Application of cell line based genomic predictors to predict response to targeted therapies in breast cancer

Cancer cell lines can be treated with a drug and the molecular comparison of responders and non-responders may yield potential predictors that could be tested in the clinic. It is a bioinformatics challenge to apply the cell line-derived multivariable response predictors to patients who respond to therapy. Using the gene expression data from 23 breast cancer cell lines, I developed three predictors of dasatinib sensitivity by selecting differentially expressed genes and applying different classification algorithms. The performance of these predictors on independent cell lines with known dasatinib response was tested. The predictor based on weighted voting method has the best overall performance. It correctly predicted dasatinib sensitivity in 11 out of 12 (92%) breast and 17 out of 23 (74%) lung cancer cell lines. These predictors were then applied to the gene expression data from 133 breast cancer patients in an attempt to predict how the patients might respond to dasatinib therapy. Two predictors identified 13 patients in common to be dasatinib sensitive. Sixty two percent of these cases are triple negative (ER-negative, HER2-negative and PR-negative) and 76% are double negative. The result is consistent with the findings from other studies, which identified a target population for dasatinib treatment to be triple negative or basal breast cancer subtype. In conclusion, we think that the cell line-derived dasatinib classifiers can be applied to the human patients. ^

The role of AKT-mediated phosphorylation in suppression of MAD1 and the development of new approach in protein complex detection

MAX dimerization protein 1 (MAD1) is a basic-helix-loop-helix transcription factors that recruits transcription repressor such as HDAC to suppress target genes transcription. It antagonizes to MYC because the promoter binding sites for MYC are usually also serve as the binding sites for MAD1 so they compete for it. However, the mechanism of the switch between MYC and MAD1 in turning on and off of genes' transcription is obscure. In this study, we demonstrated that AKT-mediated MAD1 phosphorylation inhibits MAD1 transcription repression function. The association between MAD1 and its target genes' promoter is reduced after been phosphorylated by AKT; therefore, consequently, allows MYC to occupy the binding site and activates transcription. Mutation of such phosphorylation site abrogates the inhibition from AKT. In addition, functional assays demonstrated that AKT suppressed MAD1-mediated transcription repression of its target genes hTERT and ODC. Cell cycle and cell growth were also been released from inhibition by MAD1 in the presents of AKT. Taken together, our study suggests that MAD1 is a novel substrate of AKT and AKT-mediated MAD1 phosphorylation inhibits MAD1function; therefore, activates MAD1 target genes expression. ^ Furthermore, analysis of protein-protein interaction is indispensable for current molecular biology research, but multiplex protein dynamics in cells is too complicated to be analyzed by using existing biochemical methods. To overcome the disadvantage, we have developed a single molecule level detection system with nanofluidic chip. Single molecule was analyzed based on their fluorescent profile and their profiles were plotted into 2 dimensional time co-incident photon burst diagram (2DTP). From this 2DTP, protein complexes were characterized. These results demonstrate that the nanochannel protein detection system is a promising tool for future molecular biology. ^

Calcareous dinoflagellate cycst in the mid-Cenomanian Boreal realm

A transect from the bathyal to proximal shelf facies of the Boreal Realm was investigated to compare spatial and temporal distribution changes of calcareous dinoflagellate cysts (c-dinocysts) throughout the mid-Cenomanian in order to gain information on the ecology of these organisms. Pithonelloideae dominated the cyst assemblages to more than 95% on the shelf, a prevalence that can be observed throughout most of the Upper Cretaceous. The affinity of this group with the dinoflagellates, which is still controversially discussed, can be confirmed, based on evidence from morphological features and distribution patterns. The consistent prevalence of Pithonella sphaerica and P. ovalis in c-dinocyst assemblages throughout the Upper Cretaceous indicates that they were produced more frequently than cysts of the other species and might, therefore, represent a vegetative dinoflagellate life stage. P. sphaerica and P. ovalis are interpreted as eutrophic species. P. sphaerica is the main species in a marginal-shelf upwelling area, offshore Fennoscandia. Here, sedimentary cyclicity appears to have been reduced to the strongest light/dark changes, while in the outer shelf sediments, light/dark cycles are well-developed and show pronounced temporal assemblage changes. Cyclic fluctuations in the P. sphaerica / P. ovalis ratio reflect shifts of the preferred facies zones and indicate changes in surface mixing patterns. During periods of enhanced surface mixing most parts of the shelf were well-ventilated, and nutrient-enriched surface waters led to high productivity and dominance of the Pithonelloideae. These conditions on the shelf contrasted with those in the open ocean, where more oligotrophic and probably stratified waters prevailed, and an assemblage with very few Pithonelloideae and dominance of Cubodinellum renei and Orthopithonella ? gustafsonii was characteristic. While orbitally-forced light/dark sedimentary cyclicity of the shelf sections was mainly related to surface-water carbonate productivity changes, no cyclic modulation of productivity was observed in the oceanic profile. Therefore, dark layer formation in the open ocean was predominantly controlled by the cyclic establishment of anoxic bottom water conditions. Orbitally-forced interruptions in mixing on the shelf resulted in cyclic periods of stratification and oligotrophy in the surface waters, an expansion of oceanic species to the outer shelf, and a shelfward shift of pithonelloid-facies zones, which were probably related to shelfward directed oceanic ingressions.

