bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Genome-Wide Aberrant RNA Splicing in Patients with Acute Myeloid Leukemia Identifies Novel Potential Disease Markers and Therapeutic Targets
Authors: Adamia Sophia , Haibe-Kains Benjamin , Pilarski Patrick M. , Bar-Natan Michal , Pevzner Samuel , Avet-Loiseau Herve , Lode Laurence , Verselis Sigitas , Fox Edward A. , Burke John , Galinsky Ilene , Dagogo-Jack Ibiayi , Wadleigh Martha , Steensma David P. , Motyckova Gabriela , Deangelo Daniel J. , Quackenbush John , Stone Richard , Griffin James D. 
Published: November 2013

Abstract
Purpose: Despite new treatments, acute myeloid leukemia (AML) remains an incurable disease. More effective drug design requires an expanded view of the molecular complexity that underlies AML. Alternative splicing of RNA is used by normal cells to generate protein diversity. Growing evidence indicates that aberrant splicing of genes plays a key role in cancer. We investigated genome-wide splicing abnormalities in AML and based on these abnormalities, we aimed to identify novel potential biomarkers and therapeutic targets.
Experimental Design: We used genome-wide alternative splicing screening to investigate alternative splicing abnormalities in two independent AML patient cohorts [Dana-Farber Cancer Institute (DFCI) (Boston, MA) and University Hospital de Nantes (UHN) (Nantes, France)] and normal donors. Selected splicing events were confirmed through cloning and sequencing analysis, and than validated in 193 patients with AML.
Results: Our results show that approximately 29% of expressed genes genome-wide were differentially and recurrently spliced in patients with AML compared with normal donors bone marrow CD34+ cells. Results were reproducible in two independent AML cohorts. In both cohorts, annotation analyses indicated similar proportions of differentially spliced genes encoding several oncogenes, tumor suppressor proteins, splicing factors, and heterogeneous-nuclear-ribonucleoproteins, proteins involved in apoptosis, cell proliferation, and spliceosome assembly. Our findings are consistent with reports for other malignances and indicate that AML-specific aberrations in splicing mechanisms are a hallmark of AML pathogenesis.
Conclusions: Overall, our results suggest that aberrant splicing is a common characteristic for AML. Our findings also suggest that splice variant transcripts that are the result of splicing aberrations create novel disease markers and provide potential targets for small molecules or antibody therapeutics for this disease. Clin Cancer Res; 20(5); 1135–45. ©2013 AACR.
Known players, new interplay in atherogenesis: Chronic shear stress and carbamylated-LDL induce and modulate expression of atherogenic LR11 in human coronary artery endothelium
Authors: Bajar Tarek M. , Winnicki Wolfgang , Gensberger Eva-Theres , Scharrer Susanna I. , Regele Heinz , Aumayr Klaus , Kopecky Chantal , Gmeiner Bernhard M. , Hermann Marcela , Zeillinger Robert , Sengölge Gürkan 
Published: November 2013

SummaryIn this study we examined whether low-density lipoprotein (LDL) receptor family members represent a link between blood flow characteristics and modified low-density lipoproteins involved in endothelial injury, a pivotal factor in atherogenesis. We demonstrated the expression of pro-atherogenic LDL receptor relative (LR11) for the first time in human coronary artery endothelial cells (HCAEC) in vitro and in vivo. Next, LR11 expression and regulation were explored in HCAEC cultured conventionally or on the inner surface of hollow fiber capillaries under exposure to shear stress for 10 days in the presence or absence of LDL. There was no LR11 expression under static conditions. When exposed to chronic low shear stress (2.5 dynes/cm2) transmembrane and soluble endothelial-LR11 were detected in high levels irrespective of the type of LDL added (carbamylated or native). In contrast, chronic high shear stress (25 dynes/cm2) inhibited the LR11-inducing effect of LDL such that transmembrane and soluble LR11 expression became non-detectable with native LDL. Carbamylated LDL significantly counteracted this atheroprotective effect of high shear stress as shown by lower, yet sustained expression of soluble and transmembrane LR11. Oxidised LDL showed similar effects compared to carbamylated LDL but caused significantly lower LR11 expression under chronic high shear stress. Medium from HCAEC under LR11-inducing conditions enhanced vascular smooth muscle cell migration, which was abrogated by the anti-LR11 antibody. Expression of LR11 depended entirely on p38MAPK phosphorylation. We conclude that coronary endothelial LR11 expression modulated by LDL and chronic shear stress contributes to atherogenesis. LR11 and p38MAPK are potential targets for prevention of atherosclerosis.
Disbalance between mortality and non-fatal vascular events in the CHAMPION-PHOENIX trial: The cangrelor efficacy challenge
Authors: Pokov Alex N. , Fortmann Seth D. , DiNicolantonio James J. , Serebruany Victor L. 
Published: November 2013

