Activation of c -Met contributes to growth and metastasis of human colorectal carcinoma

c-Met is the protein tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF) and mediates several normal cellular functions including proliferation, survival, and migration. Overexpression of c-Met correlates with progression and metastasis of human colorectal carcinoma (CRC). The goals of this study were to determine if overexpression of c-Met directly contributes to tumorigenicity and liver metastatic potential of colon cancer, and what are the critical pathways regulated by c-Met in this process. The studies used two colon tumor cell lines, KM12SM and KM20, which express high levels of constitutively active c-Met and are highly metastatic in nude mice. To examine the effects of c-Met overexpression, subclones of theses lines with reduced c-Met expression were obtained following transfection with a c-Met specific targeting ribozyme. Reduction of c-Met in KM12SM cells abolished liver metastases when cells were injected intrasplenically in an experimental metastasis assay. However, c-Met downregulation in theses clones was unstable. Three stable KM20 clones with a 25–35% reduction in c-Met protein levels but 60–90% reduction in basal c-Met autophosphorylation and kinase activity were obtained. While HGF increased c-Met kinase activity in the clones with reduced c-Met, the activity was less than that observed in parental or control transfected cells. Correlating with the reduction in c-Met kinase activity, subclones with reduced c-Met expression had significantly reduced in vitro growth rates, soft-agar colony forming abilities, and increased apoptosis. HGF/SF treatment did not affect anchorage-dependent growth or soft-agar colony forming abilities. Further, c-Met downregulation significantly impaired the ability of HGF/SF to induce migration. To examine the effects of reduced c-Met on tumor formation, parental and c-Met reduced KM20 cells were grown subcutaneously and intrahepatically in nude mice. c-Met downregulation delayed, but did not abolish growth at the subcutaneous site. When these cells were injected intrahepatically, both tumor incidences and size were significantly reduced. To further understand the molecular basis of c-Met in promoting tumor growth, the activation of several signaling intermediates that have been implicated in c-Met mediated growth, survival and migration were compared between KM20 parental cells and subclones with reduced c-Met expression levels. The expression and activity (as determined by phosphorylation) of AKT and Erk1/2 were unaltered. In contrast, Src kinase activity, as measured by immune complex kinase assay, was reduced 2–5 fold following c-Met downregulation. As Src has been implicated in growth, survival and migration, Src activation in c-Met overexpressing lines is likely contributing to the tumorigenic and metastatic capabilities of colon tumor cell lines that overexpress c-Met. Collectively, these results suggest that c-Met overexpression plays a causal role in the development of CRC liver metastases, and that c-Src and c-Met inhibitors may be of potential therapeutic benefit for late-stage colon cancer. ^

Description and chemical and mineral composition of iron oxide samples from two Finnish lakes

Fifteen iron oxide accumulations from the bottoms of two Finnish lakes ("lake ores") were found to contain as much as 50% Fe. Differential X-ray powder diffraction and selective dissolution by oxalate showed that the samples consisted of poorly crystallized goethite and ferrihydrite. The crust ores of one lake had higher ferrihydrite to goethite ratios than the nodular ores of the other lake. The higher ferrihydrite proportion was attributed to a higher rate of Fe2+ supply from the ground water and/or a higher rate of oxidation as a function of water depth and bottom-sediment permeability. Values of Al-for-Fe substitution of the goethites determined from unit-cell dimensions agreed with those obtained from chemical extraction if the unit-cell volume rather than the c dimension was used. In very small goethite crystals a slight expansion of the a unit-cell dimension is probaby compensated by a corresponding contraction of the c dimension, so that a contraction of the c dimension need not necessarily be caused by Al substitution. The goethites of the two lakes differed significantly in their Al-for-Fe substitutions and hence in their unit-cell sizes, OH-bending characteristics, dehydroxylation temperatures, dissolution kinetics, and Mössbauer parameters. The difference in Al substitution (0 vs. 7 mole %) is attributed to the Al-supplying power of the bottom sediments: the silty-clayey sediments in one lake appear to have supplied A1 during goethite formation, whereas the gravelly-sandy sediments in the other lake did not. The compositions of the goethites thus reflect their environments of formation.

