Src-homology 2 domain-containing tyrosine phosphatase 2 promotes oral cancer invasion and metastasis

BACKGROUND: Tumor invasion and metastasis represent a major unsolved problem in cancer pathogenesis. Recent studies have indicated the involvement of Src-homology 2 domain-containing tyrosine phosphatase 2 (SHP2) in multiple malignancies; however, the role of SHP2 in oral cancer progression has yet to be elucidated. We propose that SHP2 is involved in the progression of oral cancer toward metastasis. METHODS: SHP2 expression was evaluated in paired oral cancer tissues by using immunohistochemical staining and real-time reverse transcription polymerase chain reaction. Isogenic highly invasive oral cancer cell lines from their respective low invasive parental lines were established using a Boyden chamber assay, and changes in the hallmarks of the epithelial-mesenchymal transition (EMT) were assessed to evaluate SHP2 function. SHP2 activity in oral cancer cells was reduced using si-RNA knockdown or enforced expression of a catalytically deficient mutant to analyze migratory and invasive ability in vitro and metastasis toward the lung in mice in vivo. RESULTS: We observed the significant upregulation of SHP2 in oral cancer tissues and cell lines. Following SHP2 knockdown, the oral cancer cells markedly attenuated migratory and invasion ability. We observed similar results in phosphatase-dead SHP2 C459S mutant expressing cells. Enhanced invasiveness was associated with significant upregulation of E-cadherin, vimentin, Snail/Twist1, and matrix metalloproteinase-2 in the highly invasive clones. In addition, we determined that SHP2 activity is required for the downregulation of phosphorylated ERK1/2, which modulates the downstream effectors, Snail and Twist1 at a transcript level. In lung tissue sections of mice, we observed that HSC3 tumors with SHP2 deletion exhibited significantly reduced metastatic capacity, compared with tumors administered control si-RNA. CONCLUSIONS: Our data suggest that SHP2 promotes the invasion and metastasis of oral cancer cells. These results provide a rationale for further investigating the effects of small-molecule SHP2 inhibitors on the progression of oral cancer, and indicate a previously unrecognized SHP2-ERK1/2-Snail/Twist1 pathway that is likely to play a crucial role in oral cancer invasion and metastasis

U-series dating and isotope geochemical study of the Gellért Hill (Budapest) travertine

Abstract Travertine is quite a common formation in the area of Budapest (Hungary) indicating strong hydrothermal activity during the Pliocene and Quaternary. It covers former terraces of the Danube River and older geomorphologic horizons; thus, it is an important archive to date fluvial terraces and tectonic movements. Despite numerous investigations performed on these deposits, only few radiometric data are available so far and the absence of the exact timing information hindered paleoclimatic interpretation. The area of Gellért Hill consists mainly of Upper Triassic dolomite, but Quaternary travertine can also be found. In this study a detailed petrographic and stable isotope geochemical study of four travertine sites (1. Ifjúsági Park; 2. Számadó u. (Street); 3. Kelenhegyi u. (Street); 4. Somlói u. (Street)) of the Gellért Hill area is presented, along with analyses on the recent carbonate deposits of Gellért Hill and Sárosfürdő. The travertine of Ifjúsági Park and Számadó u. are spring cone deposits, while the travertine of the Kelenhegyi u. represents a shallow-water depositional environment. Based on the paleontological studies of Jánossy (in Scheuer and Schweitzer, 1988) the Gellért Hill travertine was thought to have been formed during the Lower Pleistocene; however, no radiometric age dating had been performed on these deposits prior our study. Our U/Th analyses yielded ages of 250±44 ky for the Ifjúsági Park travertine (220 m asl) and 180±49 ky for the Számadó u. travertine (195 m asl). These new U/Th ages are in contradiction with the previously assumed Lower Pleistocene age, implying gradual relative decrease in the paleokarst water-level and proving that the elevation of the individual travertine deposits not necessarily show their relative age. The uplift rates of Gellért Hill calculated from the U/Th age data and elevation of travertine occurrences range between 0.47 and 0.52 mm/yr, which is significantly higher than the uplift rates calculated for the Rózsadomb area (0.20 0.25 mm/yr; Kele et al., submitted). The difference in the incision rates between the individual sub-areas suggests that selective uplift was characteristic for the Buda Hills during the Middle Pleistocene; thus, up-scaling reconstruction of paleokarst waterlevel for the whole area from a given locality is not possible. Oxygen isotope analyses of recent carbonate deposits of Gellért Hill, Sárosfürdő and Rudas Spa revealed that these calcites precipitated under non-equilibrium conditions, and the measured calcitewater oxygen isotope fractionation show the same positive shift relative to “equilibrium values” as was observed in the case of the recently-forming Egerszalók travertine (Kele et al. 2008). Assuming that the water of the paleo-springs of Gellért Hill derived from precipitation infiltrated during interstadial periods of the Pleistocene and considering non-equilibrium deposition (i.e. using the empirical calcite-water oxygen isotope fractionation of Kele et al. 2008), their calculated paleotemperature could range between 22 (±4) °C and 49 (±6) °C. Based on the δ18Otravertine differences the Ifjúsági Park and the Számadó u. spring cone type travertine was deposited from the highest temperature water, while from the lowest temperature water the travertine of Kelenhegyi u. was formed

