bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Structurally Unresolved Head Segment of Defined Length Favors Proper Measles Virus Hemagglutinin Tetramerization and Efficient Membrane Fusion Triggering
Authors: Navaratnarajah Chanakha K. , Rosemarie Quincy , Cattaneo Roberto 
Published: October 2015

ABSTRACT
Paramyxoviruses include several insidious and ubiquitous pathogens of humans and animals, with measles virus (MeV) being a prominent one. The MeV membrane fusion apparatus consists of a receptor binding protein (hemagglutinin [H]) tetramer and a fusion (F) protein trimer. Four globular MeV H heads are connected to a tetrameric stalk through flexible linkers. We sought here to characterize the function of a 17-residue H-head segment proximal to the stalk that was unresolved in all five MeV H-head crystal or cocrystal structures. In particular, we assessed whether its primary sequence and length are critical for proper protein oligomerization and intracellular transport or for membrane fusion triggering. Extensive alanine substitutions had no effect on fusion triggering, suggesting that sequence identity is not critical for this function. Excessive shortening of this segment reduced or completely abrogated fusion trigger function, while length compensation restored it. We then characterized the mechanism of function loss. Mutated H proteins were efficiently transported to the cell surface, but certain alterations enhancing linker flexibility resulted in accumulation of high-molecular-weight H oligomers. Some oligomers had reduced fusion trigger capacity, while others retained this function. Thus, length and rigidity of the unresolved head segment favor proper H tetramerization and counteract interactions between subunits from different tetramers. The structurally unresolved H-head segment, together with the top of the stalk, may act as a leash to provide the right degree of freedom for the heads of individual tetramers to adopt a triggering-permissive conformation while avoiding improper contacts with heads of neighboring tetramers.

IMPORTANCE
Understanding the molecular mechanism of membrane fusion triggering may allow development of new antiviral strategies. The fusion apparatus of paramyxoviruses consists of a receptor binding tetramer and a fusion protein trimer. Structural analyses of the receptor binding hemagglutinin-neuraminidases of certain paramyxoviruses suggest that fusion triggering is preceded by relocation of its head domains, facilitated by flexible linkers. Having noted a structurally unresolved 17-residue segment linking the globular heads to the tetrameric stalk of the measles virus hemagglutinin (H), we asked whether and how it may facilitate membrane fusion triggering. We conclude that, together with the top of the stalk, the flexible linker keeps H heads on a leash long enough to adopt a triggering-permissive conformation but short enough to limit roaming and improper contacts with heads of neighboring tetramers. All morbillivirus H-protein heads appear to be connected to their stalks through a “leash,” suggesting a conserved triggering mechanism.
Effect of teleradiology upon pattern of transfer of head injured patients from a rural general hospital to a neurosurgical referral centre: follow-up study
Authors: Ashkenazi I , Zeina A R , Kessel B , Peleg K , Givon A , Khashan T , Dudkiewicz M , Oren M , Alfici R , Olsha O 
Published: October 2015

IntroductionThe optimal management strategy for patients with head injury admitted to a non-specialist hospital is uncertain. The aim of this study was to evaluate the outcomes of victims of head injury requiring hospitalisation but initially admitted to a rural level II trauma centre without a neurosurgical facility but with a system for neurosurgical consultation via teleradiology.MethodsPatients admitted for head injury during 2006–2011 were included. Late transfer of patients initially hospitalised in the level II trauma centre was evaluated for treatment failure, defined as clinical or radiological deterioration.ResultsFive hundred and sixty-two patients were initially hospitalised in the level II trauma centre. Evaluation of late transfers showed that only 23 (4.1%) represented real treatment failures due to clinical or radiological deterioration. The clinical course was altered by primary intent to hospitalise patients in the level II trauma centre in only one patient.ConclusionsSelected patients with head trauma who have a pathological CT scan may be safely managed in level II trauma centres following neurosurgical consultation using teleradiology. Review of treatment failures is necessary to ensure proper ongoing management of a system in which neurosurgical patients are selectively transferred to trauma centres with neurosurgical capacity.
Botulinum toxin type A as an adjunct in postoperative pain management in dogs undergoing radical mastectomy
Authors: Vilhegas S. , Cassu R. N. , Barbero R. C. , Crociolli G. C. , Rocha T. L. A. , Gomes D. R. 
Published: October 2015

