The impact of ABCC11 polymorphisms on the risk of early-onset fluoropyrimidine toxicity

A missense variant (c.1637C>T, T546M) in ABCC11 encoding the MRP8 (multidrug resistance protein 8), a transporter of 5-fluorodeoxyuridine monophosphate, has been associated with an increased risk of 5-fluorouracil-related severe leukopenia. To validate this association, we investigated the impact of the ABCC11 variants c.1637C>T, c.538G>A and c.395+1087C>T on the risk of early-onset fluoropyrimidine-related toxicity in 514 cancer patients. The ABCC11 variant c.1637C>T was strongly associated with severe leukopenia in patients carrying risk variants in DPYD, encoding the key fluoropyrimidine-metabolizing enzyme dihydropyrimidine dehydrogenase (odds ratio (OR): 71.0; 95% confidence interval (CI): 2.5-2004.8; Pc.1637C>T*DPYD=0.013). In contrast, in patients without DPYD risk variants, no association with leukopenia (OR: 0.95; 95% CI: 0.34-2.6) or overall fluoropyrimidine-related toxicity (OR: 1.02; 95% CI: 0.5-2.1) was observed. Our study thus suggests that c.1637C>T affects fluoropyrimidine toxicity to leukocytes particularly in patients with high drug exposure, for example, because of reduced fluoropyrimidine catabolism.

Macrofossils as records of plant responses to rapid Late Glacial climatic changes at three sites in the Swiss Alps

Plant macrofossils from the end of the Younger Dryas were analysed at three sites, Gerzensee (603 m asl), Leysin (1230 m asl), and Zeneggen (1510 m asl). For the first two sites an oxygen-isotope record is also available that was used to develop a time scale (Schwander et al., this volume); dates refer therefore to calibrated years according to the GRIP time scale. Around Gerzensee a pine forest with some tree birches grew during the Younger Dryas. With the onset of the isotopic shift initiating the rapid warming (about 11,535 cal. years before 1950), the pine forest became more productive and denser. At Leysin no trees except some juniper scrub grew during the Younger Dryas. Tree birches, pine, and poplar immigrated from lower altitudes and arrived after the end of the isotopic shift (about 11,487 B.P.), i.e., at the beginning of the Preboreal (at about 11,420 B.P.). Zeneggen is situated somewhat higher than Leysin, but single tree birches and pines survived the Younger Dryas at the site. At the beginning of the Preboreal their productivity and population densities increased. Simultaneously shifts from Nitella to Chara and from silt to gyttja are recorded, all indicating rapidly warming conditions and higher nutrient levels of the lake water (and probably of the soils in the catchment). At Gerzensee the beginning of the Younger Dryas was also analysed: the beginning of the isotopic shift correlates within one sample (about 15 years) to rapid decreases of macrofossils of pines and tree birches.

Late-glacial and Holocene vegetation history and dynamics as shown by pollen and plant macrofossil analyses in annually laminated sediments from Soppensee, central Switzerland

The palynostratigraphy of two sediment cores from Soppensee, Central Switzerland (596 m asl) was correlated with nine regional pollen assemblage zones defined for the Swiss Plateau. This biostratigraphy shows that the sedimentary record of Soppensee includes the last 15 000 years, i.e. the entire Late-glacial and Holocene environmental history. The vegetation history of the Soppensee catchment was inferred by pollen and plant-macrofossil analyses on three different cores taken in the deepest part of the lake basin (27 m). On the basis of a high-resolution varve and calibrated radiocarbonchronology it was possible to estimate pollen accumulation rates, which together with the pollen percentage data, formed the basis for the interpretation of the past vegetation dynamics. The basal sediment dates back to the last glacial. After reforestation with juniper and birch at ca. 12 700 B.P., the vegetation changed at around 12 000 B.P. to a pine-birch woodland and at the onset of the Holocene to a mixed deciduous forest. At ca. 7000 B.P., fir expanded and dominated the vegetation with beech becoming predominant at ca. 50014C-years later until sometime during the Iron Age. Large-scale deforestation, especially during the Middle Ages, altered the vegetation cover drastically. During the Late-glacial period two distinct regressive phases in vegetation development are demonstrated, namely, the Aegelsee oscillation (equivalent to the Older Dryas biozone) and the Younger Dryas biozone. No unambiguous evidence for Holocene climatic change was detected at Soppensee. Human presence is indicated by early cereal pollen and distinct pulses of forest clearance as a result of human activity can be observed from the Neolithic period onwards.