A Systems Approach for Tumor Pharmacokinetics

Recent advances in genome inspired target discovery, small molecule screens, development of biological and nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization, interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow, extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should be considered in the design of agents and treatments. An example using antibodies in mouse xenografts illustrates the different in vivo behavior. This type of transport analysis can be used to aid in model development, experimental data analysis, and imaging and therapeutic agent design.National Institutes of Health (U.S.) (grant T32 CA079443

Evolution in the Arctic:A phylogeographic analysis of the circumarctic plant, Saxifraga oppositifolia (Purple saxifrage)

A survey of chloroplast DNA variation in the circumarctic-alpine plant, Saxifraga oppositifolia, has resolved two highly divergent cpDNA lineages with geographically widespread and mainly allopatric distributions that are largely concordant with those of two subspecies, that is, subspp. oppositifolia and glandulisepala. These subspecies differ for a single morphological trait and hence level of morphological divergence does not equate to molecular divergence within the species.The two cpDNA lineages were estimated to have diverged from their most recent common ancestor 5.37-3.76 Ma, that is, during the early to mid-Pliocene.A nested clade analysis was conducted in an attempt to determine how past episodes of range fragmentation, range expansion and long distance dispersal may have influenced the geographical distribution of cpDNA haplotypes.In Alaska-a known refugium for the species during the last ice-age-high levels of cpDNA diversity may be partly explained by divergence between populations that were isolated in different ice-free regions. It remains to be established whether the two subspecies of S. oppositifolia exhibit some form of reproductive isolation from each other under conditions of sympatry.</p

Measurement of the <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mml:msup><mml:mi>e</mml:mi><mml:mo>+</mml:mo></mml:msup><mml:msup><mml:mi>e</mml:mi><mml:mo>−</mml:mo></mml:msup><mml:mo stretchy="false">→</mml:mo><mml:msup><mml:mi>π</mml:mi><mml:mo>+</mml:mo></mml:msup><mml:msup><mml:mi>π</mml:mi><mml:mo>−</mml:mo></mml:msup></mml:math> cross section from threshold to 1.2 GeV with the CMD-3 detector

The cross section of the process e+e−→π+π− has been measured in the center of mass energy range from 0.32 to 1.2 GeV with the CMD-3 detector at the electron-positron collider VEPP-2000. The measurement is based on a full dataset collected below 1 GeV during three data taking seasons, corresponding to an integrated luminosity of about 62  pb−1. In the dominant ρ-resonance region, a systematic uncertainty of 0.7% has been reached. At energies around ϕ-resonance the π+π− production cross section was measured for the first time with high beam energy resolution. The forward-backward charge asymmetry in the π+π− production has also been measured. It shows a strong deviation from the theoretical prediction based on the conventional scalar quantum electrodynamics framework, and it is in good agreement with the generalized vector-meson-dominance and dispersive-based predictions. The impact of the presented results on the evaluation of the hadronic contribution to the anomalous magnetic moment of muon is discussed. Published by the American Physical Society 2024 </jats:sec