Mineral and chemical compositions of sedimentary and volcano-sedimentary rocks drilled in DSDP Legs 43 and 44

Sedimentary cover on the bottom of the Northwest Atlantic Ocean is underlain by Late Jurassic - Cretaceous tholeiite-basalt formation. It consists of come sedimentary formations with different lithologic features and age. Their composition, stratigraphic position and, distribution are described on materials of deep-sea drilling. Mineralogical and geochemical studies of DSDP Leg 43 and Leg 44 holes lead to new ideas about composition and genesis of some sediment types of and their associations. High metal contents in the chalk formation of black clays on the Bermuda Rise probably result from exhalations. Connection of red-colored and speckled deposits with hiatuses in sedimentation is shown. Main stages of geological history of the North American Basin are reflected in accumulation of the followed formations: ancient carbonate formation (Late Jurassic - Early Cretaceous), formation of black clays rich in organic matter (Cretaceous), formation of speckled clays (Late Cretaceous), siliceous-clayey turbidite formation (Eocene), hemipelagic and pelagic clayey formation (Neogene), and terrigenous turbidite formation (Pleistocene).

Bone metabolic and hormonal characteristics of Australian Antarctic expeditioners

Summary: Serum 25(OH)D levels decline without sunlight exposure. We studied 120 expeditioners to Antarctica to determine the skeletal and hormonal responses to sunlight deprivation. With emerging vitamin D insufficiency, serum calcium decreased, PTH increased, and bone loss at the proximal femur was observed. Baseline serum 25(OH)D levels >100 nmol/L prevented vitamin D insufficiency. Introduction: Vitamin D stores deplete without adequate sunlight exposure unless supplementation is provided. We studied 120 healthy adults who spent a year in Antarctica as a model for sunlight deprivation to define the timing and magnitude of the skeletal and hormonal responses to emerging vitamin D insufficiency. Methods: Fasting blood samples were assessed at baseline, 6 and 12 months for serum 25-hydroxyvitamin D (25(OH)D), osteocalcin (OC), bone formation (P1NP) and resorption (CTx), PTH and calcium. Lumbar spine and proximal femur BMD was measured using DXA. Differences over time were determined using repeated measures ANOVA. Percent changes were expressed as (Delta value/(value A +value B)/2)x100. Relationships between outcome measures were determined using Spearman's correlations. Results: Vitamin D insufficiency (<50 nmol/L) was observed in 85% of expeditioners by 6 months when serum calcium decreased and PTH increased (p<0.01). By 12 months, OC increased by 7.4±3.0% (p<0.05), and BMD decreased by 1.0±2.0% at the total proximal femur (p<0.05). For those with vitamin D sufficiency at baseline (>50 nmol/L), sunlight deprivation produced vitamin D insufficiency within 4 months unless baseline values were >100 nmol/L. Conclusion: Supplementation may be necessary for expeditioners with limited access to UV light.

Geochemistry of metasedimentary units of the Cambro-Ordovician Ross Orogen in North Victoria Land and Oates Land, Antarctica

