Abstract: The dynamic and multiple functions of p53, together with its involvement in the most common non-infectious diseases, underscore the need to elucidate the complexity of the p53 regulatory networks. Pathological conditions such as cancer, neurodegeneration, ischemia, cholestasis, and atherosclerosis are all strongly associated with deregulated levels of apoptosis in which p53 dysfunction has a prominent role. We will highlight recent developments of p53-induced apoptosis in human diseases, with a focus on modulation of liver cell apoptosis. In addition, we will discuss controversies arising from widespread p53 activation as a therapeutic approach to cancer. Recent studies have provided relevant and unprecedented information about mechanistic antiapoptotic functions of the endogenous bile acid, ursodeoxycholic acid (UDCA), suggesting that the finely tuned, complex control of p53 by Mdm-2 (mouse double minute-2, an oncoprotein) is a key step in UDCA modulation of p53-triggered apoptosis. We will also review recent therapeutic strategies and clinical applications of targeted agents, their safety, and efficacy, with particular emphasis on potential benefits of UDCA. ... Read more

Abstract: Standard anti-cancer therapeutic modalities like chemotherapy and radiotherapy evoke host's reactions that include involvement of the immune system. Elucidation of these mechanisms offers the double advantage of enabling a more rational choice of cytotoxic therapy and exploring the combination with immunotherapy. Radiotherapy, a well established local anti-cancer approach, is a particularly interesting partner for immunotherapy, since it can be harnessed to specifically modify the immunogenicity of the primary tumor and its microenvironment, in the attempt to generate an in situ immunization against a patient's own cancer. ... Read more

Abstract: Increasing evidence suggests an important role for programmed cell death (PCD) pathways in aging phenotypes across species. PCD is critical to the homeostasis of tissues maintained by cell division, for example, the blood and the lining of the gut. During aging, accumulated cellular damage and non-optimal systemic signaling can cause too little cell death (hyperproliferation and cancer), or too much cell death (tissue atrophy and ectopic cell death), thereby limiting tissue function and life span. For these reasons PCD pathways are promising targets for interventions in aging and aging-related diseases: reactivation of PCD may be beneficial in clearing cancerous and senescent cells, whereas inhibiting PCD may help prevent muscle atrophy and nervous system degeneration. ... Read more

Abstract: The loss of ability in controlling cell cycle leads to aberrant cell growth and is a hallmark of cancer cells. Cell cycle regulation and progression mainly rely on protein phosphorylation events, therefore cell cycle kinases have long been viewed as potential targets for anticancer strategies. Consistently, cell cycle kinases are often dysregulated in different types of human cancer. Despite years of research and attempts directed at inhibiting cell cycle kinases, none of these approaches has been successfully translated to the clinic to halt tumorigenesis. Here, we review several currently pursued strategies and highlight both current challenges and some recent findings, which might help to develop new, better conceived therapeutic approaches based on cell-cycle kinase inhibition. ... Read more

Abstract: Chronic lymphocytic leukemia (CLL) is a malignancy mainly affecting elderly people and is still considered an incurable disease. Despite recent advances in CLL treatment, relapse rates are high and often accompanied by the development of resistance towards conventional chemotherapy. Thus, new agents are needed for the treatment of these patients. In recent years, our understanding of the biological mechanisms driving CLL pathogenesis has considerably improved, and novel treatment strategies are arising. This review summarizes recent insights in CLL biology and describes several new agents and treatment strategies that are currently explored in pre-clinical studies and early-phase clinical trials. ... Read more

Abstract: The evolution of the immune system has provided a multilevel system that interconnects the innate and adaptive immune systems to serve at least three central purposes: the defense from microbial pathogens, the capacity for discrimination of self- from non-self necessary for the prevention of autoimmune disease, and essential effector roles in wound repair and tissue remodeling. In recent studies, we have elucidated an unsuspected role for a class of naturally occurring autoreactive antibodies from the most primitive tier of B lymphocytes, which regulates fundamental functions of the innate immune system. Our findings also throw light onto long unresolved mysteries regarding the origins of the earliest waves of B lymphocyte development. ... Read more

Abstract: The first descriptions of apoptosis were made over 150 years ago, although the implications for tumor development were not appreciated until the 1970s. Natural cell death is a critical part of development of multicellular organisms, and also counter-balances the cell generating effects of mitosis. Disruptions in the highly regulated apoptotic pathway can lead to disease, such as tumors, due to the accumulation of excessive numbers of cells. Restoring normal apoptosis in cancer cells is one of the current challenges of cancer research. ... Read more

Abstract: As with many other molecular agents that are involved in multiple aspects of cellular processes, E2F1 plays a dual role of cellular proliferation and apoptosis. How to take advantage of the apoptosis induction and sensitization properties of E2F1 for therapeutic purposes while minimizing its other properties has a significant bearing on how to turn a functionally complex molecule such as E2F1 into a drug target. ... Read more

Abstract: Apoptosis is a ubiquitous, highly coordinated process of self-destruction. Conventional cancer therapeutic agents can cause, to a certain degree, apoptosis of cancer cells. However, they do so in an indiscriminate manner leading to unacceptable side effects. Strategies of selectively activating apoptosis of cancer cells are described. ... Read more

Abstract: In addition to the immune system, apoptosis plays a role in the nervous system. An excessive number of cells are generated during embryogenesis and only neurons that make the correct connections at the right time survive. But then, these surviving neurons do not divide and they need to make it through the entire life of the organism and cannot be replaced once they are dead. The control over death and survival is therefore vitally important. ... Read more