bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Pathways: Targeting the CXCR4–CXCL12 Axis—Untapped Potential in the Tumor Microenvironment
Authors: Scala Stefania 
Published: July 2015

Abstract
Evidence suggests that the CXC–chemokine receptor-4 pathway plays a role in cancer cell homing and metastasis, and thus represents a potential target for cancer therapy. The homeostatic microenvironment chemokine CXCL12 binds the CXCR4 and CXCR7 receptors, activating divergent signals on multiple pathways, such as ERK1/2, p38, SAPK/JNK, AKT, mTOR, and the Bruton tyrosine kinase (BTK). An activating mutation in CXCR4 is responsible for a rare disease, WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), and dominant CXCR4 mutations have also been reported in Waldenstrom macroglobulinemia. The CXCR4–CXCL12 axis regulates the hematopoietic stem cell niche—a property that has led to the approval of the CXCR4 antagonist plerixafor (AMD3100) for mobilization of hematopoietic precursors. In preclinical models, plerixafor has shown antimetastatic potential in vivo, offering proof of concept. Other antagonists are in preclinical and clinical development. Recent evidence demonstrates that inhibiting CXCR4 signaling restores sensitivity to CTLA-4 and PD-1 checkpoint inhibitors, creating a new line for investigation. Targeting the CXCR4–CXCL12 axis thus offers the possibility of affecting CXCR4-expressing primary tumor cells, modulating the immune response, or synergizing with other targeted anticancer therapies. Clin Cancer Res; 21(19); 4278–85. ©2015 AACR.
Notch Pathway Inhibition Using PF-03084014, a γ-Secretase Inhibitor (GSI), Enhances the Antitumor Effect of Docetaxel in Prostate Cancer
Authors: Cui Di , Dai Jinlu , Keller Jill M. , Mizokami Atsushi , Xia Shujie , Keller Evan T. 
Published: July 2015

AbstractPurpose: To investigate the efficacy and mechanisms of Notch signaling inhibition as an adjuvant to docetaxel in castration-resistant prostate cancer (CRPC) using a γ-secretase inhibitor (GSI), PF-03084014.Experimental Design: The effect of PF-03084014 on response to docetaxel was evaluated in docetaxel-sensitive and docetaxel-resistant CRPC cell lines in vitro and in murine models. Both soft tissue and bone sites were evaluated in vivo. Impacts on cell proliferation, apoptosis, cancer stem cells, and angiogenesis were evaluated.Results: The combination of PF-03084014 plus docetaxel reduced both docetaxel-sensitive and docetaxel-resistant CRPC tumor growth in soft tissue and bone greater than either agent alone. Antitumor activity was associated with PF-03084014–induced inhibition of Notch pathway signaling; decreased survival signals (cyclin E; MEK/ERK, PI3K/AKT, EGFR and NF-κB pathway; BCL-2, BCL-XL); increased apoptotic signals (BAK, BAX; cleaved caspase-3); reduced microvessel density; reduced epithelial–mesenchymal transition; and reduced cancer stem–like cells in the tumor.Conclusions: These results reveal that PF-03084014 enhances docetaxel-mediated tumor response and provides a rationale to explore GSIs as adjunct therapy in conjunction with docetaxel for men with CRPC. Clin Cancer Res; 21(20); 4619–29. ©2015 AACR.See related commentary by Zhang and Armstrong, p. 4505
The value of the thromboelastometry heparinase assay (HEPTEM) in cardiac surgery
Authors: Lancé Marcus Daniel , van der Steeg Robin , Boer Christa , Meesters Michael Isaäc 
Published: July 2015