Metasediments in the three early Palaeozoic Ross orogenic terranes in northern Victoria Land and Oates Land (Antarctica) are geochemically classified as immature litharenites to wackes and moderately mature shales. Highly mature lithotypes with Chemical Index of Weathering values of >=95 are typically absent. Geochemical and Rb-Sr and Sm-Nd isotope results indicate that the turbiditic metasediments of the Cambro-Ordovician Robertson Bay Group in the eastern Robertson Bay Terrane represent a very homogeneous series lacking significant compositional variations. Major variations are only found in chemical parameters which reflect differences in degree of chemical weathering of their protoliths and in mechanical sorting of the detritus. Geochemical data, 87Sr/ 86Sr t=490 Ma ratios of 0.7120 - 0.7174, epsilonNd, t=490 Ma values of -7.6 to -10.3 and single-stage Nd-model ages of 1.7 - 1.9 Ga are indicative of an origin from a chemically evolved crustal source of on average late Palaeoproterozoic formation age. There is no evidence for significant sedimentary infill from primitive "ophiolitic" sources. Metasediments of the Middle Cambrian Molar Formation (Bowers Terrane) are compositionally strongly heterogeneous. Their major and trace element data and Sm-Nd isotope data (epsilonNd, t=500 Ma values of -14.3 to -1.2 and single-stage Nd-model ages of 1.7 - 2.1 Ga) can be explained by mixing of sedimentary input from an evolved crustal source of at least early Palaeoproterozoic formation age and from a primitive basaltic source. The chemical heterogeneity of metasediments from the Wilson Terrane is largely inherited from compositional variations of their precursor rocks as indicated by the Ni vs TiO2 diagram. Single-stage Nd-model ages of 1.6 -2.2 Ga for samples from more western inboard areas of the Wilson Terrane (epsilonNd, t=510 Ma -7.0 to -14.3) indicate a relatively high proportion of material derived from a crustal source with on average early Palaeoproterozoic formation age. Metasedimentary series in an eastern, more outboard position (epsilonNd, t=510 Ma -5.4 to -10.0; single-stage Nd model ages 1.4 - 1.9) on the contrary document stronger influence of a more primitive source with younger formation ages. The chemical and isotopic characteristics of metasediments from the Bowers and Wilson terranes can be explained by variable contributions from two contrasting sources: a cratonic continental crust similar to the Antarctic Shield exposed in Georg V Land and Terre Adélie some hundred kilometers west of the study area and a primitive basaltic source probably represented by the Cambrian island-arc of the Bowers Terrane. While the data for metasediments of the Robertson Bay Terrane are also compatible with an origin from an Antarctic-Shield-type source, there is no direct evidence from their geochemistry or isotope geochemistry for an island-arc component in these series.

Distribution of Florisphaera profunda and Helicosphaera carteri in down core and surface sediments

A detailed assessment of the respective roles of production, export, and subsequent preservation of organic carbon (Corg) in the eastern Mediterranean (EMED) sediments during the formation of sapropels remains elusive. Here we present new micropaleontological results for both surface samples taken at several locations in the EMED and last interglacial sapropel S5 from core LC21 in the southeastern Aegean Sea. A strong exponential anticorrelation between relative abundances of the lower photic zone coccolithophore Florisphaera profundain the surface sediments and modern concentrations of chlorophyll a (Chl-a) at the sea surface suggests thatF. profunda percentages can be used to track past productivity changes in the EMED. Prior to S5 deposition, an abrupt and large increase of F. profunda percentages in LC21 coincided (within the multidecadal resolution of the records) with the marked freshening of EMED surface waters. This suggests a strong coupling between freshwater-bound surface to intermediate water (density) stratification and enhanced upward advection of nutrients to the base of the photic zone, fuelling a productive deep chlorophyll maximum (DCM) underneath a nutrient-starved surface layer. Our findings imply that (at least) at the onset of sapropel formation physical and biogeochemical processes likely operated in tandem, enabling high Corg accumulation at the seafloor.

Chemical composition of hydrogarnet and celadonite from ODP Hole 206-1256D

Mid-ocean-ridge basalts recovered from Hole 1256D during Ocean Drilling Program Leg 206 exhibit the effects of various low-temperature (<100°C) alteration processes, including the formation of black or dark green alteration halos adjacent to celadonite-bearing veins. In several samples from the deepest basalts, a Ti-rich hydrogarnet occurs. To our knowledge, such a mineral has never been reported in the oceanic crust. This report presents a brief description and microprobe analyses of this hydrogarnet and associated celadonite. More detailed characterizations of this mineral and a description of its relationship to other secondary minerals will be undertaken in a future study, in an attempt to determine the mineral's formation conditions and its place in the general alteration history of the Hole 1256D basalts.

Results of a Finite-Element Sea-Ice Ocean Model (FESOM) set-up to study the interannual to decadal variability in the deep-water formation rates

The characteristics of a global set-up of the Finite-Element Sea-Ice Ocean Model under forcing of the period 1958-2004 are presented. The model set-up is designed to study the variability in the deep-water mass formation areas and was therefore regionally better resolved in the deep-water formation areas in the Labrador Sea, Greenland Sea, Weddell Sea and Ross Sea. The sea-ice model reproduces realistic sea-ice distributions and variabilities in the sea-ice extent of both hemispheres as well as sea-ice transport that compares well with observational data. Based on a comparison between model and ocean weather ship data in the North Atlantic, we observe that the vertical structure is well captured in areas with a high resolution. In our model set-up, we are able to simulate decadal ocean variability including several salinity anomaly events and corresponding fingerprint in the vertical hydrography. The ocean state of the model set-up features pronounced variability in the Atlantic Meridional Overturning Circulation as well as the associated mixed layer depth pattern in the North Atlantic deep-water formation areas.

