bluuebunny/crossref_metadata_2025_split huggingface dataset:
REpeated AutoLogous Infusions of STem cells In Cirrhosis (REALISTIC): a multicentre, phase II, open-label, randomised controlled trial of repeated autologous infusions of granulocyte colony-stimulating factor (GCSF) mobilised CD133+ bone marrow stem cells in patients with cirrhosis. A study protocol for a randomised controlled trial
Authors: King A , Barton D , Beard H A , Than N , Moore J , Corbett C , Thomas J , Guo K , Guha I , Hollyman D , Stocken D , Yap C , Fox R , Forbes S J , Newsome P N 
Published: March 2015

IntroductionLiver disease mortality and morbidity are rapidly rising and liver transplantation is limited by organ availability. Small scale human studies have shown that stem cell therapy is safe and feasible and has suggested clinical benefit. No published studies have yet examined the effect of stem cell therapy in a randomised controlled trial and evaluated the effect of repeated therapy.Methods and analysisPatients with liver cirrhosis will be randomised to one of three trial groups: group 1: Control group, Standard conservative management; group 2 treatment: granulocyte colony-stimulating factor (G-CSF; lenograstim) 15 µg/kg body weight daily on days 1–5; group 3 treatment: G-CSF 15 µg/kg body weight daily on days 1–5 followed by leukapheresis, isolation and aliquoting of CD133+ cells. Patients will receive an infusion of freshly isolated CD133+ cells immediately and frozen doses at days 30 and 60 via peripheral vein (0.2×106cells/kg for each of the three doses). Primary objective is to demonstrate an improvement in the severity of liver disease over 3 months using either G-CSF alone or G-CSF followed by repeated infusions of haematopoietic stem cells compared with standard conservative management. The trial is powered to answer two hypotheses of each treatment compared to control but not powered to detect smaller expected differences between the two treatment groups. As such, the overall α=0.05 for the trial is split equally between the two hypotheses. Conventionally, to detect a relevant standardised effect size of 0.8 point reduction in Model for End-stage Liver Disease score using two-sided α=0.05(overall α=0.1 split equally between the two hypotheses) and 80% power requires 27 participants to be randomised per group (81 participants in total).Ethics and disseminationThe trial is registered at Current Controlled Trials on 18 November 2009 (ISRCTN number 91288089, EuDRACT number 2009-010335-41). The findings of this trial will be disseminated to patients and through peer-reviewed publications and international presentations.
Troponin: think before you request one
Authors: Gardezi Syed Anjum 
Published: March 2015

AbstractAcute myocardial infarction (ACS) is one of the most common presentations in acute hospital settings. Troponin (cTn) has emerged as one of the most sensitive biochemical markers for the diagnosis of ACS. However, if used inappropriately and in the absence of true clinical context then it can be elevated in a number of non cardiac conditions and lead to false clinical diagnosis, inappropriate workup, and increased patient stay in hospital. The cost of unnecessary clinical testing is another aspect of the problem.At Royal Gwent Hospital in Newport (one of the busiest district general hospitals in Wales) we retrospectively analysed the nature of troponin requests over a random period of one week, specifically looking for the indications and final diagnostic impact. In many cases it was found that requests were made without any clinical justification. One of the main and probably unavoidable reasons for this was that requests were made from triage before patient was assessed by a clinician. However, steps were taken to clarify common clinical indications for suspected cardiac diagnosis in which troponin was useful. Additionally, the "tick box" practice for inappropriate laboratory investigations was discouraged. A repeat audit was done on similar basic principles and a measurable improvement was identified, with a potential for significant impact in future.
Ethnic differences in risk factors for obesity in New Zealand infants
Authors: Howe Laura D , Ellison-Loschmann Lis , Pearce Neil , Douwes Jeroen , Jeffreys Mona , Firestone Ridvan 
Published: March 2015

