bluuebunny/crossref_metadata_2025_split huggingface dataset:
An overview of the Palaeoproterozoic geology of Peninsular India, and key stratigraphic and tectonic issues
Authors: Saha Dilip , Mazumder Rajat 
Published: March 2012

Abstract
The Archaean–Proterozoic rock successions in India have the potential to enrich the global database on Precambrian stratigraphic development, and to offer valuable clues to global tectonic reconstructions. Built over four distinct Archaean cratonic nuclei, the major Palaeoproterozoic supracrustal belts/cover sequences include the Dhanjori Group, the Singhbhum Group (including the Dalma volcanics and the Chandil Formation in eastern India), the Cuddapah Supergroup and the adjoining Nellore Schist Belt bordering the eastern Dharwar Craton, the Aravalli Supergroup in the Aravalli–Delhi Fold Belt in NW India, the lower Vindhyan (Semri Group) and the Mahakosal/Sausar/Betul belts close to the Central Indian Tectonic Zone (CITZ), and, possibly, the Dongargarh Supergroup in Bastar. A major erosional unconformity separates the Archaean tonalite–trondjhemite gneiss basement in these cratons from the overlying volcano-sedimentary successions. An overview of Palaeoproterozoic stratigraphic development in these cratonic blocks is presented to bring out the salient features for global comparison and to highlight issues requiring further attention. Multiple metamorphic, magmatic and deformation events are recorded in the fold belts at the join of the cratons or their margins, inviting application of the plate tectonic paradigm. However, a comprehensive tectonic model for the amalgamation of the Indian Archaean nuclei is yet to emerge, and is crucial for our understanding of Palaeoproterozoic supercontinent development.
Stability of chloritoid + biotite-bearing assemblages in some metapelites from the Palaeoproterozoic Singhbhum Shear Zone, eastern India and their implications
Authors: Sengupta Nandini 
Published: March 2012

Abstract

The arcuate Singhbhum Shear Zone (SSZ) of the East Indian Shield area, fringing the Archaean Singhbhum Craton, exposes a mélange-like ensemble of polymetamorphosed and highly tectonized siliciclastic sediments, mafic–ultramafic extrusive, tourmaline-rich rocks, magnetite–apatite rocks, granites and Cu–Fe–U sulphide ores of Meso- to Palaeoproterozoic age (1.5–1.77 Ga). Metapelites from two localities in the SSZ developed the enigmatic assemblage chloritoid–biotite–garnet–chlorite, which are the first reported from India and the eighth in world occurrence. Textural studies and algebraic analyses of the phase compositions in the KFMASH system indicate the operation of the reaction, chloritoid+biotite→garnet+chlorite+H
2
O and this reaction has a negative slope in pressure–temperature (
P
–
T
) space. Quantitative geothermobarometry and pseudosections in the NCMnKFMASHO system indicate that this reaction occurred during prograde metamorphism that culminated at 6.3±1 kbar and 490±40 °C. The stability of the chloritoid+biotite is also sensitive to the MnO content of the bulk rock, and to the chemical potential of H
2
O and oxygen (

μ

H

2

O

and

μ

O

2

, respectively), of the ambient fluid phase. Thrusting of continental crust in a collisional setting is invoked to explain the peak metamorphic temperatures and the clockwise
P
–
T
trajectory is construed from the petrological study of the chloritoid–biotite schist.
Will Hsp90 Inhibitors Prove Effective in BRAF-Mutant Melanomas?
Authors: Catalanotti Federica , Solit David B. 
Published: March 2012

Abstract
The RAF inhibitor vemurafenib has unprecedented activity in BRAF-mutant melanomas, but resistance invariably develops. As Hsp90 is required for the stability of several of the oncoproteins that mediate RAF inhibitor resistance, inhibitors of this cellular chaperone may be effective in patients with intrinsic or acquired resistance to RAF inhibitors. Clin Cancer Res; 18(9); 2420–2. ©2012 AACR.
Therapeutic Significance of Estrogen Receptor β Agonists in Gliomas
Authors: Sareddy Gangadhara R. , Nair Binoj C. , Gonugunta Vijay K. , Zhang Quan-guang , Brenner Andrew , Brann Darrell W. , Tekmal Rajeshwar Rao , Vadlamudi Ratna K. 
Published: March 2012