The aim of this randomised placebo‐controlled, observer‐blinded study was to evaluate the analgesic effects of botulinum toxin type A (BoNT‐A) as an adjunct for postoperative pain control in dogs. Sixteen dogs undergoing bilateral radical mastectomy for treatment of mammary tumours were enrolled. Twenty‐four hours before surgery, the subjects were distributed into two groups of eight dogs each: 7 iu/kg BoNT‐A (BoNT‐A) or saline (Control) was administered subcutaneously in each mammary gland. Following sedation with intramuscular 0.03 mg/kg acepromazine and 0.3 mg/kg morphine, anaesthesia was induced intravenously with 4 mg/kg propofol and maintained with isoflurane/O2. Postoperative analgesia was evaluated for 72 hours after extubation using the Visual Analogue Scale (VAS) and modified Glasgow Composite Measure Pain Scale (modified‐GCMPS). Rescue analgesia was provided with intramuscular morphine (0.5 mg/kg). Data were analysed using analysis of variance, Tukey's test, Mann‐Whitney U test and Friedman test (P<0.05). The pain scores were significantly lower in the BoNT‐A than in the Control from 8 hours to 60 hours and from 12 hours to 60 hours after extubation, based on the VAS and modified‐GCMPS, respectively. Rescue analgesia was required by significantly more dogs in the Control (7/8) compared with the BoNT‐A (2/8) (P=0.022). Pre‐emptive BoNT‐A appears to be effective as an adjuvant for postoperative pain management in dogs undergoing bilateral radical mastectomy.
Correlation of BRAF Mutation Status in Circulating-Free DNA and Tumor and Association with Clinical Outcome across Four BRAFi and MEKi Clinical Trials
Authors: Santiago-Walker Ademi , Gagnon Robert , Mazumdar Jolly , Casey Michelle , Long Georgina V. , Schadendorf Dirk , Flaherty Keith , Kefford Richard , Hauschild Axel , Hwu Patrick , Haney Patricia , O'Hagan Anne , Carver Jennifer , Goodman Vicki , Legos Jeffrey , Martin Anne-Marie 
Published: October 2015

Abstract
Purpose: Tumor-derived circulating cell–free DNA (cfDNA) is a potential alternative source from which to derive tumor mutation status. cfDNA data from four clinical studies of the BRAF inhibitor (BRAFi) dabrafenib or the MEK inhibitor (MEKi) trametinib were analyzed to determine the association between BRAF mutation status in cfDNA and tumor tissue, and the association of BRAF cfDNA mutation status with baseline factors and clinical outcome.
Experimental Design: Patients with BRAF V600 mutation–positive melanoma were enrolled in each study after central confirmation of BRAF status in tumor using a PCR-based assay. BRAF mutation status in cfDNA from patient plasma collected at baseline, 732 of 836 (88%) enrolled patients in total, was determined.
Results: BRAF mutations were detectable in cfDNA in 76% and 81% of patients with BRAF V600E/V600K–positive tumors, respectively. Patients negative for BRAF mutations in cfDNA had longer progression-free survival (PFS) and overall survival in each of the four studies, compared with patients with detectable cfDNA BRAF mutations. The presence of BRAF-mutant cfDNA was an independent prognostic factor for PFS after multivariate adjustment for baseline factors in three of four studies. Patients negative for BRAF mutation–positive cfDNA in plasma had higher response rates to dabrafenib and trametinib.
Conclusions: BRAF mutations in cfDNA are detectable in &gt;75% of late-stage melanoma patients with BRAF mutation–positive tumors. The lack of circulating, BRAF mutation–positive cfDNA is clinically significant for metastatic melanoma patients, and may be a prognostic marker for better disease outcome. Clin Cancer Res; 22(3); 567–74. ©2015 AACR.
Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes
Authors: Freeman-Keller Morganna , Kim Youngchul , Cronin Heather , Richards Allison , Gibney Geoffrey , Weber Jeffrey S. 
Published: October 2015

