bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disruption of Wild-Type IDH1 Suppresses D-2-Hydroxyglutarate Production in IDH1-Mutated Gliomas
Authors: Jin Genglin , Reitman Zachary J. , Duncan Christopher G. , Spasojevic Ivan , Gooden David M. , Rasheed B. Ahmed , Yang Rui , Lopez Giselle Y. , He Yiping , McLendon Roger E. , Bigner Darell D. , Yan Hai 
Published: December 2012

Abstract
Point mutations at Arg132 of the cytoplasmic NADP+-dependent isocitrate dehydrogenase 1 (IDH1) occur frequently in gliomas and result in a gain of function to produce the “oncometabolite” D-2-hydroxyglutarate (D-2HG). The mutated IDH1 allele is usually associated with a wild-type IDH1 allele (heterozygous) in cancer. Here, we identify 2 gliomas that underwent loss of the wild-type IDH1 allele but retained the mutant IDH1 allele following tumor progression from World Health Organization (WHO) grade III anaplastic astrocytomas to WHO grade IV glioblastomas. Intratumoral D-2HG was 14-fold lower in the glioblastomas lacking wild-type IDH1 than in glioblastomas with heterozygous IDH1 mutations. To characterize the contribution of wild-type IDH1 to cancer cell D-2HG production, we established an IDH1-mutated astrocytoma (IMA) cell line from a WHO grade III anaplastic astrocytoma. Disruption of the wild-type IDH1 allele in IMA cells by gene targeting resulted in an 87-fold decrease in cellular D-2HG levels, showing that both wild-type and mutant IDH1 alleles are required for D-2HG production in glioma cells. Expression of wild-type IDH1 was also critical for mutant IDH1-associated D-2HG production in the colorectal cancer cell line HCT116. These insights may aid in the development of therapeutic strategies to target IDH1-mutated cancers. Cancer Res; 73(2); 496–501. ©2012 AACR.
BRAF Inhibition Increases Tumor Infiltration by T cells and Enhances the Antitumor Activity of Adoptive Immunotherapy in Mice
Authors: Liu Chengwen , Peng Weiyi , Xu Chunyu , Lou Yanyan , Zhang Minying , Wargo Jennifer A. , Chen Jie Qing , Li Haiyan S. , Watowich Stephanie S. , Yang Yan , Frederick Dennie Tompers , Cooper Zachary A. , Mbofung Rina M. , Whittington Mayra , Flaherty Keith T. , Woodman Scott E. , Davies Michael A. , Radvanyi Laszlo G. , Overwijk Willem W. , Lizée Gregory , Hwu Patrick 
Published: December 2012

Abstract
Purpose: Treatment of melanoma patients with selective BRAF inhibitors results in objective clinical responses in the majority of patients with BRAF-mutant tumors. However, resistance to these inhibitors develops within a few months. In this study, we test the hypothesis that BRAF inhibition in combination with adoptive T-cell transfer (ACT) will be more effective at inducing long-term clinical regressions of BRAF-mutant tumors.
Experimental Design: BRAF-mutated human melanoma tumor cell lines transduced to express gp100 and H-2Db to allow recognition by gp100-specific pmel-1 T cells were used as xenograft models to assess melanocyte differentiation antigen–independent enhancement of immune responses by BRAF inhibitor PLX4720. Luciferase-expressing pmel-1 T cells were generated to monitor T-cell migration in vivo. The expression of VEGF was determined by ELISA, protein array, and immunohistochemistry. Importantly, VEGF expression after BRAF inhibition was tested in a set of patient samples.
Results: We found that administration of PLX4720 significantly increased tumor infiltration of adoptively transferred T cells in vivo and enhanced the antitumor activity of ACT. This increased T-cell infiltration was primarily mediated by the ability of PLX4720 to inhibit melanoma tumor cell production of VEGF by reducing the binding of c-myc to the VEGF promoter. Furthermore, analysis of human melanoma patient tumor biopsies before and during BRAF inhibitor treatment showed downregulation of VEGF consistent with the preclinical murine model.
Conclusion: These findings provide a strong rationale to evaluate the potential clinical application of combining BRAF inhibition with T-cell–based immunotherapy for the treatment of patients with melanoma. Clin Cancer Res; 19(2); 393–403. ©2012 AACR.
It's About Time: Lessons for Solid Tumors from Chronic Myelogenous Leukemia Therapy
Authors: Westin Jason R. , Kurzrock Razelle 
Published: December 2012

