bluuebunny/crossref_metadata_2025_split huggingface dataset:
Memantine Protects Rats Treated with Intrathecal Methotrexate from Developing Spatial Memory Deficits
Authors: Cole Peter D. , Vijayanathan Veena , Ali Nafeeza F. , Wagshul Mark E. , Tanenbaum Eric J. , Price Jeremy , Dalal Vidhi , Gulinello Maria E. 
Published: July 2013

Abstract
Purpose: To test whether memantine can prevent methotrexate-induced cognitive deficits in a preclinical model.
Experimental Design: After noting that methotrexate exposure induces prolonged elevations of the glutamate analog homocysteic acid (HCA) within cerebrospinal fluid, we tested whether intrathecal injection of HCA would produce memory deficits similar to those observed after intrathecal methotrexate. We then tested whether memantine, an antagonist of the N-methyl-d-aspartate (NMDA) subclass of glutamate receptors, could protect animals treated with clinically relevant doses of intrathecal methotrexate against developing memory deficits. Finally, we asked whether memantine affected this pathway beyond inhibiting the NMDA receptor by altering expression of the NMDA receptor or affecting concentrations of HCA or glutamate within the central nervous system.
Results: Four intrathecal doses of methotrexate induced deficits in spatial memory, persisting at least one month following the final injection. Intrathecal HCA was sufficient to reproduce this deficit. Concurrent administration of memantine during the period of methotrexate exposure was protective, decreasing the incidence of methotrexate-induced spatial memory deficits from 56% to 20% (P &lt; 0.05). Memantine neither altered expression of NMDA receptors within the hippocampus nor blunted the methotrexate-induced increases in glutamate or HCA.
Conclusions: Excitotoxic glutamate analogs including HCA contribute to cognitive deficits observed after intrathecal methotrexate. Memantine, an NMDA receptor antagonist, reduces the incidence of cognitive deficits in rats treated with intrathecal methotrexate, and may therefore benefit patients with cancer receiving similar treatment. Clin Cancer Res; 19(16); 4446–54. ©2013 AACR.
Accelerated Approval and Breakthrough Therapy Designation: Oncology Drug Development on Speed?
Authors: Yao James C. , Meric-Bernstam Funda , Lee J. Jack , Eckhardt S. Gail 
Published: July 2013

Abstract
Recent advances in biotechnology have led to discoveries resulting in major improvements in the therapy of refractory malignancies, although most advanced cancers remain incurable. Thus, there is global consensus around the need to streamline the drug approval process for effective agents. Accelerated Approval and Breakthrough Therapy Designation hold the promise of making new treatments available sooner through the use of smaller studies using intermediate endpoints. Here, we consider the inherent limitations of smaller studies and discuss the strategies for hastening oncology drug development while maintaining high-efficacy standards. Clin Cancer Res; 19(16); 4305–8. ©2013 AACR.
Targeted Cytolysins Synergistically Potentiate Cytoplasmic Delivery of Gelonin Immunotoxin
Authors: Pirie Christopher M. , Liu David V. , Wittrup K. Dane 
Published: July 2013

Abstract
Targeted endocytic uptake is a first step toward tissue-specific cytoplasmic macromolecular delivery; however, inefficient escape from the endolysosomal compartment makes this generally impractical at present. We report here a targeted cytolysin approach that dramatically potentiates endosomal release of an independently targeted potent gelonin immunotoxin. Fibronectin domains engineered for affinity to EGF receptor or carcinoembryonic antigen were fused to the plant toxin gelonin or bacterial pore-forming cytolysins. These fusion proteins display synergistic activity in both antigen-specific cytotoxicity in vitro, enhancing potency by several orders of magnitude, and in tumor growth inhibition in vivo. In addition, the number of internalized gelonin molecules required to induce apoptosis is reduced from approximately 5 × 106 to less than 103. Targeted potentiation shows promise for enhancing cytoplasmic delivery of other macromolecular payloads such as DNA, siRNA, and miRNA. Mol Cancer Ther; 12(9); 1774–82. ©2013 AACR.
Combined Inhibition of HER1/EGFR and RAC1 Results in a Synergistic Antiproliferative Effect on Established and Primary Cultured Human Glioblastoma Cells
Authors: Karpel-Massler Georg , Westhoff M.-Andrew , Zhou Shaoxia , Nonnenmacher Lisa , Dwucet Annika , Kast Richard E. , Bachem Max G. , Wirtz Christian R. , Debatin Klaus-Michael , Halatsch Marc-Eric 
Published: July 2013

