Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND Giant cell arteritis is an immune-mediated disease of medium and large-sized arteries that affects mostly people older than 50 years of age. Treatment with glucocorticoids is the gold-standard and prevents severe vascular complications but is associated with substantial morbidity and mortality. Tocilizumab, a humanised monoclonal antibody against the interleukin-6 receptor, has been associated with rapid induction and maintenance of remission in patients with giant cell arteritis. We therefore aimed to study the efficacy and safety of tocilizumab in the first randomised clinical trial in patients with newly diagnosed or recurrent giant cell arteritis. METHODS In this single centre, phase 2, randomised, double-blind, placebo-controlled trial, we recruited patients aged 50 years and older from University Hospital Bern, Switzerland, who met the 1990 American College of Rheumatology criteria for giant cell arteritis. Patients with new-onset or relapsing disease were randomly assigned (2:1) to receive either tocilizumab (8 mg/kg) or placebo intravenously. 13 infusions were given in 4 week intervals until week 52. Both groups received oral prednisolone, starting at 1 mg/kg per day and tapered down to 0 mg according to a standard reduction scheme defined in the study protocol. Allocation to treatment groups was done using a central computerised randomisation procedure with a permuted block design and a block size of three, and concealed using central randomisation generated by the clinical trials unit. Patients, investigators, and study personnel were masked to treatment assignment. The primary outcome was the proportion of patients who achieved complete remission of disease at a prednisolone dose of 0·1 mg/kg per day at week 12. All analyses were intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01450137. RESULTS Between March 3, 2012, and Sept 9, 2014, 20 patients were randomly assigned to receive tocilizumab and prednisolone, and ten patients to receive placebo and glucocorticoid; 16 (80%) and seven (70%) patients, respectively, had new-onset giant cell arteritis. 17 (85%) of 20 patients given tocilizumab and four (40%) of ten patients given placebo reached complete remission by week 12 (risk difference 45%, 95% CI 11-79; p=0·0301). Relapse-free survival was achieved in 17 (85%) patients in the tocilizumab group and two (20%) in the placebo group by week 52 (risk difference 65%, 95% CI 36-94; p=0·0010). The mean survival-time difference to stop glucocorticoids was 12 weeks in favour of tocilizumab (95% CI 7-17; p<0·0001), leading to a cumulative prednisolone dose of 43 mg/kg in the tocilizumab group versus 110 mg/kg in the placebo group (p=0·0005) after 52 weeks. Seven (35%) patients in the tocilizumab group and five (50%) in the placebo group had serious adverse events. INTERPRETATION Our findings show, for the first time in a trial setting, the efficacy of tocilizumab in the induction and maintenance of remission in patients with giant cell arteritis. FUNDING Roche and the University of Bern.

The HARPS search for southern extra-solar planets XXXVII. Five new long-period giant planets and a system update

We describe radial-velocity time series obtained by HARPS on the 3.60 m telescope in La Silla (ESO, Chile) over ten years and report the discovery of five new giant exoplanets in distant orbits; these new planets orbit the stars HD 564, HD 30669, HD 108341, and BD -114672. Their periods range from 492 to 1684 days, semi-major axes range from 1.2 to 2.69 AU, and eccentricities range from 0 to 0.85. Their minimum mass ranges from 0.33 to 3.5 MJup. We also refine the parameters of two planets announced previously around HD 113538, based on a longer series of measurements. The planets have a period of 663 ± 8 and 1818 ± 25 days, orbital eccentricities of 0.14 ± 0.08 and 0.20 ± 0.04, and minimum masses of 0.36 ± 0.04 and 0.93 ± 0.06 MJup. Finally, we report the discovery of a new hot-Jupiter planet around an active star, HD 103720; the planet has a period of 4.5557 ± 0.0001 days and a minimum mass of 0.62 ± 0.025 MJup. We discuss the fundamental parameters of these systems and limitations due to stellar activity in quiet stars with typical 2 m s-1 radial velocity precision.

Lethal giant discs, a novel C2 domain protein, restricts Notch activation during endocytosis

The Notch signaling pathway plays a central role in metazoan growth and patterning, and its deregulation leads to many human diseases, including cancer. It is therefore important to understand the modes of Notch signaling regulation. Recent discoveries have demonstrated that mutations in conserved endosomal pathway components such as Erupted and Vps25 can ectopically activate Notch signaling in Drosophila. Mutations in the tumor suppressor lethal giant discs (lgd) display similar but even stronger and more specific Notch activation than in the erupted and vps25 mutant animals. This Notch activation in lgd mutant tissues causes hyperplastic overgrowth of the Drosophila imaginal discs, and the eventual lethality of the animal. However, the gene that encodes Lgd, and its function in the Notch pathway have not yet been identified. ^ I have found that Lgd is a novel, conserved C2 domain protein that regulates Notch trafficking. Lgd cell-autonomously restricts Notch signaling in the Drosophila wing disc to the target cells in the D/V boundary. The function of Lgd lies at or upstream of Notch S3 activation, but Lgd doesn't affect the binding affinities between Notch and Delta. Lgd is also not required for cis-inhibition of Notch signaling by ligands. Notch accumulates on the early endosome in lgd mutant cells and signals in a ligand-independent manner, a result that has previously been seen in endosomal pathway mutants. Interestingly, Notch activation in lgd mutant cells is dependent on the endosomal protein Hrs, and Lgd activity appears to be downstream of Hrs function in endocytosis. Taken together, my data identify Lgd as a novel tumor suppressor protein that regulates Notch signaling by targeting Notch for degradation or recycling. ^