SummaryThe thromboelastometry INTEM clotting time (CT) with heparinase (HEPTEM) is frequently used to detect residual heparin after cardiopulmonary bypass (CPB) in cardiac surgery. This study investigated whether the HEPTEM CT reflects the presence of residual heparin and the association of the protamine-to-heparin ratio to the INTEM and HEPTEM CT. We retrospectively evaluated thromboelastometry data that were obtained before CPB and after protamine infusion following CPB in two tertiary hospitals. The number of patients with an INTEM:HEPTEM ratio (IH-ratio) > 1, suggesting residual heparin, were quantified. Moreover, the influence of different protamine-to-heparin-dosing-ratios (P:H) on the INTEM and HEPTEM CT was evaluated in the clinical setting and in blood drawn from healthy volunteers. An INTEM:HEPTEM CT ratio > 1.1 was observed in 16% of the patients prior to CPB, and in 15% after protamine administration. Interestingly, 23% and 36% of the patients had an HEPTEM CT exceeding the INTEM CT before CPB and following protamine administration. The HEPTEM CT was longer than the INTEM CT in patients with a P:H-ratio of 1:1 (265 ± 132 vs 260 ± 246 s; p=0.002) or P:H-ratio of 1.3:1 (357 ± 174 vs 292 ± 95 s; p=0.001). Increasing P:H-ratios induced a prolonged HEPTEM CT in fresh blood. In conclusion, limited agreement was observed between INTEM and HEPTEM clotting time in the absence of heparin. INTEM comparison to HEPTEM may not always reliably reflect the presence of residual heparin, while protamine may additionally affect the latter test. These observations complicate HEPTEM results interpretation in clinical situations with suspected residual heparin effect after protamine.
Impact of Contrast-Induced Acute Kidney Injury After Percutaneous Coronary Intervention on Short- and Long-Term Outcomes
Authors: Giacoppo Daniele , Madhavan Mahesh V. , Baber Usman , Warren Josephine , Bansilal Sameer , Witzenbichler Bernhard , Dangas George D. , Kirtane Ajay J. , Xu Ke , Kornowski Ran , Brener Sorin J. , Généreux Philippe , Stone Gregg W. , Mehran Roxana 
Published: July 2015

Background—
Contrast-induced acute kidney injury (CI-AKI), defined as a serum creatinine increase ≥0.5 mg/dL or ≥25% within 72 hours after contrast exposure, is a common complication of procedures requiring contrast media and is associated with increased short- and long-term morbidity and mortality. Few studies describe the effects of CI-AKI in a large-scale acute coronary syndrome population, and the relationship between CI-AKI and bleeding events has not been extensively explored. We sought to evaluate the impact of CI-AKI after percutaneous coronary intervention in patients presenting with acute coronary syndrome.

Methods and Results—

We pooled patient-level data for 9512 patients from the percutaneous coronary intervention cohorts of the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) and Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) multicenter randomized trials. Patients were classified according to CI-AKI development, and cardiovascular outcomes at 30 days and 1 year were compared between groups. A total of 1212 patients (12.7%) developed CI-AKI. Patients with CI-AKI were older, with a more extensive comorbidity profile than without CI-AKI. Multivariable analysis confirmed several previously identified predictors of CI-AKI, including diabetes mellitus, contrast volume, age, and baseline hemoglobin. Mortality rates were significantly higher in the CI-AKI group at 30 days (4.9% versus 0.7%;
P
<0.0001) and 1 year (9.8% versus 2.9%;
P
<0.0001), as were rates of 1-year myocardial infarction, definite/probable stent thrombosis, target lesion revascularization, and major adverse cardiac events. Major bleeding (13.8% versus 5.4%; hazard ratio, 2.64; 95% confidence interval, 2.21–3.15;
P
<0.0001) was also higher in patients with CI-AKI. After multivariable adjustment, results were unchanged.

Conclusions—
CI-AKI after percutaneous coronary intervention in patients presenting with acute coronary syndrome is independently associated with increased risk of short- and long-term ischemic and hemorrhagic events.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifiers: NCT00433966 (HORIZONS-AMI) and ACUITY (NCT00093158).
Combination of the Immune Modulator Fingolimod With Alteplase in Acute Ischemic Stroke
Authors: Zhu Zilong , Fu Ying , Tian Decai , Sun Na , Han Wei , Chang Guoqiang , Dong Yinhua , Xu Xiaolin , Liu Qiang , Huang DeRen , Shi Fu-Dong 
Published: July 2015

Background—
Inflammatory and immune responses triggered by brain ischemia worsen clinical outcomes of stroke and contribute to hemorrhagic transformation, massive edema, and reperfusion injury associated with intravenous alteplase. We assessed whether a combination of the immune-modulator fingolimod and alteplase is safe and effective in attenuating reperfusion injury in patients with acute ischemic stroke treated within the first 4.5 hours of symptom onset.

