bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Efficacy of the Wee1 Inhibitor MK-1775 Combined with Temozolomide Is Limited by Heterogeneous Distribution across the Blood–Brain Barrier in Glioblastoma
Authors: Pokorny Jenny L. , Calligaris David , Gupta Shiv K. , Iyekegbe Dennis O. , Mueller Dustin , Bakken Katrina K. , Carlson Brett L. , Schroeder Mark A. , Evans Debra L. , Lou Zhenkun , Decker Paul A. , Eckel-Passow Jeanette E. , Pucci Vincenzo , Ma Bennett , Shumway Stuart D. , Elmquist William F. , Agar Nathalie Y.R. , Sarkaria Jann N. 
Published: January 2015

Abstract
Purpose: Wee1 regulates key DNA damage checkpoints, and in this study, the efficacy of the Wee1 inhibitor MK-1775 was evaluated in glioblastoma multiforme (GBM) xenograft models alone and in combination with radiation and/or temozolomide.
Experimental Design: In vitro MK-1775 efficacy alone and in combination with temozolomide, and the impact on DNA damage, was analyzed by Western blotting and γH2AX foci formation. In vivo efficacy was evaluated in orthotopic and heterotopic xenografts. Drug distribution was assessed by conventional mass spectrometry (MS) and matrix-assisted laser desorption/ionization (MALDI)-MS imaging.
Results: GBM22 (IC50 = 68 nmol/L) was significantly more sensitive to MK-1775 compared with five other GBM xenograft lines, including GBM6 (IC50 &gt;300 nmol/L), and this was associated with a significant difference in pan-nuclear γH2AX staining between treated GBM22 (81% cells positive) and GBM6 (20% cells positive) cells. However, there was no sensitizing effect of MK-1775 when combined with temozolomide in vitro. In an orthotopic GBM22 model, MK-1775 was ineffective when combined with temozolomide, whereas in a flank model of GBM22, MK-1775 exhibited both single-agent and combinatorial activity with temozolomide. Consistent with limited drug delivery into orthotopic tumors, the normal brain to whole blood ratio following a single MK-1775 dose was 5%, and MALDI-MS imaging demonstrated heterogeneous and markedly lower MK-1775 distribution in orthotopic as compared with heterotopic GBM22 tumors.
Conclusions: Limited distribution to brain tumors may limit the efficacy of MK-1775 in GBM. Clin Cancer Res; 21(8); 1916–24. ©2015 AACR.
Prospective National Study of the Prevalence, Incidence, Management and Outcome of a Large Contemporary Cohort of Patients With Incident Non‐Valvular Atrial Fibrillation
Authors: Haim Moti , Hoshen Moshe , Reges Orna , Rabi Yardena , Balicer Ran , Leibowitz Morton 
Published: January 2015

Background

There are few studies of atrial fibrillation (
AF
) outside of North America or Europe. The aim of the present study was to assess the prevalence, incidence, management and outcomes of patients with new atrial fibrillation, in a large contemporary cohort (2004–2012) of adult patients.

Methods and Results

The Clalit Health Services (
CHS
) computerized database of 2 420 000 adults, includes data of community clinic visits, hospital discharge records, medical diagnoses, medications, medical interventions, and laboratory test results. The prevalence of
AF
on January 1, 2004 was 71 644 (3%). Prevalence and incidence of
AF
increased with age and was higher in men versus women. During the study period (2004–2012) 98 811 patients developed new non‐valvular
AF
(mean age −72, 50% women, 46% with cardiovascular disease, 6% with prior stroke). The rate of persistent warfarin use (dispensed for >3 months in a calendar year) was low (25.7%) and it increased with increasing stroke risk score. Individual Time in Therapeutic Range (
TTR
) among warfarin users was 42%. The incidence rate of ischemic stroke and death increased with age. The rate of stroke increased from 2 per 1000 person years in patients with CHA
2
DS
2
_VASC SCORE of 0, to 58 per 1000 person years in those with a score of 9.

