bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Functionalized Human Serine Protease Granzyme B/VEGF121 Targets Tumor Vasculature and Ablates Tumor Growth
Authors: Mohamedali Khalid A. , Cao Yu , Cheung Lawrence H. , Hittelman Walter N. , Rosenblum Michael G. 
Published: July 2013

Abstract
The serine protease granzyme B (GrB) induces apoptosis through both caspase-dependent and -independent multiple-cascade mechanisms. VEGF121 binds to both VEGF receptor (VEGFR)-1 and VEGFR-2 receptors. We engineered a unique GrB/VEGF121 fusion protein and characterized its properties in vitro and in vivo. Endothelial and tumor cell lines showed varying levels of sensitivity to GrB/VEGF121 that correlated closely to total VEGFR-2 expression. GrB/VEGF121 localized efficiently into VEGFR-2–expressing cells, whereas the internalization into VEGFR-1–expressing cells was significantly reduced. Treatment of VEGFR-2+ cells caused mitochondrial depolarization in 48% of cells by 48 hours. Exposure to GrB/VEGF121 induced apoptosis in VEGFR-2+, but not in VEGFR-1+, cells and rapid caspase activation was observed that could not be inhibited by treatment with a pan-caspase inhibitor. In vivo, GrB/VEGF121 localized in perivascular tumor areas adjacent to microvessels and in other areas in the tumor less well vascularized, whereas free GrB did not specifically localize to tumor tissue. Administration (intravenous) of GrB/VEGF121 to mice at doses up to 40 mg/kg showed no toxicity. Treatment of mice bearing established PC-3 tumor xenografts with GrB/VEGF121 showed significant antitumor effect versus treatment with GrB or saline. Treatment with GrB/VEGF121 at 27 mg/kg resulted in the regression of four of five tumors in this group. Tumors showed a two-fold lower Ki-67–labeling index compared with controls. Our results show that targeted delivery of GrB to tumor vascular endothelial cells or to tumor cells activates apoptotic cascades and this completely human construct may have significant therapeutic potential. Mol Cancer Ther; 12(10); 2055–66. ©2013 AACR.
Mutual Exclusivity Analysis of Genetic and Epigenetic Drivers in Melanoma Identifies a Link Between p14ARF and RARβ Signaling
Authors: Dahl Christina , Christensen Claus , Jönsson Göran , Lorentzen Anders , Skjødt Mette Louise , Borg Åke , Pawelec Graham , Guldberg Per 
Published: July 2013

Abstract
Melanoma genomes contain thousands of alterations including: mutations, copy number alterations, structural aberrations, and methylation changes. The bulk of this variation is stochastic and functionally neutral, with only a small minority representing “drivers” that contribute to the genesis and maintenance of tumors. Drivers are often directly or inversely correlated across tumors, reflecting the molecular and regulatory signaling pathways in which they operate. Here, a profile of genetic and epigenetic drivers in 110 human melanoma cell lines was generated and searched for non-random distribution patterns. Statistically significant mutual exclusivity was revealed among components of each of the p16INK4A-CDK4-RB, RAS-RAF-MEK-ERK and PI3K-AKT signaling pathways. In addition, an inverse correlation was observed between promoter hypermethylation of retinoic acid receptor β (RARB) and CDKN2A alterations affecting p14ARF (P &lt; 0.0001), suggesting a functional link between RARβ signaling and the melanoma-suppressive activities of p14ARF. Mechanistically, all-trans retinoic acid (ATRA) treatment increased the expression of p14ARF in primary human melanocytes and the steady-state levels of p14ARF in these cells were shown to be regulated via RARβ. Furthermore, the ability of ATRA to induce senescence is reduced in p14ARF-depleted melanocytes, and we provide proof-of-concept that ATRA can induce irreversible growth arrest in melanoma cells with an intact RARβ-p14ARF signaling axis, independent of p16INK4A and p53 status.
Implications: These data highlight the power of mutual exclusivity analysis of cancer drivers to unravel molecular pathways and establish a previously unrecognized cross-talk between RARβ and p14ARF with potential implications for melanoma treatment. Mol Cancer Res; 11(10); 1166–78. ©2013 AACR.
53BP1 Is Limiting for NHEJ Repair in ATM-deficient Model Systems That Are Subjected to Oncogenic Stress or Radiation
Authors: Rybanska-Spaeder Ivana , Reynolds Taylor L. , Chou Jeremy , Prakash Mansi , Jefferson Tameca , Huso David L. , Desiderio Stephen , Franco Sonia 
Published: July 2013