Methods and Results—

In this multicenter trial, we randomly assigned 25 eligible patients with hemispheric ischemic stroke stemming from anterior or middle cerebral arterial occlusion to receive alteplase alone and 22 patients to receive alteplase plus oral fingolimod 0.5 mg daily for 3 consecutive days within 4.5 hours of the onset of ischemic stroke. Compared with patients who received alteplase alone, patients who received the combination of fingolimod with alteplase exhibited lower circulating lymphocytes, smaller lesion volumes (10.1 versus 34.3 mL;
P
=0.04), less hemorrhage (1.2 versus 4.4 mL;
P
=0.01), and attenuated neurological deficits in National Institute of Health Stroke Scales (4 versus 2;
P
=0.02) at day 1. Furthermore, restrained lesion growth from day 1 to 7 (−2.3 versus 12.1 mL;
P
<0.01) with a better recovery at day 90 (modified Rankin Scale score 0–1, 73% versus 32%;
P
<0.01) was evident in patients given fingolimod and alteplase. No serious adverse events were recorded in all patients.

Conclusions—
In this pilot study, combination therapy of fingolimod and alteplase was well tolerated, attenuated reperfusion injury, and improved clinical outcomes in patients with acute ischemic stroke. These findings need to be tested in further clinical trials.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02002390.
Perception Versus Actual Performance in Timely Tissue Plasminogen Activation Administration in the Management of Acute Ischemic Stroke
Authors: Lin Cheryl B. , Cox Margueritte , Olson DaiWai M. , Britz Gavin W. , Constable Mark , Fonarow Gregg C. , Schwamm Lee , Peterson Eric D. , Shah Bimal R. 
Published: July 2015

Background

Timely thrombolytic therapy can improve stroke outcomes. Nevertheless, the ability of US hospitals to meet guidelines for intravenous tissue plasminogen activator (
tPA
) remains suboptimal. What is unclear is whether hospitals accurately perceive their rate of
tPA
“door‐to‐needle” (
DTN
) time within 60 minutes and how
DTN
rates compare across different hospitals.

Methods and Results

DTN
performance was defined by the percentage of treated patients who received
tPA
within 60 minutes of arrival. Telephone surveys were obtained from staff at 141 Get With The Guidelines hospitals, representing
top, middle
, and
low
DTN
performance. Less than one‐third (29.1%) of staff accurately identified their
DTN
performance. Among middle‐ and low‐performing hospitals (n=92), 56 sites (60.9%) overestimated their performance; 42% of middle performers and 85% of low performers overestimated their performance. Sites that overestimated tended to have lower annual volumes of
tPA
administration (median 8.4 patients [25th to 75th percentile 5.9 to 11.8] versus 10.2 patients [25th to 75th percentile 8.2 to 17.3],
P
=0.047), smaller percentages of eligible patients receiving
tPA
(84.7% versus 89.8%,
P
=0.008), and smaller percentages of
DTN
≤60 minutes among treated patients (10.6% versus 16.6%,
P
=0.002).

Conclusions

Hospitals often overestimate their ability to deliver timely
tPA
to treated patients. Our findings indicate the need to routinely provide comparative provider performance rates as a key step to improving the quality of acute stroke care.
The meaning of a high plasma free haemoglobin: retrospective review of the prevalence of haemolysis and circuit thrombosis in an adult ECMO centre over 5 years
Authors: Pan K C , McKenzie D P , Pellegrino V , Murphy D , Butt W 
Published: July 2015

Aims: In adults requiring extracorporeal membrane oxygenation (ECMO), we wanted to determine; i) the frequency of elevated plasma free haemoglobin (PFHb), ii) the reasons for circuit changes and iii) whether elevated PFHb was associated with higher in-hospital mortality. Materials and Methods: Patients requiring ECMO between January 2010 and August 2014 were identified from a prospectively collected ECMO database. Their scanned medical records and pathology results were reviewed. Relevant patient, biochemical and circuit data were collected on an Excel spreadsheet and analysed using Stata 13 (StataCorp, College Station, TX). The patients were analysed in three groups, depending on their peak PFHb during ECMO: ‘Normal PFHb’ (<0.1 g/L), ‘Low level PFHb’ (0.1 – 0.5 g/L), ‘High level PFHb’ (>0.5 g/L). Main Results: There were 184 ECMO runs (56 VV, 128 VA) – 61 ‘Normal PFHb’, 99 ‘Low level PFHb’, 24 ‘High level PFHb’. Circuit thrombosis (pump, oxygenator) or haemolysis requiring exchanges were significantly more common in VV ECMO compared to VA ECMO – 23.21% (13/56) vs. 0.78% (1/128), p<0.001. Elevated PFHb was associated with a longer duration of haemofiltration (p<0.001) and ECMO support (p<0.001). In-hospital mortality rates for the ‘Normal PFHb’, ‘Low level PFHb’ and ‘High level PFHb’ groups were 16.39% (10/61), 30.30% (30/99) and 37.50% (9/24), respectively, p=0.067. Conclusion: Elevated PFHb values during adult ECMO were common. Severe haemolysis or thrombosis requiring circuit changes were uncommon and occurred almost exclusively on VV ECMO. There was a non-statistically significant increase in in-hospital mortality with elevated PFHb and studies of larger registry data may clarify the prognostic value of PFHb in adult patients.
Update on the Methodological Quality of Research Published in The American Journal of Sports Medicine
Authors: Brophy Robert H. , Kluck Dylan , Marx Robert G. 
Published: July 2015