Abstract
Purpose: Retrospective analysis of irAEs in melanoma patients treated with nivolumab.
Experimental Design: Data were pooled from 148 patients (33 resected, 115 unresectable) treated with nivolumab plus peptide vaccine or nivolumab alone every 2 weeks for 12 weeks. Patients with stable disease or regression received an additional 12-week cycle, then nivolumab alone every 12 weeks for up to 2 additional years. Frequency, grade, and characteristics of immune-related adverse events (irAE) were analyzed. A 12-week landmark survival analysis using a multivariate time-dependent Cox proportional hazard model assessed difference in overall survival (OS) in the presence or absence of irAEs.
Results: IrAEs of any grade were observed in 68.2% of patients (101 of 148). Grade III/IV irAEs were infrequent: 3 (2%) had grade III rash, 2 (1.35%) had asymptomatic grade III elevation in amylase/lipase, and 2 (1.35%) had grade III colitis. A statistically significant OS difference was noted among patients with any grade of irAE versus those without (P ≤ 0.001), and OS benefit was noted in patients who reported three or more irAE events (P ≤ 0.001). Subset analyses showed statistically significant OS differences with rash [P = 0.001; HR, 0.423; 95% confidence interval (CI), 0.243–0.735] and vitiligo (P = 0.012; HR, 0.184; 95% CI, 0.036–0.94). Rash and vitiligo also correlated with statistically significant OS differences in patients with metastatic disease (P = 0.004 and P = 0.028, respectively). No significant survival differences were seen with other irAEs (endocrinopathies, colitis, or pneumonitis).
Conclusions: Cutaneous irAEs are associated with improved survival in melanoma patients treated with nivolumab, and clinical benefit should be validated in larger prospective analyses. Clin Cancer Res; 22(4); 886–94. ©2015 AACR.
Exposure and Tumor Fn14 Expression as Determinants of Pharmacodynamics of the Anti-TWEAK Monoclonal Antibody RG7212 in Patients with Fn14-Positive Solid Tumors
Authors: Meulendijks Didier , Lassen Ulrik N. , Siu Lillian L. , Huitema Alwin D.R. , Karanikas Vaios , Mau-Sorensen Morten , Jonker Derek J. , Hansen Aaron R. , Simcox Mary E. , Schostack Kathleen J. , Bottino Dean , Zhong Hua , Roessler Markus , Vega-Harring Suzana M. , Jarutat Tiantom , Geho David , Wang Karen , DeMario Mark , Goss Glenwood D. , Schellens Jan H.M. 
Published: October 2015

Abstract
Purpose: The TWEAK–Fn14 pathway represents a novel anticancer target that is being actively investigated. Understanding the relationship between pharmacokinetics of anti-TWEAK therapeutics and tumor pharmacodynamics is critical. We investigated exposure-response relationships of RG7212, an anti-TWEAK mAb, in patients with Fn14-expressing tumors.
Experimental Design: Patients with Fn14-positive tumors (IHC≥1+) treated in a phase I first-in-human study with ascending doses of RG7212 were the basis for this analysis. Pharmacokinetics of RG7212 and dynamics of TWEAK were determined, as were changes in tumor TWEAK–Fn14 signaling in paired pre- and posttreatment tumor biopsies. The objectives of the analysis were to define exposure-response relationships and the relationship between pretreatment tumor Fn14 expression and pharmacodynamic effect. Associations between changes in TWEAK–Fn14 signaling and clinical outcome were explored.
Results: Thirty-six patients were included in the analysis. RG7212 reduced plasma TWEAK to undetectable levels at all observed RG7212 exposures. In contrast, reductions in tumor Fn14 and TRAF1 protein expression were observed only at higher exposure (≥300 mg*h/mL). Significant reductions in tumor Ki-67 expression and early changes in serum concentrations of CCL-2 and MMP-9 were observed exclusively in patients with higher drug exposure who had high pretreatment tumor Fn14 expression. Pretreatment tumor Fn14 expression was not associated with outcome, but a trend toward longer time on study was observed with high versus low RG7212 exposure.
Conclusions: RG7212 reduced tumor TWEAK–Fn14 signaling in a systemic exposure-dependent manner. In addition to higher exposure, relatively high Fn14 expression might be required for pharmacodynamic effect of anti-TWEAK monoclonal antibodies. Clin Cancer Res; 22(4); 858–67. ©2015 AACR.
Sonic Hedgehog Signaling Drives Mitochondrial Fragmentation by Suppressing Mitofusins in Cerebellar Granule Neuron Precursors and Medulloblastoma
Authors: Malhotra Anshu , Dey Abhinav , Prasad Niyathi , Kenney Anna Marie 
Published: October 2015