Abstract
The use of imatinib in chronic myelogenous leukemia (CML) transformed the disease, rapidly changing the median survival from 4 years to at least 20 years. In this review, we outline the causes of this revolution, including the identification of a critical driving molecular aberration, BCR-ABL, and the development of a potent and specific inhibitor, imatinib. Equally important was the timing of the targeted therapy, specifically its administration to patients with newly diagnosed disease. In solid tumors, targeted therapies are often both developed and used in metastatic malignancies after conventional approaches have failed. We postulate that this strategy is similar to using imatinib in blast-crisis CML, in which response rates are less than 15%, all patients relapse, and median survival remains only about 1 year. We hypothesize that the imatinib-led revolution in CML, including the critically important factor of timing, may be applicable to other cancers as well. Therefore, it will be important to use promising targeted therapies in the earliest phases of biomarker-defined solid tumors, before metastatic progression, to determine if outcomes can be significantly improved and, thus, establish if the success of imatinib in CML is an anomaly or a paradigm. Mol Cancer Ther; 11(12); 2549–55. ©2012 AACR.
CLT1 Targets Bladder Cancer through Integrin α5β1 and CLIC3
Authors: Knowles Lynn M. , Zewe James , Malik Gunjan , Parwani Anil V. , Gingrich Jeffrey R. , Pilch Jan 
Published: December 2012

AbstractHigh-grade non–muscle-invasive bladder cancer is commonly treated with Bacillus Calmette-Guérin, an immunotherapeutic that depends on fibronectin and tumor cell integrin α5β1 for internalization into bladder cancer cells. We previously showed that the anti-angiogenic peptide CLT1 forms cytotoxic complexes with fibronectin that are cooperatively internalized into proliferating endothelium through ligation of integrins and chloride intracellular channel 1. While CLT1 has no effect on mature, differentiated cells, we show here that CLT1 is highly cytotoxic for a panel of bladder tumor cell lines as well as a variety of cell lines derived from kidney, lung, breast, and prostate cancer. Paralleling our previous results, we found CLT1-induced tumor cell death to be increased in the presence of fibronectin, which mediated CLT1 internalization and subsequent autophagic cell death in a mechanism that depends on tumor cell integrin α5β1 and chloride intracellular channel 3 (CLIC3). This mechanistic link was further supported by our results showing upregulation of α5β1 and CLIC3 in CLT1-responsive tumor cell lines and colocalization with CLT1 in tumor tissues. Incubating tumor tissue from patients with bladder cancer with fluorescein-conjugated CLT1 resulted in a strong and specific fluorescence whereas normal bladder tissue remained negative. On the basis of its affinity for bladder tumor tissue and strong antitumor effects, we propose that CLT1 could be useful for targeting bladder cancer. Mol Cancer Res; 11(2); 194–203. ©2012 AACR.
Effects of the Tumor Necrosis Factor-α Antagonist Adalimumab on Arterial Inflammation Assessed by Positron Emission Tomography in Patients With Psoriasis
Authors: Bissonnette Robert , Tardif Jean-Claude , Harel François , Pressacco Joséphine , Bolduc Chantal , Guertin Marie-Claude 
Published: December 2012

Background—
Psoriasis is a chronic inflammatory disease associated with increased risks of myocardial infarction and stroke. Systemic treatments for moderate to severe psoriasis can reduce skin and joint inflammation; however, their effects on vascular inflammation are unknown.

Methods and Results—

This randomized, controlled trial included 30 patients with moderate to severe psoriasis and a history, or multiple risk factors, of coronary atherosclerosis. Patients were randomized (2:1) to receive either adalimumab subcutaneously for 4 months or to control nonsystemic treatment (topical therapies or phototherapy). Vascular inflammation was measured in the carotid artery and ascending aorta at baseline and week 15, by
18
F-fluorodeoxyglucose uptake on positron emission tomography. The change in target:background ratio in the vessel with highest baseline target:background ratio (primary end point) was significant at week 15 compared with baseline for patients randomized to adalimumab (–0.23 [95% CI, –0.39 to –0.08];
P
=0.004) but not for the control group (–0.10 [95% CI, –0.32 to 0.12];
P
=0.35). The difference between study arms for this primary end point did not reach statistical significance (–0.13 [95% CI, –0.01 to 0.14];
P
=0.32). The change in target:background ratio at week 15 improved with adalimumab compared with controls both in the ascending aorta (–0.26±0.11,
P
=0.021) and in carotid arteries (–0.32±0.15,
P
=0.037) when analyzed separately (secondary end points). Changes in other positron emission tomography indices also improved significantly with adalimumab compared with controls in the ascending aorta and carotids. High-sensitivity C-reactive protein decreased by 51% at week 16 with adalimumab compared with 5% in controls (
P
=0·002).

