bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ca
2+
Regulation of Trypanosoma brucei Phosphoinositide Phospholipase C
Authors: King-Keller Sharon , Moore Christina A. , Docampo Roberto , Moreno Silvia N. J. 
Published: March 2015

ABSTRACT

We characterized a phosphoinositide phospholipase C (PI-PLC) from the procyclic form (PCF) of
Trypanosoma brucei
. The protein contains a domain organization characteristic of typical PI-PLCs, such as X and Y catalytic domains, an EF-hand calcium-binding motif, and a C2 domain, but it lacks a pleckstrin homology (PH) domain. In addition, the
T. brucei
PI-PLC (TbPI-PLC) contains an N-terminal myristoylation consensus sequence found only in trypanosomatid PI-PLCs. A peptide containing this N-terminal domain fused to green fluorescent protein (GFP) was targeted to the plasma membrane. TbPI-PLC enzymatic activity was stimulated by Ca
2+
concentrations below the cytosolic levels in the parasite, suggesting that the enzyme is constitutively active. TbPI-PLC hydrolyzes both phosphatidylinositol (PI) and phosphatidylinositol 4,5-bisphosphate (PIP
2
), with a higher affinity for PIP
2
. We found that modification of a single amino acid in the EF-hand motif greatly affected the protein's Ca
2+
sensitivity and substrate preference, demonstrating the role of this motif in Ca
2+
regulation of TbPI-PLC. Endogenous TbPI-PLC localizes to intracellular vesicles and might be using an intracellular source of PIP
2
. Knockdown of
TbPI-PLC
expression by RNA interference (RNAi) did not result in growth inhibition, although enzymatic activity was still present in parasites, resulting in hydrolysis of PIP
2
and a contribution to the inositol 1,4,5-trisphosphate (IP
3
)/diacylglycerol (DAG) pathway.
Understanding the causes of intravenous medication administration errors in hospitals: a qualitative critical incident study
Authors: Keers Richard N , Williams Steven D , Cooke Jonathan , Ashcroft Darren M 
Published: March 2015

ObjectivesTo investigate the underlying causes of intravenous medication administration errors (MAEs) in National Health Service (NHS) hospitals.SettingTwo NHS teaching hospitals in the North West of England.ParticipantsTwenty nurses working in a range of inpatient clinical environments were identified and recruited using purposive sampling at each study site.Primary outcome measuresSemistructured interviews were conducted with nurse participants using the critical incident technique, where they were asked to discuss perceived causes of intravenous MAEs that they had been directly involved with. Transcribed interviews were analysed using the Framework approach and emerging themes were categorised according to Reason's model of accident causation.ResultsIn total, 21 intravenous MAEs were discussed containing 23 individual active failures which included slips and lapses (n=11), mistakes (n=8) and deliberate violations of policy (n=4). Each active failure was associated with a range of error and violation provoking conditions. The working environment was implicated when nurses lacked healthcare team support and/or were exposed to a perceived increased workload during ward rounds, shift changes or emergencies. Nurses frequently reported that the quality of intravenous dose-checking activities was compromised due to high perceived workload and working relationships. Nurses described using approaches such as subconscious functioning and prioritising to manage their duties, which at times contributed to errors.ConclusionsComplex interactions between active and latent failures can lead to intravenous MAEs in hospitals. Future interventions may need to be multimodal in design in order to mitigate these risks and reduce the burden of intravenous MAEs.
Increasing the value of health research in the WHO African Region beyond 2015—reflecting on the past, celebrating the present and building the future: a bibliometric analysis
Authors: Uthman Olalekan A , Wiysonge Charles Shey , Ota Martin O , Nicol Mark , Hussey Gregory D , Ndumbe Peter M , Mayosi Bongani M 
Published: March 2015

