bluuebunny/crossref_metadata_2025_split huggingface dataset:
Persistence of DNMT3A mutations at long‐term remission in adult patients with AML
Authors: Pløen Gro G. , Nederby Line , Guldberg Per , Hansen Maria , Ebbesen Lene H. , Jensen Uffe Birk , Hokland Peter , Aggerholm Anni 
Published: August 2014

SummaryMutations in DNMT3A, the gene encoding DNA methyltransferase 3 alpha, have been identified as molecular drivers in acute myeloid leukaemia (AML) with possible implications for minimal residual disease monitoring and prognosis. To further explore the utility of DNMT3A mutations as biomarkers for AML, we developed assays for sensitive detection of recurrent mutations affecting residue R882. Analysis of DNA from 298 diagnostic AML samples revealed DNMT3A mutations in 45 cases (15%), which coincided with mutations in NPM1, FLT3 and IDH1. DNMT3A mutations were stable in 12 of 13 patients presenting with relapse or secondary myelodysplastic syndrome, but were also present in remission samples from 14 patients (at allele frequencies of <1–50%) up to 8 years after initial AML diagnosis, despite the loss of all other molecular AML markers. The mutant DNMT3A allele burden was not related to the clinical course of disease. Cell sorting demonstrated the presence of DNMT3A mutations in leukaemic blasts, but also at lower allele frequencies in T and B‐cells from the same patients. Our data are consistent with the recent finding of preleukaemic stem cells in AML, which are resistant to chemotherapy. The persistence of DNMT3A mutations during remission may have important implications for the management of AML.
Identification of binding sites for C‐terminal pro‐gastrin‐releasing peptide (GRP)‐derived peptides in renal cell carcinoma: a potential target for future therapy
Authors: Ischia Joseph , Patel Oneel , Sethi Kapil , Nordlund Marianne S. , Bolton Damien , Shulkes Arthur , Baldwin Graham S. 
Published: August 2014

ObjectiveTo determine the expression and biology of the neuroendocrine growth factor gastrin‐releasing peptide (GRP) and other proGRP‐derived peptides in renal cancer.Materials and MethodsReceptor binding studies, enzyme‐linked immunosorbent assay (ELISA) and radioimmunoassay, were used to quantitate the presence of proGRP‐derived peptide receptors and their ligands in renal cancer cell lines and human renal cancers. Biological activity of proGRP peptides was confirmed with proliferation, migration, and extracellular‐signal‐regulated kinases 1 and 2 (ERK1/2) activation assays in vitro. In vivo, ACHN renal cancer xenografts were treated with proGRP‐derived peptides to assess tumour size and necrosis. hypoxia‐inducible factor 1α (HIF1α) and vascular endothelial growth factor (VEGF) expression were investigated with Western blotting and ELISA respectively, to determine the possible contribution of the proGRP peptides to tumour viability.ResultsIn ACHN cells that expressed both proGRP‐ and GRP‐receptors, the expression of proGRP binding sites was 80‐fold greater than the GRP‐receptor (GRPR). C‐terminal proGRP‐derived peptides stimulated the activation of ERK1/2, but with a different time course to GRP, consistent with the suggestion that these peptides may have unique cellular functions. Both GRP and proGRP47–68 stimulated proliferation and migration of ACHN cells in vitro, but only GRP reduced the extent of tumour necrosis in ACHN xenografts. GRP, but not proGRP47–68, was able to induce HIF1α and VEGF expression in ACHN cells. This may account in part for the reduction in necrosis after GRP treatment. C‐terminal proGRP‐derived peptides were present in all three renal cancer cell lines and a panel of human renal cancers, but mature amidated GRP was absent.ConclusionC‐terminal proGRP peptides are more abundant in renal cancers and their cell lines than the more extensively studied amidated peptide, GRP. These results suggest that C‐terminal proGRP‐derived peptides may be a better target for novel renal cancer treatments.
Endothelin‐1 contributes to endothelial dysfunction and enhanced vasoconstriction through augmented superoxide production in penile arteries from insulin‐resistant obese rats: role of ETA and ETB receptors
Authors: Sánchez A , Martínez P , Muñoz M , Benedito S , García‐Sacristán A , Hernández M , Prieto D 
Published: August 2014

