ALBERT

Beschreibung: Time series of alkenone unsaturation indices gathered along the California margin reveal large (4° to 8°C) glacial-interglacial changes in sea surface temperature (SST) over the past 550,000 years. Interglacial times with SSTs equal to or exceeding that of the Holocene contain peak abundances in the pollen of redwood, the distinctive component of the temperate rainforest of the northwest coast of California. In the region now dominated by the California Current, SSTs warmed 10,000 to 15,000 years in advance of deglaciation at each of the past five glacial maxima. SSTs did not rise in advance of deglaciation south of the modern California Current front. Glacial warming along the California margin therefore is a regional signal of the weakening of the California Current during times when large ice sheets reorganized wind systems over the North Pacific. Both the timing and magnitude of the SST estimates suggest that the Devils Hole (Nevada) calcite record represents regional but not global paleotemperatures, and hence does not pose a fundamental challenge to the orbital ("Milankovitch") theory of the Ice Ages.

Beschreibung: Background: Bortezomib (Bz, VELCADE®) is a novel proteasome inhibitor that has demonstrated efficacy and safety in patients (pts) with relapsed and/or refractory multiple myeloma (MM) in clinical trials. In a large randomized phase 3 trial, Bz achieved superior response rates (RR), TTP, and survival compared with high-dose dexamethasone in relapsed MM pts after 1–3 prior therapies. Peripheral neuropathy (PN) has been dose limiting, especially in pts with pre-existing PN. The objective of this multicenter phase 2 trial was to evaluate the activity and safety of Bz as monotherapy in previously untreated MM pts and prospectively examine PN at baseline (BL) and across treatment. Methods: Pts received Bz 1.3 mg/m2 on d 1, 4, 8, 11 of a 21-d cycle, with RR (CR + PR; EBMT) assessed every 2 cycles. Eligible pts had symptomatic MM with measurable disease and no prior chemotherapy. Concomitant steroids (〉 10 mg/d), plt count 〈 30 x 109/L within 14 d of enrollment or 〉 grade (G) 2 PN were exclusion criteria. RR, TTP, safety and incidence/severity of PN were evaluated. The effect on PN of dose modification (DM) and supplements with specified interventions for symptoms was assessed. Neurologic evaluation involving a pt questionnaire and neurologist’s exam was performed before and after treatment. A 33 pt subset had BL nerve conduction studies (NCS), quantitative sensory testing (QST), autonomic testing, and skin biopsy for quantitation of small-diameter neurite densities (ND). Toxicities were assessed by NCI-CTC, v3.0. Results: 63 pts (median age 60 y) have been treated. Data are available for 50 pts; 27 pts had IgG kappa MM and 21 pts had stage III disease. BL small-fiber neuropathy (SFN; normal NCS but abnormal QST or autonomic studies) was seen in 16/33 pts (48%). BL skin biopsy showed that 18/30 pts (60%) had small-fiber ND at the 15th percentile of age-adjusted norms; global mean density was at the 23rd percentile. NCS revealed BL axonal PN in 3/33 pts (9%). Among 46 pts evaluable for response, best response after ≥ 2 cycles was CR in 5 pts (11%) and PR in 9 pts (20%) for a RR of 30%. 13 pts (28%) achieved MR, 17 (37%) had SD, and 2 had PD (4%). The most common adverse events were PN, fatigue and rash. 24 pts (48%) developed PN, including 18 with G1 and 5 with G2. One pt had G3 PN and was discontinued. DM (dose reduction or discontinuation) was required in 9 pts. 23 pts have been studied after treatment. New large-fiber neuropathy (LFN) was seen in 4/23 pts (17%) and new SFN in 8 pts. Of 3 pts with BL LFN, 1 was not restudied, 1 had worsening SFN and 1 was unchanged. Small-fiber neurite counts were increased to the 35th percentile. Of 16 pts with BL SFN, 7 had worsening SFN (by QST). Bz was otherwise generally well tolerated. Conclusion: Bz as monotherapy has shown activity in newly diagnosed MM pts, with a CR of 11% and manageable toxicity. Underlying SFN appears more common in MM than appreciated. Treatment-emergent ≥ G2 PN was observed in 12% of pts and was G3 in 1 pt. Assessment of PN, the effect of interventions and skin biopsy analyses are ongoing.

Beschreibung: Data on oxygen isotope composition of waters from the Sea of Azov.