Sedimentology on 19 cores from the South China Sea

Based on the study of 10 sediment cores and 40 core-top samples from the South China Sea (SCS) we obtained proxy records of past changes in East Asian monsoon climate on millennial to bidecadal time scales over the last 220,000 years. Climate proxies such as global sea level, estimates of paleotemperature, salinity, and nutrients in surface water, ventilation of deep water, paleowind strength, freshwater lids, fluvial and/or eolian sediment supply, and sediment winnowing on the sea floor were derived from planktonic and benthic stable-isotope records, the distribution of siliciclastic grain sizes, planktonic foraminifera species, and the UK37 biomarker index. Four cores were AMS-14C-dated. Two different regimes of monsoon circulation dominated the SCS over the last two glacial cycles, being linked to the minima and maxima of Northern Hemisphere solar insolation. (1) Glacial stages led to a stable estuarine circulation and a strong O2-minimum layer via a closure of the Borneo sea strait. Strong northeast monsoon and cool surface water occurred during winter, in part fed by an inflow from the north tip of Luzon. In contrast, summer temperatures were as high as during interglacials, hence the seasonality was strong. Low wetness in subtropical South China was opposed to large river input from the emerged Sunda shelf, serving as glacial refuge for tropical forest. (2) Interglacials were marked by a strong inflow of warm water via the Borneo sea strait, intense upwelling southeast of Vietnam and continental wetness in China during summer, weaker northeast monsoon and high sea-surface temperatures during winter, i.e. low seasonality. On top of the long-term variations we found millennial- to centennial-scale cold and dry, warm and humid spells during the Holocene, glacial Terminations I and II, and Stage 3. The spells were coeval with published variations in the Indian monsoon and probably, with the cold Heinrich and warm Dansgaard-Oeschger events recorded in Greenland ice cores, thus suggesting global climatic teleconnections. Holocene oscillations in the runoff from South China centered around periodicities of 775 years, ascribed to subharmonics of the 1500-year cycle in oceanic thermohaline circulation. 102/84-year cycles are tentatively assigned to the Gleissberg period of solar activity. Phase relationships among various monsoon proxies near the onset of Termination IA suggest that summer-monsoon rains and fluvial runoff from South China had already intensified right after the last glacial maximum (LGM) insolation minimum, coeval with the start of Antarctic ice melt, prior to the d18O signals of global sea-level rise. Vice versa, the strength of winter-monsoon winds decreased in short centennial steps only 3000-4000 years later, along with the melt of glacial ice sheets in the Northern Hemisphere.

The distributions, C- and O-isotopic compositions, and frequency of giant-ooids

Early Triassic oceans were characterized by deposition of a number of "anachronistic facies", including microbialites, seafloor carbonate cement fans, and giant ooids. Giant ooids were particularly prevalent in Lower Triassic sections across South China and exhibit unusual features that may provide insights into marine environmental conditions following the end-Permian mass extinction. The section at Moyang (Guizhou Province) contains abundant giant ooids ranging in size between 2 and 6 mm (maximum 12 mm) and exhibiting various cortical structures, including regular, deformed, compound, regenerated and "domed". Preservation of ooid cortical structure is generally good as indicated by petrographic observations, and trace element and carbon isotope analyses suggest that diagenesis occurred in a closed diagenetic system. All ooids exhibit fine concentric laminae, frequently alternating between light-colored coarsely crystalline and dark-colored finely crystalline layers probably reflecting variation in organic content or original mineralogy. Under scanning electron microscope, biomineralized filaments or biofilms and tiny carbonate fluorapatite (CFA) crystals are commonly found in the finely crystalline layers. We infer that the precipitation of CFA was related to adsorption of P via microbial activity on the surfaces of ooids following episodic incursions of deep waters rich in carbon dioxide, hydrogen sulfide and phosphate into shallow-marine environments. Giant ooid precipitation may have been promoted in shallow ramp settings during these events by increased watermass agitation and supersaturation with respect to calcium carbonate, as well as reduced carbonate removal rates through biotic skeletal formation. Spatio-temporal distribution data reveal that giant ooids were widespread in the Tethyan region during the Early Triassic, and that they were most abundant immediately after the end-Permian crisis and disappeared gradually as metazoans repopulated marine environments.

Freshwater runoff for Taylor Slough to Florida Bay for 1965 to 2000 for the FATHOM model

The Florida Bay ecosystem supports a number of economically important ecosystem services, including several recreational fisheries, which may be affected by changing salinity and temperature due to climate change. In this paper, we use a combination of physical models and habitat suitability index models to quantify the effects of potential climate change scenarios on a variety of juvenile fish and lobster species in Florida Bay. The climate scenarios include alterations in sea level, evaporation and precipitation rates, coastal runoff, and water temperature. We find that the changes in habitat suitability vary in both magnitude and direction across the scenarios and species, but are on average small. Only one of the seven species we investigate (Lagodon rhomboides, i.e., pinfish) sees a sizable decrease in optimal habitat under any of the scenarios. This suggests that the estuarine fauna of Florida Bay may not be as vulnerable to climate change as other components of the ecosystem, such as those in the marine/terrestrial ecotone. However, these models are relatively simplistic, looking only at single species effects of physical drivers without considering the many interspecific interactions that may play a key role in the adjustment of the ecosystem as a whole. More complex models that capture the mechanistic links between physics and biology, as well as the complex dynamics of the estuarine food web, may be necessary to further understand the potential effects of climate change on the Florida Bay ecosystem.