Background and PurposeWe assessed whether endothelin‐1 (ET‐1) inhibits NO and contributes to endothelial dysfunction in penile arteries in a model of insulin resistance‐associated erectile dysfunction (ED).Experimental ApproachVascular function was assessed in penile arteries, from obese (OZR) and lean (LZR) Zucker rats, mounted in microvascular myographs. Changes in basal and stimulated levels of superoxide (O2−) were detected by lucigenin‐enhanced chemiluminescence and ET receptor expression was determined by immunohistochemistry.Key ResultsET‐1 stimulated acute O2− production that was blunted by tempol and the NADPH oxidase inhibitor, apocynin, but markedly enhanced in obese animals. ET‐1 inhibited the vasorelaxant effects of ACh and of the NO donor S‐nitroso‐N‐acetyl‐DL‐penicillamine in arteries from both LZR and OZR. Selective ETA (BQ123) or ETB receptor (BQ788) antagonists reduced both basal and ET‐1‐stimulated superoxide generation and reversed ET‐1‐induced inhibition of NO‐mediated relaxations in OZR, while only BQ‐123 antagonized ET‐1 actions in LZR. ET‐1‐induced vasoconstriction was markedly enhanced by NO synthase blockade and reduced by endothelium removal and apocynin. In endothelium‐denuded penile arteries, apocynin blunted augmented ET‐1‐induced contractions in OZR. Both ETA and ETB receptors were expressed in smooth muscle and the endothelial layer and up‐regulated in arteries from OZR.Conclusions and ImplicationsET‐1 stimulates ETA‐mediated NADPH oxidase‐dependent ROS generation, which inhibits endothelial NO bioavailability and contributes to ET‐1‐induced contraction in healthy penile arteries. Enhanced vascular expression of ETB receptors contributes to augmented ROS production, endothelial dysfunction and increased vasoconstriction in erectile tissue from insulin‐resistant obese rats. Hence, antagonism of ETB receptors might improve the ED associated with insulin‐resistant states.
Autocrine secretion of 15d‐PGJ2 mediates simvastatin‐induced apoptotic burst in human metastatic melanoma cells
Authors: Wasinger Christine , Künzl Martin , Minichsdorfer Christoph , Höller Christoph , Zellner Maria , Hohenegger Martin 
Published: August 2014

Background and PurposeDespite new therapeutic approaches, metastatic melanomas still have a poor prognosis. Statins reduce low‐density lipoprotein cholesterol and exert anti‐inflammatory and anti‐proliferative actions. We have recently shown that simvastatin triggers an apoptotic burst in human metastatic melanoma cells by the synthesis of an autocrine factor.Experimental ApproachThe current in vitro study was performed in human metastatic melanoma cell lines (A375, 518a2) and primary human melanocytes and melanoma cells. The secretome of simvastatin‐stressed cells was analysed with two‐dimensional difference gel electrophoresis and MS. The signalling pathways involved were analysed at the protein and mRNA level using pharmacological approaches and siRNA technology.Key ResultsSimvastatin was shown to activate a stress cascade, leading to the synthesis of 15‐deoxy‐12,14‐PGJ2 (15d‐PGJ2), in a p38‐ and COX‐2‐dependent manner. Significant concentrations of 15d‐PGJ2 were reached in the medium of melanoma cells, which were sufficient to activate caspase 8 and the mitochondrial pathway of apoptosis. Inhibition of lipocalin‐type PGD synthase, a key enzyme for 15d‐PGJ2 synthesis, abolished the apoptotic effect of simvastatin. Moreover, 15d‐PGJ2 was shown to bind to the fatty acid‐binding protein 5 (FABP5), which was up‐regulated and predominantly detected in the secretome of simvastatin‐stressed cells. Knockdown of FABP5 abolished simvastatin‐induced activation of PPAR‐γ and amplified the apoptotic response.Conclusions and ImplicationsWe characterized simvastatin‐induced activation of the 15d‐PGJ2/FABP5 signalling cascades, which triggered an apoptotic burst in melanoma cells but did not affect primary human melanocytes. These data support the rationale for the pharmacological targeting of 15d‐PGJ2 in metastatic melanoma.
PPemd26, an anthraquinone derivative, suppresses angiogenesis via inhibiting VEGFR2 signalling
Authors: Huang S W , Lien J C , Kuo S C , Huang T F 
Published: August 2014

