ALBERT

Beschreibung: CD33 is a sialoglycan protein expressed on normal myeloid and monocytic cells as well as the vast majority of myeloid malignancies. A humanized antibody (HuM195) has been developed that specifically recognizes CD33 and induces potent effector function (ADCC, CDC, ADCP). In prior clinical testing, this antibody led to antitumor activity and objective responses in patients with relapsed and refractory AML. To further characterize a dose-response relationship and because a maximum tolerated dose for SGN-33 has never been identified, a phase I single-arm dose escalation trial was initiated at multiple sites to assess safety, immunogenicity, PK, and activity of SGN-33 at substantially increased dose intensity and in a patient (pt) population not previously tested, including untreated AML and MDS. Entry criteria included CD33 expression on 〉50% of the marrow blasts to ensure that adequate target antigen was present. Cohorts of 3–6 pts with advanced myeloid malignancies were planned to receive IV SGN-33 at weekly doses of 1.5 to 8 mg/kg for 5 weeks. Response was assessed by marrow morphology and hematologic improvement. Pts demonstrating clinical benefit were eligible for additional infusions. To date, 12 pts have been treated at a maximum weekly dose of 1.5 mg/kg (N=6), 2.5 mg/kg (N=4), or 4 mg/kg (N=2). The median age was 74.5 years (range 52–88), and the majority of pts were previously untreated. Eight pts had a diagnosis of AML and four had MDS. SGN-33 has been well tolerated; drug-related AEs so far include mild to moderate infusion reactions (Day 1 only) and mild rash. One pt experienced tumor lysis syndrome after the first week of treatment; laboratory abnormalities returned to baseline after hydration. There has been no dose-limiting toxicity or related adverse events 〉 grade 3. No anti-SGN-33 immune responses were detected among the first 8 pts tested. CD33 saturation of the marrow blasts after two infusions for Cohorts I and II averaged 55.4% and 89.0%, respectively. Three pts did not complete 1 cycle (ie five weeks) of treatment due to: disease progression (1), thrombocytopenia refractory to transfusion (1), and pt withdrawal after a Grade 2 infusion reaction (1). Six of the seven pts that completed Cycle 1 received additional infusions after demonstrating one or more of the following: improved blood counts, decreased transfusion requirements, or decreased blasts. There was no unresolved toxicity after the first cycle of therapy and no evidence of cumulative toxicity during Cycle 2. Two pts demonstrated a marked decrease in the percentage of blasts in the marrow at the end of Cycle 1 compared to baseline. In summary, SGN-33 has been well tolerated at a dose intensity substantially higher than previously achieved, and antitumor activity was observed in elderly pts with untreated AML and MDS. SGN-33 holds promise as single-agent therapy and/or in combination with other non-myeloablative therapies for the treatment of pts with myeloid malignancy who are ineligible for aggressive therapy.

Beschreibung: This study uses a Granger causality time series modeling approach to quantitatively diagnose the feedback of daily sea surface temperatures (SSTs) on daily values of the North Atlantic Oscillation (NAO) as simulated by a realistic coupled general circulation model (GCM). Bivariate vector autoregressive time series models are carefully fitted to daily wintertime SST and NAO time series produced by a 50-yr simulation of the Third Hadley Centre Coupled Ocean–Atmosphere GCM (HadCM3). The approach demonstrates that there is a small yet statistically significant feedback of SSTs on the NAO. The SST tripole index is found to provide additional predictive information for the NAO than that available by using only past values of NAO—the SST tripole is Granger causal for the NAO. Careful examination of local SSTs reveals that much of this effect is due to the effect of SSTs in the region of the Gulf Steam, especially south of Cape Hatteras. The effect of SSTs on NAO is responsible for the slower-than-exponential decay in lag-autocorrelations of NAO notable at lags longer than 10 days. The persistence induced in daily NAO by SSTs causes long-term means of NAO to have more variance than expected from averaging NAO noise if there is no feedback of the ocean on the atmosphere. There are greater long-term trends in NAO than can be expected from aggregating just short-term atmospheric noise, and NAO is potentially predictable provided that future SSTs are known. For example, there is about 10%–30% more variance in seasonal wintertime means of NAO and almost 70% more variance in annual means of NAO due to SST effects than one would expect if NAO were a purely atmospheric process.

Beschreibung: This study proposes an objective integrated seasonal forecasting system for producing well-calibrated probabilistic rainfall forecasts for South America. The proposed system has two components: (i) an empirical model that uses Pacific and Atlantic sea surface temperature anomalies as predictors for rainfall and (ii) a multimodel system composed of three European coupled ocean–atmosphere models. Three-month lead austral summer rainfall predictions produced by the components of the system are integrated (i.e., combined and calibrated) using a Bayesian forecast assimilation procedure. The skill of empirical, coupled multimodel, and integrated forecasts obtained with forecast assimilation is assessed and compared. The simple coupled multimodel ensemble has a comparable level of skill to that obtained using a simplified empirical approach. As for most regions of the globe, seasonal forecast skill for South America is low. However, when empirical and coupled multimodel predictions are combined and calibrated using forecast assimilation, more skillful integrated forecasts are obtained than with either empirical or coupled multimodel predictions alone. Both the reliability and resolution of the forecasts have been improved by forecast assimilation in several regions of South America. The Tropics and the area of southern Brazil, Uruguay, Paraguay, and northern Argentina have been found to be the two most predictable regions of South America during the austral summer. Skillful rainfall forecasts are generally only possible during El Niño or La Niña years rather than in neutral years.

Beschreibung: A physically motivated statistical model is used to diagnose variability and trends in wintertime (October–March) Global Precipitation Climatology Project (GPCP) pentad (5-day mean) precipitation. Quasigeostrophic theory suggests that extratropical precipitation amounts should depend multiplicatively on the pressure gradient, saturation specific humidity, and the meridional temperature gradient. This physical insight has been used to guide the development of a suitable statistical model for precipitation using a mixture of generalized linear models: a logistic model for the binary occurrence of precipitation and a Gamma distribution model for the wet day precipitation amount. The statistical model allows for the investigation of the role of each factor in determining variations and long-term trends. Saturation specific humidity qs has a generally negative effect on global precipitation occurrence and with the tropical wet pentad precipitation amount, but has a positive relationship with the pentad precipitation amount at mid- and high latitudes. The North Atlantic Oscillation, a proxy for the meridional temperature gradient, is also found to have a statistically significant positive effect on precipitation over much of the Atlantic region. Residual time trends in wet pentad precipitation are extremely sensitive to the choice of the wet pentad threshold because of increasing trends in low-amplitude precipitation pentads; too low a choice of threshold can lead to a spurious decreasing trend in wet pentad precipitation amounts. However, for not too small thresholds, it is found that the meridional temperature gradient is an important factor for explaining part of the long-term trend in Atlantic precipitation.