bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic and Pharmacologic Inhibition of mTORC1 Promotes EMT by a TGF-β–Independent Mechanism
Authors: Mikaelian Ivan , Malek Mouhannad , Gadet Rudy , Viallet Jean , Garcia Amandine , Girard-Gagnepain Anaïs , Hesling Cédric , Gillet Germain , Gonzalo Philippe , Rimokh Ruth , Billaud Marc 
Published: September 2013

Abstract
Epithelial-to-mesenchymal transition (EMT) is a transdifferentiation process that converts epithelial cells into highly motile mesenchymal cells. This physiologic process occurs largely during embryonic development but is aberrantly reactivated in different pathologic situations, including fibrosis and cancer. We conducted a siRNA screening targeted to the human kinome with the aim of discovering new EMT effectors. With this approach, we have identified mTOR complex 1 (mTORC1), a nutrient sensor that controls protein and lipid synthesis, as a key regulator of epithelial integrity. Using a combination of RNAi and pharmacologic approaches, we report here that inhibition of either mTOR or RPTOR triggers EMT in mammary epithelial cells. This EMT was characterized by the induction of the mesenchymal markers such as fibronectin, vimentin, and PAI-1, together with the repression of epithelial markers such as E-cadherin and ZO-3. In addition, mTORC1 blockade enhanced in vivo migratory properties of mammary cells and induced EMT independent of the TGF-β pathway. Finally, among the transcription factors known to activate EMT, both ZEB1 and ZEB2 were upregulated following mTOR repression. Their increased expression correlated with a marked reduction in miR-200b and miR-200c mRNA levels, two microRNAs known to downregulate ZEB1 and ZEB2 expression. Taken together, our findings unravel a novel function for mTORC1 in maintaining the epithelial phenotype and further indicate that this effect is mediated through the opposite regulation of ZEB1/ZEB2 and miR-200b and miR-200c. Furthermore, these results suggest a plausible etiologic explanation for the progressive pulmonary fibrosis, a frequent adverse condition associated with the therapeutic use of mTOR inhibitors. Cancer Res; 73(22); 6621–31. ©2013 AACR.
Chemoprevention of Head and Neck Cancer with Celecoxib and Erlotinib: Results of a Phase Ib and Pharmacokinetic Study
Authors: Saba Nabil F. , Hurwitz Selwyn J. , Kono Scott A. , Yang Chung S. , Zhao Yang , Chen Zhengjia , Sica Gabe , Müller Susan , Moreno-Williams Rachel , Lewis Melinda , Grist William , Chen Amy Y. , Moore Charles E. , Owonikoko Taofeek K. , Ramalingam Suresh , Beitler Jonathan J. , Nannapaneni Sreenivas , Shin Hyung Ju C. , Grandis Jennifer R. , Khuri Fadlo R. , Chen Zhuo Georgia , Shin Dong M. 
Published: October 2013

Abstract
Epidermal growth factor receptor (EGFR) and COX-2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions. Thirty-six subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma in situ were screened for study participation; 12 consented and received therapy for a median of 5.38 months. Erlotinib was escalated following a standard 3+3 design at 50, 75, and 100 mg orally daily and celecoxib was fixed at 400 mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6, and 12 months. Erlotinib pharmacokinetics were analyzed in 10 subjects. The maximum tolerated dose of erlotinib with celecoxib 400 mg BID was 50 mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response, 43%; partial response, 14%; stable disease, 29%; and disease progression, 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (approximately 308 L) and CL/F (8.3 L/h) compared with previous studies may be related to relatively large average bodyweights. Average erlotinib t1/2 was 25.6 hours. Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated. Cancer Prev Res; 7(3); 283–91. ©2013 AACR.
Echocardiographic Predictors of Reverse Remodeling After Cardiac Resynchronization Therapy and Subsequent Events
Authors: Park Jae-Hyeong , Negishi Kazuaki , Grimm Richard A. , Popovic Zoran , Stanton Tony , Wilkoff Bruce L. , Marwick Thomas H. 
Published: October 2013

Background—
Studies of echocardiographic predictors of response after cardiac resynchronization therapy (CRT) have largely involved single parameters. We hypothesized that combining parameters would be more robust and sought to develop a multiparametric echocardiographic score for predicting CRT response.