Persistent termini of 2004- and 2005-like ruptures of the Sunda megathrust

To gain insight into the longevity of subduction zone segmentation, we use coral microatolls to examine an 1100-year record of large earthquakes across the boundary of the great 2004 and 2005 Sunda megathrust ruptures. Simeulue, a 100-km-long island off the west coast of northern Sumatra, Indonesia, straddles this boundary: northern Simeulue was uplifted in the 2004 earthquake, whereas southern Simeulue rose in 2005. Northern Simeulue corals reveal that predecessors of the 2004 earthquake occurred in the 10th century AD, in AD 1394 ± 2, and in AD 1450 ± 3. Corals from southern Simeulue indicate that none of the major uplifts inferred on northern Simeulue in the past 1100 years extended to southern Simeulue. The two largest uplifts recognized at a south-central Simeulue site—around AD 1422 and in 2005—involved little or no uplift of northern Simeulue. The distribution of uplift and strong shaking during a historical earthquake in 1861 suggests the 1861 rupture area was also restricted to south of central Simeulue, as in 2005. The strikingly different histories of the two adjacent patches demonstrate that this boundary has persisted as an impediment to rupture through at least seven earthquakes in the past 1100 years. This implies that the rupture lengths, and hence sizes, of at least some future great earthquakes and tsunamis can be forecast. These microatolls also provide insight into megathrust behavior between earthquakes, revealing sudden and substantial changes in interseismic strain accumulation rates

Translational high-dimensional drug Interaction discovery and validation using health record databases and pharmacokinetics models

Polypharmacy increases the risk of drug-drug interactions (DDI's). Combining epidemiological studies with pharmacokinetic modeling, we detected and evaluated high-dimensional DDI's among thirty frequent drugs. Multi-drug combinations that increased risk of myopathy were identified in the FDA Adverse Event Reporting System (FAERS) and electronic medical record (EMR) databases by a mixture drug-count response model. CYP450 inhibition was estimated among the 30 drugs in the presence of 1 to 4 inhibitors using in vitro in vivo extrapolation. Twenty-eight 3-way and 43 4-way DDI's had significant myopathy risk in both databases and predicted increases in the area under the concentration time curve ratio (AUCR) >2-fold. The HD-DDI of omeprazole, fluconazole and clonidine was associated with a 6.41-fold (FAERS) and 18.46-fold (EMR) increase risk of myopathy (LFDR<0.005); the AUCR of omeprazole in this combination was 9.35.The combination of health record informatics and pharmacokinetic modeling is a powerful translational approach to detect high-dimensional DDI's

Fatty acids as therapeutic auxiliaries for oral and parenteral formulations

Many drugs have decreased therapeutic activity due to issues with absorption, distribution, metabolism and excretion. The co-formulation or covalent attachment of drugs with fatty acids has demonstrated some capacity to overcome these issues by improving intestinal permeability, slowing clearance and binding serum proteins for selective tissue uptake and metabolism. For orally administered drugs, albeit at low level of availability, the presence of fatty acids and triglycerides in the intestinal lumen may promote intestinal uptake of small hydrophilic molecules. Small lipophilic drugs or acylated hydrophilic drugs also show increased lymphatic uptake and enhanced passive diffusional uptake. Fatty acid conjugation of small and large proteins or peptides have exhibited protracted plasma half-lives, site-specific delivery and sustained release upon parenteral administration. These improvements are most likely due to associations with lipid-binding serum proteins, namely albumin, LDL and HDL. These molecular interactions, although not fully characterized, could provide the ability of using the endogenous carrier systems for improving therapeutic outcomes