Conclusions

In the present study the prevalence and incidence of
AF
, stroke, and death were comparable to those reported in Europe and North America. The low use of anticoagulation calls for measures to increase adherence to current treatment recommendations in order to improve outcomes.
Detecting Subtle Seasonal Transitions of Upwelling in North-Central Chile
Authors: Rahn David A. , Rosenblüth Benjamín , Rutllant José A. 
Published: January 2015

AbstractBiological productivity in the ocean along the Chilean coast is tied to upwelling that is primarily forced by equatorward wind stress and wind stress curl on the ocean surface. Southerly alongshore flow is driven by the southeast Pacific (SEP) anticyclone, and its intensity and position vary on a range of time scales. Variability of the SEP anticyclone has been linked to large-scale circulations such as El Niño–Southern Oscillation and the Madden–Julian oscillation. The actual timing, duration, and nature of the seasonal meridional drift of the SEP anticyclone are associated with the onset, demise, and strength of the local upwelling season. Seasonal variation is especially marked at the Punta Lavapié (37°S) upwelling focus, where there is a clear upwelling season associated with a change of the cumulative upwelling index (CUI) slope between positive and negative. The Punta Lengua de Vaca (30°S) focus typically exhibits upwelling year-round and has less distinct transitions, making it more difficult to identify an enhanced upwelling season. A two-phase linear regression model, which is typically used to detect subtle climate changes, is applied here to detect seasonal changes in CUI at Punta Lengua de Vaca. This method objectively finds distinct transitions for most years. The spring-to-summer transition is more readily detected and the slackening of the upwelling-favorable winds, warmer waters, and longer wind strengthening–relaxation cycles change the coastal upwelling ecosystem. While the spring-to-summer transition at Punta Lengua de Vaca could be influenced by large-scale circulations, the actual dates of transition are highly variable and do not show a clear relationship.
Analyzing the Effects of Human-Aware Motion Planning on Close-Proximity Human–Robot Collaboration
Authors: Lasota Przemyslaw A. , Shah Julie A. 
Published: January 2015

Objective: The objective of this work was to examine human response to motion-level robot adaptation to determine its effect on team fluency, human satisfaction, and perceived safety and comfort. Background: The evaluation of human response to adaptive robotic assistants has been limited, particularly in the realm of motion-level adaptation. The lack of true human-in-the-loop evaluation has made it impossible to determine whether such adaptation would lead to efficient and satisfying human–robot interaction. Method: We conducted an experiment in which participants worked with a robot to perform a collaborative task. Participants worked with an adaptive robot incorporating human-aware motion planning and with a baseline robot using shortest-path motions. Team fluency was evaluated through a set of quantitative metrics, and human satisfaction and perceived safety and comfort were evaluated through questionnaires. Results: When working with the adaptive robot, participants completed the task 5.57% faster, with 19.9% more concurrent motion, 2.96% less human idle time, 17.3% less robot idle time, and a 15.1% greater separation distance. Questionnaire responses indicated that participants felt safer and more comfortable when working with an adaptive robot and were more satisfied with it as a teammate than with the standard robot. Conclusion: People respond well to motion-level robot adaptation, and significant benefits can be achieved from its use in terms of both human–robot team fluency and human worker satisfaction. Application: Our conclusion supports the development of technologies that could be used to implement human-aware motion planning in collaborative robots and the use of this technique for close-proximity human–robot collaboration.
Does ethnicity have an impact on duration of untreated psychoses: A retrospective study in Singapore
Authors: Basu Sutapa , Subramaniam Mythily , Abdin Edimansyah , Poon Lye Yin , Verma Swapna 
Published: January 2015