Methods and Results—

Global longitudinal strain of left ventricle was added to standard echocardiographic measurements in 334 consecutive patients (224 men; mean, 65±12 years) who underwent baseline echocardiography before CRT and underwent follow-up echocardiograms at 1 year. Regression analysis was performed to create an echocardiographic score for prediction of LV reverse remodeling (defined as ≥15% reduction in the LV end-systolic volume). Cox proportional hazards models were used to identify the association of the score with death, transplantation or LV assist device implantation, and heart failure hospitalization during 57±22 months of follow-up. LV reverse remodeling (n=161; 48%) was associated with pre-CRT LV end-diastolic dimension index <3.1 cm/m
2
, global longitudinal strain of left ventricle <–7%, left atrial area <26 cm
2
, right ventricular end-diastolic area index <10.0 cm
2
/m
2
, right atrial area <20 cm
2
, and right ventricular fractional area change ≥35%. Combination of these into an echocardiographic score allowed prediction of LV reverse remodeling with a sensitivity of 84% and a specificity of 79%. During follow-up, there were 134 deaths, 18 heart transplantations/LV assist device implantations, and 93 heart failure admissions. The score was associated with heart failure admission, heart transplantation/LV assist device, or death (hazard ratio, 0.97; 95% confidence interval, 0.95–0.98;
P
<0.001) and all-cause death (hazard ratio, 0.97; 95% confidence interval, 0.96–0.98;
P
<0.001), independent of age, sex, ischemic cause, and initial functional class.

Conclusions—
A multiparametric echocardiographic score is helpful in selecting patients likely to undergo reverse remodeling after CRT and predicts clinical outcomes.
Leukocyte Count Is a Modulating Factor for the Mortality Benefit of Bivalirudin in ST-Segment–Elevation Acute Myocardial Infarction
Authors: Palmerini Tullio , Brener Sorin J. , Mehran Roxana , Dangas George , Genereux Philippe , Riva Diego Della , Mariani Andrea , Xu Ke , Stone Gregg W. 
Published: October 2013

Background—
Although the reduction in mortality with bivalirudin compared with unfractionated heparin plus glycoprotein IIb/IIIa inhibitors in the Harmonizing Outcome with Revascularization and Stent in Acute Myocardial Infarction (HORIZONS-AMI) trial has been attributed to lower rates of major bleeding, alternative mechanisms have not been investigated in depth. We sought to investigate whether there might be an interaction between white blood cell (WBC) count and bivalirudin for the risk of mortality, and whether this interaction is independent of major bleeding.

Methods and Results—

Among the 3602 patients enrolled in the HORIZONS-AMI trial, WBC count was available in 3433 (95.3%) patients. Patients were stratified according to WBC tertiles. At 1-year follow-up, bivalirudin was associated with significantly lower rates of mortality and cardiac mortality compared with unfractionated heparin plus glycoprotein IIb/IIIa inhibitors in patients in the upper WBC tertile (all-cause death: 4.1% versus 9.3%, respectively;
P
=0.0004; cardiac death: 2.0% versus 6.9%; respectively;
P
<0.0001) but not in patients in the mid-WBC or lower WBC tertiles. The reduction of mortality with bivalirudin across WBC tertiles was independent of major bleeding, and a significant interaction was apparent for 1-year all-cause mortality and cardiac mortality between WBC and bivalirudin therapy. Similar findings were apparent at 3 years.

Conclusions—
In patients with ST-segment–elevation myocardial infarction, a significant interaction between bivalirudin therapy and admission WBC count was apparent for 1-year mortality. The reduction in mortality was independent of major bleeding, suggesting that other mechanisms may be implicated in the survival benefit observed with bivalirudin.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00433966.
Impact of Chronic Kidney Disease on Carotid Atherosclerosis According to Blood Pressure Category
Authors: Ohara Tomoyuki , Kokubo Yoshihiro , Toyoda Kazunori , Watanabe Makoto , Koga Masatoshi , Nakamura Satoko , Nagatsuka Kazuyuki , Minematsu Kazuo , Nakagawa Masanori , Miyamoto Yoshihiro 
Published: October 2013

Background and Purpose—
We aimed to clarify the association of chronic kidney disease (CKD) with carotid atherosclerosis and the impact of CKD on carotid atherosclerosis according to blood pressure categories in an urban general population.

Methods—

We studied 3466 Japanese individuals (35–93 years old) in the Suita Study. Carotid atherosclerosis was expressed as the maximum carotid intima-media thickness and the presence of stenosis (>25%). The estimated glomerular filtration rate was calculated using the equations recommended by the Japanese Society of Nephrology. CKD was defined as estimated glomerular filtration rate <60 mL/min per 1.73 m
2
. Blood pressure categories were defined by the European Society of Hypertension and European Society of Cardiology 2007 criteria.