AbstractGliomas are the most common and devastating central nervous system neoplasms. A gender bias exists in their development: females are at lower risk than males, implicating estrogen-mediated protective effects. Estrogen functions are mediated by two estrogen receptor (ER) subtypes: ERα, which functions as tumor promoter, and ERβ, which functions as tumor suppressor. We examined the potential use of ERβ agonists as a novel therapeutic to curb the growth of gliomas. Western analysis of six glioma model cells showed detectable expression of ERβ with little or no ERα. Treatment of glioma cells with ERβ agonists resulted in significant decrease in proliferation. Immunohistochemical analysis of tumor tissues revealed that ERβ expression is downregulated in high-grade gliomas. We found that ERβ agonists promote both expression and tumor-suppressive functions of ERβ in glioma cells. Liquiritigenin, a plant-derived ERβ agonist significantly reduced in vivo tumor growth in a xenograft model. Compared with control mice, animals treated with liquiritigenin had greater than 50% reduction in tumor volume and size. Immunohistochemical analysis of tumors revealed a significant increase in the nuclear ERβ expression with a concomitant decrease in cell proliferation in the liquiritigenin-treated group. Our results suggest that ERβ signaling has a tumor-suppressive function in gliomas. Because ERβ agonists are currently in clinical trials and are well tolerated with fewer side effects, identification of an ERβ agonist as a therapeutic agent can be readily extended to clinical use with current chemotherapies, providing an additional tool for enhancing survival in glioma patients. Mol Cancer Ther; 11(5); 1174–82. ©2012 AACR.
Evading Pgp Activity in Drug-Resistant Cancer Cells: A Structural and Functional Study of Antitubulin Furan Metotica Compounds
Authors: Nguyen Tam Luong , Cera Maria Rosaria , Pinto Andrea , Lo Presti Leonardo , Hamel Ernest , Conti Paola , Gussio Rick , De Wulf Peter 
Published: March 2012

Abstract
Tumor resistance to antitubulin drugs resulting from P-glycoprotein (Pgp) drug-efflux activity, increased expression of the βIII tubulin isotype, and alterations in the drug-binding sites are major obstacles in cancer therapy. Consequently, novel antitubulin drugs that overcome these challenges are of substantial interest. Here, we study a novel chemotype named furan metotica that localizes to the colchicine-binding site in β-tubulin, inhibits tubulin polymerization, and is not antagonized by Pgp. To elucidate the structure–activity properties of this chiral chemotype, the enantiomers of its most potent member were separated and their absolute configurations determined by X-ray crystallography. Both isomers were active and inhibited all 60 primary cancer cell lines tested at the U.S. National Cancer Institute. They also efficiently killed drug-resistant cancer cells that overexpressed the Pgp drug-efflux pump 106-fold. In vitro, the R-isomer inhibited tubulin polymerization at least 4-fold more potently than the S-isomer, whereas in human cells the difference was 30-fold. Molecular modeling showed that the two isomers bind to β-tubulin in distinct manners: the R-isomer binds in a colchicine-like mode and the S-isomer in a podophyllotoxin-like fashion. In addition, the dynamic binding trajectory and occupancy state of the R-isomer were energetically more favorable then those of the S-isomer, explaining the observed differences in biologic activities. The ability of a racemic drug to assume the binding modes of two prototypical colchicine-site binders represents a novel mechanistic basis for antitubulin activity and paves the way toward a comprehensive design of novel anticancer agents. Mol Cancer Ther; 11(5); 1103–11. ©2012 AACR.
Negative Feedback and Adaptive Resistance to the Targeted Therapy of Cancer
Authors: Chandarlapaty Sarat 
Published: March 2012

Abstract
Mutational activation of growth factor signaling pathways is commonly observed and often necessary for oncogenic transformation. Under physiologic conditions, these pathways are subject to tight regulation through negative feedback, which limits the extent and duration of signaling events after physiologic stimulation. Until recently, the role of these negative feedback pathways in oncogene-driven cancers has been poorly understood. In this review, I discuss the evidence for the existence and relevance of negative feedback pathways within oncogenic signaling networks, the selective advantages such feedback pathways may confer, and the effects such feedback might have on therapies aimed at inhibiting oncogenic signaling.
Sigificance: Negative feedback pathways are ubiquitous features of growth factor signaling networks. Because growth factor signaling networks play essential roles in the majority of cancers, their therapeutic targeting has become a major emphasis of clinical oncology. Drugs targeting these networks are predicted to inhibit the pathway but also to relieve the negative feedback. This loss of negative feedback can itself promote oncogenic signals and cancer cell survival. Drug-induced relief of feedback may be viewed as one of the major consequences of targeted therapy and a key contributor to therapeutic resistance. Cancer Discov; 2(4): 311–9. ©2012 AACR.
Caffeine induces endothelial tissue factor expression via phosphatidylinositol 3-kinase inhibition
Authors: Holy Erik W. , Camici Giovanni G. , Akhmedov Alexander , Stämpfli Simon F. , Stähli Barbara E. , von Rickenbach Bettina , Breitenstein Alexander , Greutert Helen , Yang Zhihong , Lüscher Thomas F. , Gebhard Cathérine , Tanner Felix C. 
Published: March 2012