Conclusions—
The study did not meet its primary end point because the change in target:background ratio in patients randomized to adalimumab was not different from controls. Although adalimumab may reduce vascular inflammation in patients with moderate to severe psoriasis, this effect is not large enough to be demonstrated in a study with a small sample size.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NTC00940862.
CXC-Chemokine Receptor 4 Antagonist AMD3100 Promotes Cardiac Functional Recovery After Ischemia/Reperfusion Injury via Endothelial Nitric Oxide Synthase–Dependent Mechanism
Authors: Jujo Kentaro , Ii Masaaki , Sekiguchi Haruki , Klyachko Ekaterina , Misener Sol , Tanaka Toshikazu , Tongers Jörn , Roncalli Jérôme , Renault Marie-Ange , Thorne Tina , Ito Aiko , Clarke Trevor , Kamide Christine , Tsurumi Yukio , Hagiwara Nobuhisa , Qin Gangjian , Asahi Michio , Losordo Douglas W. 
Published: December 2012

Background—
CXC-chemokine receptor 4 (CXCR4) regulates the retention of stem/progenitor cells in the bone marrow (BM), and the CXCR4 antagonist AMD3100 improves recovery from coronary ligation injury by mobilizing stem/progenitor cells from the BM to the peripheral blood. Thus, we investigated whether AMD3100 also improves recovery from ischemia/reperfusion injury, which more closely mimics myocardial infarction in patients, because blood flow is only temporarily obstructed.

Methods and Results—

Mice were treated with single subcutaneous injections of AMD3100 (5 mg/kg) or saline after ischemia/reperfusion injury. Three days later, histological measurements of the ratio of infarct area to area at risk were smaller in AMD3100-treated mice than in mice administered saline, and echocardiographic measurements of left ventricular function were greater in the AMD3100-treated mice at week 4. CXCR4
+
cells were mobilized for just 1 day in both groups, but the mobilization of sca1
+
/flk1
+
cells endured for 7 days in AMD3100-treated mice compared with just 1 day in the saline-treated mice. AMD3100 upregulated BM levels of endothelial nitric oxide synthase (eNOS) and 2 targets of eNOS signaling, matrix metalloproteinase-9 and soluble Kit ligand. Furthermore, the loss of BM eNOS expression abolished the benefit of AMD3100 on sca1
+
/flk1
+
cell mobilization without altering the mobilization of CXCR4
+
cells, and the cardioprotective effects of AMD3100 were retained in eNOS-knockout mice that had been transplanted with BM from wild-type mice but not in wild-type mice with eNOS-knockout BM.

Conclusions—
AMD3100 prolongs BM progenitor mobilization and improves recovery from ischemia/reperfusion injury, and these benefits appear to occur through a previously unidentified link between AMD3100 and BM eNOS expression.
Cell Selective Cardiovascular Biology of Microsomal Prostaglandin E Synthase-1
Authors: Chen Lihong , Yang Guangrui , Xu Xiufeng , Grant Gregory , Lawson John A. , Bohlooly-Y Mohammad , FitzGerald Garret A. 
Published: December 2012

Background—

Global deletion of microsomal prostaglandin E synthase 1 (mPGES-1) in mice attenuates the response to vascular injury without a predisposition to thrombogenesis or hypertension. However, enzyme deletion results in cell-specific differential use by prostaglandin synthases of the accumulated prostaglandin H
2
substrate. Here, we generated mice deficient in mPGES-1 in vascular smooth muscle cells, endothelial cells, and myeloid cells further to elucidate the cardiovascular function of this enzyme.