SummaryThe recently published, largest trial with cangrelor, the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION)-PHOENIX, suggested that the experimental agent significantly reduced the rate of stent thrombosis (ST) and myocardial infarction (MI) during PCI at 48 hours (h) and 30 days. However, the declared impressive cangrelor vascular non-fatal benefit was contradicted by identical deaths at 48 h, and a trend toward excess mortality at 30 days. We analysed the mismatch between outcomes in the CHAMPION-PHOENIX trial. The trial reported identical mortality (18 death in each arm; odds ratio [OR] 1.00 (0.52–1.92); p>0.999) at 48 h, but more deaths, 60 vs 55, after cangrelor at 30 days. There was a significant reduction of ST from 0.8% (n=46) of the patients in the cangrelor group versus 1.4% (n=74) in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; p= 0.01) at 48 h, and a persistent but less impressive ST prevention benefit OR of 0.68 (0.50=0.92, p = 0.01) at 30 days. There were also 48 less MI’s following cangrelor usage enforced by a significant difference (odds ratio 0.80 (0.67–0.97) p = 0.02), which was also less prevalent at 30 days (OR 0.82 (0.68–0.98), p = 0.03). The reported ST/MI advantage should result in at least a trend towards numerically less deaths after cangrelor at 30 days follow-up, which was opposite of the results reported in CHAMPION- PHOENIX trial. Efficacy of cangrelor is challenged by the disproportional “reduction” of ST and MI conflicting with identical mortality at 48 h and worsened at day 30 fatalities. The dissociation between vascular mortality and non-fatal vascular ischaemic occlusions, unless compensated by some other unreported cause(s) of death, should be explored and explained. Unadjudicated 30-day outcomes, and all ST types should be fully disclosed. The ongoing FDA cangrelor review should focus on appropriate event count and/or possible mismatch between site-reported and extra adjudicated events in the CHAMPION-PHOENIX trial.
Structure-activity relationship of the pro- and anticoagulant effects of Fucus vesiculosus fucoidan
Authors: Zhang Zhenqing , Till Susanne , Jiang Cong , Knappe Sabine , Reutterer Sabrina , Szabo Christina M. , Dockal Michael , Scheiflinger Friedrich 
Published: November 2013

SummaryFucoidan is a highly complex sulfated polysaccharide commonly extracted from brown seaweed. In addition to their many biological activities, fucoidans have recently been demonstrated to inhibit or increase coagulation at different concentration ranges. Their structural features, i.e. molecular weight (Mw), Mw distribution, degree of sulfation, monosaccharide composition, and different linkages, are known to affect these activities. Therefore, structure-activity relationship (SAR) analysis of fucoidan is crucial for its potential use as a procoagulant. In this study, Fucus vesiculosus (F.v.) fucoidan was fractionated by charge and size as well as over- and desulfated to different degrees to yield preparations with various structural properties. The fractions’ pro- and anticoagulant activities were assessed by calibrated automated thrombography (CAT) and activated partial thromboplastin time (aPTT) assays. Binding to and inhibition of the anticoagulant protein tissue factor pathway inhibitor (TFPI) and the ability to activate coagulation via the contact pathway were also investigated. This paper discusses the impact of charge density, size, and sugar composition on fucoidan’s pro- and anticoagulant activities. Fucoidan requires a minimal charge density of 0.5 sulfates per sugar unit and a size of 70 sugar units to demonstrate desired procoagulant activities for improvement of haemostasis in factor VIII/factor IX-deficient plasma.
Effect of Niacin on High-Density Lipoprotein Apolipoprotein A-I Kinetics in Statin-Treated Patients With Type 2 Diabetes Mellitus
Authors: Pang Jing , Chan Dick C. , Hamilton Sandra J. , Tenneti Vijay S. , Watts Gerald F. , Barrett P. Hugh. R. 
Published: November 2013

Objective—
To investigate the effect of extended-release (ER) niacin on the metabolism of high-density lipoprotein (HDL) apolipoprotein A-I (apoA-I) in men with type 2 diabetes mellitus on a background of optimal statin therapy.