Abstract
Glioblastoma is the most frequent brain tumor of glial origin in adults. With the best available standard-of-care, patients with this disease have a life expectancy of only approximately 15 months after diagnosis. Because the EGF receptor (HER1/EGFR) is one of the most commonly dysregulated oncogenes in glioblastoma, HER1/EGFR–targeted agents, such as erlotinib, were expected to provide a therapeutic benefit. However, their application in the clinical setting failed. Seeking an explanation for this finding, we previously identified several candidate genes for resistance of human glioblastoma cell lines toward erlotinib. On the basis of this panel of genes, we aimed at identifying drugs that synergistically enhance the antiproliferative effect of erlotinib on established and primary glioblastoma cell lines. We found that NSC23766, an inhibitor of RAC1, enhanced the antineoplastic effects of erlotinib in U87MG, T98MG, and A172MG glioblastoma cell lines for the most part in a synergistic or at least in an additive manner. In addition, the synergistic antiproliferative effect of erlotinib and NSC23766 was confirmed in primary cultured cells, indicating a common underlying cellular and molecular mechanism in glioblastoma. Therefore, agents that suppress RAC1 activation may be useful therapeutic partners for erlotinib in a combined targeted treatment of glioblastoma. Mol Cancer Ther; 12(9); 1783–95. ©2013 AACR.
Synergistic Induction of Apoptosis in Multiple Myeloma Cells by Bortezomib and Hypoxia-Activated Prodrug TH-302, In Vivo and In Vitro
Authors: Hu Jinsong , Van Valckenborgh Els , Xu Dehui , Menu Eline , De Raeve Hendrik , De Bryune Elke , Xu Song , Van Camp Ben , Handisides Damian , Hart Charles P. , Vanderkerken Karin 
Published: July 2013

Abstract
Recently, we showed that hypoxia is a critical microenvironmental factor in multiple myeloma, and that the hypoxia-activated prodrug TH-302 selectively targets hypoxic multiple myeloma cells and improves multiple disease parameters in vivo. To explore approaches for sensitizing multiple myeloma cells to TH-302, we evaluated in this study the antitumor effect of TH-302 in combination with the clinically used proteasome inhibitor bortezomib. First, we show that TH-302 and bortezomib synergistically induce apoptosis in multiple myeloma cell lines in vitro. Second, we confirm that this synergism is related to the activation of caspase cascades and is mediated by changes of Bcl-2 family proteins. The combination treatment induces enhanced cleavage of caspase-3/8/9 and PARP, and therefore triggers apoptosis and enhances the cleavage of proapoptotic BH3-only protein BAD and BID as well as the antiapoptotic protein Mcl-1. In particular, TH-302 can abrogate the accumulation of antiapoptotic Mcl-1 induced by bortezomib, and decreases the expression of the prosurvival proteins Bcl-2 and Bcl-xL. Furthermore, we found that the induction of the proapoptotic BH3-only proteins PUMA (p53-upregulated modulator of apoptosis) and NOXA is associated with this synergism. In response to the genotoxic and endoplasmic reticulum stresses by TH-302 and bortezomib, the expression of PUMA and NOXA were upregulated in p53-dependent and -independent manners. Finally, in the murine 5T33MMvv model, we showed that the combination of TH-302 and bortezomib can improve multiple disease parameters and significantly prolong the survival of diseased mice. In conclusion, our studies provide a rationale for clinical evaluation of the combination of TH-302 and bortezomib in patients with multiple myeloma. Mol Cancer Ther; 12(9); 1763–73. ©2013 AACR.
Alternative Variants of Human HYDIN Are Novel Cancer-Associated Antigens Recognized by Adaptive Immunity
Authors: Laske Karoline , Shebzukhov Yuriy V. , Grosse-Hovest Ludger , Kuprash Dmitry V. , Khlgatian Svetlana V. , Koroleva Ekaterina P. , Sazykin Alexey Y. , Penkov Dmitry N. , Belousov Pavel V. , Stevanović Stefan , Vass Verona , Walter Steffen , Eisel David , Schmid-Horch Barbara D. , Nedospasov Sergei A. , Rammensee Hans-Georg , Gouttefangeas Cécile 
Published: July 2013