Methods and Results—
Vascular smooth muscle cell and endothelial cell mPGES-1 deletion did not alter blood pressure at baseline or in response to a high-salt diet. The propensity to evoked macrovascular and microvascular thrombogenesis was also unaltered. However, both vascular smooth muscle cell and endothelial cell mPGES-1–deficient mice exhibited a markedly exaggerated neointimal hyperplastic response to wire injury of the femoral artery in comparison to their littermate controls. The hyperplasia was associated with increased proliferating cell nuclear antigen and tenascin-C expression. In contrast, the response to injury was markedly suppressed by myeloid cell depletion of mPGES-1 with decreased hyperplasia, leukocyte infiltration, and expression of proliferating cell nuclear antigen and tenascin-C. Conditioned medium derived from mPGES-1–deficient macrophages less potently induced vascular smooth muscle cell proliferation and migration than that from wild-type macrophages.

Conclusions—
Deletion of mPGES-1 in the vasculature and myeloid cells differentially modulates the response to vascular injury, implicating macrophage mPGES-1 as a cardiovascular drug target.
Youthful Memory Capacity in Old Brains: Anatomic and Genetic Clues from the Northwestern SuperAging Project
Authors: Rogalski Emily J. , Gefen Tamar , Shi Junzi , Samimi Mehrnoosh , Bigio Eileen , Weintraub Sandra , Geula Changiz , Mesulam M.-Marsel 
Published: December 2012

AbstractThe Northwestern University SuperAging Project recruits community dwellers over the age of 80 who have unusually high performance on tests of episodic memory. In a previous report, a small cohort of SuperAgers was found to have higher cortical thickness on structural MRI than a group of age-matched but cognitively average peers. SuperAgers also displayed a patch of ACC where cortical thickness was higher than in 50- to 60-year-old younger cognitively healthy adults. In additional analyses, some SuperAgers had unusually low densities of age-related Alzheimer pathology and unusually high numbers of von Economo neurons in the anterior cingulate gyrus. SuperAgers were also found to have a lower frequency of the ɛ4 allele of apolipoprotein E than the general population. These preliminary results show that above-average memory capacity can be encountered in advanced age. They also offer clues to potential biological factors that may promote resistance to age-related involutional changes in the structure and function of the brain.
Spatial Cognition and the Hippocampus: The Anterior–Posterior Axis
Authors: Nadel Lynn , Hoscheidt Siobhan , Ryan Lee R. 
Published: December 2012

AbstractWe discuss the question of differentiation along the anterior–posterior longitudinal axis of the hippocampus. Data from a recent fMRI study are reanalyzed to determine whether activations in these hippocampal regions are affected by the nature of the information being accessed during a scanning session in which participants thought about episodes from their lives. Retrieving detailed spatial relational information preferentially activated the posterior hippocampus, whereas retrieving information about locales (or contexts) preferentially activated the anterior hippocampus. These data support the view that there is functional differentiation along the longitudinal axis in humans that matches what has been seen in rats, namely, that the posterior (dorsal) hippocampus is crucial for precise spatial behavior, and the anterior (ventral) hippocampus is crucial for context coding.
Neocortical Correlates of Vibrotactile Detection in Humans
Authors: Moore Christopher I. , Crosier Emilie , Greve Douglas N. , Savoy Robert , Merzenich Michael M. , Dale Anders M. 
Published: December 2012

Abstract
This study examined the cortical representation of vibrotactile detection in humans using event-related fMRI paired with psychophysics. Suprathreshold vibrotactile stimulation activated several areas, including primary (SI) and second somatosensory cortices (SII/PV). For threshold-level stimuli, poststimulus activity in contralateral and ipsilateral SII/PV was the best correlate of detection success. In these areas, evoked signals on hit trials were significantly greater than on missed trials in all participants, and the relative activity level across stimulation amplitudes matched perceptual performance. Activity in the anterior insula and superior temporal gyrus also correlated with hits and misses, suggesting that a “ventral stream” of somatosensory representations may play a crucial role in detection. In contrast, poststimulus activity in Area SI was not well correlated with perception and showed an overall negative response profile for threshold-level stimulation. A different correlate of detection success was, however, observed in SI. Activity in this representation immediately before stimulus onset predicted performance, a finding that was unique to SI. These findings emphasize the potential role of SII/PV in detection, the importance of state dynamics in SI for perception, and the possibility that changes in the temporal and spatial pattern of SI activity may be essential to the optimal representation of threshold-level stimuli for detection.
Evaluation of Wearable Simulation Interface for Military Training
Authors: Taylor Grant S. , Barnett John S. 
Published: December 2012

