bluuebunny/crossref_metadata_2025_split huggingface dataset:
A New Molecular Predictor of Distant Recurrence in ER-Positive, HER2-Negative Breast Cancer Adds Independent Information to Conventional Clinical Risk Factors
Authors: Filipits Martin , Rudas Margaretha , Jakesz Raimund , Dubsky Peter , Fitzal Florian , Singer Christian F. , Dietze Otto , Greil Richard , Jelen Andrea , Sevelda Paul , Freibauer Christa , Müller Volkmar , Jänicke Fritz , Schmidt Marcus , Kölbl Heinz , Rody Achim , Kaufmann Manfred , Schroth Werner , Brauch Hiltrud , Schwab Matthias , Fritz Peter , Weber Karsten E. , Feder Inke S. , Hennig Guido , Kronenwett Ralf , Gehrmann Mathias , Gnant Michael 
Published: August 2011

Abstract
Purpose: According to current guidelines, molecular tests predicting the outcome of breast cancer patients can be used to assist in making treatment decisions after consideration of conventional markers. We developed and validated a gene expression signature predicting the likelihood of distant recurrence in patients with estrogen receptor (ER)–positive, HER2-negative breast cancer treated with adjuvant endocrine therapy.
Experimental Design: RNA levels assessed by quantitative reverse transcriptase PCR in formalin-fixed, paraffin-embedded tumor tissue were used to calculate a risk score (Endopredict, EP) consisting of eight cancer-related and three reference genes. EP was combined with nodal status and tumor size into a comprehensive risk score, EPclin. Both prespecified risk scores including cutoff values to determine a risk group for each patient (low and high) were validated independently in patients from two large randomized phase III trials [Austrian Breast and Colorectal Cancer Study Group (ABCSG)-6: n = 378, ABCSG-8: n = 1,324].
Results: In both validation cohorts, continuous EP was an independent predictor of distant recurrence in multivariate analysis (ABCSG-6: P = 0.010, ABCSG-8: P &lt; 0.001). Combining Adjuvant!Online, quantitative ER, Ki67, and treatment with EP yielded a prognostic power significantly superior to the clinicopathologic factors alone [c-indices: 0.764 vs. 0.750, P = 0.024 (ABCSG-6) and 0.726 vs. 0.701, P = 0.003 (ABCSG-8)]. EPclin had c-indices of 0.788 and 0.732 and resulted in 10-year distant recurrence rates of 4% and 4% in EPclin low-risk and 28% and 22% in EPclin high-risk patients in ABCSG-6 (P &lt; 0.001) and ABCSG-8 (P &lt; 0.001), respectively.
Conclusions: The multigene EP risk score provided additional prognostic information to the risk of distant recurrence of breast cancer patients, independent from clinicopathologic parameters. The EPclin score outperformed all conventional clinicopathologic risk factors. Clin Cancer Res; 17(18); 6012–20. ©2011 AACR.
Forced Activation of β-Catenin Signaling Supports the Transformation of hTERT-Immortalized Human Fetal Hepatocytes
Authors: Wege Henning , Heim Denise , Lütgehetmann Marc , Dierlamm Judith , Lohse Ansgar W. , Brümmendorf Tim H. 
Published: August 2011

Abstract
Hepatocarcinogenesis is a multistep process driving the progressive transformation of normal liver cells into highly malignant derivatives. Unlimited proliferation and telomere maintenance have been recognized as prerequisites for the development of liver cancer. Moreover, recent studies identified illegitimate β-catenin signaling as relevant hit in a considerable subset of patients. To further investigate the currently not well-understood malignant evolution driven by telomerase and β-catenin, we monitored cytogenetic and phenotypic alterations in untransformed telomerase-immortalized human fetal hepatocytes following forced activation of β-catenin signaling. As expected, constitutive activation of β-catenin signaling significantly enhanced proliferation with decreasing serum dependence. Previously intact contact inhibition was almost completely eliminated. Interestingly, after several passages in cell culture, immortalized clones with dominant-positive β-catenin signaling acquired additional chromosomal aberrations, in particular translocations, anchorage-independent growth capabilities, and formed tumors in athymic nude mice. In further support for the driving role of β-catenin during hepatocarcinogenesis, improved colony growth in soft agar and accelerated tumor formation was also confirmed in Huh7 cells following stable expression of the constitutively active S33Y β-catenin mutant. Telomerase inhibition showed that short-term expansion of transformed clones was not telomerase dependent. Finally, cancer pathway profiling in derived tumors revealed upregulation of characteristic genes associated with invasion and angiogenesis. In conclusion, illegitimate activation of β-catenin signaling enhances the transformation from immortalization to malignant growth in human fetal hepatocytes. Our data functionally confirm a permissive role for β-catenin signaling in the initial phase of hepatocarcinogenesis. Mol Cancer Res; 9(9); 1222–31. ©2011 AACR.
Bleeding Risk in Very Old Patients on Vitamin K Antagonist Treatment
Authors: Poli Daniela , Antonucci Emilia , Testa Sophie , Tosetto Alberto , Ageno Walter , Palareti Gualtiero ,   for the Italian Federation of Anticoagulation Clinics (FCSA)
Published: August 2011

