bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protocol of the Australasian Malignant Pleural Effusion (AMPLE) trial: a multicentre randomised study comparing indwelling pleural catheter versus talc pleurodesis
Authors: Fysh Edward T H , Thomas Rajesh , Read Catherine A , Lam Ben C H , Yap Elaine , Horwood Fiona C , Lee Pyng , Piccolo Francesco , Shrestha Ranjan , Garske Luke A , Lam David C L , Rosenstengel Andrew , Bint Michael , Murray Kevin , Smith Nicola A , Lee Y C Gary 
Published: November 2014

IntroductionMalignant pleural effusion can complicate most cancers. It causes breathlessness and requires hospitalisation for invasive pleural drainages. Malignant effusions often herald advanced cancers and limited prognosis. Minimising time spent in hospital is of high priority to patients and their families. Various treatment strategies exist for the management of malignant effusions, though there is no consensus governing the best choice. Talc pleurodesis is the conventional management but requires hospitalisation (and substantial healthcare resources), can cause significant side effects, and has a suboptimal success rate. Indwelling pleural catheters (IPCs) allow ambulatory fluid drainage without hospitalisation, and are increasingly employed for management of malignant effusions. Previous studies have only investigated the length of hospital care immediately related to IPC insertion. Whether IPC management reduces time spent in hospital in the patients’ remaining lifespan is unknown. A strategy of malignant effusion management that reduces hospital admission days will allow patients to spend more time outside hospital, reduce costs and save healthcare resources.Methods and analysisThe Australasian Malignant Pleural Effusion (AMPLE) trial is a multicentred, randomised trial designed to compare IPC with talc pleurodesis for the management of malignant pleural effusion. This study will randomise 146 adults with malignant pleural effusions (1:1) to IPC management or talc slurry pleurodesis. The primary end point is the total number of days spent in hospital (for any admissions) from treatment procedure to death or end of study follow-up. Secondary end points include hospital days specific to pleural effusion management, adverse events, self-reported symptom and quality-of-life scores.Ethics and disseminationThe Sir Charles Gairdner Group Human Research Ethics Committee has approved the study as have the ethics boards of all the participating hospitals. The trial results will be published in peer-reviewed journals and presented at scientific conferences.Trial registration numbersAustralia New Zealand Clinical Trials Registry—ACTRN12611000567921; National Institutes of Health—NCT02045121.
Diffuse decidual leucocytoclastic necrosis and NK cell aggregates: two distinct features of miscarriage
Authors: Lee Joong Yeup , Kim Eun Na , Hong Joon-Seok , Shim Jae-Yoon , Hwang Doyeong , Kim Ki Chul , Lee JungBok , Kim Chong Jai 
Published: November 2014

AimsPrimary histopathology of miscarriage remains undetermined in the majority of cases. This study was conducted to determine histological characteristics pertinent to miscarriage.MethodsThe study groups were composed of elective abortions (n=29) and miscarriages (n=45) comprised of chromosomally normal (n=15) and abnormal cases (n=30). Immunohistochemistry was done against CD3, CD8, TIA-1 and CD56.ResultsTwo histological features—diffuse decidual leucocytoclastic necrosis (DDLN) and decidual natural killer cell aggregates (NKCA)—were relatively common in miscarriages. The frequencies of DDLN and NKCA were different between the groups (p<0.05 and p<0.05, respectively). DDLN was found in 13.8% (4/29) of elective abortions, while it was observed in 60.0% (9/15) and 23.3% (7/30) of chromosomally normal and abnormal miscarriages, respectively. DDLN was more frequent in chromosomally normal miscarriages than in elective abortions (p=0.004). NKCA was present in 13.8% (4/29) of elective abortions, while being found in 33.3% (5/15) and 43.3% (13/30) of chromosomally normal and abnormal miscarriages, respectively. NKCA was more frequent in chromosomally abnormal miscarriages than in elective abortions (p=0.020).ConclusionsThe findings strongly suggest that defective placentation and abnormal maternal immune response are associated with miscarriage. DDLN and NKCA seem to have diagnostic values in the pathological evaluation of miscarriage.
Endotoxin detection in end-stage kidney disease
Authors: Wong Jonathan , Jeraj Hassan , Vilar Enric , Viljoen Adie , Farrington Ken 
Published: November 2014