BackgroundIn New Zealand, the burden of childhood obesity is greatest in Māori and Pacific children.MethodsIn 687 infants from an internet-based birth cohort in New Zealand, we investigated ethnic differences in early life risk factors for later obesity, the degree to which these were explained by sociodemographic factors, and the extent to which ethnic differences in weight at age 3 months were explained by measured risk factors.ResultsThe risk of having an obese mother was double in Māori and Pacific infants compared with NZ European infants (prevalence 24% and 14%, respectively; OR 2.23, 95% CI 1.23 to 4.04). Māori and Pacific infants had higher weights in the first week of life and at 3 months (mean difference 0.19 kg, 95% CI 0.01 to 0.38), and their mothers had higher scores on a ‘snacks’ dietary pattern and lower scores on ‘healthy’ and ‘sweet’ dietary patterns. These inequalities were not explained by maternal education, maternal age or area-based deprivation. No ethnic differences were observed for maternal pre-pregnancy physical activity, hypertension or diabetes in pregnancy, exclusive breastfeeding or early introduction of solid foods. Ethnic inequalities in infant weight at 3 months were not explained by sociodemographic variables, maternal pre-pregnancy body mass index or dietary pattern scores or by other measured risk factors.ConclusionsThis study shows excess prevalence of early life risk factors for obesity in Māori and Pacific infants in New Zealand and suggests an urgent need for early interventions for these groups.
Targeting Glutamine Metabolism in Breast Cancer with Aminooxyacetate
Authors: Korangath Preethi , Teo Wei Wen , Sadik Helen , Han Liangfeng , Mori Noriko , Huijts Charlotte M. , Wildes Flonne , Bharti Santosh , Zhang Zhe , Santa-Maria Cesar A. , Tsai Hualing , Dang Chi V. , Stearns Vered , Bhujwalla Zaver M. , Sukumar Saraswati 
Published: March 2015

Abstract
Purpose: Glutamine addiction in c-MYC–overexpressing breast cancer is targeted by the aminotransferase inhibitor, aminooxyacetate (AOA). However, the mechanism of ensuing cell death remains unresolved.
Experimental Design: A correlation between glutamine dependence for growth and c-MYC expression was studied in breast cancer cell lines. The cytotoxic effects of AOA, its correlation with high c-MYC expression, and effects on enzymes in the glutaminolytic pathway were investigated. AOA-induced cell death was assessed by measuring changes in metabolite levels by magnetic resonance spectroscopy (MRS), the effects of amino acid depletion on nucleotide synthesis by cell-cycle and bromodeoxyuridine (BrdUrd) uptake analysis, and activation of the endoplasmic reticulum (ER) stress–mediated pathway. Antitumor effects of AOA with or without common chemotherapies were determined in breast cancer xenografts in immunodeficient mice and in a transgenic MMTV-rTtA-TetO-myc mouse mammary tumor model.
Results: We established a direct correlation between c-MYC overexpression, suppression of glutaminolysis, and AOA sensitivity in most breast cancer cells. MRS, cell-cycle analysis, and BrdUrd uptake measurements indicated depletion of aspartic acid and alanine leading to cell-cycle arrest at S-phase by AOA. Activation of components of the ER stress–mediated pathway, initiated through GRP78, led to apoptotic cell death. AOA inhibited growth of SUM159, SUM149, and MCF-7 xenografts and c-myc–overexpressing transgenic mouse mammary tumors. In MDA-MB-231, AOA was effective only in combination with chemotherapy.
Conclusions: AOA mediates its cytotoxic effects largely through the stress response pathway. The preclinical data of AOA's effectiveness provide a strong rationale for further clinical development, particularly for c-MYC–overexpressing breast cancers. Clin Cancer Res; 21(14); 3263–73. ©2015 AACR.
The p53 Target Gene SIVA Enables Non–Small Cell Lung Cancer Development
Authors: Van Nostrand Jeanine L. , Brisac Alice , Mello Stephano S. , Jacobs Suzanne B.R. , Luong Richard , Attardi Laura D. 
Published: March 2015