Tsengwen Reservoir Watershed Hydrological Flood Simulation Under Global Climate Change Using the 20 km Mesh Meteorological Research Institute Atmospheric General Circulation Model (MRI-AGCM)

Severe rainstorms have occurred more frequently in Taiwan over the last decade. To understand the flood characteristics of a local region under climate change, a hydrological model simulation was conducted for the Tsengwen Reservoir watershed. The model employed was the Integrated Flood Analysis System (IFAS), which has a conceptual, distributed rainfall-runoff analysis module and a GIS data-input function. The high-resolution rainfall data for flood simulation was categorized into three terms: 1979 - 2003 (Present), 2015 - 2039 (Near-future), and 2075 - 2099 (Future), provided by the Meteorological Research Institute atmospheric general circulation model (MRI-AGCM). Ten extreme rainfall (top ten) events were selected for each term in descending order of total precipitation volume. Due to the small watershed area the MRI-AGCM3.2S data was downsized into higher resolution data using the Weather Research and Forecasting Model. The simulated discharges revealed that most of the Near-future and Future peaks caused by extreme rainfall increased compared to the Present peak. These ratios were 0.8 - 1.6 (Near-future/Present) and 0.9 - 2.2 (Future/Present), respectively. Additionally, we evaluated how these future discharges would affect the reservoir¡¦s flood control capacity, specifically the excess water volume required to be stored while maintaining dam releases up to the dam¡¦s spillway capacity or the discharge peak design for flood prevention. The results for the top ten events show that the excess water for the Future term exceeded the reservoir¡¦s flood control capacity and was approximately 79.6 - 87.5% of the total reservoir maximum capacity for the discharge peak design scenario

Rupture and variable coupling behavior of the Mentawai segment of the Sunda megathrust during the supercycle culmination of 1797 to 1833

We refer to periods of subduction strain accumulation beneath the Mentawai Islands, Sumatra, as “supercycles,” because each culminates in a series of partial ruptures of the megathrust in its final decades. The finale of the previous supercycle comprised two giant earthquakes in 1797 and 1833 and whatever happened in between. This behavior between two great ruptures has implications for how the megathrust will behave between its more recent partial failure, during the M_w 8.4 earthquake of 2007, and subsequent large ruptures. We synthesize previously published coral microatoll records and a large new coral data set to constrain not only these two giant ruptures but also the intervening interseismic megathrust behavior. We present detailed maps of coseismic uplift during the two earthquakes and of interseismic deformation during the periods 1755–1833 and 1950–2000, as well as models of the corresponding slip and coupling on the underlying megathrust. The large magnitudes we derive (M_w 8.6–8.8 for 1797 and M_w 8.8–8.9 for 1833) confirm that the 2007 earthquakes released only a fraction of the moment released during the previous rupture sequence. Whereas megathrust behavior leading up to the 1797 and 2007 earthquakes was similar and comparatively simple, behavior between 1797 and 1833 was markedly different and more complex: several patches of the megathrust became weakly coupled following the 1797 earthquake. We conclude that while major earthquakes generally do not involve rupture of the entire Mentawai segment, they may significantly change the state of coupling on the megathrust for decades to follow, influencing the progression of subsequent ruptures

Label-free quantitative proteomics of CD133-positive liver cancer stem cells

Abstract Background CD133-positive liver cancer stem cells, which are characterized by their resistance to conventional chemotherapy and their tumor initiation ability at limited dilutions, have been recognized as a critical target in liver cancer therapeutics. In the current work, we developed a label-free quantitative method to investigate the proteome of CD133-positive liver cancer stem cells for the purpose of identifying unique biomarkers that can be utilized for targeting liver cancer stem cells. Label-free quantitation was performed in combination with ID-based Elution time Alignment by Linear regression Quantitation (IDEAL-Q) and MaxQuant. Results Initially, IDEAL-Q analysis revealed that 151 proteins were differentially expressed in the CD133-positive hepatoma cells when compared with CD133-negative cells. We then analyzed these 151 differentially expressed proteins by MaxQuant software and identified 10 significantly up-regulated proteins. The results were further validated by RT-PCR, western blot, flow cytometry or immunofluorescent staining which revealed that prominin-1, annexin A1, annexin A3, transgelin, creatine kinase B, vimentin, and EpCAM were indeed highly expressed in the CD133-positive hepatoma cells. Conclusions These findings confirmed that mass spectrometry-based label-free quantitative proteomics can be used to gain insights into liver cancer stem cells.http://deepblue.lib.umich.edu/bitstream/2027.42/113089/1/12953_2012_Article_407.pd