Objective: This research evaluated the training effectiveness of a novel simulation interface, a wearable computer integrated into a soldier’s load-bearing equipment. Background: Military teams often use game-based simulators on desktop computers to train squad-level procedures. A wearable computer interface that mimics the soldier’s equipment was expected to provide better training through increased realism and immersion. Method: A heuristic usability evaluation and two experiments were conducted. Eight evaluators interacted with both wearable and desktop interfaces and completed a usability survey. The first experiment compared the training retention of the wearable interface with a desktop simulator and interactive training video. The second experiment compared the training transfer of the wearable and desktop simulators with a live training environment. Results: Results indicated the wearable interface was more difficult to use and elicited stronger symptoms of simulator sickness. There was no significant difference in training retention between the wearable, desktop, or interactive video training methods. The live training used in the second experiment provided superior training transfer than the simulator conditions, with no difference between the desktop and wearable. Conclusion: The wearable simulator interface did not provide better training than the desktop computer interface. It also had poorer usability and caused worse simulator sickness. Therefore, it was a less effective training tool. Application: This research illustrates the importance of conducting empirical evaluations of novel training technologies. New and innovative technologies are always coveted by users, but new does not always guarantee improvement.
The Application of Reduced-Processing Decision Support Systems to Facilitate the Acquisition of Decision-Making Skills
Authors: Perry Nathan C. , Wiggins Mark W. , Childs Merilyn , Fogarty Gerard 
Published: December 2012

Objective: The study was designed to examine whether the availability of reduced-processing decision support system interfaces could improve the decision making of inexperienced personnel in the context of firefighting. Background: Although research into reduced-processing decision support systems has demonstrated benefits in minimizing cognitive load, these benefits have not typically translated into direct improvements in decision accuracy because of the tendency for inexperienced personnel to focus on less-critical information. The authors investigated whether reduced-processing interfaces that direct users’ attention toward the most critical cues for decision making can produce improvements in decision-making performance. Method: Novice participants made incident command-related decisions in experimental conditions that differed according to the amount of information that was available within the interface, the level of control that they could exert over the presentation of information, and whether they had received decision training. Results: The results revealed that despite receiving training, participants improved in decision accuracy only when they were provided with an interface that restricted information access to the most critical cues. Conclusion: It was concluded that an interface that restricts information access to only the most critical cues in the scenario can facilitate improvements in decision performance. Application: Decision support system interfaces that encourage the processing of the most critical cues have the potential to improve the accuracy and timeliness of decisions made by inexperienced personnel.
The Cultural Dimensions of Urban Fragmentation
Authors: Bayón María Cristina , Saraví Gonzalo A. 
Published: December 2012

In the past few decades, Mexico City has experienced the continuity of traditional patterns of urbanization and the emergence of new urban processes after globalization and neoliberal reforms. The result of this confluence of persistent and emerging trends is not wholly transparent, and the social and urban fragmentation of the city is under debate. Structural trends are not enough to understand these processes; sociocultural dimensions should also be addressed. The experience of the city and the patterns of sociability in the privileged and disadvantaged classes are characterized by contrasting urban lifestyles, as well as social homogeneity, reciprocal isolation and closure, mutual indifference, stigmatization, and fear. The scale of urban segregation is decreasing; the rich and the poor may live physically closer, but the spaces for interaction and encounter are becoming increasingly homogeneous and distant in social terms. These sociocultural dimensions shed light on a new Latin American geography of urban inequality that undermines social cohesion and the experience of citizenship. En las ultimas décadas la Ciudad de México ha experimentado tanto la continuación de su patrón tradicional de urbanización como la aparición de nuevos procesos urbanos como consecuencia de la globalización y las reformas neoliberales. El resultado de esta confluencia de corrientes persistentes y emergentes no es del todo transparente, y se debate la fragmentación social y urbana de la ciudad. No basta con examinar tendencias estructurales, también se tiene que dirigir atención a las dimensiones socioculturales. La experiencia de la ciudad y el patrón de sociabilidad dentro de las clases privilegiadas y desventajadas se contrastan por sus formas de vida urbana, como por su respectiva homogeneidad social, su aislamiento reciproco y cierre, su indiferencia mutua, su estigmatización, y sus temores. Se va disminuyendo la escala de la segregación; los ricos y pobres pueden vivir mas cercanos físicamente, pero los espacios para la interacción y encuentro se tornan cada vez mas homogéneos y distantes en términos sociales. Estas dimensiones socioculturales iluminan una nueva geografía latinoamericana de desigualdad urbana que mina la cohesión social y la experiencia de la ciudadanía.