Abstract
Although p53 transcriptional activation potential is critical for its ability to suppress cancer, the specific target genes involved in tumor suppression remain unclear. SIVA is a p53 target gene essential for p53-dependent apoptosis, although it can also promote proliferation through inhibition of p53 in some settings. Thus, the role of SIVA in tumorigenesis remains unclear. Here, we seek to define the contribution of SIVA to tumorigenesis by generating Siva conditional knockout mice. Surprisingly, we find that SIVA loss inhibits non–small cell lung cancer (NSCLC) development, suggesting that SIVA facilitates tumorigenesis. Similarly, SIVA knockdown in mouse and human NSCLC cell lines decreases proliferation and transformation. Consistent with this protumorigenic role for SIVA, high-level SIVA expression correlates with reduced NSCLC patient survival. SIVA acts independently of p53 and, instead, stimulates mTOR signaling and metabolism in NSCLC cells. Thus, SIVA enables tumorigenesis in a p53-independent manner, revealing a potential new cancer therapy target.
Significance: These findings collectively reveal a novel role for the p53 target gene SIVA both in regulating metabolism and in enabling tumorigenesis, independently of p53. Importantly, these studies further identify SIVA as a new prognostic marker and as a potential target for NSCLC cancer therapy. Cancer Discov; 5(6); 622–35. ©2015 AACR.
See related commentary by Resnick-Silverman and Manfredi, p. 581
This article is highlighted in the In This Issue feature, p. 565
BRAFV600E Co-opts a Conserved MHC Class I Internalization Pathway to Diminish Antigen Presentation and CD8+ T-cell Recognition of Melanoma
Authors: Bradley Sherille D. , Chen Zeming , Melendez Brenda , Talukder Amjad , Khalili Jahan S. , Rodriguez-Cruz Tania , Liu Shujuan , Whittington Mayra , Deng Wanleng , Li Fenge , Bernatchez Chantale , Radvanyi Laszlo G. , Davies Michael A. , Hwu Patrick , Lizée Gregory 
Published: March 2015

Abstract
Oncogene activation in tumor cells induces broad and complex cellular changes that contribute significantly to disease initiation and progression. In melanoma, oncogenic BRAFV600E has been shown to drive the transcription of a specific gene signature that can promote multiple mechanisms of immune suppression within the tumor microenvironment. We show here that BRAFV600E also induces rapid internalization of MHC class I (MHC-I) from the melanoma cell surface and its intracellular sequestration within endolysosomal compartments. Importantly, MAPK inhibitor treatment quickly restored MHC-I surface expression in tumor cells, thereby enhancing melanoma antigen-specific T-cell recognition and effector function. MAPK pathway–driven relocalization of HLA-A*0201 required a highly conserved cytoplasmic serine phosphorylation site previously implicated in rapid MHC-I internalization and recycling by activated immune cells. Collectively, these data suggest that oncogenic activation of BRAF allows tumor cells to co-opt an evolutionarily conserved MHC-I trafficking pathway as a strategy to facilitate immune evasion. This link between MAPK pathway activation and the MHC-I cytoplasmic tail has direct implications for immunologic recognition of tumor cells and provides further evidence to support testing therapeutic strategies combining MAPK pathway inhibition with immunotherapies in the clinical setting. Cancer Immunol Res; 3(6); 602–9. ©2015 AACR.
Endothelial Uncoupling Protein 2 Regulates Mitophagy and Pulmonary Hypertension During Intermittent Hypoxia
Authors: Haslip Maria , Dostanic Iva , Huang Yan , Zhang Yi , Russell Kerry S. , Jurczak Michael J. , Mannam Praveen , Giordano Frank , Erzurum Serpil C. , Lee Patty J. 
Published: March 2015

Objectives—
Pulmonary hypertension (PH) is a process of lung vascular remodeling, which can lead to right heart dysfunction and significant morbidity. The underlying mechanisms leading to PH are not well understood, and therapies are limited. Using intermittent hypoxia (IH) as a model of oxidant-induced PH, we identified an important role for endothelial cell mitophagy via mitochondrial uncoupling protein 2 (Ucp2) in the development of IH-induced PH.

