Clonality and evolutionary history of rhabdomyosarcoma.

To infer the subclonality of rhabdomyosarcoma (RMS) and predict the temporal order of genetic events for the tumorigenic process, and to identify novel drivers, we applied a systematic method that takes into account germline and somatic alterations in 44 tumor-normal RMS pairs using deep whole-genome sequencing. Intriguingly, we find that loss of heterozygosity of 11p15.5 and mutations in RAS pathway genes occur early in the evolutionary history of the PAX-fusion-negative-RMS (PFN-RMS) subtype. We discover several early mutations in non-RAS mutated samples and predict them to be drivers in PFN-RMS including recurrent mutation of PKN1. In contrast, we find that PAX-fusion-positive (PFP) subtype tumors have undergone whole-genome duplication in the late stage of cancer evolutionary history and have acquired fewer mutations and subclones than PFN-RMS. Moreover we predict that the PAX3-FOXO1 fusion event occurs earlier than the whole genome duplication. Our findings provide information critical to the understanding of tumorigenesis of RMS

Estimation of proteinuria as a predictor of complications of pre-eclampsia: a systematic review

Background Proteinuria is one of the essential criteria for the clinical diagnosis of pre-eclampsia. Increasing levels of proteinuria is considered to be associated with adverse maternal and fetal outcomes. We aim to determine the accuracy with which the amount of proteinuria predicts maternal and fetal complications in women with pre-eclampsia by systematic quantitative review of test accuracy studies. Methods We conducted electronic searches in MEDLINE (1951 to 2007), EMBASE (1980 to 2007), the Cochrane Library (2007) and the MEDION database to identify relevant articles and hand-search of selected specialist journals and reference lists of articles. There were no language restrictions for any of these searches. Two reviewers independently selected those articles in which the accuracy of proteinuria estimate was evaluated to predict maternal and fetal complications of pre-eclampsia. Data were extracted on study characteristics, quality and accuracy to construct 2 × 2 tables with maternal and fetal complications as reference standards. Results Sixteen primary articles with a total of 6749 women met the selection criteria with levels of proteinuria estimated by urine dipstick, 24-hour urine proteinuria or urine protein:creatinine ratio as a predictor of complications of pre-eclampsia. All 10 studies predicting maternal outcomes showed that proteinuria is a poor predictor of maternal complications in women with pre-eclampsia. Seventeen studies used laboratory analysis and eight studies bedside analysis to assess the accuracy of proteinuria in predicting fetal and neonatal complications. Summary likelihood ratios of positive and negative tests for the threshold level of 5 g/24 h were 2.0 (95% CI 1.5, 2.7) and 0.53 (95% CI 0.27, 1) for stillbirths, 1.5 (95% CI 0.94, 2.4) and 0.73 (95% CI 0.39, 1.4) for neonatal deaths and 1.5 (95% 1, 2) and 0.78 (95% 0.64, 0.95) for Neonatal Intensive Care Unit admission. Conclusion Measure of proteinuria is a poor predictor of either maternal or fetal complications in women with pre-eclampsia

Applications of Nature-Inspired Algorithms for Dimension Reduction: Enabling Efficient Data Analytics

In [1], we have explored the theoretical aspects of feature selection and evolutionary algorithms. In this chapter, we focus on optimization algorithms for enhancing data analytic process, i.e., we propose to explore applications of nature-inspired algorithms in data science. Feature selection optimization is a hybrid approach leveraging feature selection techniques and evolutionary algorithms process to optimize the selected features. Prior works solve this problem iteratively to converge to an optimal feature subset. Feature selection optimization is a non-specific domain approach. Data scientists mainly attempt to find an advanced way to analyze data n with high computational efficiency and low time complexity, leading to efficient data analytics. Thus, by increasing generated/measured/sensed data from various sources, analysis, manipulation and illustration of data grow exponentially. Due to the large scale data sets, Curse of dimensionality (CoD) is one of the NP-hard problems in data science. Hence, several efforts have been focused on leveraging evolutionary algorithms (EAs) to address the complex issues in large scale data analytics problems. Dimension reduction, together with EAs, lends itself to solve CoD and solve complex problems, in terms of time complexity, efficiently. In this chapter, we first provide a brief overview of previous studies that focused on solving CoD using feature extraction optimization process. We then discuss practical examples of research studies are successfully tackled some application domains, such as image processing, sentiment analysis, network traffics / anomalies analysis, credit score analysis and other benchmark functions/data sets analysis