AimsEndotoxin detection assays are not validated for use in end-stage kidney disease (ESKD). We investigated the accuracy and precision of the kinetic turbidimetric Limulus amoebocyte lysate (LAL) assay to detect endotoxin in plasma from patients with ESKD. Optimisation of endotoxin recovery from plasma using the detergent Tween 80 was also explored.MethodsPlasma samples from 7 patients with ESKD and 7 healthy subjects were spiked with different concentrations of endotoxin. Repeated measurements for endotoxin at each level of spike were performed to assess the accuracy and precision of spike recovery. Endotoxin recovery in plasma samples diluted in Tween 80 and water was compared.ResultsMean endotoxin spike recovery was 111.6% and 125.2% in ESKD and healthy subjects, respectively. There was no statistical difference in spike recovery between ESKD and healthy plasma. Precision of the LAL assay in plasma spiked with low (0.05 EU/mL) and high (0.5 EU/mL) concentration of endotoxin spikes was 24.1% and 8.9%, respectively. The use of Tween 80 as a diluent for plasma significantly improved spike recovery in ESKD plasma (100.1% vs 70.4%, p<0.001).ConclusionsThe kinetic LAL turbidimetric assay is a valid tool for the detection of blood endotoxin in patients with ESKD, although in blood specimens with low-level endotoxemia (≤0.05 EU/mL) the assay may be less accurate and precise. Tween 80 can be used as a diluent to optimise recovery of endotoxin in ESKD plasma.
Ion Torrent next-generation sequencing for routine identification of clinically relevant mutations in colorectal cancer patients
Authors: Malapelle Umberto , Vigliar Elena , Sgariglia Roberta , Bellevicine Claudio , Colarossi Lorenzo , Vitale Domenico , Pallante Pierlorenzo , Troncone Giancarlo 
Published: November 2014

AimsTo evaluate the accuracy, consumable cost and time around testing (TAT) of a next-generation sequencing (NGS) assay, the Ion Torrent AmpliSeq Colon and Lung Cancer Panel, as an alternative to Sanger sequencing to genotype KRAS, NRAS and BRAF in colorectal cancer patients.MethodsThe Ion Torrent panel was first verified on cell lines and on control samples and then prospectively applied to routine specimens (n=114), with Sanger sequencing as reference.ResultsThe Ion Torrent panel detected mutant alleles at the 5% level on cell lines and correctly classified all control tissues. The Ion Torrent assay was successfully carried out on most (95.6%) routine diagnostic samples. Of these, 12 (11%) harboured mutations in the BRAF gene and 47 (43%) in either of the two RAS genes, in two cases with a low abundance of RAS mutant allele which was missed by Sanger sequencing. The mean TAT, from sample receipt to reporting, was 10.4 (Sanger) and 13.0 (Ion Torrent) working days. The consumable cost for genotyping KRAS, NRAS and BRAF was €196 (Sanger) and €187 (Ion Torrent).ConclusionsIon Torrent AmpliSeq Colon and Lung Cancer Panel sequencing is as robust as Sanger sequencing in routine diagnostics to select patients for anti-epidermal growth factor receptor (EGFR) therapy for metastatic colorectal cancer.
Myoclonus and hyperalgesia following intended epidural morphine administration in a dog
Authors: Robson Katherine , Alderson Briony 
Published: November 2014

A West Highland White Terrier was presented after development of hindlimb myoclonus and hyperalgesia following intended epidural administration of morphine at a referring veterinary practice. MRI was unremarkable, except for the spinal cord extending to the caudal half of the L7 vertebrae. Treatment with systemic analgesia of methadone and sedation/analgesia with medetomidine resolved the clinical signs within 24 hours. The mechanism by which morphine causes adverse neurological side effects has yet to be fully determined; the morphine‐3‐glucuronide (M‐3‐G) metabolite is suspected to be responsible for the adverse effects seen. Hypotheses include action of morphine or the M‐3‐G metabolite on non‐opioid inhibitory (glycine) or excitatory (N‐methyl D‐aspartate) receptors. However, more work is needed to determine the exact pathogenesis. Neuroexcitatory side effects are rarely reported following administration of morphine in dogs and this case demonstrates successful treatment with the use of an alternative opioid, methadone.
Horse impoundments under Control of Horses legislation in the Munster region of Ireland: factors affecting euthanasia
Authors: Cullinane M. , O'Sullivan E. , Collins D. M. , Byrne A. W. , More S. J. 
Published: November 2014