ObjectiveTo assess the profile and determinants of health research productivity in Africa since the onset of the new millennium.DesignBibliometric analysis.Data collection and synthesisIn November 2014, we searched PubMed for articles published between 2000 and 2014 from the WHO African Region, and obtained country-level indicators from World Bank data. We used Poisson regression to examine time trends in research publications and negative binomial regression to explore determinants of research publications.ResultsWe identified 107 662 publications, with a median of 727 per country (range 25–31 757). Three countries (South Africa, Nigeria and Kenya) contributed 52% of the publications. The number of publications increased from 3623 in 2000 to 12 709 in 2014 (relative growth 251%). Similarly, the per cent share of worldwide research publications per year increased from 0.7% in 2000 to 1.3% in 2014. The trend analysis was also significant to confirm a continuous increase in health research publications from Africa, with productivity increasing by 10.3% per year (95% CIs +10.1% to +10.5%). The only independent predictor of publication outputs was national gross domestic product. For every one log US$ billion increase in gross domestic product, research publications rose by 105%: incidence rate ratio (IRR=2.05, 95% CI 1.39 to 3.04). The association of private health expenditure with publications was only marginally significant (IRR=1.86, 95% CI 1.00 to 3.47).ConclusionsThere has been a significant improvement in health research in the WHO African Region since 2000, with some individual countries already having strong research profiles. Countries of the region should implement the WHO Strategy on Research for Health: reinforcing the research culture (organisation); focusing research on key health challenges (priorities); strengthening national health research systems (capacity); encouraging good research practice (standards); and consolidating linkages between health research and action (translation).
Application of a tool for the evaluation of public and patient involvement in research
Authors: Stocks Susan Jill , Giles Sally J , Cheraghi-Sohi Sudeh , Campbell Stephen M 
Published: March 2015

ObjectivesPublic and patient involvement (PPI) is required at all stages of research by many funding bodies such as the National Institute for Health Research (NIHR). Given the high priority of PPI within NIHR programmes and the associated costs, it is important that the process of involvement and impact of PPI on health services research is evaluated. We aimed to develop a tool to quantitatively evaluate the quality of PPI in research from a PPI participant's perspective in order to inform the researchers about absolute level of quality (cross-sectional aspect) and changes in quality over time (longitudinal aspect).SettingA primary care patient safety translational research centre.ParticipantsThe 12 members of the Research User Group (RUG) of Greater Manchester Primary Care Patient Safety Translational Research Centre.InterventionsBy their own choice each RUG member supported a specific research theme. The level of involvement varied from commenting on documents through to designing their own research projects.Primary and secondary outcome measures plannedMeasure absolute score and change in score over time in a nine-point Likert score within individuals. Compare Likert scores before undertaking PPI with scores after PPI activities. Evaluate the usefulness of a questionnaire based on a theoretical framework of personal and research factors.ResultsThe questionnaire had an acceptable to good level of internal consistency (Cronbach's α 0.74–0.81). The majority of the individuals met their initial expectations (11/12) and scored high across all factors. There was no significant change over time in the aggregate score over all factors and all individuals, but there were differences within individuals and factors. A ceiling effect limited the questionnaire's usefulness to measure increasing scores.ConclusionsThe questionnaire has been useful in evaluating the early stages of a PPI group and may be generalisable to another setting.
Surgical learning curves and operative efficiency: a cross-specialty observational study
Authors: Maruthappu Mahiben , Duclos Antoine , Lipsitz Stuart R , Orgill Dennis , Carty Matthew J 
Published: March 2015

ObjectivesTo evaluate the learning curves of three high-volume procedures, from distinct surgical specialties.SettingTertiary care academic hospital.ParticipantsA prospectively collected database comprising all medical records of patients undergoing isolated coronary artery bypass grafting (CABG), total knee replacement (TKR) and bilateral reduction mammoplasty (BRM) at the Brigham and Women's Hospital, USA, 1996–2010. Multivariate generalised estimating equation (GEE) regression models were used to adjust for patient risk and clustering of procedures by surgeon.Primary outcome measureOperative efficiency.ResultsA total of 1052 BRMs, 3254 CABGs and 3325 TKRs performed by 30 surgeons were analysed. Median number of procedures per surgeon was 61 (range 11–502), 290 (52–973) and 99 (10–1871) for BRM, CABG and TKR, respectively. Mean operative times were 134.4 (SD 34.5), 180.9 (62.3) and 101.9 (30.3) minutes, respectively. For each procedure, attending surgeon experience was associated with significant reductions in operative time (p<0.05). After 15 years of experience, BRM operative time decreased by 69.8 min (38.3%), CABG operative time decreased by 17.5 min (7.8%) and TKR operative time decreased by 94.4 min (48.4%).ConclusionsCommon trends in surgical learning exist. Dependent on the procedure, experience can serve as a powerful driver of improvement or have clinically insignificant impacts on operative time.
Barriers to early diagnosis of symptomatic breast cancer: a qualitative study of Black African, Black Caribbean and White British women living in the UK
Authors: Jones Claire E L , Maben Jill , Lucas Grace , Davies Elizabeth A , Jack Ruth H , Ream Emma 
Published: March 2015