Primary and malignant cholangiocytes undergo CD40 mediated Fas dependent Apoptosis, but are insensitive to direct activation with exogenous fas ligand

Introduction Cholangiocarcinoma is a rare malignancy of the biliary tract, the incidence of which is rising, but the pathogenesis of which remains uncertain. No common genetic defects have been described but it is accepted that chronic inflammation is an important contributing factor. We have shown that primary human cholangiocyte and hepatocyte survival is tightly regulated via co-operative interactions between two tumour necrosis family (TNF) receptor family members; CD40 and Fas (CD95). Functional deficiency of CD154, the ligand for CD40, leads to a failure of clearance of biliary tract infections and a predisposition to cholangiocarcinoma implying a direct link between TNF receptor-mediated apoptosis and the development of cholangiocarcinoma. Aims To determine whether malignant cholangiocytes display defects in CD40 mediated apoptosis. By comparing CD40 and Fas-mediated apoptosis and intracellular signalling in primary human cholangiocytes and three cholangiocyte cell lines. Results Primary cholangiocytes and cholangiocyte cell lines were relatively insensitive to direct Fas-mediated killing with exogenous FasL when compared with Jurkat cells, which readily underwent Fas-mediated apoptosis, but were extremely sensitive to CD154 stimulation. The sensitivity of cells to CD40 activation was similar in magnitude in both primary and malignant cells and was STAT-3 and AP-1 dependent in both. Conclusions 1) Both primary and malignant cholangiocytes are relatively resistant to Fas–mediated killing but show exquisite sensitivity to CD154, suggesting that the CD40 pathway is intact and fully functional in both primary and malignant cholangiocytes 2) The relative insensitivity of cholangiocytes to Fas activation demonstrates the importance of CD40 augmentation of Fas dependent death in these cells. Agonistic therapies which target CD40 and associated intracellular signalling pathways may be effective in promoting apoptosis of malignant cholangiocytes

Peripheral artery disease assessed by ankle-brachial index in patients with established cardiovascular disease or at least one risk factor for atherothrombosis - CAREFUL Study: A national, multi-center, cross-sectional observational study

<p>Abstract</p> <p>Background</p> <p>To investigate the presence of peripheral artery disease (PAD) via the ankle brachial index (ABI) in patients with known cardiovascular and/or cerebrovascular diseases or with at least one risk factor for atherothrombosis.</p> <p>Methods</p> <p>Patients with a history of atherothrombotic events, or aged 50-69 years with at least one cardiovascular risk factor, or > = 70 years of age were included in this multicenter, cross-sectional, non-interventional study (DIREGL04074). Demographics, medical history, physical examination findings, and physician awareness of PAD were analyzed. The number of patients with low ABI (< = 0.90) was analyzed.</p> <p>Results</p> <p>A total of 530 patients (mean age, 63.4 ± 8.7 years; 50.2% female) were enrolled. Hypertension and dyslipidemia were present in 88.7% and 65.5% of patients, respectively. PAD-related symptoms were evident in about one-third of the patients, and at least one of the pedal pulses was negative in 6.5% of patients. The frequency of low ABI was 20.0% in the whole study population and 30% for patients older than 70 years. Older age, greater number of total risk factors, and presence of PAD-related physical findings were associated with increased likelihood of low ABI (<it>p </it>< 0.001). There was no gender difference in the prevalence of low ABI, PAD symptoms, or total number of risk factors. Exercise (33.6%) was the most common non-pharmacological option recommended by physicians, and acetylsalicylic acid (ASA) (45.4%) was the most frequently prescribed medication for PAD.</p> <p>Conclusion</p> <p>Our results indicate that advanced age, greater number of total risk factors and presence of PAD-related physical findings were associated with increased likelihood of low ABI. These findings are similar to those reported in similar studies of different populations, and document a fairly high prevalence of PAD in a Mediterranean country.</p

Identification of the initial molecular changes in response to circulating angiogenic cells-mediated therapy in critical limb ischemia