Approach and Results—

Twelve men with type 2 diabetes mellitus were recruited for a randomized, crossover design trial. Patients were randomized to rosuvastatin or rosuvastatin plus ER niacin for 12 weeks and then crossed over to the alternate therapy after a 3-week washout period. Metabolic studies were performed at the end of each treatment period. HDL apoA-I kinetics were measured after a standardized liquid mixed meal and a bolus injection of d3-leucine for 96 hours. Compartmental analysis was used to model the data. ER niacin significantly decreased plasma triglyceride, plasma cholesterol, non-HDL cholesterol, low-density lipoprotein cholesterol, and apoB (all
P
<0.05) and significantly increased HDL cholesterol and apoA-I concentrations (
P
<0.005 and
P
<0.05, respectively). ER niacin also significantly increased HDL apoA-I pool size (6088±292 versus 5675±305 mg;
P
<0.001), and this was attributed to a lower HDL apoA-I fractional catabolic rate (0.33±0.01 versus 0.37±0.02 pools/d;
P
<0.005), with no significant changes in HDL apoA-I production (20.93±0.63 versus 21.72±0.85 mg/kg per day;
P
=0.28).

Conclusions—
ER niacin increases HDL apoA-I concentration in statin-treated subjects with type 2 diabetes mellitus by lowering apoA-I fractional catabolic rate. The effect on HDL metabolism was independent of the reduction in plasma triglyceride with ER niacin treatment. Whether this finding applies to other dyslipidemic populations remains to be investigated.
Delta-6-desaturase Links Polyunsaturated Fatty Acid Metabolism With Phospholipid Remodeling and Disease Progression in Heart Failure
Authors: Le Catherine H. , Mulligan Christopher M. , Routh Melissa A. , Bouma Gerrit J. , Frye Melinda A. , Jeckel Kimberly M. , Sparagna Genevieve C. , Lynch Joshua M. , Moore Russell L. , McCune Sylvia A. , Bristow Michael , Zarini Simona , Murphy Robert C. , Chicco Adam J. 
Published: November 2013

Background—
Remodeling of myocardial phospholipids has been reported in various forms of heart failure for decades, but the mechanism and pathophysiological relevance of this phenomenon have remained unclear. We examined the hypothesis that δ-6 desaturase (D6D), the rate-limiting enzyme in long-chain polyunsaturated fatty acid biosynthesis, mediates the signature pattern of fatty acid redistribution observed in myocardial phospholipids after chronic pressure overload and explored plausible links between this process and disease pathogenesis.

Methods and Results—
Compositional analysis of phospholipids from hearts explanted from patients with dilated cardiomyopathy revealed elevated polyunsaturated fatty acid product/precursor ratios reflective of D6D hyperactivity, manifesting primarily as lower levels of linoleic acid with reciprocally higher levels of arachidonic and docosahexaenoic acids. This pattern of remodeling was attenuated in failing hearts chronically unloaded with a left ventricular assist device. Chronic inhibition of D6D in vivo reversed similar patterns of myocardial polyunsaturated fatty acid redistribution in rat models of pressure overload and hypertensive heart disease and significantly attenuated cardiac hypertrophy, fibrosis, and contractile dysfunction in both models. D6D inhibition also attenuated myocardial elevations in pathogenic eicosanoid species, lipid peroxidation, and extracellular receptor kinase 1/2 activation; normalized cardiolipin composition in mitochondria; reduced circulating levels of inflammatory cytokines; and elicited model-specific effects on cardiac mitochondrial respiratory efficiency, nuclear factor κ B activation, and caspase activities.

Conclusions—
These studies demonstrate a pivotal role of essential fatty acid metabolism in myocardial phospholipid remodeling induced by hemodynamic stress and reveal novel links between this phenomenon and the propagation of multiple pathogenic systems involved in maladaptive cardiac remodeling and contractile dysfunction.
Vitamin C Intake, Circulating Vitamin C and Risk of Stroke: A Meta‐Analysis of Prospective Studies
Authors: Chen Guo‐Chong , Lu Da‐Bing , Pang Zhi , Liu Qing‐Fang 
Published: November 2013

Background
Though vitamin C supplementation has shown no observed effects on stroke prevention in several clinical trials, uncertainty remains as to whether long‐term, low‐dose intake influences the development of stroke among general populations. Furthermore, the association between circulating vitamin C and the risk of stroke is also unclear. For further clarification of these issues, we conducted a meta‐analysis of prospective studies.