Abstract
The DNA damage response (DDR) factors ataxia telangiectasia mutated (ATM) and p53 binding protein 1 (53BP1) function as tumor suppressors in humans and mice, but the significance of their mutual interaction to the suppression of oncogenic translocations in vivo has not been investigated. To address this question, the phenotypes of compound mutant mice lacking 53BP1 and ATM (Trp53bp1−/−/Atm−/−), relative to single mutants, were examined. These analyses revealed that loss of 53BP1 markedly decreased the latency of T-lineage lymphomas driven by RAG-dependent oncogenic translocations in Atm−/− mice (average survival, 14 and 23 weeks for Trp53bp1−/−/Atm−/− and Atm−/− mice, respectively). Mechanistically, 53BP1 deficiency aggravated the deleterious effect of ATM deficiency on nonhomologous end-joining (NHEJ)—mediated double-strand break repair. Analysis of V(D)J recombinase-mediated coding joints and signal joints in Trp53bp1−/−/Atm−/− primary thymocytes is, however, consistent with canonical NHEJ-mediated repair. Together, these findings indicate that the greater NHEJ defect in the double mutant mice resulted from decreased efficiency of rejoining rather than switching to an alternative NHEJ-mediated repair mechanism. Complementary analyses of irradiated primary cells indicated that defects in cell-cycle checkpoints subsequently function to amplify the NHEJ defect, resulting in more frequent chromosomal breaks and translocations in double mutant cells throughout the cell cycle. Finally, it was determined that 53BP1 is dispensable for the formation of RAG-mediated hybrid joints in Atm−/− thymocytes but is required to suppress large deletions in a subset of hybrid joints.
Implications: The current study uncovers novel ATM-independent functions for 53BP1 in the suppression of oncogenic translocations and in radioprotection.
Visual Overview: http://mcr.aacrjournals.org/content/11/10/1223/F1.large.jpg.
Mol Cancer Res; 11(10); 1223–34. ©2013 AACR.
Stratified Meta-Analysis of Intermittent Pneumatic Compression of the Lower Limbs to Prevent Venous Thromboembolism in Hospitalized Patients
Authors: Ho Kwok M. , Tan Jen Aik 
Published: July 2013

Background—
Optimal thromboprophylaxis for patients at risk of bleeding remains uncertain. This meta-analysis assessed whether intermittent pneumatic compression (IPC) of the lower limbs was effective in reducing venous thromboembolism and whether combining pharmacological thromboprophylaxis with IPC would enhance its effectiveness.

Methods and Results—

Two reviewers searched MEDLINE, EMBASE, and the Cochrane controlled trial register (1966—February 2013) for randomized, controlled trials and assessed the outcomes and quality of the trials independently. Trials comparing IPC with pharmacological thromboprophylaxis, thromboembolic deterrent stockings, no prophylaxis, and a combination of IPC and pharmacological thromboprophylaxis were considered. Trials that used IPC <24 hours or compared different types of IPC were excluded. A total of 16 164 hospitalized patients from 70 trials met the inclusion criteria and were subjected to meta-analysis. IPC was more effective than no IPC prophylaxis in reducing deep vein thrombosis (7.3% versus 16.7%; absolute risk reduction, 9.4%; 95% confidence interval [CI], 7.9–10.9; relative risk, 0.43; 95% CI, 0.36–0.52;
P
<0.01;
I
2
=34%) and pulmonary embolism (1.2% versus 2.8%; absolute risk reduction, 1.6%; 95% CI, 0.9–2.3; relative risk, 0.48; 95% CI, 0.33–0.69;
P
<0.01;
I
2
=0%). IPC was also more effective than thromboembolic deterrent stockings in reducing deep vein thrombosis and appeared to be as effective as pharmacological thromboprophylaxis but with a reduced risk of bleeding (relative risk, 0.41; 95% CI, 0.25–0.65;
P
<0.01;
I
2
=0%). Adding pharmacological thromboprophylaxis to IPC further reduced the risk of deep vein thrombosis (relative risk, 0.54; 95% CI, 0.32–0.91;
P
=0.02;
I
2
=0%) compared with IPC alone.

