ALBERT

Description: Introduction Adult patients (pts) diagnosed with acute lymphocytic leukemia (ALL) are known to have a poor clinical outcome as compared to children. Studies report a 2 year event free survival of 30-40% for Philadelphia chromosome negative (Ph-) patients age 〉30 yrs and 17% for age 〉50 yrs. In order to improve outcome for adult ALL, agents that are effective, safe and associated with a low morbidity are needed. Clofarabine, a second generation purine nucleoside analog, has clinical activity as a single agent and in combination with cytosine arabinoside (ara-C) against refractory and relapsed ALL. Clofarabine exerts its cytotoxicity through multiple mechanisms of action, with major effects via inhibition of ribonucleotide reductase (RR) and DNA polymerase-alpha, and incorporation into DNA leading to DNA damage and activation of apoptotic pathways. Histone deacetylases (HDACs) are important regulators of chromatin involved in silencing of tumor suppressor genes. HDAC inhibitors are shown to be apoptogenic in vitro for ALL cell lines and have received FDA approval for the treatment of CTCL and peripheral T cell lymphoma. Pre-treatment with entinostat has been shown to enhance the cytotoxic activity of fludarabine in leukemia cell lines in vitro (Maggio et al, Cancer Research 2004). Given the similarity of clofarabine to fludarabine, and its FDA approval for children with refractory ALL, the combination of entinostat with clofarabine was pursued. Methods A Phase I window of opportunity study using overlapping schedule of entinostat and clofarabine was used in adult pts with ALL (B precursor) or Acute Bilineage Leukemia (ABL). Pts were enrolled onto one of two arms; arm “A” received repeated cycles of entinostat-clofarabine every 21 days as long as there was evidence of response (CR, CRi, or PR following cycle 1) and pts on arm “B” received one cycle of entinostat-clofarabine prior to standard multi-agent chemotherapy. Entinostat was administered orally on day 1 and day 8 (with dose escalation from flat dosing of 4mg to 6mg to 8mg from cohort 1 to 3). Clofarabine was administered intravenously at a fixed dose for all dose cohorts at 10mg/m2 for 5 days (day 3-7). Adults 〉40 yrs with newly diagnosed, Ph- B-lineage ALL or ABL were eligible. Additionally, adults 〉 21 yrs with relapsed and refractory, Ph- ALL or ABL were eligible. Eligibility criteria included serum creatinine 〈 2.0 mg/dl, hepatic enzymes 〈 or = 2.5 ULN and bilirubin

Description: A mid-Holocene climate optimum is inferred from a palaeosalinity reconstruction of a closed saline lake (Beall Lake) from the Windmill Islands, East Antarctica using an expanded diatom salinity weighted averaging (WA) regression and calibration model. The addition of 14 lakes and ponds from the Windmill Islands, East Antarctica, to an existing weighted averaging regression and calibration palaeosalinity model of 33 lakes from the Vestfold Hills, East Antarctica expands the number of taxa and lakes and the range of salinity in the existing model and improves the model's predictive ability. This improved model was used to infer Holocene changes in lake water salinity in Beall Lake, Windmill Islands. Six changes in diatom-inferred salinity in Beall Lake are put into broad chronological context based on three radiocarbon dates: as the East Antarctic Ice Sheet (EAIS) retreated from the Windmill Islands during the early Holocene (~9000-8130 corr. yr BP), Beall Lake formed as a melt water-fed freshwater lake, which gradually became more saline as marine influence increased from ~8000 corr. yr BP. Between ~8000 and 4800 corr. yr BP, the diatom assemblage included planktonic marine taxa such as Chaetoceros spp. and cryophilic taxa such as Fragilariopsis cylindrus, which indicate favourable summer growth conditions. A mid-Holocene warm period produced a climate that was warmer and more humid with increased precipitation and snow accumulation. This is reflected in the Beall Lake core as a reduction in the salinity of the lake diatom assemblage from ~4800-4600 corr. yr BP. Holocene isostatic uplift rates in the Windmill Islands vary from 5-6 m/1000 yr. By applying this uplift rate, it is calculated that the bedrock would have risen above sea level by ~4000 yr BP. The Beall Lake core diatom assemblage from ~4600-2900 corr. yr BP includes both marine cryophilic and planktonic taxa together with freshwater benthic and planktonic lacustrine taxa. This mix of species indicates the emergence of the lake from the sea around ~4600 corr. yr BP. From ~2800 corr. yr BP, retreat of the ice margin led to increasing melt water inputs and associated freshening of the lake basin until ~1900 corr. yr BP. The lake basin had no oceanic influence by this time, allowing a terrestrial freshwater flora to establish and thrive for the next ~1000 yr. At ~1850 corr. yr BP, a sudden and rapid salinity change is evident in Beall Lake. A late Holocene warm period between 2000 and 1000 yr BP has been observed in ice core records from Law Dome (an ice cap abutting the Windmill Islands to the east and north). It is therefore inferred that, at ~1850 corr. yr BP, summer temperatures within the Beall Lake catchment area were much higher than present summer temperatures. The climate optimum identified in the Beall Lake core ~4800 yr BP confirms mid-Holocene warming of the Windmill Islands and suggests a synchronous mid-Holocene climate optimum occurred across coastal East Antarctica. In addition, the abrupt climate change inferred at ~1850 yr BP suggests that higher resolution sampling of sediment cores from coastal East Antarctic limnological oases will provide more evidence of rapid climate change events over coastal East Antarctica in future.