Underway physical oceanography and carbonate chemistry measured during the EURO-BASIN cruise M87/1 (Deep Convection Cruise)

The track of the cruise, and the location of the different stations cover a large range of water masses, many of which take part in the exchange across the Greenland-Scotland Ridge, and of importance for the biogeochemical fluxes in the region. These water masses are of very different origins, which can be observed in the concentration of the different biogeochemical parameters. The concentrations are a result of the combination of the physical and biogeochemical environment in each formation region, and the processes acting on the water masses as they are transported away from the formation areas. The aim of the biogeochemistry measurements was to achieve a better understanding of the strength and variability of the biological carbon pump in the North Atlantic and Nordic Seas.

Body sizes and dive characteristics of narwhals (Monodon monoceros) from Kakiak Point and Melville Bay (2005-2007)

We report on wintertime data collected from Baffin Bay and northern Davis Strait, a major gateway linking the Arctic with the subpolar North Atlantic, using narwhals (Monodon monoceros) as an oceanographic sampling platform. Fourteen narwhals were instrumented with satellite-linked time-depth-temperature recorders between 2005 and 2007. Transmitters collected and transmitted water column temperature profiles from each dive between December and April, where >90% of maximum daily dive depths reached the bottom. Temperature measurements were combined with 15 helicopter-based conductivity-temperature-depth (CTD) casts taken in April 2007 across central Baffin Bay and compared with hydrographic climatology values used for the region in Arctic climate models. Winter temperature maxima for whale and CTD data were in good agreement, ranging between 4.0°C and 4.6°C in inshore and offshore Baffin Bay and in Davis Strait. The warm Irminger Water was identified between 57°W and 59°W (at 68°N) between 200 and 400 m depths. Whale data correlated well with climatological temperature maxima; however, they were on average 0.9°C warmer ±0.6°C (P < 0.001). Furthermore, climatology data overestimated the winter surface isothermal layer thickness by 50-80 m. Our results suggest the previously documented warming in Baffin Bay has continued through 2007 and is associated with a warmer West Greenland Current in both of its constituent water masses. This research demonstrates the feasibility of using narwhals as ocean observation platforms in inaccessible Arctic areas where dense sea ice prevents regular oceanographic measurements and where innate site fidelity, affinity for winter pack ice, and multiple daily dives to >1700 m offer a useful opportunity to sample the area.

Geochemistry of the Kimmeridge Clay Formation, Dorset Coast

The Kimmeridge Clay Formation (KCF) and its equivalents worldwide represent one of the most prolonged periods of organic carbon accumulation of the Mesozoic. In this study, we use the molybdenum (Mo) stable isotope system in conjunction with a range of trace metal paleoredox proxies to assess how seawater redox varied both locally and globally during the deposition of the KCF. Facies with lower organic carbon contents (TOC 1-7 wt %) were deposited under mildly reducing (suboxic) conditions, while organic-rich facies (TOC >7 wt %) accumulated under more strongly reducing (anoxic or euxinic) local conditions. Trace metal abundances are closely linked to TOC content, suggesting that the intensity of reducing conditions varied repeatedly during the deposition of the KCF and may have been related to orbitally controlled climate changes. Long-term variations in d98/95Mo are associated with the formation of organic-rich intervals and are related to third-order fluctuations in relative sea level. Differences in the mean d98/95Mo composition of the organic-rich intervals suggest that the global distribution of reducing conditions was more extensive during the deposition of the Pectinatites wheatleyensis and lower Pectinatites hudlestoni zones than during the deposition of the upper Pectinatites hudlestoni and Pectinatites pectinatus zones. The global extent of reducing conditions during the Kimmerigidan was greater than today but was less widespread than during the Toarcian (Early Jurassic) oceanic anoxic event. This study also demonstrates that the Mo isotope system in Jurassic seawater responded to changes in redox conditions in a manner consistent with its behavior in present-day sedimentary environments.