Methods and Results

PubMed and
EMBASE
databases were searched, and the bibliographies of the retrieved articles were also reviewed to identify eligible studies. Summary relative risk (
RR
s) with corresponding 95% confidence intervals (
CI
s) were computed with a random‐effects model. The summary
RR
for the high‐versus‐low categories was 0.81 (95%
CI
: 0.74 to 0.90) for dietary vitamin C intake (11 studies), and 0.62 (95%
CI
: 0.49 to 0.79) for circulating vitamin C (6 studies). The summary
RR
for each 100 mg/day increment in dietary vitamin C was 0.83 (95%
CI
: 0.75 to 0.93) (10 studies), and for each 20 μmol/L increment in circulating vitamin C was 0.81 (95%
CI
: 0.75 to 0.88) (5 studies). Few studies reported results for vitamin C supplements (
RR
for high‐versus‐low intake=0.83, 95%
CI
: 0.62 to 1.10, 3 studies).

Conclusions
This meta‐analysis suggests significant inverse relationships between dietary vitamin C intake, circulating vitamin C, and risk of stroke.
Anatomic, Arthroscopically Assisted, Mini-Open Fibular Collateral Ligament Reconstruction
Authors: Liu Ping , Wang Jianquan , Zhao Feng , Xu Yan , Ao Yingfang 
Published: November 2013

Background: The fibular collateral ligament (FCL) is the primary restraint to varus rotation of the knee joint. Arthroscopic techniques are widely used and minimally invasive, but anatomic arthroscopic reconstruction of an isolated FCL injury has not been reported. Hypothesis: Anatomic reconstruction of an isolated FCL injury can be performed arthroscopically and will restore the knee to near-normal stability. Study Design: Controlled laboratory study. Methods: A total of 12 nonpaired, fresh-frozen cadaveric knees were biomechanically subjected to a 10-N·m varus moment and 5-N·m external and internal rotation torques at 0°, 15°, 30°, 60°, 90°, and 120° of knee flexion, respectively (0° only for varus loading). Testing was performed with an intact and sectioned FCL and also after an anatomic reconstruction of the FCL by arthroscopic technique. Kinematics of each knee under various loading conditions was determined with a robotic universal force/moment sensor testing system. Results: After sectioning, significant increases were found in varus rotation at 0°, 15°, 30°, 60°, 90°, and 120° of knee flexion; in external rotation at 15°, 30°, and 60° of knee flexion; and in internal rotation at 30°, 60°, and 90° of knee flexion. After reconstruction, full recovery of knee stability was observed in varus rotation at 0°, 15°, 30°, and 60°; in external rotation at 0°, 15°, 30°, 60°, 90°, and 120°; and in internal rotation at 0°, 15°, 30°, 60°, 90°, and 120°. When the sectioned and intact FCL knee conditions were compared, significant increases of 3.4° at 90° of flexion and 3.4° at 120° of flexion were found ( P < .001, both conditions); when the reconstructed and sectioned FCL knee conditions were compared, significant decreases of 1.7° at 90° of flexion and 1.7° at 120° of knee flexion were found ( P = .033 and .043, respectively). Conclusion: An anatomic reconstruction of the FCL can be performed by an arthroscopically assisted mini-open technique with an isolated FCL injury, and near-normal stability of the knee can be restored. Clinical Relevance: Anatomic reconstruction of the FCL by an arthroscopically assisted mini-open technique is a viable, less invasive option to treat nonrepairable isolated FCL injury.
Complications After Arthroscopic Knee Surgery
Authors: Salzler Matthew J. , Lin Albert , Miller Chealon D. , Herold Sarah , Irrgang James J. , Harner Christopher D. 
Published: November 2013