Approach and Results—

Ucp2 endothelial knockout (VE-KO) and Ucp2 Flox (Flox) mice were subjected to 5 weeks of IH. Ucp2 VE-KO mice exhibited higher right ventricular systolic pressure and worse right heart hypertrophy, as measured by increased right ventricle weight/left ventricle plus septal weight (RV/LV+S) ratio, at baseline and after IH. These changes were accompanied by increased mitophagy. Primary mouse lung endothelial cells transfected with Ucp2 siRNA and subjected to cyclic exposures to CoCl
2
(chemical hypoxia) showed increased mitophagy, as measured by PTEN-induced putative kinase 1 and LC3BII/I ratios, decreased mitochondrial biogenesis, and increased apoptosis. Similar results were obtained in primary lung endothelial cells isolated from VE-KO mice. Moreover, silencing PTEN-induced putative kinase 1 in the endothelium of Ucp2 knockout mice, using endothelial-targeted lentiviral silencing RNA in vivo, prevented IH-induced PH. Human pulmonary artery endothelial cells from people with PH demonstrated changes similar to Ucp2-silenced mouse lung endothelial cells.

Conclusions—
The loss of endothelial Ucp2 leads to excessive PTEN-induced putative kinase 1–induced mitophagy, inadequate mitochondrial biosynthesis, and increased apoptosis in endothelium. An endothelial Ucp2–PTEN-induced putative kinase 1 axis may be effective therapeutic targets in PH.
Poorly Cited Articles in Peer-Reviewed Cardiovascular Journals from 1997 to 2007
Authors: Ranasinghe Isuru , Shojaee Abbas , Bikdeli Behnood , Gupta Aakriti , Chen Ruijun , Ross Joseph S. , Masoudi Frederick A. , Spertus John A. , Nallamothu Brahmajee K. , Krumholz Harlan M. 
Published: March 2015

Background—
The extent to which articles are cited is a surrogate of the impact and importance of the research conducted; poorly cited articles may identify research of limited use and potential wasted investments. We assessed trends in the rates of poorly cited articles and journals in the cardiovascular literature from 1997 to 2007.

Methods and Results—

We identified original articles published in cardiovascular journals and indexed in the Scopus citation database from 1997 to 2007. We defined poorly cited articles as those with ≤5 citations in the 5 years following publication and poorly cited journals as those with >75% of journal content poorly cited. We identified 164 377 articles in 222 cardiovascular journals from 1997 to 2007. From 1997 to 2007, the number of cardiovascular articles and journals increased by 56.9% and 75.2%, respectively. Of all the articles, 75 550 (46.0%) were poorly cited, of which 25 650 (15.6% overall) had no citations. From 1997 to 2007, the proportion of poorly cited articles declined slightly (52.1%–46.2%, trend
P
<0.001), although the absolute number of poorly cited articles increased by 2595 (trend
P
<0.001). At a journal level, 44% of cardiovascular journals had more than three-fourths of the journal’s content poorly cited at 5 years.

Conclusion—
Nearly half of all peer-reviewed articles published in cardiovascular journals are poorly cited 5 years after publication, and many are not cited at all. The cardiovascular literature and the number of poorly cited articles both increased substantially from 1997 to 2007. The high proportion of poorly cited articles and journals suggests inefficiencies in the cardiovascular research enterprise.
Fibroblast Growth Factor 21 Prevents Atherosclerosis by Suppression of Hepatic Sterol Regulatory Element-Binding Protein-2 and Induction of Adiponectin in Mice
Authors: Lin Zhuofeng , Pan Xuebo , Wu Fan , Ye Dewei , Zhang Yi , Wang Yu , Jin Leigang , Lian Qizhou , Huang Yu , Ding Hong , Triggle Chris , Wang Kai , Li Xiaokun , Xu Aimin 
Published: March 2015

Background—
Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. It acts as a key downstream target of both peroxisome proliferator-activated receptor α and γ, the agonists of which have been used for lipid lowering and insulin sensitization, respectively. However, the role of FGF21 in the cardiovascular system remains elusive.