Recently, considerable international attention has been paid to the problem of unwanted horses. In Ireland, stray horses, particularly in urban areas, are a further problem. The Control of Horses Act 1996 was enacted in response to an ongoing problem of uncontrolled horses in public places. As yet, no research work has been conducted focusing on stray horses in Ireland. This paper describes horses impounded under the Act in the Munster region of Ireland during 2005–2012 and the factors influencing decisions regarding their disposal. A logistic regression model was developed to investigate factors influencing the probability that a horse was euthanised during impoundment. In total, 3625 seizure events were recorded, most towards the end of the study period. Predictors for euthanasia during 2010–2012 included seizure location, sex, age, colour, body condition score and year. This study highlights the problem of stray horses in Ireland, particularly in urban areas. There is a need for rigorous enforcement of newly enacted horse identification legislation, allowing a fully integrated traceability system. More is required to manage the long‐established societal problems of stray horses in urban settings, with a uniform approach by all Local Authorities being long overdue.
Iterated effective embeddings of abelian p-groups
Authors: Downey Rod , Melnikov Alexander G. , Ng Keng Meng 
Published: November 2014

This paper contributes to the theory of recursively presented (see Higman [Subgroups of finitely presented groups, Proc. R. Soc. Ser. A 262 (1961) 455–475]) infinitely generated abelian groups with solvable word problem. Mal'cev [On recursive Abelian groups, Dokl. Akad. Nauk SSSR 146 (1962) 1009–1012] and independently Rabin [Computable algebra, general theory and theory of computable fields, Trans. Amer. Math. Soc. 95 (1960) 341–360] initiated the study of such groups in the early 1960's. In this paper, we develop a technique that we call iterated effective embeddings. The significance of our new technique is that it extends existing methods from the realm of iterated 0″ arguments to iterated 0‴ ones. This is a new phenomenon in computable algebra. We use this technique to confirm a 30 year-old conjecture of Ash, Knight and Oates [Recursive abelian p-groups of small length, https://dl.dropbox.com/u/4752353/Homepage/AKO.pdf ]. More specifically, Ash, Knight and Oates [Recursive abelian p-groups of small length. https://dl.dropbox.com/u/4752353/Homepage/AKO.pdf ] conjectured that there exists a computable reduced abelian p-group of Ulm type ω such that its effective invariants, defined using limitwise monotonic functions, cannot be found uniformly. We construct a computable reduced abelian p-group of Ulm type ω where its invariants are at the maximum possible level of non-uniformity. The result confirms the conjecture in a strong way, and it provides us with an explanation of why computable reduced p-groups of Ulm type ω seem hard to classify in general. We also use p-basic trees and their iterated embeddings to solve a problem posed in [W. Calvert, D. Cenzer, V. S. Harizanov and A. Morozov, Effective categoricity of abelian p-groups, Ann. Pure Appl. Logic 159(1–2) (2009) 187–197].
An efficient algorithm for pairwise local alignment of protein interaction networks
Authors: Chen Wenbin , Schmidt Matthew , Tian Wenhong , Samatova Nagiza F. , Zhang Shaohong 
Published: November 2014

Recently, researchers seeking to understand, modify, and create beneficial traits in organisms have looked for evolutionarily conserved patterns of protein interactions. Their conservation likely means that the proteins of these conserved functional modules are important to the trait's expression. In this paper, we formulate the problem of identifying these conserved patterns as a graph optimization problem, and develop a fast heuristic algorithm for this problem. We compare the performance of our network alignment algorithm to that of the MaWISh algorithm [Koyutürk M, Kim Y, Topkara U, Subramaniam S, Szpankowski W, Grama A, Pairwise alignment of protein interaction networks, J Comput Biol13(2):182–199, 2006.], which bases its search algorithm on a related decision problem formulation. We find that our algorithm discovers conserved modules with a larger number of proteins in an order of magnitude less time. The protein sets found by our algorithm correspond to known conserved functional modules at comparable precision and recall rates as those produced by the MaWISh algorithm.
Serine Deprivation Enhances Antineoplastic Activity of Biguanides
Authors: Gravel Simon-Pierre , Hulea Laura , Toban Nader , Birman Elena , Blouin Marie-José , Zakikhani Mahvash , Zhao Yunhua , Topisirovic Ivan , St-Pierre Julie , Pollak Michael 
Published: November 2014