Abstract
A mutation in the hydin gene has been recently described as one possible mechanism leading to lethal congenital hydrocephalus in mice, and a similar defect is proposed to be involved in an autosomal recessive form of hydrocephalus in human. Here, we report for the first time on the cancer association and immunogenicity of two HYDIN variants in humans. One is a previously described sequence derived from the chromosome 1 gene copy, that is, KIAA1864. The second is encoded by a novel alternative transcript originating from the chromosome 16, which we identified by immunoscreening of a testis-derived cDNA expression library with sera of patients with colorectal cancer, and called MO-TES391. Both variants are targeted by immunoglobulin G antibodies in a significant subset of cancer patients but only rarely in healthy donors. Moreover, we identify HLA-A*0201–restricted sequences derived from MO-TES391 and KIAA1864, which are specifically recognized by human cytotoxic CD8+ T cells. Taken together, these results suggest frequent and coordinated adaptive immune responses against HYDIN variants in patients with cancer and propose HYDIN as a novel cancer-associated antigen. Cancer Immunol Res; 1(3); 190–200. ©2013 AACR.
Reduced Myocardial 123-Iodine Metaiodobenzylguanidine Uptake
Authors: Coutinho Maria C. Azevedo , Cortez-Dias Nuno , Cantinho Guilhermina , Conceição Isabel , Oliveira António , Bordalo e Sá Armando , Gonçalves Susana , Almeida Ana G. , de Carvalho Mamede , Diogo António Nunes 
Published: July 2013

Background—
Transthyretin familial amyloid polyneuropathy is a hereditary form of amyloidosis characterized by sensorimotor and autonomic neuropathy, cardiac conduction defects, and infiltrative cardiomyopathy. Previous studies have suggested that myocardial sympathetic denervation assessed by 123-iodine metaiodobenzylguanidine (MIBG) imaging occurs early in disease progression. However, its prognostic significance was never evaluated. We aimed to study the long-term prognostic value of myocardial sympathetic denervation detected by MIBG imaging in transthyretin familial amyloid polyneuropathy.

Methods and Results—

A total of 143 individuals with V30M transthyretin mutation underwent Holter, ambulatory blood pressure monitoring, echocardiography, and MIBG imaging. Time to all-cause death was compared with late heart-to-mediastinum MIBG uptake ratio (H/M; either in relation to the estimated lower limit of normal [1.60] or as a continuous variable) using Cox proportional hazards regression. Multivariable analyses were performed to test the prognostic accuracy of clinical, neurological, and cardiovascular parameters. During a median follow-up of 5.5 years, 32 (22%) patients died. Five-year mortality rate was 42% for late H/M <1.60 and 7% for late H/M ≥1.60 (hazard ratio, 7.19;
P
<0.001). Late H/M was identified as an independent prognostic predictor. Fifty-three patients were submitted to liver transplantation. In comparison with neurophysiological score–matched controls, transplanted patients had lower long-term mortality (hazard ratio, 0.32;
P
=0.012). Patients with late H/M<1.60 were at higher risk of unfavorable outcome but seemed to have benefited from liver transplantation.

Conclusions—
Cardiac sympathetic denervation as assessed by MIBG imaging is a useful prognostic marker in transthyretin familial amyloid polyneuropathy.
Myocardial Steatosis and Left Ventricular Contractile Dysfunction in Patients With Severe Aortic Stenosis
Authors: Mahmod Masliza , Bull Sacha , Suttie Joseph J. , Pal Nikhil , Holloway Cameron , Dass Sairia , Myerson Saul G. , Schneider Jurgen E. , De Silva Ravi , Petrou Mario , Sayeed Rana , Westaby Stephen , Clelland Colin , Francis Jane M. , Ashrafian Houman , Karamitsos Theodoros D. , Neubauer Stefan 
Published: July 2013

Background—
Aortic stenosis (AS) leads to left ventricular (LV) hypertrophy and dysfunction. We hypothesized that cardiac steatosis is involved in the pathophysiology and also assessed whether it is reversible after aortic valve replacement.