BackgroundCritical limb ischemia (CLI) constitutes the most aggressive form of peripheral arterial occlusive disease, characterized by the blockade of arteries supplying blood to the lower extremities, significantly diminishing oxygen and nutrient supply. CLI patients usually undergo amputation of fingers, feet, or extremities, with a high risk of mortality due to associated comorbidities.Circulating angiogenic cells (CACs), also known as early endothelial progenitor cells, constitute promising candidates for cell therapy in CLI due to their assigned vascular regenerative properties. Preclinical and clinical assays with CACs have shown promising results. A better understanding of how these cells participate in vascular regeneration would significantly help to potentiate their role in revascularization.Herein, we analyzed the initial molecular mechanisms triggered by human CACs after being administered to a murine model of CLI, in order to understand how these cells promote angiogenesis within the ischemic tissues.MethodsBalb-c nude mice (n:24) were distributed in four different groups: healthy controls (C, n:4), shams (SH, n:4), and ischemic mice (after femoral ligation) that received either 50 mu l physiological serum (SC, n:8) or 5x10(5) human CACs (SE, n:8). Ischemic mice were sacrificed on days 2 and 4 (n:4/group/day), and immunohistochemistry assays and qPCR amplification of Alu-human-specific sequences were carried out for cell detection and vascular density measurements. Additionally, a label-free MS-based quantitative approach was performed to identify protein changes related.ResultsAdministration of CACs induced in the ischemic tissues an increase in the number of blood vessels as well as the diameter size compared to ischemic, non-treated mice, although the number of CACs decreased within time. The initial protein changes taking place in response to ischemia and more importantly, right after administration of CACs to CLI mice, are shown.ConclusionsOur results indicate that CACs migrate to the injured area; moreover, they trigger protein changes correlated with cell migration, cell death, angiogenesis, and arteriogenesis in the host. These changes indicate that CACs promote from the beginning an increase in the number of vessels as well as the development of an appropriate vascular network.Institute of Health Carlos III, ISCIII; Junta de Andaluci

Optimal functional outcome measures for assessing treatment for Dupuytren's disease: A systematic review and recommendations for future practice

This article is available through the Brunel Open Access Publishing Fund. Copyright © 2013 Ball et al.; licensee BioMed Central Ltd.Background: Dupuytren's disease of the hand is a common condition affecting the palmar fascia, resulting in progressive flexion deformities of the digits and hence limitation of hand function. The optimal treatment remains unclear as outcomes studies have used a variety of measures for assessment. Methods: A literature search was performed for all publications describing surgical treatment, percutaneous needle aponeurotomy or collagenase injection for primary or recurrent Dupuytren’s disease where outcomes had been monitored using functional measures. Results: Ninety-one studies met the inclusion criteria. Twenty-two studies reported outcomes using patient reported outcome measures (PROMs) ranging from validated questionnaires to self-reported measures for return to work and self-rated disability. The Disability of Arm, Shoulder and Hand (DASH) score was the most utilised patient-reported function measure (n=11). Patient satisfaction was reported by eighteen studies but no single method was used consistently. Range of movement was the most frequent physical measure and was reported in all 91 studies. However, the methods of measurement and reporting varied, with seventeen different techniques being used. Other physical measures included grip and pinch strength and sensibility, again with variations in measurement protocols. The mean follow-up time ranged from 2 weeks to 17 years. Conclusions: There is little consistency in the reporting of outcomes for interventions in patients with Dupuytren’s disease, making it impossible to compare the efficacy of different treatment modalities. Although there are limitations to the existing generic patient reported outcomes measures, a combination of these together with a disease-specific questionnaire, and physical measures of active and passive individual joint Range of movement (ROM), grip and sensibility using standardised protocols should be used for future outcomes studies. As Dupuytren’s disease tends to recur following treatment as well as extend to involve other areas of the hand, follow-up times should be standardised and designed to capture both short and long term outcomes

Gene expression profiling may improve diagnosis in patients with carcinoma of unknown primary

Carcinomas of unknown primary (CUP) represent between 3 and 10% of malignancies. Treatment with nonspecific chemotherapy is commonly unhelpful and the median survival is between 3 and 6 months. Gene expression microarray (GEM) analysis has demonstrated that molecular signatures can aid in tumour classification and propose foster primaries. In this study, we demonstrate the clinical utility of a diagnostic gene expression profiling tool and discuss its potential implications for patient management strategies. Paraffin tumour samples from 21 cases of ‘true' CUP patients in whom standard investigation had failed to determine a primary site of malignancy were investigated using diagnostic gene profiling. The results were reviewed in the context of histology and clinical history. