, are subject to skepticism and face a higher risk of rejection. Indeed, atypical actors combine features and behaviors in unconventional ways, thereby generating confusion in the audience and instilling doubts about their propositions' legitimacy. However, the same atypicality is often cited as the precursor to socio-cultural innovation and a strategic act to expand the capacity for delivering valued goods and services. Contextualizing the conditions under which atypicality is celebrated or punished has been a significant theoretical challenge for scholars interested in reconciling this tension. Nevertheless, prior work has focused on audience side factors or on actor-side characteristics that are only scantily under an actor's control (e.g., status and reputation). This dissertation demonstrates that atypical actors can use strategically crafted narratives to mitigate against the audience’s negative response. In particular, when atypical actors evoke conventional features in their story, they are more likely to overcome the illegitimacy discount usually applied to them. Moreover, narratives become successful navigational devices for atypicality when atypical actors use a more abstract language. This simplifies classification and provides the audience with more flexibility to interpret and understand them.