• ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial.

      Ranson, Malcolm; Hammond, Lisa A.; Ferry, David R.; Kris, Mark; Tullo, Andrew; Murray, Philip I.; Miller, Vince; Averbuch, Steve; Ochs, Judy; Morris, Charles; et al. (American Society of Clinical Oncology, 2002)
      PURPOSE: To investigate the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 in patients with solid malignant tumors. PATIENTS AND METHODS: This was an open, phase I, escalating multiple-dose tolerability and pharmacokinetic trial. ZD1839 was administered once daily for 14 consecutive days followed by 14 days off treatment. Dose escalation started at 50 mg/d and continued to 925 mg or until consistent dose-limiting toxicity (DLT) was observed. RESULTS: Sixty-four patients were entered at eight dose levels. The most frequent dose-related grade 1 and 2 adverse events were an acne-like (or folliculitis) rash, nausea, and diarrhea. Three of nine patients treated at 700 mg/d developed DLT (reversible grade 3 diarrhea); grade 3 and 4 events were uncommon. Exposure to ZD1839 was dose proportional, and the mean terminal half-life was 48 hours (range, 37 to 65). Four of 16 patients with non-small-cell lung cancer (NSCLC) had objective partial responses observed from ZD1839 300 to 700 mg/d. Overall, 16 patients remained on study for > or = 3 months, with seven of these patients (five with NSCLC, including three of the patients with partial response) remaining on study for > or = 6 months. CONCLUSION: ZD1839 was well tolerated, with DLT observed at a dose well above that at which antitumor activity was seen. Pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation. Phase II monotherapy and phase III combination trials in NSCLC are being conducted to investigate further the efficacy, tolerability, and optimal daily dose of ZD1839.
    • Zeolite L Synthesis using Different Molar Gel Compositions for the Purpose of Minimising Reagent Water.

      Wan, Ya; Williams, Craig D.; Duke, Catherine V. A.; Cox, Jeffrey J. (Amsterdam: Elsevier, 2001)
      A new starting molar gel composition 1.3K2O:Al2O3:6.0SiO2:37H2O containing much less silica, potassium and water than a conventional gel composition has been successfully used for the synthesis of zeolite L with minimum chemical waste. Inductively coupled plasma analysis on the mother liquors showed that conversion of 99.7% for Al, 90.9% for Si and 82.2% for K had been achieved when the new gel composition was used for the synthesis. The zeolite L synthesized from the new gel composition showed a well-defined cylindrical morphology. Zeolite L has also been synthesized from two other modified molar gel compositions 1.5K2O:Al2O3:6.0SiO2:37H2O and 1.9K2O:1.0Al2O3:6.0SiO2:67H2O. The chemical waste associated with those two synthesis gel compositions is also greatly reduced.
    • Zeolite Materials.

      Williams, Craig D. (RSC Press, 2002)
      SYNOPSIS: This book introduces the molecular world, surveys the role and scope of chemistry and illustrates its central role in science and its application to diverse areas, from biological systems to new technology. Co-published by the RSC and the Open University, this series provides an integrated introduction to all branches of chemistry both for students wishing to specialize and those wishing to gain a broad understanding of chemistry and its relevance to the everyday world and to other areas of science. The books, with their case studies and accompanying CD-ROMS, should also provide useful resource material for teachers and lecturers. (The CD-ROMs are designed for use on a PC running Windows 95, 98, ME or 2000.)
    • Zero Augmentation: A method for fitting zero-modified count models that allows both zero-inflation and zero-deflation

      Wilson, Paul; Bowman, Adrian W. (Statistical Modelling Society, 2010-07-05)
      The concept of zero-inflation is now well established, and several software packages exist that fit zero-inflated models. Whilst there is some mention of zero-deflation in the literature, there is very little published evidence of research into zero-modified models that allow for both zero-inflation and zero-deflation within the one model. We present a very simple method that enables the fitting of zero-modified models via any software that fits zero-inflated models, and investigate the benefits of fitting zero-modified models.
    • Zoo-led initiatives and their role in lemur conservation in situ