Abstract
Sonic hedgehog (Shh) signaling is closely coupled with bioenergetics of medulloblastoma, the most common malignant pediatric brain tumor. Shh-associated medulloblastoma arises from cerebellar granule neuron precursors (CGNP), a neural progenitor whose developmental expansion requires signaling by Shh, a ligand secreted by the neighboring Purkinje neurons. Previous observations show that Shh signaling inhibits fatty acid oxidation although driving increased fatty acid synthesis. Proliferating CGNPs and mouse Shh medulloblastomas feature high levels of glycolytic enzymes in vivo and in vitro. Because both of these metabolic processes are closely linked to mitochondrial bioenergetics, the role of Shh signaling in mitochondrial biogenesis was investigated. This report uncovers a surprising decrease in mitochondrial membrane potential (MMP) and overall ATP production in CGNPs exposed to Shh, consistent with increased glycolysis resulting in high intracellular acidity, leading to mitochondrial fragmentation. Ultrastructural examination of mitochondria revealed a spherical shape in Shh-treated cells, in contrast to the elongated appearance in vehicle-treated postmitotic cells. Expression of mitofusin 1 and 2 was reduced in these cells, although their ectopic expression restored the MMP to the nonproliferating state and the morphology to a fused, interconnected state. Mouse Shh medulloblastoma cells featured drastically impaired mitochondrial morphology, restoration of which by ectopic mitofusin expression was also associated with a decrease in the expression of Cyclin D2 protein, a marker for proliferation.
Implications: This report exposes a novel role for Shh in regulating mitochondrial dynamics and rescue of the metabolic profile of tumor cells to that of nontransformed, nonproliferating cells and represents a potential avenue for development of medulloblastoma therapeutics. Mol Cancer Res; 14(1); 114–24. ©2015 AACR.
BRCA2 gene mutations and coagulation-associated biomarkers
Authors: Acosta Daniel , Santos-Sancho Juana María , Modrego Javier , Caldés Trinidad , Hoya Miguel de la , Díaz-Rubio Eduardo , Díaz-Millán Isabel , Heras Natalia de las , Zalba Luis Alfonso Rico , Lahera Vicente , Melander Olle , Perez-Segura Pedro , Zamorano-León José J , López Farré Antonio 
Published: October 2015

SummaryThromboembolic events are the second cause of death in cancer patients, although the mechanisms underlying this increased thromboembolic risk remain unclear. The aims of this study were to examine whether BRCA2 gene mutations may modify the circulating levels of thrombocoagulation biomarkers and whether breast cancer development may influence changes in such circulating biomarkers. The study was performed in 25 women with mutations in the BRCA2 gene (n=12 breast cancer, n=13 breast cancer-free) and in 13 BRCA2 nonmutant controls. Results revealed that plasma levels of fibrinogen gamma chain isotypes 2 and 3, haptoglobin isotypes 4 and 5, serotransferrin isotypes 3 and 4 and convertase C3/C5 isotypes 4 and 5 were significantly higher in BRCA2 mutation carriers compared to controls. However, plasma levels of vitamin D binding protein isotype 1 and alpha1-antitrypsin isotypes 2, 3 and 4 were significantly decreased in BRCA2 mutation carriers compared to controls. Plasma expression of PF4 and P-selectin was significantly higher in BRCA2 mutations carriers than in controls. BRCA2 truncated mutations conserving a binding region for RAD51 were associated with increased plasma levels of alpha1-antitrypsin isotypes 3 and 4 with respect to women showing BRCA2 mutations that loss the binding RD51 region to BRCA2. Only plasma levels of vitamin D binding protein isotypes 1 and 3 were significantly reduced and alpha 1-antitrypsin isotype 1 was increased in cancer-free BRCA2 mutation carriers compared to BRCA2 mutation carriers with breast cancer. The presence of BRCA2 mutations is associated with increased plasma levels of thrombo-coagulating-related proteins, which are independent to breast cancer development.
Women’s Rights in Intellectual Property and Traditional Knowledge Protection in Lao pdr
Authors: Phochanthilath Champathong 
Published: October 2015

Lao People’s Democratic Republic is a multicultural country within the Association of South East Asian Nations. It recently adopted the Intellectual Property Law in the context of enhancing regional and global economic integration. The traditional handicraft textile sector is important in Laos. It is of benefit to the country’s economic development, as well as being recognized as an important element of both national culture and the identity of Lao women. However, Lao craftswomen are facing a strong challenge preserving their traditional knowledge due to the extremely cheap imitations of items such as scarves and Lao skirts, which are being sold in Laos.
This article aims to discuss the existing international instruments and related national laws regarding intellectual property and protection of traditional knowledge with particular regard to women’s rights. Intellectual property and traditional knowledge issues attract more attention than intellectual property rights under the World Intellectual Property Organization regime; unesco, trips, cbd and human rights treaties, all to which Lao is a party, are also relevant. Nationally, Laos is still lacking adequate and appropriate means to protect rights of women as traditional knowledge holders in terms of national laws.
Equality and Singapore’s First Constitutional Challenges to the Criminalization of Male Homosexual Conduct
Authors: Lee Jack Tsen-Ta 
Published: October 2015

