Clinical Pharmacology & Therapeutics: Past, Present, and Future.

Clinical Pharmacology & Therapeutics (CPT), the definitive and timely source for advances in human therapeutics, transcends the drug discovery, development, regulation, and utilization continuum to catalyze, evolve, and disseminate discipline-transformative knowledge. Prioritized themes and multidisciplinary content drive the science and practice of clinical pharmacology, offering a trusted point of reference. An authoritative herald across global communities, CPT is a timeless information vehicle at the vanguard of discovery, translation, and application ushering therapeutic innovation into modern healthcare

Temporal naturalism

Two people may claim both to be naturalists, but have divergent conceptions of basic elements of the natural world which lead them to mean different things when they talk about laws of nature, or states, or the role of mathematics in physics. These disagreements do not much affect the ordinary practice of science which is about small subsystems of the universe, described or explained against a background, idealized to be fixed. But these issues become crucial when we consider including the whole universe within our system, for then there is no fixed background to reference observables to. I argue here that the key issue responsible for divergent versions of naturalism and divergent approaches to cosmology is the conception of time. One version, which I call temporal naturalism, holds that time, in the sense of the succession of present moments, is real, and that laws of nature evolve in that time. This is contrasted with timeless naturalism, which holds that laws are immutable and the present moment and its passage are illusions. I argue that temporal naturalism is empirically more adequate than the alternatives, because it offers testable explanations for puzzles its rivals cannot address, and is likely a better basis for solving major puzzles that presently face cosmology and physics. This essay also addresses the problem of qualia and experience within naturalism and argues that only temporal naturalism can make a place for qualia as intrinsic qualities of matter

Back to Parmenides

After a brief introduction to issues that plague the realization of a theory of quantum gravity, I suggest that the main one concerns a quantization of the principle of relative simultaneity. This leads me to a distinction between time and space, to a further degree than that present in the canonical approach to general relativity. With this distinction, one can make sense of superpositions as interference between alternative paths in the relational configuration space of the entire Universe. But the full use of relationalism brings us to a timeless picture of Nature, as it does in the canonical approach (which culminates in the Wheeler-DeWitt equation). After a discussion of Parmenides and the Eleatics' rejection of time, I show that there is middle ground between their view of absolute timelessness and a view of physics taking place in timeless configuration space. In this middle ground, even though change does not fundamentally exist, the illusion of change can be recovered in a way not permitted by Parmenides. It is recovered through a particular density distribution over configuration space which gives rise to 'records'. Incidentally, this distribution seems to have the potential to dissolve further aspects of the measurement problem that can still be argued to haunt the application of decoherence to Many-Worlds quantum mechanics. I end with a discussion indicating that the conflict between the conclusions of this paper and our view of the continuity of the self may still intuitively bother us. Nonetheless, those conclusions should be no more challenging to our intuition than Derek Parfit's thought experiments on the subject.Comment: 25 pages, 1 figure. Winner of the essay contest: "Space-time after quantum gravity" (University of Illinois and Universit\'e de Geneve). To be published in special editio

Security Policy Consistency

With the advent of wide security platforms able to express simultaneously all the policies comprising an organization's global security policy, the problem of inconsistencies within security policies become harder and more relevant. We have defined a tool based on the CHR language which is able to detect several types of inconsistencies within and between security policies and other specifications, namely workflow specifications. Although the problem of security conflicts has been addressed by several authors, to our knowledge none has addressed the general problem of security inconsistencies, on its several definitions and target specifications.Comment: To appear in the first CL2000 workshop on Rule-Based Constraint Reasoning and Programmin

Associations of clock genes polymorphisms with soft tissue sarcoma susceptibility and prognosis

BACKGROUND: Dysfunction of the circadian clock and polymorphisms of some circadian genes have been linked to cancer development and progression. We investigated the relationship between circadian genes germline variation and susceptibility or prognosis of patients with soft tissue sarcoma. PATIENTS AND METHODS: We considered the 14 single nucleotide polymorphisms (SNPs) of 6 core circadian genes that have a minor allele frequency >\u20095% and that are known to be associated with cancer risk or prognosis. Genotyping was performed by q-PCR. Peripheral blood and clinic-pathological data were available for 162 patients with liposarcoma or leiomyosarcoma and 610 healthy donors. Associations between the selected clock genes polymorphisms and sarcoma susceptibility or prognosis were tested assuming 3 models of inheritance: additive, recessive and dominant. Subgroup analysis based on sarcoma histotype was performed under the additive genetic model. Multivariate logistic regression and multivariate Cox proportional hazard regression analyses were utilized to assess the association between SNPs with patient susceptibility and survival, respectively. Pathway variation analysis was conducted employing the Adaptive Rank Truncated Product method. RESULTS: Six out of the 14 analyzed SNPs were statistically significantly associated with susceptibility or prognosis of soft tissue sarcoma (P <\u20090.05). The present analysis suggested that carriers of the minor allele of the CLOCK polymorphism rs1801260 (C) or of PER2 rs934945 (T) had a reduced predisposition to sarcoma (26% and 35% respectively with the additive model) and liposarcoma (33% and 41% respectively). The minor allele (A) of NPAS2 rs895520 was associated with an increased predisposition to sarcoma of 33% and leiomyosarcoma of 44%. RORA rs339972 C allele was associated with a decreased predisposition to develop sarcoma assuming an additive model (29%) and leiomyosarcoma (36%). PER1 rs3027178 was associated with a reduced predisposition only in liposarcoma subgroup (32%). rs7602358 located upstream PER2 was significantly associated with liposarcoma survival (HR: 1.98; 95% CI 1.02-3.85; P\u2009=\u20090.04). Germline genetic variation in the circadian pathway was associated with the risk of developing soft tissue sarcoma (P\u2009=\u20090.035). CONCLUSIONS: Genetic variation of circadian genes appears to play a role in the determinism of patient susceptibility and prognosis. These findings prompt further studies to fully dissect the molecular mechanisms