Background: In recent years, the number of articles in The American Journal of Sports Medicine (AJSM) has risen dramatically, with an increasing emphasis on evidence-based medicine in orthopaedics and sports medicine. Hypothesis: Despite the increase in the number of articles published in AJSM over the past decade, the methodological quality of articles in 2011-2013 has improved relative to those in 2001-2003 and 1991-1993. Study Design: Meta-analysis. Methods: All articles published in AJSM during 2011-2013 were reviewed and classified by study design. For each article, the use of pertinent methodologies, such as prospective data collection, randomization, control groups, and blinding, was recorded. The frequency of each article type and the use of evidence-based techniques were compared relative to 1991-1993 and 2001-2003 by use of Pearson χ2 testing. Results: The number of research articles published in AJSM more than doubled from 402 in 1991-1993 and 423 in 2001-2003 to 953 in 2011-2013. Case reports decreased from 15.2% to 10.6% to 2.1% of articles published over the study period ( P < .001). Cadaveric/human studies and meta-analysis/literature review studies increased from 5.7% to 7.1% to 12.4% ( P < .001) and from 0.2% to 0.9% to 2.3% ( P = .01), respectively. Randomized, prospective clinical trials increased from 2.7% to 5.9% to 7.4% ( P = .007). Fewer studies used retrospective compared with prospective data collection ( P < .001). More studies tested an explicit hypothesis ( P < .001) and used controls ( P < .001), randomization ( P < .001), and blinding of those assessing outcomes ( P < .001). Multi-investigator trials increased ( P < .001), as did the proportion of articles citing a funding source ( P < .001). Conclusion: Despite a dramatic increase in the number of published articles, the research published in AJSM shifted toward more prospective, randomized, controlled, and blinded designs during 2011-2013 compared with 2001-2003 and 1991-1993, demonstrating a continued improvement in methodological quality.
Population attributable fractions and joint effects of key risk factors for multiple sclerosis
Authors: van der Mei IAF , Lucas RM , Taylor BV , Valery PC , Dwyer T , Kilpatrick TJ , Pender MP , Williams D , Chapman C , Otahal P , Ponsonby A-L 
Published: July 2015

Aim: We examined the combined effect of having multiple key risk factors and the interactions between the key risk factors of multiple sclerosis (MS). Methods: We performed an incident case-control study including cases with a first clinical diagnosis of central nervous system demyelination (FCD) and population-based controls. Results: Compared to those without any risk factors, those with one, two, three, and four or five risk factors had increased odds of being an FCD case of 2.12 (95% confidence interval (CI), 1.11–4.03), 4.31 (95% CI, 2.24–8.31), 7.96 (95% CI, 3.84–16.49), and 21.24 (95% CI, 5.48–82.40), respectively. Only HLA-DR15 and history of infectious mononucleosis interacted significantly on the additive scale (Synergy index, 3.78; p = 0.03). The five key risk factors jointly accounted for 63.8% (95% CI, 43.9–91.4) of FCD onset. High anti-EBNA IgG was another important contributor. Conclusions: A high proportion of FCD onset can be explained by the currently known risk factors, with HLA-DR15, ever smoking and low cumulative sun exposure explaining most. We identified a significant interaction between HLA-DR15 and history of IM in predicting an FCD of CNS demyelination, which together with previous observations suggests that this is a true interaction.
Biotinidase deficiency mimicking neuromyelitis optica: Initially exhibiting symptoms in adulthood
Authors: Bottin Laure , Prud’hon Sabine , Guey Stéphanie , Giannesini Claire , Wolf Barry , Pindolia Kirit , Stankoff Bruno 
Published: July 2015