ObjectivesUnderstanding barriers to early diagnosis of symptomatic breast cancer among Black African, Black Caribbean and White British women in the UK.DesignIn-depth qualitative interviews using grounded theory methods to identify themes. Findings validated through focus groups.Participants94 women aged 33–91 years; 20 Black African, 20 Black Caribbean and 20 White British women diagnosed with symptomatic breast cancer were interviewed. Fourteen Black African and 20 Black Caribbean women with (n=19) and without (n=15) breast cancer participated in six focus groups.SettingEight cancer centres/hospital trusts in London (n=5), Somerset (n=1), West Midlands (n=1) and Greater Manchester (n=1) during 2012–2013.ResultsThere are important differences and similarities in barriers to early diagnosis of breast cancer between Black African, Black Caribbean and White British women in the UK. Differences were influenced by country of birth, time spent in UK and age. First generation Black African women experienced most barriers and longest delays. Second generation Black Caribbean and White British women were similar and experienced fewest barriers. Absence of pain was a barrier for Black African and Black Caribbean women. Older White British women (≥70 years) and first generation Black African and Black Caribbean women shared conservative attitudes and taboos about breast awareness. All women viewed themselves at low risk of the disease, and voiced uncertainty over breast awareness and appraising non-lump symptoms. Focus group findings validated and expanded themes identified in interviews.ConclusionsFindings challenged reporting of Black women homogenously in breast cancer research. This can mask distinctions within and between ethnic groups. Current media and health promotion messages need reframing to promote early presentation with breast symptoms. Working with communities and developing culturally appropriate materials may lessen taboos and stigma, raise awareness, increase discussion of breast cancer and promote prompt help-seeking for breast symptoms among women with low cancer awareness.
Synergistic effect of interaction between perceived health and social activity on depressive symptoms in the middle-aged and elderly: a population-based longitudinal study
Authors: Chun Sung-Youn , Han Kyu-Tae , Lee Seo Yoon , Kim Chan Ok , Park Eun-Cheol 
Published: March 2015

ObjectiveTo examine the synergistic effect of interaction between perceived health and social activity on depressive symptoms.MethodsWe investigated whether the interaction between perceived health and social activity has a synergistic effect on depressive symptoms in the middle-aged and elderly using data from 6590 respondents aged 45 and older in the Korean Longitudinal Study on Aging (KLoSA), 2006–2012. A generalised linear mixed-effects model was used to investigate the association in a longitudinal data form. Depressive symptoms were measured using the Center for Epidemiological Studies Depression 10 Scale (CES-D10). Perceived health and level of social activity were categorical variables with three values. Participation in six social activities was assessed.ResultsInteractions between perceived health status and social activity were statistically significant for almost all social activity/perceived health combinations. Addition of the interaction term significantly decreased CES-D10 scores, confirming the synergistic effect of the interaction between perceived health status and social activity (‘normal×moderate’, β=−0.1826; ‘poor×moderate’, β=−0.5739; ‘poor×active’, β=−0.8935). In addition, we performed stratified analyses by region: urban or rural. In urban respondents, the additional effect of the interaction term decreased CES-D10 scores and all social activity/perceived health combinations were statistically significant (‘normal×moderate’, β=−0.2578; ‘normal×active’, β=−0.3945; ‘poor×moderate’, β=−0.5739; ‘poor×active’, β=−0.8935). In rural respondents, only one social activity/perceived health combination was statistically significant, and the additional effect of the interaction term showed no consistent trend on CES-D10 scores.ConclusionsThe interaction between perceived health and social activity has a synergistic effect on depressive symptoms; the additional effect of the interaction term significantly decreased CES-D10 scores in our models.
Expression of CD133 in differentiated thyroid cancer of young patients
Authors: Decaussin-Petrucci Myriam , Deladoëy Johnny , Hafdi-Nejjari Zakia , Sassolas Geneviève , Borson-Chazot Françoise , Abu-Khudir Rasha , Fusco Alfredo , Descotes Francoise , Cournoyer Sonia , Sartelet Hervé ,   and the group of Pathologists of the Rhône Alpes Region
Published: March 2015