In 2013, in Lim Meng Suang and Kenneth Chee Mun-Leon v Attorney-General1 and Tan Eng Hong v Attorney-General,2 the High Court of Singapore delivered the first judgments in the jurisdiction considering the constitutionality of section 377A of the Penal Code, which criminalizes acts of ‘gross indecency’ between two men, whether they occur in public or private. The Court ruled that the provision was not inconsistent with the guarantees of equality before the law and equal protection of the law stated in Article 12(1) of the Constitution of the Republic of Singapore. The result was upheld in 2014 by the Court of Appeal in Lim Meng Suang and another v Attorney-General3 with slight differences in the reasoning. This article examines the courts’ analysis of equality law, and submits in particular that the courts ought to re-evaluate whether they should apply a presumption of constitutionality, refuse to assess the legitimacy of the object of the impugned provision, and rely on a standard of mere reasonableness or lack of arbitrariness when determining if a rational relation exists between the provision’s object and the differentia underlying a classification used in the provision.
Factors Controlling Low-Cloud Evolution over the Eastern Subtropical Oceans: A Lagrangian Perspective Using the A-Train Satellites
Authors: Eastman Ryan , Wood Robert 
Published: October 2015

Abstract
A Lagrangian technique is developed to sample satellite data to quantify and understand factors controlling temporal changes in low-cloud properties (cloud cover, areal-mean liquid water path, and droplet concentration). Over 62 000 low-cloud scenes over the eastern subtropical/tropical oceans are sampled using the A-Train satellites. Horizontal wind fields at 925 hPa from the ERA-Interim are used to compute 24-h, two-dimensional, forward, boundary layer trajectories with trajectory locations starting on the CloudSat/CALIPSO track. Cloud properties from MODIS and AMSR-E are sampled at the trajectory start and end points, allowing for direct measurement of the temporal cloud evolution. The importance of various controls (here, boundary layer depth, lower-tropospheric stability, and precipitation) on cloud evolution is evaluated by comparing cloud evolution for different initial values of these controls. Viewing angle biases are removed and cloud anomalies (diurnal and seasonal cycles removed) are used throughout to quantify cloud evolution relative to the climatological-mean evolution. Cloud property anomalies show temporal changes similar to those expected for a stochastic red noise process, with linear relationships between initial anomalies and their mean 24-h changes. This creates a potential bias when comparing the evolutions of sets of trajectories with different initial anomalies; three methods are introduced and evaluated to account for this. Results provide statistically robust observational support for theoretical/modeling studies by showing that low clouds in deep boundary layers and under weak inversions are prone to break up. Precipitation shows a more complex and less statistically significant relationship with cloud breakup. Cloud cover in shallow precipitating boundary layers is more persistent than in deep precipitating boundary layers. Liquid water path and cloud droplet concentration decrease more rapidly for precipitating clouds and in deep boundary layers.
Mechanisms of Heat Content and Thermocline Change in the Subtropical and Subpolar North Atlantic
Authors: Williams Richard G. , Roussenov Vassil , Lozier M. Susan , Smith Doug 
Published: October 2015

Abstract
In the North Atlantic, there are pronounced gyre-scale changes in ocean heat content on interannual-to-decadal time scales, which are associated with changes in both sea surface temperature and thermocline thickness; the subtropics are often warm with a thick thermocline when the subpolar gyre is cool with a thin thermocline, and vice versa. This climate variability is investigated using a semidiagnostic dynamical analysis of historical temperature and salinity data from 1962 to 2011 together with idealized isopycnic model experiments. On time scales of typically 5 yr, the tendencies in upper-ocean heat content are not simply explained by the area-averaged atmospheric forcing for each gyre but instead dominated by heat convergences associated with the meridional overturning circulation. In the subtropics, the most pronounced warming events are associated with an increased influx of tropical heat driven by stronger trade winds. In the subpolar gyre, the warming and cooling events are associated with changes in western boundary density, where increasing Labrador Sea density leads to an enhanced overturning and an influx of subtropical heat. Thus, upper-ocean heat content anomalies are formed in a different manner in the subtropical and subpolar gyres, with different components of the meridional overturning circulation probably excited by the local imprint of atmospheric forcing.