bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes
Authors: Lang Sven A. , Schachtschneider Philipp , Moser Christian , Mori Akira , Hackl Christina , Gaumann Andreas , Batt David , Schlitt Hans J. , Geissler Edward K. , Stoeltzing Oliver 
Published: November 2008

Abstract
The Ras/Raf/MEK pathway represents an important oncogenic signaling pathway in gastrointestinal malignancies, including pancreatic cancer. Although activating B-Raf mutations are infrequent in pancreatic cancer, we hypothesized that targeting Raf could be valuable for therapy of this cancer entity. Moreover, as vascular endothelial growth factor receptor 2 (VEGFR2) is involved in tumor angiogenesis, we sought to investigate the effects of dual inhibition of Raf and VEGFR2 on pancreatic tumor growth, vascularization, and metastasis. Effects of a Raf/VEGFR2 inhibitor (NVP-AAL881) on pancreatic cancer cells, endothelial cells, and vascular smooth muscle cells were determined by Western blotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, and migration assays, respectively. Changes in the expression of VEGF-A or survivin were investigated by ELISA and/or real-time PCR. The growth-inhibitory effects of Raf/VEGFR2 inhibition were additionally evaluated in orthotopic tumor models. Results showed that various Raf isoforms were activated in pancreatic cancer cells and NVP-AAL881 diminished the activation of MEK, Akt, Erk, and also STAT3. Moreover, dual inhibition of Raf/VEGFR2 significantly reduced VEGF expression and impaired cancer cell migration. Importantly, besides blocking VEGF-induced Erk and SAPK phosphorylation in endothelial cells, the Raf inhibitor diminished STAT3 phosphorylation, independent of a VEGFR2 blockade, and reduced the expression of survivin. In addition, cell proliferation and migration of both endothelial cells and vascular smooth muscle cells were significantly reduced. In vivo, blocking Raf/VEGFR2 significantly inhibited orthotopic tumor growth and vascularization and reduced cancer metastasis. In conclusion, blocking Raf exerts growth-inhibitory effects on pancreatic tumor cells, endothelial cells, and pericytes and elicits antiangiogenic properties. Dual targeting of Raf and VEGFR2 appears to be a valid strategy for therapy of pancreatic cancer. [Mol Cancer Ther 2008;7(11):3509–18]
Bortezomib is ineffective in an orthotopic mouse model of pancreatic adenocarcinoma
Authors: Märten Angela , Zeiss Nina , Serba Susanne , Mehrle Stefan , von Lilienfeld-Toal Marie , Schmidt Jan 
Published: November 2008

Abstract
The purpose of the present study was to evaluate the potency of the proteasome inhibitor bortezomib ± gemcitabine in vitro and in vivo in pancreatic carcinoma. It could be shown that bortezomib induced apoptosis and inhibited proliferation of pancreatic carcinoma very efficiently in vitro. In contrast, in an orthotopic pancreatic adenocarcinoma mouse model, gemcitabine treatment inhibited tumor growth, whereas bortezomib promoted it. Bortezomib-treated animals showed significantly higher tumor burden compared with gemcitabine-treated and control animals, although bortezomib was locally active and induced a decrease of proteasome activity, which was most pronounced following the simultaneous administration of gemcitabine. Also, tumor progression was not caused by immunosuppression as a result of proteasome inhibition. Interestingly, anti-CD31 staining of tumors showed that angiogenesis was significantly increased in the tumors of bortezomib-treated mice compared with the tumors of control animals. In addition, bortezomib resulted an increase of pericytes, vascular endothelial growth factor, RGS-5, and hypoxia-inducible factor-1α in the tumor. Although this study supports efficacy of bortezomib against pancreatic carcinoma in vitro, it strongly indicates that bortezomib therapy has a significant tumor-promoting effect in vivo by induction of angiogenesis. The data are in accordance with the complete failure of bortezomib in a phase II trial for this indication. Choosing the right schedule of gemcitabine and bortezomib showed some synergistic effects, but the gain might not be big enough to compensate the potentially detrimental effects. [Mol Cancer Ther 2008;7(11):3624–31]
Coupling of Integrated Biosphere Simulator to Regional Climate Model Version 3
Authors: Winter Jonathan M. , Pal Jeremy S. , Eltahir Elfatih A. B. 
Published: November 2008