Background and PurposeAngiogenesis contributes to coronary heart disease, immune disorders and numerous malignancies. VEGF‐A and its receptors (VEGFRs) play a pivotal role in regulating angiogenesis. In an effort to discover more effective inhibitors of tumour angiogenesis, we have analysed the actions of a novel anthraquinone derivative, PPemd26, and explored its anti‐angiogenic mechanisms.Experimental ApproachThe effects of PPemd26 were evaluated in vitro using HUVEC cultures to assess proliferation, migration, invasion and tube formation. Immunoblotting was used to analyse phosphorylation of signalling kinases. Effects in vivo were assayed using Matrigel plug and xenograft mouse models.Key ResultsPPemd26 significantly inhibited VEGF‐A‐induced proliferation, migration, invasion and tube formation of HUVECs. PPemd26 also attenuated VEGF‐A‐induced microvessel sprouting from rat aortic rings ex vivo and suppressed formation of new blood vessels in implanted Matrigel plugs in models of angiogenesis in vivo. In addition, PPemd26 inhibited VEGF‐A‐induced phosphorylation of VEGFR2 and its downstream protein kinases including Akt, focal adhesion kinase, ERK and Src. Furthermore, systemic administration of PPemd26 suppressed the growth of s.c. xenografts of human colon carcinoma in vivo. Histochemical analysis of the xenografts revealed a marked reduction in stainingfor the vascular marker CD31 and proliferation marker Ki‐67.Conclusions and ImplicationsThis study provides evidence that PPemd26 suppressed tumour angiogenesis through inhibiting VEGFR2 signalling pathways, suggesting that PPemd26 is a potential drug candidate for developing anti‐angiogenic agents for the treatment of cancer and angiogenesis‐related diseases.
Optimal progeny body size in a solitary bee, Osmia bicornis (Apoidea: Megachilidae)
Authors: SEIDELMANN KARSTEN 
Published: August 2014

1. Females of solitary, nest‐constructing bees determine both sex (haplo‐diploidy) as well as body size (by amount of provision) of each single offspring.2. According to the Optimal Allocation Theory, females should allocate resources in portions that maximise fitness returns. A key fitness component in bees is body size that is determined solely by the provisions supplied by the mother.3. The optimal progeny body size relies on different factors in both sexes. In females, provision efficiency is crucial for reproductive success. In males, however, fitness depends primarily on mating success.4. Provision efficiency of Osmia bicornis L. females depends on the capacity to stow pollen (scopa) and their ability to carry the packed loads. Scopa capacity increases isometrically with body size whereas indices of flight performance (EPI, free lift) decrease. These complementary effects substantially contribute to the adjustment of optimal body size in daughters.5. The impact of body mass on fitness of males is determined by the mating system. Owing to the opportunistic polygyny in O. bicornis, there was no detectable correlation between body size and male mating success. Consequently, mother bees distribute their provisions to many, but small sons to increase the number of descendant competitors in the race for matings. Optimal body size in sons is a trade‐off between a large male advantage in rare scrambles over receptive females and small‐size‐related disadvantages in viability.
Prevalence of renal dysfunction in ischaemic stroke and transient ischaemic attack patients with or without atrial fibrillation
Authors: Laible M. , Horstmann S. , Rizos T. , Rauch G. , Zorn M. , Veltkamp R. 
Published: August 2014

Background and purposeChronic kidney disease (CKD) is associated with a higher risk of stroke and atrial fibrillation (AF). There are limited data on the comorbidity of renal dysfunction and AF in stroke patients. Our aim was to determine the frequency of kidney dysfunction in ischaemic stroke patients with and without AF.MethodsIn a prospectively collected, single center cohort of acute ischaemic stroke and transient ischaemic attack (TIA) patients, glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease equation on admission. Renal function was graded into five categories (cat.): cat. 1, eGRF ≥90 ml/min/1.73 m2; cat. 2, 60–89; cat. 3, 30–59; cat. 4, 15–29; cat. 5, <15. The diagnosis of AF was based on medical history, a 12‐lead electrocardiogram (ECG) and 24‐h Holter or continuous ECG monitoring.ResultsIn total, 2274 patients (1727 stroke, 547 TIA; median age 71.0) were included. Median eGFR was 78.6 ml/min/1.73 m2 (interquartile range 61/95); 21.1% were in cat. 3, 2.1% in cat. 4, 0.7% in cat. 5. In all, 535 patients (23.5%) suffered from AF; 28.0% of these were in cat. 3, 2.6% and 0.8% in cat. 4 and cat. 5, respectively. In multivariable analysis, age [odds ratio (OR) 1.1], diabetes (OR 1.8), heart failure (OR 1.7) and AF (OR 1.4) were independently associated with kidney dysfunction (eGFR < 60).ConclusionsRenal dysfunction is far more common in stroke patients than in the general population and more common in AF‐related stroke. These findings may have implications for the choice of anticoagulants.
Epilepsy is ubiquitous, but more devastating in the poorer regions of the world… or is it?
Authors: Wilmshurst Jo M. , Birbeck Gretchen L. , Newton Charles R. 
Published: August 2014