Results—

The multivariable-adjusted maximum carotid intima-media thickness and odds ratio for stenosis in subjects with estimated glomerular filtration rate <50 mL/min per 1.73 m
2
were greater than those in subjects with estimated glomerular filtration rate ≥90 mL/min per 1.73 m
2
. When subjects were stratified according to blood pressure categories, the multivariable-adjusted maximum carotid intima-media thickness was significantly greater in CKD subjects than in non-CKD subjects only in subjects with hypertension. Similarly, the impact of CKD on stenosis was evident only in subjects with hypertension (multivariable-adjusted odds ratios for stenosis [95% confidence interval] were 2.21 [1.53–3.19] in non-CKD/hypertension and 3.16 [2.05–4.88] in CKD/hypertension compared with non-CKD/optimal blood pressure).

Conclusions—
In a general population, the association of CKD with carotid atherosclerosis was modest, but CKD was independently associated with carotid atherosclerosis in subjects with hypertension.
Making Land Sacred: Inscriptional Evidence for Buddhist Kings and Brahman Priests in Medieval Bengal
Authors: Fleming Benjamin J. 
Published: October 2013

AbstractIn research on premodern South Asia, land-grant inscriptions have typically been mined for historical and geographical data. This article suggests that copperplate land-grant inscriptions may also provide an overlooked source of evidence for ideas about sacred space within and between South Asian religions. It focuses on inscriptions recording the granting of land by Buddhist kings to Brahman priests in medieval Bengal, and it hones in on the literary, oral, ritual, and performative elements of the inscriptions in relation to the spaces delineated by acts of granting. Drawing upon broader theoretical discussions concerning gift-giving in relation to economies and exchanges of religious prestige and royal power, it attempts to offer new perspectives towards gift-giving and the economy of the sacred in Hindu and Buddhist traditions. In the process, it attempts to draw out some of the broader ritual and “religious” implications of what is typically treated as an “economic” transaction – namely, the transfer of land from royal to priestly control, which forms the heart of the copperplate’s function and formation.
Space in Relation to God or the Absolute in the Thought of Henry More and Śaṅkara: An Exercise in Comparative Philosophy
Authors: Duquette Jonathan 
Published: October 2013

AbstractSince Antiquity thinkers of all civilizations have speculated on the concept of space. The idea arose under various typologies and descriptions in different areas of knowledge ranging from cosmology, physics, and mathematics to philosophy and psychology. However, less known are the role and implications of space in theological and religio-philosophical discourse. This article aims to examine and characterize the claim that space is intimately related to God or the absolute from the perspective of two thinkers rooted in different historical, cultural, and religious settings: the Cambridge Platonist Henry More and the Advaita Vedāntin Śaṅkara. A comparative approach will bring forward the meeting points in their respective assessment of the relationship between space and God/the absolute, as well as the distinctiveness in their arguments, approach, and motivations. The present discussion may demonstrate alternative ways of addressing a valuable problem recurring at the intersection of philosophy and religion at different times and places throughout history.
On the Term “Monotheism”
Authors: Herbener Jens-André P. 
Published: October 2013

AbstractThe category of monotheism is not only central to the study of religion, it is also well known outside of academia. Yet there is no real consensus as to its content. Considering existing literature on the subject, one will observe that the term monotheism is defined in a diversity of ways and may be applied to a variety of religions as well as to a variety of different elements in religion.This is problematic for several reasons: for one thing, this ambiguity means that it is not necessarily very informative to categorize a given phenomenon as monotheistic. For another, in several cases the use of the term corresponds rather poorly with the meaning that can be inferred from the etymological root of the word. Furthermore, it is often used where it would be more accurate to use other categories.The present article intends to break away from the loose application of the category of monotheism often found in the literature. First, it will examine, discuss, and criticize four significant examples of the status quo. Secondly, drawing inspiration from the recent debate on monotheism, it will advocate a “restricted” definition of monotheism and thus a reduced application of the term, as well as an extended use of categories such as henotheism, summodeism, and monolatry.
Utterly Incapacitated
Authors: Holmes Christopher T. 
Published: October 2013

Abstract
This article considers the appropriate translation of πάρεσις in Romans 3:25, which is the only attestation of the word in the Greek Bible. The author argues that “incapacitation” should be considered as an appropriate translation based on the use of the term in other authors of the Hellenistic period, especially the medical writer Aretaeus of Cappadocia. Although some have mentioned “paralysis” as a possible meaning of πάρεσις in scholarly articles and monographs, no one has given serious consideration to understanding the term in this way or how such an understanding might align with Paul’s larger argument.
Interference from Indian diet on the internal standard in a commercial method for the measurement of urinary metanephrines by high-performance liquid chromatography with electrochemical detection
Authors: Madhavaram Hima , Woollard Gerald A 
Published: October 2013