Abstract
A description of the coupling of Integrated Biosphere Simulator (IBIS) to Regional Climate Model version 3 (RegCM3) is presented. IBIS introduces several key advantages to RegCM3, most notably vegetation dynamics, the coexistence of multiple plant functional types in the same grid cell, more sophisticated plant phenology, plant competition, explicit modeling of soil/plant biogeochemistry, and additional soil and snow layers.
A single subroutine was created that allows RegCM3 to use IBIS for surface physics calculations. A revised initialization scheme was implemented for RegCM3–IBIS, including an IBIS-specific prescription of vegetation and soil properties.
To illustrate the relative strengths and weaknesses of RegCM3–IBIS, one 4-yr numerical experiment was completed to assess ability of both RegCM3–IBIS (with static vegetation) and RegCM3 with its native land surface model, Biosphere–Atmosphere Transfer Scheme 1e (RegCM3–BATS1e), to simulate the energy and water budgets. Each model was evaluated using the NASA Surface Radiation Budget, FLUXNET micrometeorological tower observations, and Climate Research Unit Time Series 2.0. RegCM3–IBIS and RegCM3–BATS1e simulate excess shortwave radiation incident and absorbed at the surface, especially during the summer months. RegCM3–IBIS limits evapotranspiration, which allows for the correct estimation of latent heat flux, but increases surface temperature, sensible heat flux, and net longwave radiation. RegCM3–BATS1e better simulates temperature, net longwave radiation, and sensible heat flux, but systematically overestimates latent heat flux. This objective comparison of two different land surface models will help guide future adjustments to surface physics schemes within RegCM3.
Will Extratropical Storms Intensify in a Warmer Climate?
Authors: Bengtsson Lennart , Hodges Kevin I. , Keenlyside Noel 
Published: November 2008

Abstract
Extratropical cyclones and how they may change in a warmer climate have been investigated in detail with a high-resolution version of the ECHAM5 global climate model. A spectral resolution of T213 (63 km) is used for two 32-yr periods at the end of the twentieth and twenty-first centuries and integrated for the Intergovernmental Panel on Climate Change (IPCC) A1B scenario. Extremes of pressure, vorticity, wind, and precipitation associated with the cyclones are investigated and compared with a lower-resolution simulation. Comparison with observations of extreme wind speeds indicates that the model reproduces realistic values.
This study also investigates the ability of the model to simulate extratropical cyclones by computing composites of intense storms and contrasting them with the same composites from the 40-yr ECMWF Re-Analysis (ERA-40). Composites of the time evolution of intense cyclones are reproduced with great fidelity; in particular the evolution of central surface pressure is almost exactly replicated, but vorticity, maximum wind speed, and precipitation are higher in the model. Spatial composites also show that the distributions of pressure, winds, and precipitation at different stages of the cyclone life cycle compare well with those from ERA-40, as does the vertical structure.
For the twenty-first century, changes in the distribution of storms are very similar to those of previous study. There is a small reduction in the number of cyclones but no significant changes in the extremes of wind and vorticity in both hemispheres. There are larger regional changes in agreement with previous studies.
The largest changes are in the total precipitation, where a significant increase is seen. Cumulative precipitation along the tracks of the cyclones increases by some 11% per track, or about twice the increase in global precipitation, while the extreme precipitation is close to the globally averaged increase in column water vapor (some 27%). Regionally, changes in extreme precipitation are even higher because of changes in the storm tracks.
Regional Differences in the Influence of Irrigation on Climate
Authors: Lobell David , Bala Govindasamy , Mirin Art , Phillips Thomas , Maxwell Reed , Rotman Doug 
Published: November 2008