      Spiezio, Caterina; Regaiolli, Barbara; Savonitto, Margherita; Bruslund, Simon; Vaglio, Stefano (MDPI, 2022-10-14)
      We examined wider society’s ability to achieve biodiversity conservation and management targets using lemurs as a case study. We evaluated the impact on lemur conservation in situ by conservation initiatives led by European zoos in Madagascar exploring the European Association of Zoos and Aquaria’s Conservation Database projects in terms of performed actions and achieved goals as well as communication to the public. We found that zoo-led conservation initiatives may have a positive impact on the ground and tend to achieve most conservation goals related to wild lemurs. However, we suggest that such conservation programmes should underline that they target further lemur species beyond the flagship charismatic species and that enhanced communication efforts would be beneficial to further raise public awareness.
    • Zoonotic transfer of clostridium difficile harboring antimicrobial resistance between farm animals and humans

      Knetsch, CW; Kumar, N; Forster, SC; Connor, TR; Browne, HP; Harmanus, C; Sanders, IM; Harris, SR; Turner, L; Morris, T; et al. (American Society for Microbiology, 2017-12-13)
      The emergence of Clostridium difficile as a significant human diarrheal pathogen is associated with the production of highly transmissible spores and the acquisition of antimicrobial resistance genes (ARGs) and virulence factors. Unlike the hospital-associated C. difficile RT027 lineage, the community-associated C. difficile RT078 lineage is isolated from both humans and farm animals; however, the geographical population structure and transmission networks remain unknown. Here, we applied whole-genome phylogenetic analysis of 248 C. difficile RT078 strains from 22 countries. Our results demonstrate limited geographical clustering for C. difficile RT078 and extensive coclustering of human and animal strains, thereby revealing a highly linked intercontinental transmission network between humans and animals. Comparative whole-genome analysis reveals indistinguishable accessory genomes between human and animal strains and a variety of antimicrobial resistance genes in the pangenome of C. difficile RT078. Thus, bidirectional spread of C. difficile RT078 between farm animals and humans may represent an unappreciated route disseminating antimicrobial resistance genes between humans and animals. These results highlight the importance of the “One Health” concept to monitor infectious disease emergence and the dissemination of antimicrobial resistance genes.
    • α-catenin structure and nanoscale dynamics in solution and in complex with f-actin

      Nicholl, Iain; Matsui, Tsutomu; Weiss, Thomas M; Stanley, Christopher B; Heller, William T; Martel, Anne; Farago, Bela; Callaway, David JE; Bu, Zimei (Elsevier, 2018-07-11)
      As a core component of the adherens junction, α-catenin stabilizes the cadherin/catenin complexes to the actin cytoskeleton for the mechanical coupling of cell-cell adhesion. α-catenin also modulates actin dynamics, cell polarity, and cell-migration functions that are independent of the adherens junction. We have determined the solution structures of the α-catenin monomer and dimer using in-line size-exclusion chromatography small-angle X-ray scattering, as well as the structure of α-catenin dimer in complex to F-actin filament using selective deuteration and contrast-matching small angle neutron scattering. We further present the first observation, to our knowledge, of the nanoscale dynamics of α-catenin by neutron spin-echo spectroscopy, which explicitly reveals the mobile regions of α-catenin that are crucial for binding to F-actin. In solution, the α-catenin monomer is more expanded than either protomer shown in the crystal structure dimer, with the vinculin-binding M fragment and the actin-binding domain being able to adopt different configurations. The α-catenin dimer in solution is also significantly more expanded than the dimer crystal structure, with fewer interdomain and intersubunit contacts than the crystal structure. When in complex to F-actin, the α-catenin dimer has an even more open and extended conformation than in solution, with the actin-binding domain further separated from the main body of the dimer. The α-catenin-assembled F-actin bundle develops into an ordered filament packing arrangement at increasing α-catenin/F-actin molar ratios. Together, the structural and dynamic studies reveal that α-catenin possesses dynamic molecular conformations that prime this protein to function as a mechanosensor protein.