Background: Some studies have suggested ethnicity as being one of the causes leading to a longer duration of untreated psychosis (DUP) in first episode psychosis. Aim: We sought to investigate this issue, in a large cohort of patients with a first episode of psychosis, in Singapore. Method: In this naturalistic retrospective study, 794 patients accepted into Early Psychosis Intervention Programme (EPIP) services in Singapore were recruited. Diagnosis was made based on SCID 1 (Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), Axis I Disorders). Information about DUP and sociodemographic characteristics was collected from patients and relatives. Positive and Negative Symptom Scale (PANSS) and Global Assessment of Functioning (GAF) Scale were used as tools to assess the severity of symptoms and functioning of the patient, respectively, at baseline, 3, 6, 12 and 24  months. Results: The mean and 50th quantile (median) of DUP for this sample were 14.2 and 6, respectively. The mean and median DUP were higher among Indians than in the other ethnic groups. After adjusting for demographic variables, Indian ethnicity was significantly associated with higher median and 75th Percentile DUP than Chinese. Secondary and tertiary education and diagnosis of affective psychosis and brief psychotic disorder (vs. schizophrenia spectrum and delusional disorder) were also significantly associated with lower mean, median and 75th percentile DUP symptoms. Increase in age was significantly associated with higher mean, median and 75th percentile DUP while married and separated/divorced (vs. single) was significantly associated with lower mean and 75th percentile DUP. Conclusion: This study found a positive correlation between certain ethnic groups and DUP. Indian ethnicity, older age, single, lower education and patients diagnosed with schizophrenia spectrum and delusional disorders were more likely to be associated with longer DUP.
Inhibitory effect of chronic oral treatment with fluoxetine on capsaicin-induced external carotid vasodilatation in anaesthetised dogs
Authors: Muñoz-Islas Enriqueta , González-Hernández Abimael , Lozano-Cuenca Jair , Ramírez-Rosas Martha Beatríz , Medina-Santillán Roberto , Centurión David , MaassenVanDenBrink Antoinette , Villalón Carlos M 
Published: January 2015

Background During migraine, capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), resulting in cranial vasodilatation and central nociception. Moreover, 5-HT is involved in the pathophysiology of migraine and depression. Interestingly, some limited lines of evidence suggest that fluoxetine may be effective in migraine prophylaxis, but the underlying mechanisms are uncertain. Hence, this study investigated the canine external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine before and after acute and chronic oral treatment with fluoxetine. Methods Forty-eight vagosympathectomised male mongrel dogs were prepared to measure blood pressure, heart rate and external carotid blood flow. The thyroid artery was cannulated for infusions of agonists. In 16 of these dogs, a spinal cannula was inserted (C1–C3) for infusions of 5-HT. Results The external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine remained unaffected after intracarotid or i.v. fluoxetine. In contrast, the vasodilator responses to capsaicin, but not those to α-CGRP or acetylcholine, were inhibited after chronic oral treatment with fluoxetine (300 µg/kg; for 90 days) or intrathecal 5-HT. Conclusions Chronic oral fluoxetine inhibited capsaicin-induced external carotid vasodilatation, and this inhibition could partly explain its potential prophylactic antimigraine action.
Renal outcomes among Egyptian lupus nephritis patients: a retrospective analysis of 135 cases from a single centre
Authors: Mahmoud G A , Zayed H S , Ghoniem S A 
Published: January 2015

Objectives The objective of this paper is to describe renal outcomes in a group of Egyptian patients with lupus nephritis and to identify variable prognostic factors. Patients and methods The records of 135 patients (129 females, six males) with biopsy-proven lupus nephritis seen between 1999 and 2011 at Kasr Al-Aini Hospital, Cairo University, were reviewed and included in a retrospective analysis. Biopsies were classified according to the WHO classification. Renal outcomes were defined according to the Renal Subcommittee of Renal Insufficiency of the American College of Rheumatology. Results The mean follow-up period was 55.64 ± 25.68 (range 4–156) months. Thirty-nine patients (29.9%) developed an adverse final outcome. This composite outcome, defined as persistent elevation of serum creatinine ≥ 1.2 mg/dl, chronic renal insufficiency, end-stage renal disease or death, was seen in 12 (8.9%), seven (5.2%), three (2.2%) and 17 (12.6%) patients, respectively. The overall patient survival was 93.5% and 87.5% at five and 10 years, respectively. Factors associated with an adverse outcome included male gender ( p = 0.037), hypertension at nephritis onset ( p = 0.001), serum creatinine ≥1.2 mg/dl ( p < 0.001), urinary casts ( p = 0.006), anticardiolipin antibodies ( p = 0.03), class IV nephritis ( p < 0.001), hyaline thrombosis (0.003), glomerular sclerosis ( p = 0.002), tubular atrophy( p < 0.001), interstitial fibrosis ( p < 0.001) and a higher chronicity index ( p = 0.006). Time-dependent factors associated with an adverse outcome included failure to achieve remission within the first year, uncontrolled hypertension, persistently low C3 and development of flares ( p = 0.003, < 0.001, = 0.004, = 0.003, respectively). Conclusion The association of several adverse prognostic factors with the development of poor renal outcome has been confirmed in this study.
Amphotericin B stimulates γδ T and NK cells, and enhances protection from Salmonella infection
Authors: Hedges Jodi F , Mitchell Angela M , Jones Kerri , Kimmel Emily , Ramstead Andrew G , Snyder Deann T , Jutila Mark A 
Published: January 2015