SummaryThe incidence and prevalence of active epilepsy are greatest in Africa compared to all other continents, even those with equivalent poor settings. This is a reflection of the high levels of structural and metabolic causes and may reflect an increased risk in parts of the continent. The full burden of epilepsy, which includes the social and medical morbidity of the disorder and where people with epilepsy are heavily stigmatized and frequently untreated, cannot be fully assessed even using the disability adjusted life‐years, since the assigned disability weights are not specific to these regions. The burden is further exacerbated by social, geographic, and economic barriers to care and the inability of African health systems to manage people with epilepsy effectively because of lack of trained personnel, limited facilities, and poor access to effective or sustained supplies of antiepileptic drugs, or even therapy at all. The situation is compounded by a probable underestimation of the prevalence and incidence of people with epilepsy related to the major stigma associated with the condition in Africa, and the limited training available to most health care workers who are the primary point of assessing most people with epilepsy. Finding innovative ways to address the huge barriers faced by people with epilepsy in Africa needs to be a major goal for the millennium.A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Shared Space, Conflicting Perceptions, and the Degradation of an Indonesian Fishery
Authors: Ammarell Gene 
Published: August 2014

AbstractThis article takes as its subject the degradation, through blast and cyanide fishing, of one of the world's largest and most species diverse coral reefs. Drawing attention to the role of culturally founded spatial models in orienting local perceptions and practices, it provides a case study of how such degradation can proceed unchecked when the social meanings inscribed upon a seascape by those who rely upon it as an economic resource find themselves at the intersection of conflicting cultural models of natural spaces. It is based upon ethnographic fieldwork carried out for over two decades on the small Indonesian island of Balobaloang. Relying upon indigenous cognitive models of both the fishery itself and apposite features of the social structure, including reciprocity and hierarchy, this article demonstrates how, even as they engage with the forces of global capital and universalist models of development, individual actors may continue to privilege social relationships over economic considerations and reciprocity over individual interests.
Space and Culture: Giving Directions in Tonga
Authors: Bennardo Giovanni 
Published: August 2014

AbstractGiving directions is highly revealing of one's spatial competence, and it has been extensively investigated when researching universality and variation in the representation and use of spatial relationships. When giving directions in real‐world situations, cultural parameters coparticipate in the production of linguistic production. This work reports about two “giving directions” tasks submitted in Tonga, Polynesia, to a number of subjects. The findings of the analysis conducted on the results of the tasks reveal a “Tongan” approach to giving directions that is very effective as long as you share the localized sociocultural knowledge.
Multiple Models of Space and Movement on Taumako, a Polynesian Island in the Southeastern Solomons
Authors: Feinberg Richard 
Published: August 2014

AbstractPeople of Taumako, a Polynesian community in the Solomon Islands, employ a variety of spatial models, some binary and linear, others concentric or radial. The existence of multiple models means that individuals, as they confront the challenges of daily life, must choose among alternatives and draw upon whichever ones appear most helpful at the moment. But utility depends on judgment, memory, and the selective focus of attention. Consequently, spatial understandings differ from person to person and, sometimes, in the same person from one occasion to another, highlighting the complex expression of spatial cultures in everyday contexts. As is true elsewhere, social and spatial cognition, to a degree, are intertwined. Perhaps owing to a relatively egalitarian political and social structure, however, the connection between spatial symbolism and social structure on Taumako seems attenuated. Moreover, “radiality” assumes a multiplicity of shapes and does not represent social hierarchy among the Taumako, as it does in such hierarchically ordered societies as Samoa.
Complementarity of Cognitive and Experiential Ways of Knowing the Ocean in Marshallese Navigation
Authors: Genz Joseph 
Published: August 2014