Abstract
A global climate model experiment is performed to evaluate the effect of irrigation on temperatures in several major irrigated regions of the world. The Community Atmosphere Model, version 3.3, was modified to represent irrigation for the fraction of each grid cell equipped for irrigation according to datasets from the Food and Agriculture Organization. Results indicate substantial regional differences in the magnitude of irrigation-induced cooling, which are attributed to three primary factors: differences in extent of the irrigated area, differences in the simulated soil moisture for the control simulation (without irrigation), and the nature of cloud response to irrigation. The last factor appeared especially important for the dry season in India, although further analysis with other models and observations are needed to verify this feedback. Comparison with observed temperatures revealed substantially lower biases in several regions for the simulation with irrigation than for the control, suggesting that the lack of irrigation may be an important component of temperature bias in this model or that irrigation compensates for other biases. The results of this study should help to translate the results from past regional efforts, which have largely focused on the United States, to regions in the developing world that in many cases continue to experience significant expansion of irrigated land.
Global and Continental Drought in the Second Half of the Twentieth Century: Severity–Area–Duration Analysis and Temporal Variability of Large-Scale Events
Authors: Sheffield J. , Andreadis K. M. , Wood E. F. , Lettenmaier D. P. 
Published: November 2008

Abstract
Using observation-driven simulations of global terrestrial hydrology and a cluster algorithm that searches for spatially connected regions of soil moisture, the authors identified 296 large-scale drought events (greater than 500 000 km2 and longer than 3 months) globally for 1950–2000. The drought events were subjected to a severity–area–duration (SAD) analysis to identify and characterize the most severe events for each continent and globally at various durations and spatial extents. An analysis of the variation of large-scale drought with SSTs revealed connections at interannual and possibly decadal time scales. Three metrics of large-scale drought (global average soil moisture, contiguous area in drought, and number of drought events shorter than 2 years) are shown to covary with ENSO SST anomalies. At longer time scales, the number of 12-month and longer duration droughts follows the smoothed variation in northern Pacific and Atlantic SSTs. Globally, the mid-1950s showed the highest drought activity and the mid-1970s to mid-1980s the lowest activity. This physically based and probabilistic approach confirms well-known droughts, such as the 1980s in the Sahel region of Africa, but also reveals many severe droughts (e.g., at high latitudes and early in the time period) that have received relatively little attention in the scientific and popular literature.
Potential Value of Quantitative Analysis of Cerebral PET in Early Cognitive Decline
Authors: Patterson James C. , Lilien David L. , Takalkar Amol , Kelley Roger E. , Minagar Alireza 
Published: November 2008

Background. In patients diagnosed with Alzheimer's disease, positron emission tomography brain scans can have characteristic hypometabolic patterns that strongly support this diagnosis, but this pattern is often subtle or absent in early stages. A sensitive and objective method for detection of positron emission tomography abnormalities may have value in early detection of Alzheimer's disease. Methods. A 2-fluoro-2-deoxy-D-glucose positron emission tomography scans from cognitively impaired patients (n = 43) were compared individually to 28 normal controls using statistical parametric mapping, hypometabolic regions visualized, and clinically correlated. The objective SPM results were compared to the official Nuclear Medicine report based upon subjective interpretation criteria. Results. A total of 22/43 had abnormalities per the Nuclear Medicine physician, while 21/43 appeared normal. The objective analysis detected abnormalities in 41/43 participants, including 19 of 21 that appeared normal. In these 19, 8 had findings consistent with early Alzheimer's disease. Conclusion. Objective analysis of positron emission tomography brain scans may extend the ability to detect early brain abnormalities in patients with cognitive decline.
Group, Individual, and Staff Therapy: An Efficient and Effective Cognitive Behavioral Therapy in Long-Term Care
Authors: Hyer Lee , Yeager Catherine A. , Hilton Nathan , Sacks Amanda 
Published: November 2008