Background—
Vitamin K antagonist (VKA) therapy is increasingly being used for the prevention of venous thromboembolism and stroke in atrial fibrillation. Bleeds are the major concern for VKA prescription, especially in very old patients who carry many risk factors for bleeding. We performed a large multicenter prospective observational study that enrolled very old patients to evaluate the quality of anticoagulation and the incidence of bleedings.

Methods and Results—

The study included 4093 patients ≥80 years of age who were naïve to VKA for thromboprophylaxis of atrial fibrillation or after venous thromboembolism. Patients' demographic and clinical data were collected, and the quality of anticoagulation and the incidence of bleeding were recorded. The follow-up was 9603 patient-years; median age at the beginning of follow-up was 84 years (range, 80 to 102 years). We recorded 179 major bleedings (rate, 1.87 per 100 patient-years), 26 fatal (rate, 0.27 per 100 patient-years). The rate of bleeding was higher in men compared with women (relative risk, 1.4; 95% confidence interval, 1.12 to 1.72;
P
=0.002) and among patients ≥85 years of age compared with younger patients (relative risk, 1.3; 95% confidence interval, 1.0 to 1.65;
P
=0.048). Time in therapeutic range was 62% (interquartile range, 49% to 75%). History of bleeding, active cancer, and history of falls were independently associated with bleeding risk in Cox regression analysis.

Conclusion—
In this large study on very old patients on VKA carefully monitored by anticoagulation clinics, the rate of bleedings was low, suggesting that age in itself should not be considered a contraindication to treatment. Adequate management of VKA therapy in specifically trained center allows very old and frail patients to benefit from VKA thromboprophylaxis.
Involvement of Endoplasmic Stress Protein C/EBP Homologous Protein in Arteriosclerosis Acceleration With Augmented Biological Stress Responses
Authors: Gao Junhong , Ishigaki Yasushi , Yamada Tetsuya , Kondo Keiichi , Yamaguchi Suguru , Imai Junta , Uno Kenji , Hasegawa Yutaka , Sawada Shojiro , Ishihara Hisamitsu , Oyadomari Seiichi , Mori Masataka , Oka Yoshitomo , Katagiri Hideki 
Published: August 2011

Background—
The processes of arteriosclerosis, including atherosclerosis and vascular remodeling, are affected by interactions among numerous biological pathways such as responses to inflammation, oxidative stress, and endoplasmic reticulum stress. C/EBP homologous protein (CHOP), which is well known to induce cellular apoptosis in response to severe endoplasmic reticulum stress, is reportedly upregulated in plaque lesions.

Methods and Results—

We examined the effects of CHOP deficiency on 2 types of arteriosclerosis: cuff injury–induced neointimal formation and hypercholesterolemia-induced atherosclerosis. Cuff injury–induced neointimal formation was markedly inhibited in CHOP
−/−
mice with suppressed aortic expression of inflammatory factors and smooth muscle cell proliferation–related proteins. A CHOP deficiency also inhibited aortic plaque formation in hypercholesterolemic apolipoprotein E
−/−
mice with suppressed aortic expression of inflammatory factors and oxidative stress markers. Bone marrow transplantation experiments revealed that recipient CHOP deficiency significantly suppressed both cuff injury–induced neointimal formation and hypercholesterolemia-induced atherosclerotic plaque formation to a greater extent than donor CHOP deficiency, suggesting the importance of CHOP in vascular cells for arteriosclerosis progression. Furthermore, in our in vitro experiments, in not only macrophages but also endothelial and smooth muscle cell lines, endoplasmic reticulum stress inducers upregulated inflammation-, adhesion-, or smooth muscle cell proliferation–related proteins, whereas decreased CHOP expression remarkably suppressed endoplasmic reticulum stress–induced upregulation of these proteins.