AimsCD133 expression in cancer is frequently associated with poor outcome. Thyroid carcinomas are rare in childhood and adolescence and are associated with a higher risk of recurrence and more metastases than the adult tumours. The aim of the study was to assess whether the expression of CD133 in thyroid carcinomas of children, adolescents and young adults was correlated with clinical prognostic factors.MethodsTissue microarrays were constructed with 235 tumours coming from 208 young adults with a median age of 28 years and 27 children with a median age of 13 years. An immunohistochemical study was performed with anti-CD133 antibody. CD133 expression was evaluated, using a semiquantitative score based on the percentage of positive cells. The mutation status of tumours was evaluated by reverse transcriptase PCR. Three cell lines were used to confirm CD133 expression by western blot.ResultsCD133 expression was found in 43% of adult and 37% of child tumours and was confirmed by western blot in cell lines. In young adults, the expression of CD133 was significantly more frequent in patients with tumours >3 cm (p=0.04) and in patients with lymph node metastases (p=0.02). The expression of CD133 was more frequent in patients in whom the tumour presented aBRAF mutation (p=0.03).ConclusionsCD133 expression is correlated with tumour size, lymph nodes metastases andBRAFmutations in young adults. The presence of these cancer stem cells could offer new therapeutic alternatives for aggressive thyroid cancers.
Genetic variations in the SOCS3 gene in patients with Graves’ ophthalmopathy
Authors: Yan Ruijia , Yang Junjie , Jiang Ping , Jin Ling , Ma Jing , Huang Rong , Ma Nan , Jiang Fagang 
Published: March 2015

AimsTo explore the role of the suppressor of cytokine signalling 3 (SOCS3) gene in Graves’ ophthalmopathy (GO) patients.MethodsA case–control study was conducted in a Chinese Han population by recruiting 114 Graves’ disease (GD) patients with GO and 156 GD patients without GO. We determined SOCS3 mRNA and protein levels in Epstein–Barr virus-transformed lymphoblastoid cell lines (EBV-LCLs) from peripheral blood mononuclear cells (PBMCs) by quantitative real-time (QRT)-PCR analysis and western blot analysis. We also genotyped five single nucleotide polymorphisms (SNPs) in the SOCS3 locus (SOCS3 rs12952093, rs4969170, rs4969168, rs4969169 and rs2280148) in all 270 GD patients using ligase detection reaction and multiplex PCR analyses. QRT-PCR and western blot assays were then performed to compare SOCS3 mRNA and protein levels between the rs4969170 AA and GG genotype groups from 20 GO patients.ResultsBasal SOCS3 mRNA and protein expression levels were significantly increased in patients with GO (p<0.05). The SOCS3 rs4969170 AA genotype was strongly associated with GO (OR=3.5, 95% CI 1.6 to 7.5, p=0.001). The AA genotype carriers had significantly higher SOCS3 mRNA and protein levels than those with the GG genotype (p<0.05).ConclusionsPatients with GD who carry the AA genotype of the rs4969170 SNP in SOCS3 are more susceptible to the development of GO.
Physico-mechanical properties and durability performance of natural building and decorative carbonate stones from Cyprus
Authors: Modestou S. , Theodoridou M. , Fournari R. , Ioannou I. 
Published: March 2015

Abstract

Natural stone was the primary building material in Cyprus in the past. Nowadays, its use is mostly confined to decorative purposes and restoration projects. This study represents the first thorough and systematic investigation of the characteristics of local carbonate stone. The variety of the results recorded highlights the complexity of this natural geomaterial and, hence, the particular attention needed before selecting the appropriate lithotype in construction practice. Stones coming from the same geological formation exhibit significant variations in their physico-mechanical properties. The materials’ durability against salt crystallization is explained with reference to their pore structure and flexural strength, revealing that, in many cases, small differences may have a significant impact on stone performance. The study also investigates the use of novel microdestructive techniques in the prediction of the mechanical properties of the stones under study. These techniques can be especially useful in the characterization of monumental stone, where sampling is limited, or when
in situ
characterization of stone is required.
miR-21 Inhibition Reduces Liver Fibrosis and Prevents Tumor Development by Inducing Apoptosis of CD24+ Progenitor Cells
Authors: Zhang Jing , Jiao Jingjing , Cermelli Silvia , Muir Kyle , Jung Kwang Hwa , Zou Ruhai , Rashid Asif , Gagea Mihai , Zabludoff Sonya , Kalluri Raghu , Beretta Laura 
Published: March 2015

