Interplay between geometry and flow distribution in an airway tree

Uniform fluid flow distribution in a symmetric volume can be realized through a symmetric branched tree. It is shown here, however, that the flow partitioning can be highly sensitive to deviations from exact symmetry if inertial effects are present. This is found by direct numerical simulation of the Navier-Stokes equations in a 3D tree geometry. The flow asymmetry is quantified and found to depend on the Reynolds number. Moreover, for a given Reynolds number, we show that the flow distribution depends on the aspect ratio of the branching elements as well as their angular arrangement. Our results indicate that physiological variability should be severely restricted in order to ensure uniform fluid distribution in a tree. This study suggests that any non-uniformity in the air flow distribution in human lungs should be influenced by the respiratory conditions, rest or hard exercise

The heats of formation of the haloacetylenes XCCY [X, Y = H, F, Cl]: basis set limit ab initio results and thermochemical analysis

The heats of formation of haloacetylenes are evaluated using the recent W1 and W2 ab initio computational thermochemistry methods. These calculations involve CCSD and CCSD(T) coupled cluster methods, basis sets of up to spdfgh quality, extrapolations to the one-particle basis set limit, and contributions of inner-shell correlation, scalar relativistic effects, and (where relevant) first-order spin-orbit coupling. The heats of formation determined using W2 theory are: \hof(HCCH) = 54.48 kcal/mol, \hof(HCCF) = 25.15 kcal/mol, \hof(FCCF) = 1.38 kcal/mol, \hof(HCCCl) = 54.83 kcal/mol, \hof(ClCCCl) = 56.21 kcal/mol, and \hof(FCCCl) = 28.47 kcal/mol. Enthalpies of hydrogenation and destabilization energies relative to acetylene were obtained at the W1 level of theory. So doing we find the following destabilization order for acetylenes: FCCF $>$ ClCCF $>$ HCCF $>$ ClCCCl $>$ HCCCl $>$ HCCH. By a combination of W1 theory and isodesmic reactions, we show that the generally accepted heat of formation of 1,2-dichloroethane should be revised to -31.8$\pm$0.6 kcal/mol, in excellent agreement with a very recent critically evaluated review. The performance of compound thermochemistry schemes such as G2, G3, G3X and CBS-QB3 theories has been analyzed.Comment: Mol. Phys., in press (E. R. Davidson issue

Measurement of the critical DNA lesions produced by antibody-directed enzyme prodrug therapy (ADEPT) in vitro, in vivo and in clinical material

An antibody-directed enzyme prodrug therapy (ADEPT) system against CEA-positive tumours is currently in phase I clinical trials. It consists of a prodrug, 4-[N,N-bis(2-iodoethyl) amino] phenoxycarbonyl L -glutamic acid (ZD2767P) and a conjugate of the F(ab')2 anti-CEA antibody A5B7 and the bacterial enzyme carboxypeptidase G2 (CPG2). ZD2767P is converted by antibody-targeted CPG2 into an active bifunctional alkylating drug (ZD2767) at the tumour site. The IC 50 value of the prodrug against the human colorectal tumour LS174T cell line was 55 ± 9 μM following a 1 h exposure. In contrast, co-incubation of ZD2767P with CPG2 resulted in 229-fold increase in activity. Using a modified comet assay, DNA interstrand cross links (ISC) were detected within 1 h of ZD2767P + CPG2 treatment and were repaired by 24 h. A clear dose–response was seen between the level of ISC, growth inhibition and ZD2767 concentration. Administration of a therapeutic dose of ZD2767P 72 h after the F(ab′)2 A5B7 conjugate to mice bearing LS147T xenografts resulted in extensive ISC in the tumour after 1 h; repair was seen at 24 h. Tumour biopsies and peripheral lymphocytes were studied in 5 patients on the ADEPT phase I clinical trial. In 4 patients no ISC were detected. These patients also demonstrated poor localization of conjugate and no tumour response was seen. However a significant level of ISC was detected in one tumour biopsy, which also showed evidence of conjugate localization and clinical response. These studies demonstrate the application of the comet assay in the measurement of ISC in vitro and in clinical material and confirm that activation of ZD2767P results in the formation of DNA crosslinks. © 2001 Cancer Research Campaign http://www.bjcancer.co

Fractionated 131I anti-CEA radioimmunotherapy: effects on xenograft tumour growth and haematological toxicity in mice

Dose fractionation has been proposed as a method to improve the therapeutic ratio of radioimmunotherapy (RIT). This study compared a single administration of 7.4 MBq 131I-anti-CEA antibody given on day 1 with the same total activity given as fractionated treatment: 3.7 MBq (days 1 and 3), 2.4 MBq (days 1, 3, and 5) or 1.8 MBq (days 1, 3, 5, and 8). Studies in nude mice, bearing the human colorectal xenograft LS174T, showed that increasing the fractionation significantly reduced the efficacy of therapy. Fractionation was associated with a decrease in systemic toxicity as assessed by weight, but did not lead to any significant decrease in acute haematological toxicity. Similarly, no significant decrease in marrow toxicity, as assessed by colony-forming unit assays for granulocytes and macrophages (CFUgm), was seen. However, there was a significant depression of CFUgm counts when all treated animals were compared with untreated controls, suggesting that treatment did suppress marrow function. In conclusion, in this tumour model system, fractionated RIT causes less systemic toxicity, but is also less effective at treating tumours