Regulation of cell death in cancer - possible implications for immunotherapy

Since most anticancer therapies including immunotherapy trigger programmed cell death in cancer cells, defective cell death programs can lead to treatment resistance and tumor immune escape. Therefore, evasion of programmed cell death may provide one possible explanation as to why cancer immunotherapy has so far only shown modest clinical benefits for children with cancer. A better understanding of the molecular mechanisms that regulate sensitivity and resistance to programmed cell death is expected to open new perspectives for the development of novel experimental treatment strategies to enhance the efficacy of cancer immunotherapy in the future

Alternative cell death pathways and cell metabolism

While necroptosis has for long been viewed as an accidental mode of cell death triggered by physical or chemical damage, it has become clear over the last years that necroptosis can also represent a programmed form of cell death in mammalian cells. Key discoveries in the field of cell death research, including the identification of critical components of the necroptotic machinery, led to a revised concept of cell death signaling programs. Several regulatory check and balances are in place in order to ensure that necroptosis is tightly controlled according to environmental cues and cellular needs. This network of regulatory mechanisms includes metabolic pathways, especially those linked to mitochondrial signaling events. A better understanding of these signal transduction mechanisms will likely contribute to open new avenues to exploit our knowledge on the regulation of necroptosis signaling for therapeutic application in the treatment of human diseases

How to target apoptosis signaling pathways for the treatment of pediatric cancers

Apoptosis represents one of the most important forms of cell death in higher organisms and is typically dysregulated in human cancers, including pediatric tumors. This implies that ineffective engagement of cell death programs can contribute to tumor formation as well as tumor progression. In addition, the majority of cytotoxic therapeutic principles rely on the activation of cell death signaling pathways in cancer cells. Blockade of signaling networks that lead to cell death can therefore confer treatment resistance. A variety of genetic and epigenetic events as well as dysfunctional regulation of signaling networks have been identified as underlying causes of cell death resistance in childhood malignancies. Apoptosis pathways can be therapeutically exploited by enhancing proapoptotic signals or by neutralizing antiapoptotic programs. The challenge in the coming years will be to successfully transfer this knowledge into the development of innovative treatment approaches for children with cancer

Targeting apoptosis signaling in pancreatic cancer

The ability to escape apoptosis or programmed cell death is a hallmark of human cancers, for example pancreatic cancer. This can promote tumorigenesis, since too little cell death by apoptosis disturbs tissue homeostasis. Additionally, defective apoptosis signaling is the underlying cause of failure to respond to current treatment approaches, since therapy-mediated antitumor activity requires the intactness of apoptosis signaling pathways in cancer cells. Thus, the elucidation of defects in the regulation of apoptosis in pancreatic carcinoma can result in the identification of novel targets for therapeutic interference and for exploitation for cancer drug discovery. Keywords: apoptosis; pancreatic cancer; TRAIL; IAPs; mitochondri

Working with Constrained Systems: A Review of A. K. Joshi's IJCAI-97 Research Excellence Award Acceptance Lecture

This is a brief review of Joshi's award acceptance lecture published in <I>AI Magazine</I>. This review appeared in the AI Watch column in <I>Computers and Society</I>, a quarterly magazine

Partially Resolving the Tension between Omniscience and Free Will: A Mathematical Argument

We put forward a probability-based theory of temptation with implications for philosophy of religion and philosophy of mind, alike

"The Extended Mind"--Extended

We review the argument made by Clark and Chalmers in <I>Analysis</I> for a limited externalism and extend their argument from declarative knowledge to procedural knowledge

Can One Really Reason about Laws?

Precedent decides legal cases, but few precedents make the case at bar <I>res judicata</I>. Instead, analogical reasoning is used, together with canons of statutory interpretation and theories of constitutional jurisprudence. The work under review provides a model and algorithm for analogical reasoning in the legal context. Technically, the paper represents very fine work, except that in order to find the ground of a rule, some human input is required. The rule is denied and consequences of the negation are automatically derived; then, those which a person has previously marked as undesirable are candidates for the rule's ground. So this is a man-machine system, something not emphasized by the authors. Still, it is very fine work. Aside from its technical excellence and, on the other hand, an annoying number of missing articles, misplaced modifiers, and failures of agreement, the authors imply a certain understanding of law and how laws are made. The paper uses an ordinance rather than cases for analogical reasoning, after all, a practice that makes little sense unless the legislature is always perfectly consistent. Hence, the whole epistemological basis for the paper may be flawed

An Expert System for an Idiosyncratic Domain: Love, Intimacy, and Friendship.

No abstract available