Amphotericin B (AmB) is a commonly used antifungal drug, with well-documented effects on cellular immune responses. We determined that AmB-stimulated γδ T-cell activation and proliferation in vitro at very low concentrations. AmB also enhanced IFN-γ production by NK cells in combination with IL-18. AmB had a greater effect on IFN-γ production in cells isolated from very young animals. Although innate immunostimulatory aspects of AmB have been defined, AmB has not been extensively applied in non-fungal infection settings. Given that γδ T cells are increased and activated in Salmonella infection in cattle, we assessed the effects of AmB in protection from Salmonella enterocolitis in calves. One injection of AmB, at approximately one-tenth of the concentration used in human patients to counter fungal infection, or saline control, was delivered intravenously to calves prior to infection with Salmonella. This single injection caused no adverse effects, reduced disease symptoms from Salmonella enterocolitis and significantly reduced Salmonella bacteria shed in feces of infected animals. Our findings suggest that AmB may be an inexpensive and readily available prophylactic approach for the prevention of bacterial infection in calves.
Prophylactic Fresh Frozen Plasma Infusion is Ineffective in Reversing Warfarin Anticoagulation and Preventing Delayed Intracranial Hemorrhage After Falls
Authors: Reddy Subhash , Sharma Rohit , Grotts Jonathan , Ferrigno Lisa , Kaminski Stephen 
Published: January 2015

Background: Elderly patients, with considerable fall risk, are increasingly anticoagulated to prevent thromboembolic disease. We hypothesized that a policy of prophylactic fresh frozen plasma (FFP) infusion in patients having falls would reverse vitamin K antagonists (VKAs) and that reversal would decrease delayed intracranial hemorrhage (ICH). Methods: A retrospective review of patients with trauma admitted to a level 2 community trauma center was performed from January 2010 until November 2012. Inclusion criteria were: ground level fall (GLF) with suspected head trauma, on VKA, an international normalized ratio (INR) of >1.5, and a negative head computed tomography (CT). Patients were transfused with FFP to a goal INR of <1.5 while observed. Patients were classified as reversed (REV) if the lowest INR achieved within 4 to 24 hours after initial INR was <1.5 or unreversed (NREV) if lowest INR achieved was >1.5. Chi-square and logistic regression were performed. Results: A total of 194 patients met the criteria. In all, 43 (22%) patients were able to be REV, and 151 (78%) patients remained NREV. Unreversed patients were male and younger ( P < .05). There was no difference in mean FFP received. Unreversed patients had a higher initial INR of 3.0 compared to REV patients (2.5; P = .018). One patient developed a delayed ICH and belonged to the REV group. Conclusion: The incidence of delayed hemorrhage was 0.5%. A strategy of prophylactic FFP infusion was ineffective in VKA reversal. We recommend against prophylactic infusion of FFP during a period of observation for patients on VKA with suspected head trauma and a negative initial CT.
Social Enterprises in Lima: Notions and Operating Models
Authors: Farber Vanina Andrea , Caballero Susy , Prialé María Angela , Fuchs Rosa María 
Published: January 2015