Description: The diatom flora of three lakes in the ice-free Amery Oasis, East Antarctica, was studied. Two of the lakes are meltwater reservoirs, Terrasovoje Lake (31 m depth) and Radok Lake (362 m depth), while Beaver Lake (〉435 m depth) is an epishelf lake. The lakes can be characterized as cold, ultra-oligotrophic and alkaline, displaying moderate (Radok and Terrasovoje lakes) to high (Beaver Lake) conductivities. There was no diatom phytoplankton present in any of the three lakes. While 34 benthic diatom taxa were identified from modern and Holocene sediments of Terrasovoje and Radok lakes, a 30-cm long sediment core recovered in Beaver Lake was barren. Five species (Luticola muticopsis, Muelleria peraustralis, Pinnularia cymatopleura, Psammothidium metakryophilum, P. stauroneioides) are endemic to the Antarctic region. All identified taxa are photographically documented and brief notes on their taxonomy, biogeography and ecology are provided. The most abundant diatom taxa are Amphora veneta, Craticula cf. molesta, Diadesmis spp, M. peraustralis and Stauroneis anceps. This is the first report on the diatom flora in lakes of the Amery Oasis.

Description: The late Quaternary palaeoenvironmental history of the southern Windmill Islands, East Antarctica, has been reconstructed using diatom assemblages from two long, well-dated sediment cores taken in two marine bays. The diatom assemblage of the lowest sediment layers suggests a warm climate with mostly open water conditions during the late Pleistocene. During the following glacial, the Windmill Islands were covered by grounded ice preventing any in situ bioproductivity. Following deglaciation, a sapropel with a well-preserved diatom assemblage was deposited from ~10500 cal yr BP. Between ~10500 and ~4000 cal yr BP, total organic carbon (Corg) and total diatom valve concentrations as well as the diatom species composition suggest relatively cool summer temperatures. Hydrological conditions in coastal bays were characterised by combined winter sea-ice and open water conditions. This extensive period of glacial retreat was followed by the Holocene optimum (~4000 to ~1000 cal yr BP), which occurred later in the southern Windmill Islands than in most other Antarctic coastal regions. Diatom assemblages in this period suggest ice-free conditions and meltwater-stratified waters in the marine bays during summer, which is also reflected in high proportions of freshwater diatoms in the sediments. The diatom assemblage in the upper sediments of both cores indicates Neoglacial cooling from ~1000 cal yr BP, which again led to seasonally persistent sea-ice on the bays. The Holocene optimum and cooling trends in the Windmill Islands did not occur contemporaneously with other Antarctic coastal regions, showing that the here presented record reflects partly local environmental conditions rather than global climatic trends.

Description: A 100 cm long sediment sequence was recovered from Beaver Lake in Amery Oasis, East Antarctica, using gravity and piston corers. Sedimentological and mineralogical analyses and the absence of micro and macrofossils indicate that the sediments at the base of the sequence formed under glacial conditions, probably prior to c. 12 500 cal. yr BP. The sediments between c. 81 and 31 cm depth probably formed under subaerial conditions, indicating that isostatic uplift since deglaciation has been substantially less than eustatic sea-level rise and that large areas of the present-day floor of Beaver Lake must have been subaerially exposed following deglaciation. The upper 31 cm of the sediment sequence were deposited under glaciomarine conditions similar to those of today, supporting geomorphic observations that the Holocene was a period of relative sea-level highstand in Amery Oasis.