Conclusions—
In addition to the well-known signaling for apoptosis induction, CHOP may play important roles in augmenting potentially pathological biological stress responses. This noncanonical role of CHOP, especially that expressed in vascular cells, may contribute to the progression of vascular remodeling and atherosclerosis.
Randomized Comparison of Everolimus-Eluting Stent Versus Sirolimus-Eluting Stent Implantation for De Novo Coronary Artery Disease in Patients With Diabetes Mellitus (ESSENCE-DIABETES)
Authors: Kim Won-Jang , Lee Seung-Whan , Park Seong-Wook , Kim Young-Hak , Yun Sung-Cheol , Lee Jong-Young , Park Duk-Woo , Kang Soo-Jin , Lee Cheol Whan , Lee Jae-Hwan , Choi Si Wan , Seong In-Whan , Lee Bong-Ki , Lee Nae-Hee , Cho Yoon Haeng , Shin Won-Yong , Lee Seung-Jin , Lee Se-Whan , Hyon Min-Su , Bang Duk-Won , Park Woo-Jung , Kim Hyun-Sook , Chae Jei Keon , Lee Keun , Park Hoon-Ki , Park Chang-Bum , Lee Sang-Gon , Kim Min-Kyu , Park Kyoung-Ha , Choi Young-Jin , Cheong Sang-Sig , Yang Tae-Hyun , Jang Jae-Sik , Her Sung Ho , Park Seung-Jung 
Published: August 2011

Background—
Drug-eluting stents significantly improved angiographic and clinical outcomes compared with bare metal stents in diabetic patients. However, a comparison of everolimus-eluting stents and sirolimus-eluting stents in diabetic patients has not been evaluated. Therefore we compared effectiveness of everolimus-eluting stents and sirolimus-eluting stents in patients with diabetes mellitus.

Methods and Results—

This prospective, multicenter, randomized study compared everolimus-eluting stent (n=149) and sirolimus-eluting stent (n=151) implantation in diabetic patients. The primary end point was noninferiority of angiographic in-segment late loss at 8 months. Clinical events were also monitored for at least 12 months. Everolimus-eluting stents were noninferior to sirolimus-eluting stents for 8-month in-segment late loss (0.23±0.27 versus 0.37±0.52 mm; difference, −0.13 mm; 95% confidence interval, −0.25 to −0.02; upper 1-sided 95% confidence interval, −0.04;
P
<0.001 for noninferiority), with reductions in in-stent restenosis (0% versus 4.7%;
P
=0.029) and in-segment restenosis (0.9% versus 6.5%;
P
=0.035). However, in-stent late loss (0.11±0.26 versus 0.20±0.49 mm;
P
=0.114) was not statistically different between the 2 groups. At 12 months, ischemia-driven target lesion revascularization (0.7% versus 2.6%;
P
=0.317), death (1.3% versus 3.3%;
P
=0.448), and myocardial infarction (0% versus 1.3%;
P
=0.498) were not statistically different between the 2 groups. Major adverse cardiac events, including death, myocardial infarction, and ischemia-driven target lesion revascularization (2.0% versus 5.3%;
P
=0.218), were also not statistically different between the 2 groups.

Conclusions—
Everolimus-eluting stents were noninferior to sirolimus-eluting stents in reducing in-segment late loss and reduced angiographic restenosis at 8 months in patients with diabetes mellitus and coronary artery disease.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00997763.
Connexin 37 Limits Thrombus Propensity by Downregulating Platelet Reactivity
Authors: Angelillo-Scherrer Anne , Fontana Pierre , Burnier Laurent , Roth Isabelle , Sugamele Rocco , Brisset Anne , Morel Sandrine , Nolli Séverine , Sutter Esther , Chassot Alexandra , Capron Claude , Borgel Delphine , Saller François , Chanson Marc , Kwak Brenda R. 
Published: August 2011

Background—

Formation of platelet plug initiates hemostasis after vascular injury and triggers thrombosis in ischemic disease. However, the mechanisms leading to the formation of a stable thrombus are poorly understood. Connexins comprise a family of proteins that form gap junctions enabling intercellular coordination of tissue activity, a process termed
gap junctional intercellular communication
.