The social enterprise movement in Lima is gathering momentum. An increasing number of people are taking an interest in this field of activity, in events that help spread the word about its significance, and in a range of initiatives aimed at promoting the phenomenon. In Peru, in general, and in Lima, in particular, there has been a growing interest in promoting the social enterprise movement in recent years, with good results. Young people in particular are more aware of social and environmental issues and look upon enterprises as organisations with the legitimacy and the potential to address these problems. The interest in social enterprises has not, however, been accompanied by the creation of a knowledge base that may help us understand better the peculiarities and complexities of this promising sector. Our article proposes to bridge this gap in knowledge. It is is divided into two sections: ( i) definitions; and ( ii) operating models for social enterprises. The first section sets out various definitions and interpretations of the term ‘social enterprise’, while the second part provides an empirical account of six different operating models for social enterprises that are active in Lima. Specifically, this part explains the relationship between social enterprises, the market and the intended beneficiaries. We contend that understanding this three-dimensional relationship is essential for developing a credible knowledge base for social enterprises and their value to the wider economy and society. We use qualitative methodology to support our empirical observations. Our extensive review of the literature enables us to draw down three conceptual and practical propositons which we explore through 39 in-depth interviews were held with government officials, social entrepreneurs, academics and representatives of non-governmental, multilateral aid and private-sector organisations related in some way to social enterprises. The study was carried out as part of the ‘International Comparative Social Enterprise Models’ project, financed by the Belgian Science Policy Office in collaboration with the EMES International Research Network.
Socialising Entrepreneurship: An Activist Approach
Authors: Pillay Poppet , Mitra Jay 
Published: January 2015

Our objective is to explain critically the possibility of direct participation of researchers and respondents in the development of information technology (IT)-based social entrepreneurship projects at a further education and training (FET) college in KwaZulu-Natal, South Africa. We use concepts of innovative social practice, risk-taking, the motivation of entrepreneurs and the creation of social value ( Dees, 2001 ; Smith, Barr, Barbosa & Kickul, 2008 ; Trexler, 2008) . We use these ideas to inform our methodology of action research and participatory involvement of researchers to locate our work in both theory and practice ( Bornstein & Davis, 2010 ; Kemmis, 2008 ; Reason & Bradbury, 2008 ; Stringer, 2007 ). We use Stringer's (2007) community-based participatory research model which includes three major stages: looking, thinking and acting while observation and reflection are processes that occur in the evolution of each stage. The need to work collaboratively with the participants and to build a network of relationships to improve the economic and social lives of individuals and communities is central to our approach. The data collected in the research were arranged in themes using the sustainable livelihoods framework. Our findings demonstrate how the development of social enterprises can be contextualised to provide a greater understanding of the challenges faced by marginalised communities in terms of developing enterprises and the actions necessary for creating value from this research. Of the two important outcomes, the first was the formation of a cooperative called Xumana-IT by the participants and the researchers. The second outcome involved the development of a model for developing social entrepreneurship at FET colleges. The research outcomes show first how the involvement of non-profit and non-governmental organisations together with for-profit social enterprises in South African regions can be brought together for collaborative effort. Second, we show how FE institutions could become centres of social entrepreneurship in both urban and rural areas to support marginalised communities using a ‘socially-involved’ approach. They could be supported by universities by way of curriculum development for social entrepreneurship since there is nothing currently available. Third, the value of our research is in the demonstration of the value of entrepreneurial activism through research-based activity which enables enquiry and action to combine critically to open up new routes to entrepreneurship research.
Rbfox proteins regulate tissue-specific alternative splicing of Mef2D required for muscle differentiation
Authors: Runfola Valeria , Sebastian Soji , Dilworth F. Jeffrey , Gabellini Davide 
Published: January 2015

Among Mef2 family of transcription factors, Mef2D is unique in that it undergoes tissue-specific splicing to generate an isoform essential for muscle differentiation. However, the mechanisms mediating this muscle-specific processing of Mef2D remain unknown. Using bioinformatics, we identified Rbfox proteins as putative modulators of Mef2D muscle-specific splicing. Accordingly, we found direct and specific Rbfox1 and 2 binding to Mef2D pre-mRNA in vivo. Gain and loss of function experiments demonstrated that Rbfox1 and 2 cooperate in promoting Mef2D splicing and subsequent myogenesis.
Thus, our findings reveal a novel role for Rbfox1/2 proteins in regulating myogenesis through activation of essential muscle-specific splicing events.