Abstract
Metformin, a biguanide widely used in the treatment of type II diabetes, clearly exhibits antineoplastic activity in experimental models and has been reported to reduce cancer incidence in diabetics. There are ongoing clinical trials to evaluate its antitumor properties, which may relate to its fundamental activity as an inhibitor of oxidative phosphorylation. Here, we show that serine withdrawal increases the antineoplastic effects of phenformin (a potent biguanide structurally related to metformin). Serine synthesis was not inhibited by biguanides. Instead, metabolic studies indicated a requirement for serine to allow cells to compensate for biguanide-induced decrease in oxidative phosphorylation by upregulating glycolysis. Furthermore, serine deprivation modified the impact of metformin on the relative abundance of metabolites within the citric acid cycle. In mice, a serine-deficient diet reduced serine levels in tumors and significantly enhanced the tumor growth–inhibitory actions of biguanide treatment. Our results define a dietary manipulation that can enhance the efficacy of biguanides as antineoplastic agents that target cancer cell energy metabolism. Cancer Res; 74(24); 7521–33. ©2014 AACR.
Antitumor Activity of the MEK Inhibitor TAK-733 against Melanoma Cell Lines and Patient-Derived Tumor Explants
Authors: Micel Lindsey N. , Tentler John J. , Tan Aik-Choon , Selby Heather M. , Brunkow Kelsey L. , Robertson Kelli M. , Davis S. Lindsey , Klauck Peter J. , Pitts Todd M. , Gangolli Esha , Fabrey Robyn , O'Connell Shawn M. , Vincent Patrick W. , Eckhardt S. Gail 
Published: November 2014

Abstract
The goal of this study was to investigate the activity of the selective MEK1/2 inhibitor TAK-733 in both melanoma cell lines and patient-derived melanoma xenograft models. In vitro cell proliferation assays using the sulforhodamine B assay were conducted to determine TAK-733 potency and melanoma responsiveness. In vivo murine modeling with eleven patient-derived melanoma explants evaluated daily dosing of TAK-733 at 25 or 10 mg/kg. Immunoblotting was performed to evaluate on-target activity and downstream inhibition by TAK-733 in both in vitro and in vivo studies. TAK-733 demonstrated broad activity in most melanoma cell lines with relative resistance observed at IC50 &gt; 0.1 μmol/L in vitro. TAK-733 also exhibited activity in 10 out of 11 patient-derived explants with tumor growth inhibition ranging from 0% to 100% (P &lt; 0.001–0.03). Interestingly, BRAFV600E and NRAS mutational status did not correlate with responsiveness to TAK-733. Pharmacodynamically, pERK was suppressed in sensitive cell lines and tumor explants, confirming TAK-733–mediated inhibition of MEK1/2, although the demonstration of similar effects in the relatively resistant cell lines and tumor explants suggests that escape pathways are contributing to melanoma survival and proliferation. These data demonstrate that TAK-733 exhibits robust tumor growth inhibition and regression against human melanoma cell lines and patient-derived xenograft models, suggesting that further clinical development in melanoma is of scientific interest. Particularly interesting is the activity in BRAF wild-type models, where current approved therapy such as vemurafenib has been reported not to be active. Mol Cancer Ther; 14(2); 317–25. ©2014 AACR.
Modeling Targeted Inhibition of MEK and PI3 Kinase in Human Pancreatic Cancer
Authors: Junttila Melissa R. , Devasthali Vidusha , Cheng Jason H. , Castillo Joseph , Metcalfe Ciara , Clermont Anne C. , Otter Douglas Den , Chan Emily , Bou-Reslan Hani , Cao Tim , Forrest William , Nannini Michelle A. , French Dorothy , Carano Richard , Merchant Mark , Hoeflich Klaus P. , Singh Mallika 
Published: November 2014

Abstract
Activating mutations in the KRAS oncogene occur in approximately 90% of pancreatic cancers, resulting in aberrant activation of the MAPK and the PI3K pathways, driving malignant progression. Significant efforts to develop targeted inhibitors of nodes within these pathways are underway and several are currently in clinical trials for patients with KRAS-mutant tumors, including patients with pancreatic cancer. To model MEK and PI3K inhibition in late-stage pancreatic cancer, we conducted preclinical trials with a mutant Kras-driven genetically engineered mouse model that faithfully recapitulates human pancreatic ductal adenocarcinoma development. Treatment of advanced disease with either a MEK (GDC-0973) or PI3K inhibitor (GDC-0941) alone showed modest tumor growth inhibition and did not significantly enhance overall survival. However, combination of the two agents resulted in a significant survival advantage as compared with control tumor-bearing mice. To model the clinical scenario, we also evaluated the combination of these targeted agents with gemcitabine, the current standard-of-care chemotherapy for pancreatic cancer. The addition of MEK or PI3K inhibition to gemcitabine, or the triple combination regimen, incrementally enhanced overall survival as compared with gemcitabine alone. These results are reminiscent of the survival advantage conferred in this model and in patients by the combination of gemcitabine and erlotinib, an approved therapeutic regimen for advanced nonresectable pancreatic cancer. Taken together, these data indicate that inhibition of MEK and PI3K alone or in combination with chemotherapy do not confer a dramatic improvement as compared with currently available therapies for patients with pancreatic cancer. Mol Cancer Ther; 14(1); 40–47. ©2014 AACR.
Inhibition of FOXO1/3 Promotes Vascular Calcification
Authors: Deng Liang , Huang Lu , Sun Yong , Heath Jack M. , Wu Hui , Chen Yabing 
Published: November 2014