Conclusions—
IPC was effective in reducing venous thromboembolism, and combining pharmacological thromboprophylaxis with IPC was more effective than using IPC alone.
Neural and Psychological Maturation of Decision-making in Adolescence and Young Adulthood
Authors: Christakou Anastasia , Gershman Samuel J. , Niv Yael , Simmons Andrew , Brammer Mick , Rubia Katya 
Published: July 2013

AbstractWe examined the maturation of decision-making from early adolescence to mid-adulthood using fMRI of a variant of the Iowa gambling task. We have previously shown that performance in this task relies on sensitivity to accumulating negative outcomes in ventromedial PFC and dorsolateral PFC. Here, we further formalize outcome evaluation (as driven by prediction errors [PE], using a reinforcement learning model) and examine its development. Task performance improved significantly during adolescence, stabilizing in adulthood. Performance relied on greater impact of negative compared with positive PEs, the relative impact of which matured from adolescence into adulthood. Adolescents also showed increased exploratory behavior, expressed as a propensity to shift responding between options independently of outcome quality, whereas adults showed no systematic shifting patterns. The correlation between PE representation and improved performance strengthened with age for activation in ventral and dorsal PFC, ventral striatum, and temporal and parietal cortices. There was a medial-lateral distinction in the prefrontal substrates of effective PE utilization between adults and adolescents: Increased utilization of negative PEs, a hallmark of successful performance in the task, was associated with increased activation in ventromedial PFC in adults, but decreased activation in ventrolateral PFC and striatum in adolescents. These results suggest that adults and adolescents engage qualitatively distinct neural and psychological processes during decision-making, the development of which is not exclusively dependent on reward-processing maturation.
Blue Light Stimulates Cognitive Brain Activity in Visually Blind Individuals
Authors: Vandewalle Gilles , Collignon Olivier , Hull Joseph T. , Daneault Véronique , Albouy Geneviève , Lepore Franco , Phillips Christophe , Doyon Julien , Czeisler Charles A. , Dumont Marie , Lockley Steven W. , Carrier Julie 
Published: July 2013

Abstract
Light regulates multiple non-image-forming (or nonvisual) circadian, neuroendocrine, and neurobehavioral functions, via outputs from intrinsically photosensitive retinal ganglion cells (ipRGCs). Exposure to light directly enhances alertness and performance, so light is an important regulator of wakefulness and cognition. The roles of rods, cones, and ipRGCs in the impact of light on cognitive brain functions remain unclear, however. A small percentage of blind individuals retain non-image-forming photoreception and offer a unique opportunity to investigate light impacts in the absence of conscious vision, presumably through ipRGCs. Here, we show that three such patients were able to choose nonrandomly about the presence of light despite their complete lack of sight. Furthermore, 2 sec of blue light modified EEG activity when administered simultaneously to auditory stimulations. fMRI further showed that, during an auditory working memory task, less than a minute of blue light triggered the recruitment of supplemental prefrontal and thalamic brain regions involved in alertness and cognition regulation as well as key areas of the default mode network. These results, which have to be considered as a proof of concept, show that non-image-forming photoreception triggers some awareness for light and can have a more rapid impact on human cognition than previously understood, if brain processing is actively engaged. Furthermore, light stimulates higher cognitive brain activity, independently of vision, and engages supplemental brain areas to perform an ongoing cognitive process. To our knowledge, our results constitute the first indication that ipRGC signaling may rapidly affect fundamental cerebral organization, so that it could potentially participate to the regulation of numerous aspects of human brain function.
The Effect of Moist Convection on the Tropospheric Response to Tropical and Subtropical Zonally Asymmetric Torques
Authors: Boos William R. , Shaw Tiffany A. 
Published: July 2013