Methods and Results—

Thirty-nine patients with severe AS (symptomatic=25, asymptomatic=14) with normal LV ejection fraction and no significant coronary artery disease and 20 age- and sex-matched healthy controls underwent cardiac 1H-magnetic resonance spectroscopy and imaging for the determination of steatosis (myocardial triglyceride content) and cardiac function, including circumferential strain (measured by magnetic resonance tagging). Strain was lower in both symptomatic and asymptomatic AS (−16.4±2.5% and −18.1±2.9%, respectively, versus controls −20.7±2.0%, both
P
<0.05). Myocardial steatosis was found in both symptomatic and asymptomatic patients with AS (0.89±0.42% in symptomatic AS; 0.75±0.36% in asymptomatic AS versus controls 0.45±0.17, both
P
<0.05). Importantly, multivariable analysis indicated that steatosis was an independent correlate of impaired LV strain. Spectroscopic measurements of myocardial triglyceride content correlated significantly with histological analysis of biopsies obtained during aortic valve replacement. At 8.0±2.1 months after aortic valve replacement, steatosis and strain had recovered toward normal.

Conclusions—
Pronounced myocardial steatosis is present in severe AS, regardless of symptoms, and is independently associated with the degree of LV strain impairment. Myocardial triglyceride content measured by magnetic resonance spectroscopy correlates with histological quantification. Steatosis and strain impairment are reversible after aortic valve replacement. Our findings suggest a novel pathophysiological mechanism in AS, myocardial steatosis, which may be amenable to treatment, thus potentially delaying onset of LV dysfunction.
Sensory determinants of agonistic interactions in the red-backed salamander, Plethodon cinereus
Authors: Duhaime-Ross Arielle , Martel Geneviève , Laberge Frédéric 
Published: July 2013

Many animals use and react to multimodal signals — signals that occur in more than one sensory modality. This study focused on the respective roles of vision, chemoreception, and their possible interaction in determining agonistic responses of the red-backed salamander, Plethodon cinereus. The use of a computer display allowed separate or combined presentation of visual and chemical cues. A cue isolation experiment using adult male and juvenile salamanders showed that both visual and chemical cues from unfamiliar male conspecifics could increase aggressive displays. Submissive displays were only increased in juveniles, and specifically by the visual cue. The rate of chemoinvestigation of the substrate was increased only by chemical cues in adults, whereas both chemical and visual cues increased this behaviour in juveniles. Chemoinvestigation appears, thus, more dependent on sensory input in juvenile salamanders. A follow-up experiment comparing responses to visual cues of different animals (conspecific salamander, heterospecific salamander and earthworm) or an inanimate object (wood stick) showed that exploratory behaviour was higher in the presence of the inanimate object stimulus. The heterospecific salamander stimulus produced strong submissive and escape responses, while the conspecific salamander stimulus promoted aggressive displays. Finally, the earthworm stimulus increased both aggressive and submissive behaviours at intermediate levels when compared to salamander cues. These specific combinations of agonistic and exploratory responses to each stimulus suggest that salamanders could discriminate the cues visually. This study sheds some light on how information from different sensory modalities guides social behaviour at different life stages in a salamander.
The Demonstrative iyyā-: A Little-Considered Aspect of Arabic Deixis
Authors: Wilmsen David 
Published: July 2013

Abstract
The familiar Arabic pronominal object marker iyyā- performs other functions within the language. One of these, the demonstrative, has been recognized in spoken Egyptian Arabic but passes virtually unremarked in written Arabic. Nevertheless, it is so used by writers from the eastern Arabophone world more often than by those from the west. As such, it usually performs four roles in structuring information: expressing contrast, emphatic reflexivity, and two degrees of distal deixis. While modern Arab writers appear to use it demonstratively more often than did those of medieval and classical Arabic, that earlier writers were using it suggests that its demonstrative property is an inherent feature. This is confirmed by comparing object markers in other Semitic languages, which may function as demonstratives in Hebrew and Aramaic, reflexives in Syriac, and in remote deixis in Amharic.
L’histoire de la judicature musulmane revisitée: l’exercice de la justice sous les Abbassides
Authors: Daaif Lahcen 
Published: July 2013

Abstract
While it is true that little is known about justice (qaḍāʾ) and how it functioned in the first century of Islam, this is no longer the case for Iraq during the Abbasid period (up to the arrival of the Būyids in 334/945), the subject of Mathieu Tillier’s recent study. In the following pages, I will provide a presentation that traces, chapter by chapter, the history of the judicial institution during this period according to the author’s outline, both in the evolution of its practices and of its means of expression and in its troubled relationship, often one of subordination to political power. When necessary, I will examine points that seem subject to debate and I will suggest some small improvements and formal corrections.
ʿAdālat al-Ṣaḥāba: The Construction of a Religious Doctrine
Authors: Osman Amr 
Published: July 2013