SummaryTissue factor (TF) is the key activator of coagulation and is involved in acute coronary syndromes. Caffeine is often reported to increase cardiovascular risk; however, its effect on cardiovascular morbidity and mortality is controversial. Hence, this study was designed to investigate the impact of caffeine on endothelial TF expression in vitro. Caffeine concentration-dependently enhanced TF protein expression and surface activity in human endothelial cells stimulated by tumour necrosis factor (TNF)-α or thrombin. Caffeine inhibited phosphatidylinositol 3-kinase (PI3K) activity and this effect was comparable to that of the known PI3K inhibitor LY294002. Consistently, treatment of endothelial cells with LY294002 enhanced TNF-α induced TF expression to a similar extent as caffeine, and adenoviral expression of the active PI3K mutant (p110) reversed the effect of both caffeine and LY294002 on TF expression. Caffeine and LY294002 increased DNA binding capacity of the transcription factor nuclear factor κB, whereas the activation pattern of mitogen-activated protein kinases (MAPK) remained unaltered. Luciferase reporter assay revealed a caffeine dependent activation of the TF promoter, and RT-PCR revealed a dose dependent increase in TF mRNA levels when stimulated with caffeine in the presence of TNF-α. In conclusion, caffeine enhances TNF-α-induced endothelial TF protein expression as well as surface activity by inhibition of PI3K signalling. Since the caffeine concentrations applied in the present study are within the plasma range measured in humans, our findings indicate that caffeine enhances the prothrombotic potential of endothelial cells and underscore the importance of PI3K in mediating these effects.
Impact of dabigatran on a large panel of routine or specific coagulation assays
Authors: Robert Séverine , Chatelain Christian , Douxfils Jonathan , Mullier François , Chatelain Bernard , Dogné Jean-Michel 
Published: March 2012

SummaryDue to low bioavailability and high inter-individual variability, monitoring of dabigatran may be required in specific situations to prevent the risk of bleedings or thrombosis. The aim of the study was to determine which coagulation assay(s) could be used to assess the impact of dabig-atran on secondary haemostasis. Dabigatran was spiked at concentrations ranging from 4.7 ng/ml to 943.0 ng/ml in pooled citrated human platelet-poor plasma. The following clotting assays were performed: prothrombin time (PT); activated partial thromboplastin time (aPTT); thrombin time (TT); ecarin clotting time (ECT); ecarin chromo-genic assay (ECA); prothrombinase-induced clotting time (PiCT); activated clotting time (ACT); Hemoclot Thrombin Inhibitor (HTI) and thrombin generation assay (TGA). A concentration-dependent prolongation of PT, dPT, and aPTT was observed with aPTT being the more sensitive test. The results varied mostly due to the clotting reagent. HTI, ECT and TGA were the most sensitive tests but are not available 24 hours a day. In addition, HTI showed a linear correlation with a good reproduci-bility. Dabigatran induced a concentration-dependent delay and inhibition of tissue factor-induced TGA. Cut-offs related with higher risk of bleedings or thrombosis were defined for each reagent of aPTT and HTI. In conclusion, aPTT could be used for the monitoring of dabigatran and as screening test for the risk of overdose. However, because of its higher sensitivity, good reproducibility, excellent linear correlation at all doses, its simplicity of use, and possibilities of automation, HTI should be considered as the gold-standard.
Fibrin formation by staphylothrombin facilitates Staphylococcus aureus-induced platelet aggregation
Authors: Vanassche Thomas , Kauskot Alexandre , Verhaegen Jan , Peetermans Willy , van Ryn Joanne , Schneewind Olaf , Hoylaerts Marc , Verhamme Peter 
Published: March 2012