Objective—
Vascular calcification is a characteristic feature of atherosclerosis, diabetes mellitus, and end-stage renal disease. We have demonstrated that activation of protein kinase B (AKT) upregulates runt-related transcription factor 2 (Runx2), a key osteogenic transcription factor that is crucial for calcification of vascular smooth muscle cells (VSMC). Using mice with SMC-specific deletion of phosphatase and tensin homolog (PTEN), a major negative regulator of AKT, the present studies uncovered a novel molecular mechanism underlying PTEN/AKT/FOXO (forkhead box O)-mediated Runx2 upregulation and VSMC calcification.

Approach and Results—

SMC-specific PTEN deletion mice were generated by crossing PTEN floxed mice with SM22α-Cre transgenic mice. The PTEN deletion resulted in sustained activation of AKT that upregulated Runx2 and promoted VSMC calcification in vitro and arterial calcification ex vivo. Runx2 knockdown did not affect proliferation but blocked calcification of the PTEN-deficient VSMC, suggesting that PTEN deletion promotes Runx2-depedent VSMC calcification that is independent of proliferation. At the molecular level, PTEN deficiency increased the amount of Runx2 post-transcriptionally by inhibiting Runx2 ubiquitination. AKT activation increased phosphorylation of FOXO1/3 that led to nuclear exclusion of FOXO1/3. FOXO1/3 knockdown in VSMC phenocopied the PTEN deficiency, demonstrating a novel function of FOXO1/3, as a downstream signaling of PTEN/AKT, in regulating Runx2 ubiquitination and VSMC calcification. Using heterozygous SMC-specific PTEN-deficient mice and atherogenic ApoE
−/−
mice, we further demonstrated AKT activation, FOXO phosphorylation, and Runx2 ubiquitination in vascular calcification in vivo.

Conclusions—
Our studies have determined a new causative effect of SMC-specific PTEN deficiency on vascular calcification and demonstrated that FOXO1/3 plays a crucial role in PTEN/AKT-modulated Runx2 ubiquitination and VSMC calcification.
Interaction Between Digoxin and Dronedarone in the PALLAS Trial
Authors: Hohnloser Stefan H. , Halperin Jonathan L. , Camm A. John , Gao Peggy , Radzik David , Connolly Stuart J. 
Published: November 2014

Background—
Elevated serum digoxin concentration can cause toxicity, including death. Dronedarone increases digoxin concentration by P-glycoprotein interaction. In Permanent Atrial Fibrillation Outcome Study Using Dronedarone On Top Of Standard Therapy Trial (PALLAS), dronedarone was associated with both increased cardiovascular death and heart failure in patients with permanent atrial fibrillation. The present analysis examines whether the dronedarone–digoxin interaction might explain these adverse outcomes.

Methods and Results—

Subgroup analysis was performed to compare outcomes of patients on digoxin at baseline or not. In PALLAS, 1619 patients were randomized to dronedarone and 1617 to placebo, of whom 544 (33.6%) and 526 (32.5%) were receiving digoxin, respectively. Median (Q1,Q3) digoxin serum concentration on day 7 was 1.1 (0.7,1.5) ng/mL on dronedarone and 0.7 (0.5,1.1) ng/mL on placebo (
P
<0.001). Among patients on digoxin, there were 15 (8.6%/year) cardiovascular deaths on dronedarone and 2 (1.2%/year) on placebo (adjusted hazard ratio, 7.31; 95% confidence interval, 1.66–32.20;
P
=0.009). Among patients not on digoxin, there were 6 cardiovascular deaths on dronedarone (1.7%/year) and 8 on placebo (2.2%/year; adjusted hazard ratio, 0.67; 95% confidence interval, 0.23–1.95;
P
=0.46; interaction
P
value 0.01). In patients on digoxin, there were 11 arrhythmic deaths on dronedarone and none on placebo; and in patients not on digoxin, there were 2 arrhythmic deaths on dronedarone and 4 on placebo (
P
value for interaction 0.002). There was no interaction between baseline digoxin use and the adverse effect of dronedarone on heart failure events.

Conclusions—
In PALLAS, there was a strong effect of concurrent digoxin use on the adverse effect of dronedarone on cardiovascular death, but not on occurrence of heart failure.

Clinical Trial Registration—
http://www.clinicaltrials.gov. Unique identifier: NCT01151137.