Abstract
This article investigates the development of ʿadālat al-ṣaḥāba, a central doctrine in Sunnī orthodoxy that stresses the integrity of the Prophet Muḥammad’s Companions. The examination of relevant Sunnī works indicates that the doctrine crystalized in the 5th/11th century, by which time the basic tenets of the doctrine had been developed. These include, among other things, the definition of Companions and their essential role in securing the authenticity of Islam. Furthermore, it was around that time that medieval Sunnī scholars developed an epistemological—rather than a historical or theological—basis for the doctrine. Establishing the integrity of the Companions during the Prophet’s lifetime on the presumption of innocence that is further confirmed by textual evidence, they argued that good Muslims must continue to accept that integrity given the lack of conclusive evidence that they lost it at a later time, particularly when they participated in civil wars. I argue that this epistemological ground was furnished by Murğiʾism, as the examination of some Murğiʾī texts demonstrates.1
Women and Feminine Images in Muslim Traditions of the End
Authors: Livne-Kafri Ofer 
Published: July 2013

Abstract
Heroes of apocalyptic traditions are generally men, such as messiahs and anti-messiahs, leaders and warriors, participants in the dispute over the power in the Muslim community, and others. Nevertheless, the role of women is not entirely ignored. This article deals with women as transmitters of apocalyptic traditions, women playing a role in those traditions, and feminine images. Women in traditions of the End seem to provide a measuring-rod for different situations in Muslim society during times of foretold tribulations, such as horrors, torture, captivity, or threats of moral decline. The feminine images mainly relate to towns in the Last Day and in the apocalyptic times that will precede it. They reflect the impact of the Judaeo-Christian heritage on Muslim traditions through the adaptation of old texts, themes and images to the needs of the Muslim community and its value system.
Submissions to the UN Commission on the Limits of the Continental Shelf: The Practice of Developing States in Cases of Disputed and Unresolved Maritime Boundary Delimitations or Other Land or Maritime Disputes. Part One
Authors: Kwiatkowska Barbara 
Published: July 2013

Abstract
This is the first part of a two-part article surveying state practice regarding Disputed and Unresolved Maritime Boundary Delimitations or Other Land or Maritime Disputes under the Commission on the Limits of the Continental Shelf (CLCS) Rules. It reviews basic principles and the interpretation of the 1982 UN Law of the Sea Convention and the CLCS Rules. As the 2006 Annex VII Barbados/Trinidad and Tobago Award and the 2012 ITLOS Bangladesh v. Myanmar Judgment reaffirmed, the CLCS Recommendations must in no way prejudice existing and prospective boundary delimitations, nor must they prejudice other land or maritime disputes. All practical means of giving effect to such “without prejudice” principles are carefully analysed. The present Part covers Latin America and the Wider Caribbean, Northeast and Southeast Asia, and the South Pacific. Part Two will cover South Asia and the Middle East, East Africa—Indian Ocean, South Africa, West Africa and North Africa.
Driving With the Wandering Mind
Authors: Yanko Matthew R. , Spalek Thomas M. 
Published: July 2013

Objective: The principal objective of the present work was to examine the effects of mind state (mind-wandering vs. on-task) on driving performance in a high-fidelity driving simulator. Background: Mind-wandering is thought to interfere with goal-directed thought. It is likely, then, that when driving, mind-wandering might lead to impairments in critical aspects of driving performance. In two experiments, we assess the extent to which mind-wandering interferes with responsiveness to sudden events, mean velocity, and headway distance. Method: Using a car-following procedure in a high-fidelity driving simulator, participants were probed at random times to indicate whether they were on-task at that moment or mind-wandering. The dependent measures were analyzed based on the participant’s response to the probe. Results: Compared to when on-task, when mind-wandering participants showed longer response times to sudden events, drove at a higher velocity, and maintained a shorter headway distance. Conclusion: Collectively, these findings indicate that mind-wandering affects a broad range of driving responses and may therefore lead to higher crash risk. Application: The results suggest that situations that are likely associated with mind-wandering (e.g., route familiarity) can impair driving performance.