Organic geochemistry of sediments from North Alex Mud Vulcano

Hydrocarbon seeps are ubiquitous at gas-prone Cenozoic deltas such as the Nile Deep Sea Fan (NDSF) where seepage into the bottom water has been observed at several mud volcanoes (MVs) including North Alex MV (NAMV). Here we investigated the sources of hydrocarbon gases and sedimentary organic matter together with biomarkers of microbial activity at four locations of NAMV to constrain how venting at the seafloor relates to the generation of hydrocarbon gases in deeper sediments. At the centre, high upward flux of hot (70 °C) hydrocarbon-rich fluids is indicated by an absence of biomarkers of Anaerobic Oxidation of Methane (AOM) and nearly constant methane (CH4) concentration depth-profile. The presence of lipids of incompatible thermal maturities points to mixing between early-mature petroleum and immature organic matter, indicating that shallow mud has been mobilized by the influx of deep-sourced hydrocarbon-rich fluids. Methane is enriched in the heavier isotopes, with values of d13C ~-46.6 per mil VPDB and dD ~-228 per mil VSMOW, and is associated with high amounts of heavier homologues (C2+) suggesting a co-genetic origin with the petroleum. On the contrary at the periphery, a lower but sustained CH4 flux is indicated by deeper sulphate-methane transition zones and the presence of 13C-depleted biomarkers of AOM, consistent with predominantly immature organic matter. Values of d13C-CH4 ~-60 per mil VPDB and decreased concentrations of 13C-enriched C2+ are typical of mixed microbial CH4 and biodegraded thermogenic gas from Plio-Pleistocene reservoirs of the region. The maturity of gas condensate migrated from pre-Miocene sources into Miocene reservoirs of the Western NDSF is higher than that of the gas vented at the centre of NAMV, supporting the hypothesis that it is rather released from the degradation of oil in Neogene reservoirs. Combined with the finding of hot pore water and petroleum at the centre, our results suggest that clay mineral dehydration of Neogene sediments, which takes place posterior to reservoir filling, may contribute to intense gas generation at high sedimentation rate deltas.

Sedimentology, magnetics and chemistry on palaeolake core D100 from the Gobi Desert

The Gaxun Nur Basin in arid China is tectonically influenced by the left-lateral displacements along the Gobi-Altay and Qilian Shan shear zones, resulting in a large pull-apart basin with strong subsidence in the interior. The up to 300 m thick basin fills consist of fluvio-lacustrine fine-grained deposits mainly transported by river discharges from the Tibetan Plateau. They led to a large depositional area of more than 28,000 qkm in size with presently dry terminal lakes at the outer edges. This vast area serves as a main source for loess transport to south-eastern regions of China (Loess Plateau) caused by the variable winter monsoon. Based on geochemical and sedimentological analyses of the sediment core D100 retrieved from a deep drilling in the centre of the Gaxun Nur Basin following questions have to be answered: 1. Reconstruction of the water balance and determination of hydrological cycles during interglacial and glacial periods. 2. Reconstructing variations in lacustrine environment and aeolian activities with respect to transitional phases fro, warm to cold stages (MIS 4 to 5 and older stages). 3. Establishing a sustainable chronology for the last 250 ka.

Mineralogical and geochemical data from five lake sediment cores of Lake Donggi Cona

Sediments of Lake Donggi Cona on the northeastern Tibetan Plateau were studied to infer changes in the lacustrine depositional environment, related to climatic and non-climatic changes during the last 19 kyr. The lake today fills a 30 X 8 km big and 95 m deep tectonic basin, associated with the Kunlun Fault. The study was conducted on a sediment-core transect through the lake basin, in order to gain a complete picture of spatiotemporal environmental change. The recovered sediments are partly finely laminated and are composed of calcareous muds with variable amounts of carbonate micrite, organic matter, detrital silt and clay. On the basis of sedimentological, geochemical, and mineralogical data up to five lithological units (LU) can be distinguished that document distinct stages in the development of the lake system. The onset of the lowermost LU with lacustrine muds above basal sands indicates that lake level was at least 39 m below the present level and started to rise after 19 ka, possibly in response to regional deglaciation. At this time, the lacustrine environment was characterized by detrital sediment influx and the deposition of siliciclastic sediment. In two sediment cores, upward grain-size coarsening documents a lake-level fall after 13 cal ka BP, possibly associated with the late-glacial Younger Dryas stadial. From 11.5 to 4.3 cal ka BP, grainsize fining in sediment cores from the profundal coring sites and the onset of lacustrine deposition at a litoral core site (2m water depth) in a recent marginal bay of Donggi Cona document lake-level rise during the early tomid-Holocene to at least modern level. In addition, high biological productivity and pronounced precipitation of carbonate micrites are consistent with warm and moist climate conditions related to an enhanced influence of summer monsoon. At 4.3 cal ka BP the lake system shifted from an aragonite- to a calcite-dominated system, indicating a change towards a fully open hydrological lake system. The younger clay-rich sediments are moreover non-laminated and lack any diagenetic sulphides, pointing to fully ventilated conditions, and the prevailing absence of lake stratification. This turning point in lake history could imply either a threshold response to insolation-forced climate cooling or a response to a non-climatic trigger, such as an erosional event or a tectonic pulse that induced a strong earthquake, which is difficult to decide from our data base.