Background: Knee arthroscopies are among the most common procedures performed by orthopaedic surgeons, yet little is known about the associated complications and complication rates. Purpose: To examine the nature and frequency of complications after the most common arthroscopic knee procedures, with particular attention to fellowship training, geographic location of practice, and age and sex of the patient. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Data were obtained from the American Board of Orthopaedic Surgery database for orthopaedic surgeons who sat for the part II examination from 2003 to 2009. The database was queried to determine the type and frequency of complications for patients who underwent knee arthroscopy and for those who underwent sports medicine knee arthroscopy, including arthroscopic partial meniscectomy, meniscal repair, chondroplasty, microfracture, anterior cruciate ligament reconstruction, or posterior cruciate ligament reconstruction. Factors affecting complication rates that were investigated included type of procedure, fellowship training status, geographic location of practice, and age and sex of the patient. Results: There were 4305 complications out of 92,565 knee arthroscopic procedures obtained from the American Board of Orthopaedic Surgery database for an overall candidate-reported complication rate of 4.7%. The complication rates were highest for posterior cruciate ligament reconstruction (20.1%) and anterior cruciate ligament reconstruction (9.0%); complication rates for meniscectomy, meniscal repair, and chondroplasty were 2.8%, 7.6%, and 3.6%, respectively. The complication rate for sports fellowship–trained candidates was higher than for non–sports trained candidates (5.1% sports, 4.1% no sports; P < .0001) and for male patients (4.9% male vs 4.3% female; P < .0001). Younger patients (<40 years; 6.2%) had a higher complication rate than older patients (≥40 years; 3.58%) ( P < .0001). Procedure complexity is a likely confounding factor affecting sports-trained candidates and younger patients. There were no geographic differences ( P = .125). The overall rate of pulmonary embolus was 0.11%. Surgical complications (3.68%) were more common than medical (0.77%) or anesthetic complications (0.22%), and infection was the most common complication overall (0.84%). Conclusion: The overall self-reported complication rate for arthroscopic knee procedures was 4.7%. Knee arthroscopy is not a benign procedure, and patients should be aware of the risk of complications.
Effects of fish oil on lipid profile and other metabolic outcomes in HIV-infected patients on antiretroviral therapy: a randomized placebo-controlled trial
Authors: Oliveira Julicristie M , Rondó Patrícia HC , Yudkin John S , Souza José MP , Pereira Tatiane N , Catalani Andrea W , Picone Camila M , Segurado Aluisio AC 
Published: November 2013

Summary Although antiretroviral therapy has revolutionized the care of HIV-infected patients, it has been associated with metabolic abnormalities. Hence, this study was planned to investigate the effects of fish oil on lipid profile, insulin resistance, and body fat distribution in HIV-infected Brazilian patients on antiretroviral therapy, considering that marine omega-3 fatty acids seem to improve features of the metabolic syndrome. We conducted a randomized, parallel, placebo-controlled trial that assessed the effects of 3 g fish oil/day (540 mg of eicosapentaenoic acid plus 360 mg of docosahexaenoic acid) or 3 g soy oil/day (placebo) on 83 HIV-infected Brazilian men and non-pregnant women on antiretroviral therapy. No statistically significant relationships between fish oil supplementation and longitudinal changes in triglyceride ( p = 0.335), low-density lipoprotein cholesterol ( p = 0.078), high-density lipoprotein cholesterol ( p = 0.383), total cholesterol ( p = 0.072), apolipoprotein B ( p = 0.522), apolipoprotein A1 ( p = 0.420), low-density lipoprotein cholesterol/apolipoprotein B ratio ( p = 0.107), homeostasis model assessment for insulin resistance index ( p = 0.387), body mass index ( p = 0.068), waist circumference ( p = 0.128), and waist/hip ratio ( p = 0.359) were observed. A low dose of fish oil did not alter lipid profile, insulin resistance, and body fat distribution in HIV-infected patients on antiretroviral therapy.
Collapsing glomerulopathy in collagen vascular-like disease
Authors: Nasr R , Johns C , Gertner E 
Published: November 2013

Objective Collapsing glomerulopathy (CG) is a podocytopathy that is usually associated with human immunodeficiency virus (HIV) and parvovirus B19 infections. CG has been reported in association with definite collagen vascular diseases, mainly systemic lupus erythematosus (SLE). There are a few case reports in the nephrology literature of patients with CG and marked serological abnormalities who do not have sufficient clinical findings to diagnose definite collagen vascular disease. We wish to expand the spectrum of rheumatologic disease that accompanies CG. We describe four patients with CG and collagen vascular-like disease and compare these with 14 similar cases reported in the medical literature. Methods Case reports of four new patients with CG and collagen vascular-like disease are presented. We performed a systematic literature review to find all other cases and construct a profile of patients with CG and collagen vascular-like disease. Results All patients had a similar mode of presentation with severe nephrotic range proteinuria and renal insufficiency resistant to steroids and usual immunomodulatory therapy. All patients had positive antinuclear antibodies (ANA) as well as other marked serological abnormalities but few if any clinical findings that would allow for a definitive diagnosis of a specific collagen vascular disease. Almost all patients became dialysis dependent. Mycophenolate mofetil (MMF) may possibly be a therapeutic option. Conclusion Rheumatologists may be asked to consult on patients with severe proteinuria and renal insufficiency in the presence of marked serological abnormalities but few clinical symptoms and should be aware of this podocytopathy.