Methods and Results—

The roles of FGF21 in atherosclerosis were investigated by evaluating the impact of FGF21 deficiency and replenishment with recombinant FGF21 in apolipoprotein E
−/−
mice. FGF21 deficiency causes a marked exacerbation of atherosclerotic plaque formation and premature death in apolipoprotein E
−/−
mice, which is accompanied by hypoadiponectinemia and severe hypercholesterolemia. Replenishment of FGF21 protects against atherosclerosis in apolipoprotein E
−/−
mice via 2 independent mechanisms, inducing the adipocyte production of adiponectin, which in turn acts on the blood vessels to inhibit neointima formation and macrophage inflammation, and suppressing the hepatic expression of the transcription factor sterol regulatory element-binding protein-2, thereby leading to reduced cholesterol synthesis and attenuation of hypercholesterolemia. Chronic treatment with adiponectin partially reverses atherosclerosis without obvious effects on hypercholesterolemia in FGF21-deficient apolipoprotein E
−/−
mice. By contrast, the cholesterol-lowering effects of FGF21 are abrogated by hepatic expression of sterol regulatory element-binding protein-2.

Conclusions—
FGF21 protects against atherosclerosis via fine tuning the multiorgan crosstalk among liver, adipose tissue, and blood vessels.
Myocardial Fibrosis Burden Predicts Left Ventricular Ejection Fraction and Is Associated With Age and Steroid Treatment Duration in Duchenne Muscular Dystrophy
Authors: Tandon Animesh , Villa Chet R. , Hor Kan N. , Jefferies John L. , Gao Zhiqian , Towbin Jeffrey A. , Wong Brenda L. , Mazur Wojciech , Fleck Robert J. , Sticka Joshua J. , Benson D. Woodrow , Taylor Michael D. 
Published: March 2015

Background
Patients with Duchenne muscular dystrophy exhibit progressive cardiac and skeletal muscle dysfunction. Based on prior data, cardiac dysfunction in Duchenne muscular dystrophy patients may be influenced by myocardial fibrosis and steroid therapy. We examined the longitudinal relationship of myocardial fibrosis and ventricular dysfunction using cardiac magnetic resonance in a large Duchenne muscular dystrophy cohort.

Methods and Results

We reviewed 465 serial cardiac magnetic resonance studies (98 Duchenne muscular dystrophy patients with ≥4 cardiac magnetic resonance studies) for left ventricular ejection fraction (
LVEF
) and presence of late gadolinium enhancement (
LGE
), a marker for myocardial fibrosis.
LVEF
was modeled by examining
LGE
status, myocardial fibrosis burden (as assessed by the number of
LGE
‐positive left ventricular segments), patient age, and steroid treatment duration. An age‐only model demonstrated that
LVEF
declined 0.58±0.10% per year. In patients with both
LGE
‐negative and
LGE
‐positive studies (n=51),
LVEF
did not decline significantly over time if
LGE
was absent but declined 2.2±0.31% per year when
LGE
was present. Univariate modeling showed significant associations between
LVEF
and steroid treatment duration, presence of
LGE
, and number of
LGE
‐positive left ventricular segments; multivariate modeling showed that
LVEF
declined by 0.93±0.09% for each
LGE
‐positive left ventricular segment, whereas age and steroid treatment duration were not significant. The number of
LGE
‐positive left ventricular segments increased with age, and longer steroid treatment duration was associated with lower age‐related increases.