Methods and Results—

In the present study, we show that megakaryocytes and platelets express connexin 37 (Cx37). Deletion of the
Cx37
gene in mice shortens bleeding time and increases thrombus propensity. Aggregation is increased in murine
Cx37
−/−
platelets or in murine
Cx37
+/+
and human platelets treated with gap junction blockers. Intracellular microinjection of neurobiotin, a Cx37-permeant tracer, revealed gap junctional intercellular communication in platelet aggregates, which was impaired in
Cx37
−/−
platelets and in human platelets exposed to gap junction blockers. Finally, healthy subjects homozygous for Cx37–1019C, a prognostic marker for atherosclerosis, display increased platelet responses compared with subjects carrying the Cx37–1019T allele. Expression of these polymorphic channels in communication-deficient cells revealed a decreased permeability of Cx37–1019C channels for neurobiotin.

Conclusions—
We propose that the establishment of gap junctional communication between Cx37-expressing platelets provides a mechanism to limit thrombus propensity. To our knowledge, these data provide the first evidence incriminating gap junctions in the pathogenesis of thrombosis.
Ultrafast and Whole-Body Cooling With Total Liquid Ventilation Induces Favorable Neurological and Cardiac Outcomes After Cardiac Arrest in Rabbits
Authors: Chenoune M. , Lidouren F. , Adam C. , Pons S. , Darbera L. , Bruneval P. , Ghaleh B. , Zini R. , Dubois-Randé J.-L. , Carli P. , Vivien B. , Ricard J.-D. , Berdeaux A. , Tissier R. 
Published: August 2011

Background—
In animal models of cardiac arrest, the benefit afforded by hypothermia is closely linked to the rapidity of the decrease in body temperature after resuscitation. Because total liquid ventilation (TLV) with temperature-controlled perfluorocarbons induces a very rapid and generalized cooling, we aimed to determine whether this could limit the post–cardiac arrest syndrome in a rabbit model. We especially focused on neurological, cardiac, pulmonary, liver and kidney dysfunctions.

Methods and Results—
Anesthetized rabbits were submitted to either 5 or 10 minutes of untreated ventricular fibrillation. After cardiopulmonary resuscitation and resumption of a spontaneous circulation, the animals underwent either normothermic life support (control) or therapeutic hypothermia induced by TLV. The latter procedure decreased esophageal and tympanic temperatures to 32°C to 33°C within only 10 minutes. After rewarming, the animals submitted to TLV exhibited an attenuated neurological dysfunction and decreased mortality 7 days later compared with control. The neuroprotective effect of TLV was confirmed by a significant reduction in brain histological damages. We also observed limitation of myocardial necrosis, along with a decrease in troponin I release and a reduced myocardial caspase 3 activity, with TLV. The beneficial effects of TLV were directly related to the rapidity of hypothermia induction because neither conventional cooling (cold saline infusion plus external cooling) nor normothermic TLV elicited a similar protection.

Conclusions—
Ultrafast cooling instituted by TLV exerts potent neurological and cardiac protection in an experimental model of cardiac arrest in rabbits. This could be a relevant approach to provide a global and protective hypothermia against the post–cardiac arrest syndrome.
Multimodel Analysis of Energy and Water Fluxes: Intercomparisons between Operational Analyses, a Land Surface Model, and Remote Sensing
Authors: Vinukollu Raghuveer K. , Sheffield Justin , Wood Eric F , Bosilovich Michael G. , Mocko David 
Published: August 2011

Abstract
Using data from seven global model operational analyses (OA), one land surface model, and various remote sensing retrievals, the energy and water fluxes over global land areas are intercompared for 2003/04. Remote sensing estimates of evapotranspiration (ET) are obtained from three process-based models that use input forcings from multisensor satellites. An ensemble mean (linear average) of the seven operational (mean-OA) models is used primarily to intercompare the fluxes with comparisons performed at both global and basin scales. At the global scale, it is found that all components of the energy budget represented by the ensemble mean of the OA models have a significant bias. Net radiation estimates had a positive bias (global mean) of 234 MJ m−2 yr−1 (7.4 W m−2) as compared to the remote sensing estimates, with the latent and sensible heat fluxes biased by 470 MJ m−2 yr−1 (13.3 W m−2) and −367 MJ m−2 yr−1 (11.7 W m−2), respectively. The bias in the latent heat flux is affected by the bias in the net radiation, which is primarily due to the biases in the incoming shortwave and outgoing longwave radiation and to the nudging process of the operational models. The OA models also suffer from improper partitioning of the surface heat fluxes. Comparison of precipitation (P) analyses from the various OA models, gauge analysis, and remote sensing retrievals showed better agreement than the energy fluxes. Basin-scale comparisons were consistent with the global-scale results, with the results for the Amazon in particular showing disparities between OA and remote sensing estimates of energy fluxes. The biases in the fluxes are attributable to a combination of errors in the forcing from the OA atmospheric models and the flux calculation methods in their land surface schemes. The atmospheric forcing errors are mainly attributable to high shortwave radiation likely due to the underestimation of clouds, but also precipitation errors, especially in water-limited regions.
Microscale Numerical Prediction over Montreal with the Canadian External Urban Modeling System
Authors: Leroyer Sylvie , Bélair Stéphane , Mailhot Jocelyn , Strachan Ian B. 
Published: August 2011