SummaryInteractions of Staphylococcus aureus (S. aureus) and platelets play an important role in the pathogenesis of intravascular infections such as infective endocarditis (IE). A typical feature of S. aureus is the ability to generate thrombin activity through the secretion of two prothrombin activating molecules, staphylocoagulase and von Willebrand factor-binding protein (vWbp), which bind to human prothrombin to form the enzymatically active staphylothrombin complex. The role of staphylothrombin in the interaction between S. aureus and platelets has not yet been studied. We found that in contrast with thrombin, staphylothrombin did not directly activate human platelets. However, the staphylothrombin-mediated conversion of fibrinogen to fibrin initiated platelet aggregation and secondary activation and facilitated S. aureus-platelet interactions. Both the genetic absence of staphylocoagulase and vWbp and pharmacological inhibition of staphylothrombin increased the lag time to aggregation, and reduced platelet trapping by S. aureus in high shear stress conditions. The combined inhibition of staphylothrombin and immunoglobulin binding to platelets completely abolished the ability of S. aureus to aggregate platelets in vitro. In conclusion, although staphylothrombin did not directly activate platelets, the formation of a fibrin scaffold facilitated bacteria-platelet interaction, and the inhibition of staphylothrombin resulted in a reduced activation of platelets by S. aureus.
Anxiety Sensitivity Moderates Prognostic Importance of Rhythm-Control Versus Rate-Control Strategies in Patients With Atrial Fibrillation and Congestive Heart Failure
Authors: Frasure-Smith Nancy , Lespérance François , Talajic Mario , Khairy Paul , Dorian Paul , O’Meara Eileen , Roy Denis 
Published: March 2012

Background—
Patients with high anxiety sensitivity (AS) become extremely anxious with heart rate increases, palpitations, and symptoms of psychological arousal. AS predicts panic attacks. In atrial fibrillation (AF), AS correlates with symptom preoccupation and reduced quality of life. We assessed whether AS is associated with outcomes of rhythm-control versus rate-control in congestive heart failure (CHF) patients with AF.

Methods and Results—

Before random assignment, 933 participants (172 women) in the Atrial Fibrillation and Congestive Heart Failure Trial completed the Anxiety Sensitivity Inventory (ASI). Cox proportional hazards models showed no main effects of treatment (
P
=0.61) or AS (
P
=0.72) for time to cardiovascular death, but these factors interacted significantly (
P
=0.020). High AS patients (upper quartile, ASI ≥33) randomly assigned to rhythm-control had significantly lower cardiovascular mortality than those receiving rate-control (hazard ratio, 0.54; 95% confidence interval, 0.32–0.93;
P
=0.022). With lower ASI scores (<33), treatments did not differ (hazard ratio, 1.12; 95% confidence interval, 0.83–1.51;
P
=0.46). The interaction between treatment and dichotomized ASI scores remained significant (
P
=0.009) after adjustment for covariates including age, sex, hypertension, diabetes, creatinine, ejection fraction, time since first diagnosis of AF, New York Heart Association functional class, depression symptoms, marital status, and baseline β-blockers, angiotensin-converting enzyme inhibitors, oral anticoagulants, and implantable cardioverter-defibrillators.

Conclusions—
Atrial fibrillation and congestive heart failure patients with high AS had better long-term prognosis with rhythm- than rate-control. If replicated, AS should be considered in treatment selection. Research is also needed concerning mechanisms and possible joint AS-AF treatments.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT88597077.
Renal Dysfunction in Patients With Heart Failure With Preserved Versus Reduced Ejection Fraction
Authors: McAlister Finlay A. , Ezekowitz Justin , Tarantini Luigi , Squire Iain , Komajda Michel , Bayes-Genis Antoni , Gotsman Israel , Whalley Gillian , Earle Nikki , Poppe Katrina K. , Doughty Robert N. ,   Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) Investigators
Published: March 2012

Background—
Prior studies in heart failure (HF) have used the Modification of Diet in Renal Disease (MDRD) equation to calculate estimated glomerular filtration rate (eGFR). The Chronic Kidney Disease-Epidemiology Collaboration Group (CKD-EPI) equation provides a more-accurate eGFR than the MDRD when compared against the radionuclide gold standard. The prevalence and prognostic import of renal dysfunction in HF if the CKD-EPI equation is used rather than the MDRD is uncertain.

Methods and Results—
We used individual patient data from 25 prospective studies to stratify patients with HF by eGFR using the CKD-EPI and the MDRD equations and examined survival across eGFR strata. In 20 754 patients (15 962 with HF with reduced ejection fraction [HF-REF] and 4792 with HF with preserved ejection fraction [HF-PEF]; mean age, 68 years; deaths per 1000 patient-years, 151; 95% CI, 146–155), 10 589 (51%) and 11 422 (55%) had an eGFR <60 mL/min using the MDRD and CKD-EPI equations, respectively. Use of the CKD-EPI equation resulted in 3760 (18%) patients being reclassified into different eGFR risk strata; 3089 (82%) were placed in a lower eGFR category and exhibited higher all-cause mortality rates (net reclassification improvement with CKD-EPI, 3.7%; 95% CI, 1.5%–5.9%). Reduced eGFR was a stronger predictor of all-cause mortality in HF-REF than in HF-PEF.