Conclusion

Progressive myocardial fibrosis, as detected by
LGE
, was strongly correlated with the
LVEF
decline in Duchenne muscular dystrophy patients. Longer steroid treatment duration was associated with a lower age‐related increase in myocardial fibrosis burden.
A Change in Inflammatory Footprint Precedes Plaque Instability: A Systematic Evaluation of Cellular Aspects of the Adaptive Immune Response in Human Atherosclerosis
Authors: van Dijk R. A. , Duinisveld A. J. F. , Schaapherder A. F. , Mulder‐Stapel A. , Hamming J. F. , Kuiper J. , de Boer O. J. , van der Wal A. C. , Kolodgie F. D. , Virmani R. , Lindeman J. H. N. 
Published: March 2015

Background
Experimental studies characterize adaptive immune response as a critical factor in the progression and complications of atherosclerosis. Yet, it is unclear whether these observations translate to the human situation. This study systematically evaluates cellular components of the adaptive immune response in a biobank of human aortas covering the full spectrum of atherosclerotic disease.

Methods and Results

A systematic analysis was performed on 114 well‐characterized perirenal aortic specimens with immunostaining for T‐cell subsets (CD3/4/8/45RA/45RO/FoxP3) and the Th1/non‐Th1/Th17 ratio (CD4
+
T‐bet
+
/CD4
+
T‐bet
−
/CD4
+
/interleukin‐17
+
double staining). CD20 and CD138 were used to identify B cells and plasma cells, while B‐cell maturation was evaluated by AID/CD21 staining and expression of lymphoid homeostatic CXCL13. Scattered CD4 and CD8 cells with a T memory subtype were found in normal aorta and early, nonprogressive lesions. The total number of T cells increases in progressive atherosclerotic lesions (≈1:5 CD4/CD8 T‐cell ratio). A further increase in medial and adventitial T cells is found upon progression to vulnerable lesions.

This critical stage is further hallmarked by de novo formation of adventitial lymphoidlike structures containing B cells and plasma cells, a process accompanied by transient expression of CXCL13. A dramatic reduction of T‐cell subsets, disappearance of lymphoid structures, and loss of CXCL13 expression characterize postruptured lesions. FoxP3 and Th17 T cells were minimally present throughout the atherosclerotic process.

Conclusions
Transient CXCL13 expression, restricted presence of B cells in human atherosclerosis, along with formation of nonfunctional extranodal lymphoid structures in the phase preceding plaque rupture, indicates a “critical” change in the inflammatory footprint before and during plaque destabilization.
Lower Serum Calcium Level Is Associated With Hemorrhagic Transformation After Thrombolysis
Authors: Guo Yang , Yan Shenqiang , Zhang Sheng , Zhang Xiaocheng , Chen Qingmeng , Liu Keqin , Liebeskind David S. , Lou Min 
Published: March 2015

Background and Purpose—
We aim to investigate whether lower admission serum calcium levels are associated with hemorrhagic transformation (HT) after intravenous thrombolysis (IVT).

Methods—
A total of 362 patients treated with IVT was divided into 4 quartiles based on admission serum calcium levels (Q1[<2.16], Q2[2.16, 2.23], Q3[2.24, 2.31], and Q4[>2.31] mmol/L). HT was classified as hemorrhagic infarction and parenchymal hemorrhage. Logistic regression was applied to assess the association between serum calcium levels and the incidence of HT.

Results—

Compared with Q4, HT was more common in Q1 (odds ratio, 2.580; 95% CI, [1.258–5.292];
P
=0.010), Q2 (odds ratio, 2.382; 95% CI, [1.163–4.877];
P
=0.018), and Q3 (odds ratio, 2.293; 95% CI, [1.133–4.637];
P
=0.021). Hemorrhagic infarction was more common in Q1 (
P
=0.037), and Q2 (
P
=0.018), compared with Q4, and parenchymal hemorrhage was more common in Q1 (
P
=0.029) than Q4.

Conclusions—
Lower admission serum calcium level is independently associated with HT after IVT, and this hypothesis needs larger confirmatory trials.