Abstract
Tropospheric winds can be altered by vertical transfers of momentum due to orographic gravity waves and convection. Previous work showed that, in dry models, such zonally asymmetric torques produce a pattern of tropical ascent that is well described by linear dynamics, together with meridional shifts of the midlatitude jet. Here a series of idealized models is used to understand the effects of moisture on the tropospheric response to tropical and subtropical zonally asymmetric, upper-tropospheric torques.
The vertical motion response to a torque is shown to be amplified by the reduction in effective static stability that occurs in moist convecting atmospheres. This amplification occurs only in precipitating regions, and the magnitude of subsidence in nonprecipitating regions saturates when clear-sky radiative cooling balances induced adiabatic warming. For basic states in which precipitation is concentrated in an intertropical convergence zone (ITCZ), most of the vertical motion response is thus confined within the basic-state ITCZ, even when the torque is remote from the ITCZ. Tropical and subtropical torques perturb the extratropical baroclinic eddy field and the convectively coupled equatorial wave field. Resulting changes in momentum flux convergence by transient eddies induce secondary meridional overturning circulations that modify the zonal-mean response to a torque. The net effect allows tropical torques to merge a double ITCZ into a single equatorial ITCZ. The response of tropical transient eddies is highly sensitive to the representation of convection, so the zonal-mean response to a torque is similarly sensitive, even when the torque is located in the subtropics.
Internal Gravity Waves in a Saturated Moist Neutral Atmosphere
Authors: Muraki David J. , Rotunno Richard 
Published: July 2013

AbstractThis work is motivated by an unusual feature associated with the start-up of a moist nearly neutral atmospheric flow over a mountain ridge that was previously observed in a full-physics numerical model. In that study, the upstream propagation of a wave of subsidence precluded the establishment of upward-displaced and saturated flow that might be expected upstream of the topography. This phenomenon was hypothesized to be a consequence of the peculiar property of saturated moist neutral flow: an upward air parcel displacement produces zero buoyancy, while a downward displacement desaturates the air parcel and produces a positive buoyancy anomaly. In the present study, this hypothesis is confirmed within numerical solutions to a reduced system of equations that incorporates the saturated-atmosphere property in a particularly simple manner. The relatively uncomplicated nature of these solutions motivates the numerical solution of a further simplified initial-value problem for both nonhydrostatic and hydrostatic flow. Exact analytic solutions are developed for the latter hydrostatic case, which explains the upstream-propagating wave of subsidence as a shock phenomenon.
Combined staining for immunohistochemical markers in the diagnosis of papillary thyroid carcinoma: Improvement in the sensitivity or specificity?
Authors: Wu Gang , Wang Jie , Zhou Zhongwen , Li Tianyi , Tang Feng 
Published: July 2013

Objectives To investigate the ability of cytokeratin (CK)-19, galectin-3, human bone marrow endothelial cell (HBME)-1 and tyrosine kinase-type cell surface receptor HER2 (HER-2/neu) to differentiate papillary thyroid carcinoma (PTC) from benign thyroid nodules. Methods Archival specimens of PTC and benign thyroid nodules were included in this retrospective immunohistochemical study. CK-19, galectin-3, HBME-1, and HER-2/neu protein levels were analysed immunohistochemically using routinely prepared tissue sections. Results Specimens from 331 patients with PTC and 664 patients with benign thyroid nodules were reviewed. For all four protein markers, the percentage of samples with cells that demonstrated positive immunostaining was significantly higher in PTC specimens than in benign thyroid nodules. As a single protein marker, CK-19 was the most sensitive (92.7%) and HBME-1 was the most specific (97.9%). The combination of CK-19 and galectin-3 was the most sensitive (82.8%), and the combinations of HBME-1 with CK-19 or galectin-3 or HER-2/neu were the most specific (98.3%). Conclusions The combination of HBME-1 and either CK19 or galectin-3 or HER-2/neu can improve the specificity of the diagnosis of PTC.
Reference Values for Proximal Femoral Anatomy in Adolescents Based on Sex, Physis, and Imaging Plane
Authors: Bixby Sarah D. , Kienle Karl-Philipp , Nasreddine Adam , Zurakowski David , Kim Young-Jo , Yen Yi-Meng 
Published: July 2013

