Patrick Cech

We enriched in CO2 the canopy of 14 broad- leaved trees in a species-rich, ca. 30-m-tall forest in NW Switzerland to test whether elevated CO2 reduces water use in mature forest trees. Measurements of sap flux density (JS) were made prior to CO2 enrichment (summer 2000) and throughout the first whole growing season of CO2 exposure (2001) using the constant heat-flow technique. The short-term responses of sap flux to brief (1.5-3 h) interruptions of CO2 enrichment were also examined. There were no significant a priori differences in morphological and physiological traits between trees which were later exposed to elevated CO2 (n=14) and trees later used as controls (n=19). Over the entire growing season, CO2 enrichment resulted in an average 10.7% reduction in mean daily JS across all species compared to control trees. Responses were most pro- nounced in Carpinus, Acer, Prunus and Tilia, smaller in Quercus and close to zero in Fagus trees. The JS of treated trees significantly increas...

The quantities and spatial distribution of nutrients in savanna ecosystems are affected by many factors, of which fire, herbivory and symbiotic N 2 -fixation are particularly important. We measured soil nitrogen (N) pools and the relative abundance of N and phosphorus (P) in herbaceous vegetation in five vegetation types in a humid savanna in Tanzania. We also performed a factorial fertilization experiment to investigate which nutrients most limit herbaceous production. N pools in the top 10 cm of soil were low at sites where fires were frequent, and higher in areas with woody legume encroachment, or high herbivore excretion. Biomass production was co-limited by N and P at sites that were frequently burnt or heavily grazed by native herbivores. In contrast, aboveground production was limited by N in areas receiving large amounts of excreta from livestock. N 2 -fixation by woody legumes did not lead to P-limitation, but did increase the availability of N relative to P. We conclude th...

PURPOSE RG7716 is a novel bispecific antibody that simultaneously binds vascular endothelial growth factor (VEGF) and another key angiogenic factor, angiopoietin 2. A phase I study of intravitreal RG7716 was conducted to evaluate single-dose and multiple-dose safety in patients with neovascular age-related macular degeneration (AMD). DESIGN Open-label, single and multiple ascending-dose study. PARTICIPANTS Twenty-four patients diagnosed with neovascular AMD with best-corrected visual acuity (BCVA) of 20/40 to 20/400 (Snellen equivalent) and refractory subfoveal choroidal neovascularization defined as leakage on fluorescein angiography or fluid on spectral-domain optical coherence tomography despite 3 or more intravitreal anti-VEGF treatments in the preceding 6 months. METHODS Single intravitreal doses of 0.5 mg, 1.5 mg, 3 mg, and 6 mg RG7716 were administered in stepwise dose-escalation groups, each with 3 patients. In the multiple-dose phase, 6 patients were enrolled and received 3 treatments each of 3 mg and 6 mg RG7716. MAIN OUTCOME MEASURES Safety and tolerability, changes in baseline BCVA, and central subfield thickness (CST). RESULTS There were no dose-limiting toxicities in either the single-dose or multiple-dose group. Treatment-emergent ocular adverse events were mild. There was a single withdrawal and 1 serious adverse event, both deemed to be unrelated to the study drug by principal investigators. In the combined single-dose groups and in the 6-mg multiple-dose group, BCVA increased from baseline to 28 days after the last dose administration by a median of 7 letters (range, 0-18 letters; n = 11) and 7.5 letters (range, 3-18 letters; n = 6), respectively. The corresponding median reduction from baseline in CST were 42 μm (range, -101 to 10 μm; n = 11) and -117 μm (range, -252 to -7 μm; n = 6), respectively. After multiple 3-mg RG7716 doses, no changes were observed in either BCVA (median, -0.5 letters; range, -9 to 8 letters; n = 6) or CST (median, -9 μm; range, -188 to -1 μm; n = 6). CONCLUSIONS RG7716 was well tolerated and exhibited an overall favorable safety profile, with evidence of improvements in BCVA and anatomic parameters. These data support further evaluation of RG7716 in phase II trials.

Beta-thalassemia is a hereditary blood disorder characterized by reduced or absent synthesis of the beta-globin chain, one of the major components of adult hemoglobin (Hb). The unbalanced synthesis of globin chains leads to a relative excess of alpha-globin and heme, resulting in hemichrome-induced cellular damage in bone marrow erythroblasts and circulating erythrocytes. This, in turn, contributes to ineffective erythropoiesis, hemolysis and reduced red blood cell (RBC) survival, hallmarks of beta-thalassemia. We have previously reported that reduction in cellular heme synthesis by bitopertin, an oral, reversible, potent and selective glycine transporter 1 (GlyT1) inhibitor, positively impacts the disease pathology in a beta-thalassemia mouse model. It was hypothesized that reduced heme synthesis down-regulates globin production and as such diminishes the alpha-chain excess, driving the observed improvements in Hb, hemolysis and RBC survival in beta-thalassemia mice. In study BP396...