AbstractThe Canadian urban and land surface external modeling system (known as urban GEM-SURF) has been developed to provide surface and near-surface meteorological variables to improve numerical weather prediction and to become a tool for environmental applications. The system is based on the Town Energy Balance model for the built-up covers and on the Interactions between the Surface, Biosphere, and Atmosphere land surface model for the natural covers. It is driven by coarse-resolution forecasts from the 15-km Canadian regional operational model. This new system was tested for a 120-m grid-size computational domain covering the Montreal metropolitan region from 1 May to 30 September 2008. The numerical results were first evaluated against local observations of the surface energy budgets, air temperature, and humidity taken at the Environmental Prediction in Canadian Cities (EPiCC) field experiment tower sites. As compared with the regional deterministic 15-km model, important improvements have been achieved with this system over urban and suburban sites. GEM-SURF’s ability to simulate the Montreal surface urban heat island was also investigated, and the radiative surface temperatures from this system and from two systems operational at the Meteorological Service of Canada were compared, that is, the 15-km regional deterministic model and the so-called limited-area model with 2.5-km grid size. Comparison of urban GEM-SURF outputs with remotely sensed observations from the Moderate Resolution Imaging Spectroradiometer (MODIS) reveals relatively good agreement for urban and natural areas.
A Multidiagnostic Intercomparison of Tropical-Width Time Series Using Reanalyses and Satellite Observations
Authors: Davis Sean M. , Rosenlof Karen H. 
Published: August 2011

Abstract
Poleward migration of the latitudinal edge of the tropics of 0.25°–3.0° decade−1 has been reported in several recent studies based on satellite and radiosonde data and reanalysis output covering the past ~30 yr. The goal of this paper is to identify the extent to which this large range of trends can be explained by the use of different data sources, time periods, and edge definitions, as well as how the widening varies as a function of hemisphere and season. Toward this end, a suite of tropical edge latitude diagnostics based on tropopause height, winds, precipitation–evaporation, and outgoing longwave radiation (OLR) are analyzed using several reanalyses and satellite datasets. These diagnostics include both previously used definitions and new definitions designed for more robust detection. The wide range of widening trends is shown to be primarily due to the use of different datasets and edge definitions and only secondarily due to varying start–end dates. This study also shows that the large trends (&gt;~1° decade−1) previously reported in tropopause and OLR diagnostics are due to the use of subjective definitions based on absolute thresholds. Statistically significant Hadley cell expansion based on the mean meridional streamfunction of 1.0°–1.5° decade−1 is found in three of four reanalyses that cover the full time period (1979–2009), whereas other diagnostics yield trends of −0.5°–0.8° decade−1 that are mostly insignificant. There are indications of hemispheric and seasonal differences in the trends, but the differences are not statistically significant.
The 2010 Pakistan Flood and Russian Heat Wave: Teleconnection of Hydrometeorological Extremes
Authors: Lau William K. M. , Kim Kyu-Myong 
Published: August 2011

AbstractIn this paper, preliminary results are presented showing that the two record-setting extreme events during 2010 summer (i.e., the Russian heat wave–wildfires and Pakistan flood) were physically connected. It is found that the Russian heat wave was associated with the development of an extraordinarily strong and prolonged extratropical atmospheric blocking event in association with the excitation of a large-scale atmospheric Rossby wave train spanning western Russia, Kazakhstan, and the northwestern China–Tibetan Plateau region. The southward penetration of upper-level vorticity perturbations in the leading trough of the Rossby wave was instrumental in triggering anomalously heavy rain events over northern Pakistan and vicinity in mid- to late July. Also shown are evidences that the Russian heat wave was amplified by a positive feedback through changes in surface energy fluxes between the atmospheric blocking pattern and an underlying extensive land region with below-normal soil moisture. The Pakistan heavy rain events were amplified and sustained by strong anomalous southeasterly flow along the Himalayan foothills and abundant moisture transport from the Bay of Bengal in connection with the northward propagation of the monsoonal intraseasonal oscillation.