ZD6474 – clinical experience to date

ZD6474 selectively targets two key pathways in tumour growth by inhibiting vascular endothelial growth factor (VEGF)-dependent tumour angiogenesis and epidermal growth factor (EGF)-dependent tumour cell proliferation and survival. Phase I clinical evaluation has shown ZD6474 to be generally well tolerated, with a pharmacokinetic profile appropriate for once-daily oral dosing. Phase II evaluation of ZD6474 at doses of 100−300 mg is ongoing in a range of patient types in single and combination regimens. These include three randomised studies of patients with non-small-cell lung cancer. In one of these trials, the efficacy of ZD6474 monotherapy is being compared with that of the EGF receptor tyrosine kinase inhibitor gefitinib (Iressa™) in previously treated patients. In the other two trials, the efficacy of ZD6474 in combination with certain standard chemotherapy regimens is being compared with that of standard chemotherapy alone: one with carboplatin and paclitaxel in previously untreated patients, and the second with docetaxel in patients who progressed after platinum-containing therapy. The advent of novel molecular-targeted agents such as ZD6474 has necessitated a re-evaluation of conventional cancer study design in order to optimise appraisal of this new generation of anticancer agents. The specific considerations of the ZD6474 clinical programme are discussed

Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma

Epidermal growth factor receptor (EGFR) mutations are a potential predictor of the effectiveness of EGFR inhibitors for the treatment of lung cancer. Although EGFR mutations were reported to occur with high frequency in nonsmoking Japanese adenocarcinoma patients, the exact nature has not been fully elucidated. We examined EGFR gene mutations within exons 18–21 and their correlations to clinico-pathological factors and other genetic alterations in tumour specimens from 154 patients who underwent resection for lung cancer at Kyoto University Hospital. Epidermal growth factor receptor mutations were observed in 60 tumours (39.0%), all of which were adenocarcinoma. Among the patients with adenocarcinoma (n=108), EGFR mutations were more frequently observed in nonsmokers than former smokers or current smokers (83.0, 50.0, 15.2%, respectively), in women than men (76.3 vs 34.0%), in tumours with bronchio-alveolar component than those without bronchio-alveolar component (78.9 vs 42.9%), and in well or moderately differentiated tumours than poorly differentiated tumours (72.0, 64.4, 34.2%). No tumours with EGFR mutations had any K-ras codon 12 mutations, which were well-known smoking-related gene mutations. In conclusion, adenocarcinomas with EGFR mutation had a distinctive clinico-pathological feature unrelated to smoking. Epidermal growth factor receptor mutations may play a key role in the development of smoking-independent adenocarcinoma

First Precambrian palaeomagnetic data from the Mawson Craton (East Antarctica) and tectonic implications

A pilot palaeomagnetic study was conducted on the recently dated with in situ SHRIMP U-Pb method at 1134 ± 9 Ma (U-Pb, zircon and baddeleyite) Bunger Hills dykes of the Mawson Craton (East Antarctica). Of the six dykes sampled, three revealed meaningful results providing the first well-dated Mesoproterozoic palaeopole at 40.5°S, 150.1°E (A95 = 20°) for the Mawson Craton. Discordance between this new pole and two roughly coeval poles from Dronning Maud Land and Coats Land (East Antarctica) demonstrates that these two terranes were not rigidly connected to the Mawson Craton ca. 1134 Ma. Comparison between the new pole and that of the broadly coeval Lakeview dolerite from the North Australian Craton supports the putative ~40° late Neoproterozoic relative rotation between the North Australian Craton and the combined South and West Australian cratons. A mean ca. 1134 Ma pole for the Proto-Australia Craton is calculated by combining our new pole and that of the Lakeview dolerite after restoring the 40° intracontinental rotation. A comparison of this mean pole with the roughly coeval Abitibi dykes pole from Laurentia confirms that the SWEAT reconstruction of Australia and Laurentia was not viable for ca. 1134 Ma

Species' geographic distributions through time: Playing catchup with changing climates

This is the author's accepted manuscript.Species’ ranges are often treated as a rather fixed characteristic, rather than a fluid, ever-changing manifestation of their ecological requirements and dispersal abilities. Paleontologists generally have had a more flexible point of view on this issue than neontologists, but each perspective can improve by appreciating the other. Here, we provide an overview of paleontological and neontological perspectives on species’ geographic distributions, focusing on what can be learned about historical variations in distributions. The cross-disciplinary view, we hope, offers some novel perspectives on species-level biogeography

The two phases of the Cambrian Explosion

Abstract The dynamics of how metazoan phyla appeared and evolved – known as the Cambrian Explosion – remains elusive. We present a quantitative analysis of the temporal distribution (based on occurrence data of fossil species sampled in each time interval) of lophotrochozoan skeletal species (n = 430) from the terminal Ediacaran to Cambrian Stage 5 (~545 – ~505 Million years ago (Ma)) of the Siberian Platform, Russia. We use morphological traits to distinguish between stem and crown groups. Possible skeletal stem group lophophorates, brachiopods, and molluscs (n = 354) appear in the terminal Ediacaran (~542 Ma) and diversify during the early Cambrian Terreneuvian and again in Stage 2, but were devastated during the early Cambrian Stage 4 Sinsk extinction event (~513 Ma) never to recover previous diversity. Inferred crown group brachiopod and mollusc species (n = 76) do not appear until the Fortunian, ~537 Ma, radiate in the early Cambrian Stage 3 (~522 Ma), and with minimal loss of diversity at the Sinsk Event, continued to diversify into the Ordovician. The Sinsk Event also removed other probable stem groups, such as archaeocyath sponges. Notably, this diversification starts before, and extends across the Ediacaran/Cambrian boundary and the Basal Cambrian Carbon Isotope Excursion (BACE) interval (~541 to ~540 Ma), ascribed to a possible global perturbation of the carbon cycle. We therefore propose two phases of the Cambrian Explosion separated by the Sinsk extinction event, the first dominated by stem groups of phyla from the late Ediacaran, ~542 Ma, to early Cambrian stage 4, ~513 Ma, and the second marked by radiating bilaterian crown group species of phyla from ~513 Ma and extending to the Ordovician Radiation