Objective. Depression is a major problem in long-term care (LTC) as is the lack of related empirically supported psychological treatments. This small study addressed a variant of cognitive behavioral therapy, GIST (group, individual, and staff therapy), against treatment as usual (TAU) in long-term care. Method. 25 residents with depression were randomized to GIST (n = 13) or TAU (n = 12). Outcome measures included geriatric depression scale-short form (GDS-S), life satisfaction index Z (LSI-Z), and subjective ratings of treatment satisfaction. The GIST group participated in 15 group sessions. TAU crossed over to GIST at the end of the treatment trial. Results. There were significant differences between GIST and TAU in favor of GIST on the GDS-S and LSI-Z. The GIST group maintained improvements over another 14 sessions. After crossover to GIST, TAU members showed significant improvement from baseline. Participants also reported high subjective ratings of treatment satisfaction. Discussion. This trial demonstrated GIST to be more effective for depression in LTC than standard treatments.
Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases
Authors: Joshi Ila , Minter Lisa M. , Telfer Janice , Demarest Renée M. , Capobianco Anthony J. , Aster Jon C. , Sicinski Piotr , Fauq Abdul , Golde Todd E. , Osborne Barbara A. 
Published: November 2008

AbstractNotch signaling plays a role in normal lymphocyte development and function. Activating Notch1-mutations, leading to aberrant downstream signaling, have been identified in human T-cell acute lymphoblastic leukemia (T-ALL). While this highlights the contribution of Notch signaling to T-ALL pathogenesis, the mechanisms by which Notch regulates proliferation and survival in normal and leukemic T cells are not fully understood. Our findings identify a role for Notch signaling in G1-S progression of cell cycle in T cells. Here we show that expression of the G1 proteins, cyclin D3, CDK4, and CDK6, is Notch-dependent both in vitro and in vivo, and we outline a possible mechanism for the regulated expression of cyclin D3 in activated T cells via CSL (CBF-1, mammals; suppressor of hairless, Drosophila melanogaster; Lag-1, Caenorhabditis elegans), as well as a noncanonical Notch signaling pathway. While cyclin D3 expression contributes to cell-cycle progression in Notch-dependent human T-ALL cell lines, ectopic expression of CDK4 or CDK6 together with cyclin D3 shows partial rescue from γ-secretase inhibitor (GSI)-induced G1 arrest in these cell lines. Importantly, cyclin D3 and CDK4 are highly overexpressed in Notch-dependent T-cell lymphomas, justifying the combined use of cell-cycle inhibitors and GSI in treating human T-cell malignancies.
Accuracy of death certification and hospital record linkage for identification of incident stroke
Authors: Sinha Shubhada , Myint Phyo K , Luben Robert N , Khaw Kay-Tee 
Published: November 2008

Abstract

Background
There is little information on the validity of using record linkage with routinely collected data for case ascertainment of stroke in large population-based studies in the UK. We examined the accuracy of these routine record linkage approaches for identifying incident stroke cases in a large UK population-based study, the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort.

Methods
We examined a sample of hospital records of incident stroke cases identified by linkage with two routine data sources, death certificates and a national hospital record linkage system (ENCORE), using predefined study criteria. Two senior Specialist Registrars with clinical experience in stroke medicine examined the hospital records and searched for the evidence of stroke recorded in these records between 1993/97–2003.

Results
Of 520 incident strokes identified between 1993/1997–2003 using record linkage systems in the EPIC-Norfolk, a sample of 250 medical case notes were examined between March and July 2004. Using the predefined study criteria, there were 191 definite strokes (76%), 20 probable strokes (8%), 11 possible strokes and 11 cases of transient ischaemic attacks (4% each) i.e. 233/250 (93%) with possible or definite stroke or transient ischaemic attacks. Stroke could not be verified using hospital records in 13 cases (5%) and 4 cases (2%) had other diagnoses: 3 cases of vascular dementia and 1 case of benign intracranial hypertension. The diagnosis of stroke in 185 out of 250 cases identified in the EPIC-Norfolk (74.0%) was supported by radiological evidence using WHO criteria.

Conclusion
Death certificates and hospital record linkage in this British prospective study have a high accuracy or positive predictive value in correctly identifying incident stroke cases.
Predictors of gastrointestinal lesions on endoscopy in iron deficiency anemia without gastrointestinal symptoms
Authors: Majid Shahid , Salih Mohammad , Wasaya Rozina , Jafri Wasim 
Published: November 2008

Abstract

Background
Iron deficiency anaemia (IDA) due to occult gastrointestinal (GI) blood loss usually remains unnoticed until patient become symptomatic. There is sparse data in IDA patients without gastrointestinal symptoms. This study was designed to find out the frequency and predictors of endoscopic lesions in IDA without gastrointestinal symptoms. Cross-sectional study performed on a convenience sample of consecutive subjects.