Introduction: Urinary metanephrines are widely used in the diagnosis of catecholamine secreting tumours. Over the past two years we have been using the commercial Recipe® ClinRep® Complete Kit for Metanephrines in Urine coupled with high-performance liquid chromatography and coulometric detection. It was noticed that the internal standards on the patient chromatograms were sporadically raised due to interference. Methods: The interference had identical chromatographic and electrochemical properties to the Recipe® internal standard (undisclosed identity). Inspection of the patient names showed it seemingly had a higher frequency and magnitude in patients of Indian origin. The source of the interference was tracked by dietary observation and intervention to curry leaves, a common component of Indian foods. Results: The interference was chromatographically and electrochemically indistinguishable from the internal standard. The mass spectrum of the pentafluoropropionate derivative of the interference matched the Recipe® internal standard and was identified as methoxyhydroxybenzylamine by library match. Conclusion: The component co-elutes exactly with internal standard and artifactually decreases the metanephrine and normetanephrine results. It is surprising that it has not been described previously. Patients being assessed for catecholamine secreting tumours should be advised to withdraw from eating Indian foods at least 24 h prior to commencement of urinary collection.
Performance of two-stage continual reassessment method relative to an optimal benchmark
Authors: Wages Nolan A , Conaway Mark R , O’Quigley John 
Published: October 2013

Background The two-stage, likelihood-based continual reassessment method (CRM-L) entails the specification of a set of design parameters prior to the beginning of its use in a study. The impression of clinicians is that the success of model-based designs, such as CRM-L, depends upon some of the choices made with regard to these specifications, such as the choice of parametric dose–toxicity model and the initial guess of toxicity probabilities. Purpose In studying the efficiency and comparative performance of competing dose-finding designs for finite (typically small) samples, the nonparametric optimal benchmark is a useful tool. When comparing a dose-finding design to the optimal design, we are able to assess how much room there is for potential improvement. Methods The optimal method, based only on an assumption of monotonicity of the dose–toxicity function, is a valuable theoretical construct serving as a benchmark in theoretical studies, similar to that of a Cramér–Rao bound. We consider the performance of CRM-L under various design specifications and how it compares to the optimal design across a range of practical situations. Results Using simple recommendations for design specifications, the CRM-L will produce performances, in terms of identifying doses at and around the maximum tolerated dose (MTD), that are close to the optimal method on average over a broad group of dose–toxicity scenarios. Limitations Although the simulation settings vary in the number of doses considered, the target toxicity rate, and the sample size, the results here are presented for a small, though widely used, set of two-stage CRM designs. Conclusions Based on simulations here, and many others not shown, CRM-L is almost as accurate, in many scenarios, as the nonparametric optimal design. On average, there appears to be very little margin for improvement. Even if a finely tuned skeleton offers some improvement over a simple skeleton, the improvement is necessarily very small.
Marker Sequential Test (MaST) design
Authors: Freidlin Boris , Korn Edward L , Gray Robert 
Published: October 2013

Background New targeted anticancer therapies often benefit only a subset of patients with a given cancer. Definitive evaluation of these agents may require phase III randomized clinical trial designs that integrate evaluation of the new treatment and the predictive ability of the biomarker that putatively determines the sensitive subset. Purpose We propose a new integrated biomarker design, the Marker Sequential Test (MaST) design, that allows sequential testing of the treatment effect in the biomarker subgroups and overall population while controlling the relevant type I error rates. Methods After defining the testing and error framework for integrated biomarker designs, we review the commonly used approaches to integrated biomarker testing. We then present a general form of the MaST design and describe how it can be used to provide proper control of false-positive error rates for biomarker-positive and biomarker-negative subgroups. The operating characteristics of the MaST design are compared by analytical methods and simulations to the sequential subgroup-specific design that sequentially assesses the treatment effect in the biomarker subgroups. Practical aspects of MaST design implementation are discussed. Results The MaST design is shown to have higher power relative to the sequential subgroup-specific design in situations where the treatment effect is homogeneous across biomarker subgroups, while preserving the power for settings where treatment benefit is limited to biomarker-positive subgroup. For example, in the time-to-event setting considered with 30% biomarker-positive prevalence, the MaST design provides up to a 30% increase in power in the biomarker-positive and biomarker-negative subgroups when the treatment benefits all patients equally, while sustaining less than a 2% loss of power against alternatives where the benefit is limited to the biomarker-positive subgroup. Limitations The proposed design is appropriate for settings where it is reasonable to assume that the treatment will not be effective in the biomarker-negative patients unless it is effective in the biomarker-positive patients. Conclusion The MaST trial design is a useful alternative to the sequential subgroup-specific design when it is important to consider the treatment effect in the biomarker-positive and biomarker-negative subgroups.