Background: Morphological alterations of the hip joint are important contributors to the development of osteoarthritis. While plane-specific variations in the shape of the proximal femur have been described, there are no defined reference standards for measurements in adolescent patients. Purpose: To evaluate hips in asymptomatic adolescent patients using radially reformatted multidetector computed tomography (MDCT) to define the morphological characteristics of the femoral head-neck (FHN) junction with respect to patient sex and physeal status, and to establish reference values for α angle, FHN offset, and epiphyseal extension (EE). Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 132 pelvic MDCT scans in adolescent patients with abdominal pain were reformatted into radially oriented planes along the femoral necks. The diameter of the femoral head, α angle, EE, and FHN offset were measured. Reference values for α angle, EE, and FHN offset were determined, and the α angle, EE, and FHN offset were compared between open versus closed physeal status for each sex. Results: The α angle measurements in male patients were higher than in female patients in anterior (A), anterosuperior (AS), and superior (S) planes ( P < .001). The median α angle was highest for all patients in the AS plane (male, 52°; female, 49°). Open physes correlated with higher α angles compared with closed physes in all imaging planes except the AS plane. The FHN offset was lowest in the AS plane for all patients and was increased in female patients with closed physes compared with open physes in the A plane and in the A, S, posterosuperior, and posterior planes in male patients ( P < .05). There were subtle plane-specific variations in EE. Conclusion: The α angle is higher and FHN offset is lower in the AS plane in patients with closed versus open physes, whereas the opposite is true in all other planes. The α angles in male patients were higher than in female patients, although there were no significant sex-based differences in the FHN offset. The α angles were highest and FHN offset was lowest in the AS plane. There were subtle variations in EE across all planes, and the EE was higher in patients with closed versus open physes. Clinical Relevance: Plane- and sex-specific reference values for α angle, FHN offset, and EE in asymptomatic adolescent patients will assist orthopaedic surgeons and radiologists in appropriately suggesting femoroacetabular impingement based on the imaging evaluation of patients with hip pain, whose measurements lie at the periphery of or outside the reference intervals in the appropriate clinical context.
Growth of Research Associations and Journals in the Emerging Discipline of Altruistics
Authors: Smith David Horton 
Published: July 2013

This article sketches the development of the organized, interdisciplinary, global field, and emerging academic discipline of altruistics, focusing on academic journals and mainly on researcher associations founded since the Association for Research on Nonprofit Organizations and Voluntary Action (ARNOVA) in 1971. About 55 similar interdisciplinary altruistics researcher associations have been founded worldwide (48 described here; including 9 defunct), 25 of them national in geographic scope, but seven covering a world region and 11 global. Over 100 academic journals that publish research on altruistics or its sub-topics have been published, with 95 active ones described here. The author estimates that there are at least 8,000 active altruistics researchers worldwide, and perhaps as many as 20,000. The author devised the neologism “altruistics” (or alternatively, “voluntaristics”) to refer to all the phenomena of our field, individual and collective. Included are philanthropy, nonprofit sector, third sector, voluntary sector, civil society, social economy, volunteering, associations, and nonprofit organizations, among other topics. The term is similar to the term linguistics.
Fabrication and evaluation of polyaniline nanofibers via ethyl cellulose template
Authors: RenChun Fu , Jun Du , hui Huang , Zhong-Cheng Guo 
Published: July 2013

The template method for polymerization has high potential for synthesizing polymer nanotubes, nanofibers, and nanobelts because it controls the diameter and length of the material microstructure. In this study, polyaniline (PANI) nanofibers were successfully prepared with ethyl cellulose as the template. The chemical constituents and crystallinity of the PANI nanofiber samples were investigated by Fourier transform infrared spectroscopy and x-ray powder diffraction. Sample morphology was characterized by scanning and transmission electron microscopy. The size uniformity and electrical conductivity of the PANI nanofibers were also determined. The electrical conductivity of the PANI nanofibers reached up to 13.5 S cm−1 at a hydrochloric acid concentration of 1 mol L−1. The PANI nanoparticles had uniform size, and the PANI nanofibers were disordered. The mechanism of ethyl cellulose as a template for synthesizing PANI nanofibers was also analyzed. This study provides a simple method for synthesizing uniform conductive PANI nanofibers.