AbstractWay‐finders and navigators throughout the world have developed ways to think about and move through their particular environments. This article provides details of a wave‐based system of navigation in the Marshall Islands, in which navigators mentally recall information of the ocean from models and maps (commonly known as “stick charts”) but place a strong emphasis on perceiving the movement of waves. I argue that in Marshallese navigation a powerful dynamic emerges in the complementarity of information‐processing modes. A successful sea journey involves a combination of egocentric sensing of environmental phenomena and abstract, allocentrically framed representations. Recognition of Marshallese navigators’ ability to shift back and forth strategically among these cognitive and experiential ways of knowing the ocean offers new insights for traditional navigation in the Pacific and advances the integration of psychological and cognitive approaches to way‐finding in general.
Oriented and Disoriented Space in the Gambier, French Polynesia
Authors: Mawyer Alexander 
Published: August 2014

AbstractThis article questions the limits of reductive models of spatial orientation (e.g., land/sea or front/back dichotomies) given growing evidence of the manifold organization of space in culture and cognition. In a Pacific context, this work affirms the necessity of attending to the multiplicity of spatial models at play in the thoroughly contextually complex dynamics of even putatively straightforward everyday moments. Noting that too close attention to certain cultural models, however efficacious in their explanatory and interpretive function, can overshadow the dynamics of multiple‐encoding of lived space, this article also suggests that attention be paid not only to how spatial cultures provide toolkits that orient persons and foster efficient navigation of environmental paths and social moments, but also to how active and present cultures of space can disorient persons who may in fact be competent possessors of cultural knowledge. Finally, it observes that the stakes for careful accounting for space in Polynesia are extraordinarily high as languages such as Mangarevan in French Polynesia's Gambier islands are now under intense local and regional challenges to everyday use and long‐term survival in the ethnographic context of language change and language loss.
Feasibility of Certified Quality Management in a Comprehensive Stroke Care Network Using Telemedicine: STENO Project
Authors: Handschu René , Scibor Mateusz , Wacker Angela , Stark David R. , Köhrmann Martin , Erbguth Frank , Oschmann Patrick , Schwab Stefan , Marquardt Lars 
Published: August 2014

Background Stroke care networks with and without telemedicine have been established in several countries over the last decade to provide specialized stroke expertise to patients in rural areas. Acute consultation is a first step in the management of stroke, but not the only one. Methods of standardization of care and treatment are much needed. So far, quality management systems have only been used for single stroke units. To the best of our knowledge, we are the first stroke network worldwide to aim for certification of a network-wide quality management system. Methods The Stroke Network Using Telemedicine in Northern Bavaria (STENO), currently with 20 associated medical institutions, is one of the world's largest stroke networks, caring for over 5000 stroke patients each year. In 2010, we initiated the implementation of a network-wide ‘total’ quality management system according to ISO standard 9001:2008 in cooperation with the German Stroke Society and a third-party certification organization (LGA InterCert). Results Certification according to ISO 9001:2008 was awarded in March 2011 and maintained over a complete certification cycle of 3 years without major deviation from the norm in three external third-party audits. Thrombolysis rate significantly increased from 8·2% (2009) to 12·8% (2012). Conclusions Certified quality management within a large stroke network using telemedicine is possible and might improve stroke care procedures and thrombolysis rates. Outcome studies comparing conventional stroke care and telestroke care are inevitable.
Disclosure‐protected Inference Using Generalised Linear Models
Authors: Chipperfield James O. , O'Keefe Christine M. 
Published: August 2014

SummaryVast amounts of data that could be used in the development and evaluation of policy for the benefit of society are collected by statistical agencies. It is therefore no surprise that there is very strong demand from analysts, within business, government, universities and other organisations, to access such data. When allowing access to micro‐data, a statistical agency is obliged, often legally, to ensure that it is unlikely to result in the disclosure of information about a particular person or organisation. Managing the risk of disclosure is referred to as statistical disclosure control (SDC). This paper describes an approach to SDC for output from analysis using generalised linear models, including estimates of regression parameters and their variances, diagnostic statistics and plots. The Australian Bureau of Statistics has implemented the approach in a remote analysis system, which returns analysis output from remotely submitted queries. A framework for measuring disclosure risk associated with a remote server is proposed. The disclosure risk and utility of approach are measured in two real‐life case studies and in simulation.