Conclusions—
Use of the CKD-EPI rather than the MDRD equation to calculate eGFR leads to higher estimates of renal dysfunction in HF and a more-accurate categorization of mortality risk. Renal function is more closely related to outcomes in HF-REF than in HF-PEF.
Predictors of Rapid Brain Imaging in Acute Stroke
Authors: Kelly Adam G. , Hellkamp Anne S. , Olson DaiWai , Smith Eric E. , Schwamm Lee H. 
Published: March 2012

Background and Purpose—
National guidelines recommend patients with acute stroke undergo brain imaging within 25 minutes of emergency department arrival. Delayed brain imaging may reduce the effectiveness of thrombolysis or render patients ineligible.

Methods—
Data from the Get With The Guidelines–Stroke program from 2003 to 2009 were analyzed to determine overall imaging rates, temporal trends, and predictive variables associated with door-to-imaging times in patients who presented to an emergency department within 2 hours of stroke symptom onset and did not have clear reasons for withholding thrombolysis. Multivariable logistic regression adjusting for within-hospital clustering was performed to identify independent predictors of brain imaging within 25 minutes of emergency department arrival.

Results—
Brain imaging was performed within 25 minutes in 41.7% of patients. Rates of imaging within 25 minutes increased from 2003 to 2009 (33.3%–44.5%). In the multivariable model, the following variables were associated with less likelihood of imaging being completed within 25 minutes: age >70 years; female gender; nonwhite race; history of diabetes, peripheral vascular disease, or prosthetic heart valve; transportation other than ambulance; arrival >60 minutes after symptom onset; and hospital location in the Northeast. Patients with National Institutes of Health Stroke Scale scores of 16 to 25 (compared with other strata) were most likely to have imaging completed within 25 minutes.

Conclusions—
Most patients with acute stroke symptoms do not have brain imaging performed within the recommended 25 minutes. Future quality improvement initiatives should focus on reducing door-to-imaging times with a specific emphasis on the predictive variables identified in this analysis.
Single-Center Experience of Cerebral Artery Thrombectomy Using the TREVO Device in 60 Patients With Acute Ischemic Stroke
Authors: San Román Luis , Obach Victor , Blasco Jordi , Macho Juan , Lopez Antonio , Urra Xabier , Tomasello Alejandro , Cervera Alvaro , Amaro Sergio , Perandreu Joan , Branera Jordi , Capurro Sebastián , Oleaga Laura , Chamorro Angel 
Published: March 2012

Background and Purpose—
We sought to explore the safety and efficacy of the new TREVO stent-like retriever in consecutive patients with acute stroke.

Methods—
We conducted a prospective, single-center study of 60 patients (mean age, 71.3 years; male 47%) with stroke lasting <8 hours in the anterior circulation (n=54) or <12 hours in the vertebrobasilar circulation (n=6) treated if CT perfusion/CT angiography confirmed a large artery occlusion, ruled out a malignant profile, or showed target mismatch if symptoms >4.5 hours. Successful recanalization (Thrombolysis In Cerebral Infarction 2b–3), good outcome (modified Rankin Scale score 0–2) and mortality at Day 90, device-related complications, and symptomatic hemorrhage (parenchymal hematoma Type 1 or parenchymal hematoma Type 2 and National Institutes of Health Stroke Scale score increment ≥4 points) were prospectively assessed.

Results—
Median (interquartile range) National Institutes of Health Stroke Scale score on admission was 18 (12–22). The median (interquartile range) time from stroke onset to groin puncture was 210 (173–296) minutes. Successful revascularization was obtained in 44 (73.3%) of the cases when only the TREVO device was used and in 52 (86.7%) when other devices or additional intra-arterial tissue-type plasminogen activator were also required. The median time (interquartile range) of the procedure was 80 (45–114) minutes. Good outcome was achieved in 27 (45%) of the patients and the mortality rate was 28.3%. Seven patients (11.7%) presented a symptomatic intracranial hemorrhage. No other major complications were detected.

Conclusions—
The TREVO device was reasonably safe and effective in patients with severe stroke. These results support further investigation of the TREVO device in multicentric registries and randomized clinical trials.