Background: Children with untreated biotinidase deficiency can experience variable symptoms depending on their age of presentation. Older children and adolescents can exhibit predominant neurological deficits including para- or tetraparesis and vision loss. Methods: We report the first case of delayed-onset biotinidase deficiency in a young adult. Results: A 22-year-old man presented with a disabling extensive myelopathy and bilateral optic neuropathy which mimicked the findings of a (seronegative) neuromyelitis optica. Imaging investigations were characterized by an MRI T2 hyper-intensity involving the spinal cord, the optic nerves, the fornix and the mammillar bodies, together with an increased 18F-FDG uptake on positron emission tomography. He was ultimately shown to have profound biotinidase deficiency due to a novel missense mutation and was partly improved by oral biotin therapy. Conclusion: This individual exemplifies the need to include biotinidase deficiency in the differential diagnosis of patients with extensive myelopathy and/or bilateral optic neuropathy and argues for newborn screening for the disorder.
Theoretical examination of behavioural feedback in the application of teledietetics to weight reduction
Authors: Chung Louisa MY , Fong Shirley SM , Law Queenie PS , Ma Ada WW , Chow Lina PY , Chung Joanne WY 
Published: July 2015

Introduction Behavioural feedback can be attained through electronic self-monitoring with teledietetics. This study examined the theoretical framework of the theory of planned behaviour, which suggests that behavioural feedback contributes to the intention to initiate and maintain weight loss. Methods A quasi-experiment involving adults aged 20–50 years with a body mass index greater than 23 kg/m2 was conducted. The experimental group (EG) comprised 25 participants who used electronic dietary records for self-monitoring. The control group (CG) comprised 25 participants who used paper-format dietary records for self-monitoring. Data pertaining to the theory of planned behaviour were obtained using a self-administered questionnaire. After an initial measurement, each participant’s body weight was measured again at Week 12 and at Week 24, following a 12-week observation period. Hierarchical regression analyses of planned behaviour components were conducted for each power to predict the participants’ intentions to lose 10% of their body weight. Logistic regression analysis was performed to investigate the odds ratio of intention, perceived behavioural control (PBC) and the group effect (CG vs EG) for predicting the initiation and maintenance of 10% weight loss. Results At Week 12, the odds ratios for intention, the PBC and the group effect were 2.154, 0.330 and 0.654, respectively, and those at Week 24 were 3.255, 0.499 and 24.592, respectively. The group effect contributed significantly to weight-loss maintenance at Week 24. Discussion Behavioural feedback through electronic self-monitoring improved the intention to achieve weight-loss maintenance, which may indicate the importance of behaviour reflection in weight-loss maintenance.
Piaget, Pedagogy, and Evolutionary Psychology
Authors: Genovese Jeremy E. C. 
Published: July 2015

Constructivist pedagogy draws on Piaget's developmental theory. Because Piaget depicted the emergence of formal reasoning skills in adolescence as part of the normal developmental pattern, many constructivists have assumed that intrinsic motivation is possible for all academic tasks. This paper argues that Piaget's concept of a formal operational stage has not been empirically verified and that the cognitive skills associated with that stage are in fact “biologically secondary abilities” ( Geary and Bjorklund, 2000 ) culturally determined abilities that are difficult to acquire. Thus, it is unreasonable to expect that intrinsic motivation will suffice for most students for most higher level academic tasks. In addition, a case is made that educational psychology must incorporate the insights of evolutionary psychology.
Low-dose irradiation affects the functional behavior of oral microbiota in the context of mucositis
Authors: Vanhoecke Barbara WA , De Ryck Tine RG , De boel Kevin , Wiles Siouxsie , Boterberg Tom , Van de Wiele Tom , Swift Simon 
Published: July 2015

The role of host–microbe interactions in the pathobiology of oral mucositis is still unclear; therefore, this study aimed to unravel the effect of irradiation on behavioral characteristics of oral microbial species in the context of mucositis. Using various experimental in vitro setups, the effects of irradiation on growth and biofilm formation of two Candida spp., Streptococcus salivarius and Klebsiella oxytoca in different culture conditions were evaluated. Irradiation did not affect growth of planktonic cells, but reduced the number of K. oxytoca cells in newly formed biofilms cultured in static conditions. Biofilm formation of K. oxytoca and Candida glabrata was affected by irradiation and depended on the culturing conditions. In the presence of mucins, these effects were lost, indicating the protective nature of mucins. Furthermore, the Galleria melonella model was used to study effects on microbial virulence. Irradiated K. oxytoca microbes were more virulent in G. melonella larvae compared to the nonirradiated ones. Our data indicate that low-dose irradiation can have an impact on functional characteristics of microbial species. Screening for pathogens like K. oxytoca in the context of mucosits could be useful to allow early detection and immediate intervention.