Abstract
miR-21 is upregulated in hepatocellular carcinoma and intrahepatic cholangiocarcinoma, where it is associated with poor prognosis. Here, we offer preclinical evidence that miR-21 offers a therapeutic and chemopreventive target in these liver cancers. In mice with hepatic deletion of Pten, anti-miR-21 treatment reduced liver tumor growth and prevented tumor development. These effects were accompanied with a decrease in liver fibrosis and a concomitant reduction of CD24+ liver progenitor cells and S100A4+ cancer-associated stromal cells. Notch2 inhibition also occurred in tumors following anti-miR-21 treatment. We further showed that miR-21 is necessary for the survival of CD24+ progenitor cells, a cellular phenotype mediated by Notch2, osteopontin, and integrin αv. Our results identify miR-21 as a key regulator of tumor-initiating cell survival, malignant development, and growth in liver cancer, highlighting the role of CD24+ cells in the expansion of S100A4+ cancer-associated stromal cells and associated liver fibrosis. Cancer Res; 75(9); 1859–67. ©2015 AACR.
Induction of Vasculogenic Mimicry Overrides VEGF-A Silencing and Enriches Stem-like Cancer Cells in Melanoma
Authors: Schnegg Caroline I. , Yang Moon Hee , Ghosh Subrata K. , Hsu Mei-Yu 
Published: March 2015

Abstract
The basis for resistance to VEGF inhibition is not fully understood despite its clinical importance. In this study, we examined the adaptive response to VEGF-A inhibition by a loss-of-function analysis using plasmid-based shRNA. Tumor xenografts that initially responded to VEGF-A inhibition underwent an adaptation in vivo, leading to acquired resistance. VEGF-A blockade in tumors was associated with HIF1α expression and an increase in CD144+ vasculogenic mimicry (VM), leading to formation of channels displaying Tie-1 and MMP-2 upregulation. CD133+ and CD271+ melanoma stem-like cells (MSLC) accumulated in the perivascular niche. Tumor xenografts of melanoma cell populations that were intrinsically resistant to VEGF-A blockade did not exhibit any of these features, compared with nontarget control counterparts. Thus, melanomas that are initially sensitive to VEGF-A blockade acquire adaptive resistance by adopting VM as an alternate angiogenic strategy, thereby enriching for deposition of MSLC in the perivascular niche through an HIF1α-dependent process. Conversely, melanomas that are intrinsically resistant to VEGF-A blockade do not show any evidence of compensatory survival mechanisms that promote MSLC accumulation. Our work highlights the potential risk of anti-VEGF treatments owing to a selective pressure for an adaptive resistance mechanism that empowers the development of stem-like cancer cells, with implications for how to design combination therapies that can improve outcomes in patients. Cancer Res; 75(8); 1682–90. ©2015 AACR.
Paracrine WNT5A Signaling Inhibits Expansion of Tumor-Initiating Cells
Authors: Borcherding Nicholas , Kusner David , Kolb Ryan , Xie Qing , Li Wei , Yuan Fang , Velez Gabriel , Askeland Ryan , Weigel Ronald J. , Zhang Weizhou 
Published: March 2015

Abstract
It is not well understood how paracrine communication between basal and luminal cell populations in the mammary gland affects tumorigenesis. During ErbB2-induced mammary tumorigenesis, enriched mammary stem cells that represent a subpopulation of basal cells exhibit enhanced tumorigenic capacity compared with the corresponding luminal progenitors. Transcript profiling of tumors derived from basal and luminal tumor-initiating cells (TIC) revealed preferential loss of the noncanonical Wnt ligand WNT5A in basal TIC-derived tumors. Heterozygous loss of WNT5A was correlated with shorter survival of breast cancer patients. In a mouse model of ErbB2-induced breast cancer, Wnt5a heterozygosity promoted tumor multiplicity and pulmonary metastasis. As a TGFβ substrate, luminal cell-produced WNT5A induced a feed-forward loop to activate SMAD2 in a RYK and TGFβR1-dependent manner to limit the expansion of basal TIC in a paracrine fashion, a potential explanation for the suppressive effect of WNT5A in mammary tumorigenesis. Our results identify the WNT5A/RYK module as a spatial regulator of the TGFβ–SMAD signaling pathway in the context of mammary gland development and carcinogenesis, offering a new perspective on tumor suppression provided by basal–luminal cross-talk in normal mammary tissue. Cancer Res; 75(10); 1972–82. ©2015 AACR.