Methods
Ninety five consecutive patients with laboratory based diagnosis of IDA having no gastrointestinal symptoms were interviewed and their clinical and biochemical variables were recorded. All the study patients underwent esophago-gastroduodenoscopy (EGD) and colonoscopy. Endoscopic findings were documented as presence/absence of bleeding related lesion and presence/absence of cause of IDA. Multiple logistic regressions were performed to identify variables significantly related to outcome variables.

Results
Possible cause of anaemia was found in 71% and bleeding related lesions were found in 53% of patients. Upper gastrointestinal tract lesions were found in 41% of patients with bleeding related lesions. On multivariable logistic regression; advancing age, low mean corpuscular volume (MCV ≤ 60 fl), and positive fecal occult blood test were predictive factors for bleeding related GI lesions and cause of IDA

Conclusion
Clinical and Biochemical markers can predict gastrointestinal lesions on endoscopy in IDA patients without gastrointestinal symptoms. High proportion of upper gastrointestinal involvement warrants EGD as initial endoscopic procedure however, this needs validation by further studies.
Streptococcus intermedius causing infective endocarditis and abscesses: a report of three cases and review of the literature
Authors: Tran MaryAnn P , Caldwell-McMillan Molly , Khalife Walid , Young Vincent B 
Published: November 2008

Abstract

Background

Streptococcus intermedius is a member of the Streptococcus anginosus group. Clinical disease with S. intermedius is characterized by abscess formation and rarely endocarditis. Identification of Streptococcus intermedius is difficult, leading to the development of molecular methods to more accurately identify and characterize this organism.

Case presentation
Over a period of 6 months we encountered three cases of invasive Streptococcus intermedius infection presenting as hepatic abscesses, brain abscess, and endocarditis. We confirmed our microbiologic diagnosis through 16S sequencing and found a common virulence gene in each case.

Conclusion
Our report illustrates three different clinical manifestations due to Streptococcus intermedius infection that can be encountered in healthy individuals in a community hospital setting. To our knowledge, this is the first case of Streptococcus intermedius endocarditis confirmed by 16S sequencing analysis. The use of molecular methods may allow a better understanding of the epidemiology and pathogenesis of this organism.
Frameshift mutations in coding repeats of protein tyrosine phosphatase genes in colorectal tumors with microsatellite instability
Authors: Korff Sebastian , Woerner Stefan M , Yuan Yan P , Bork Peer , von Knebel Doeberitz Magnus , Gebert Johannes 
Published: November 2008

Abstract

Background
Protein tyrosine phosphatases (PTPs) like their antagonizing protein tyrosine kinases are key regulators of signal transduction thereby assuring normal control of cellular growth and differentiation. Increasing evidence suggests that mutations in PTP genes are associated with human malignancies. For example, mutational analysis of the tyrosine phosphatase (PTP) gene superfamily uncovered genetic alterations in about 26% of colorectal tumors. Since in these studies tumors have not been stratified according to genetic instability status we hypothesized that colorectal tumors characterized by high-level of microsatellite instability (MSI-H) might show an increased frequency of frameshift mutations in those PTP genes that harbor long mononucleotide repeats in their coding region (cMNR).

Results
Using bioinformatic analysis we identified 16 PTP candidate genes with long cMNRs that were examined for genetic alterations in 19 MSI-H colon cell lines, 54 MSI-H colorectal cancers, and 17 MSI-H colorectal adenomas. Frameshift mutations were identified only in 6 PTP genes, of which PTPN21 show the highest mutation frequency at all in MSI-H tumors (17%).

Conclusion
Although about 32% of MSI-H tumors showed at least one affected PTP gene, and cMNR mutation rates in PTPN21, PTPRS, and PTPN5 are higher than the mean mutation frequency of MNRs of the same length, mutations within PTP genes do not seem to play a common role in MSI tumorigenesis, since no cMNR mutation frequency reached statistical significance and therefore, failed prediction as a Positive Selective Target Gene.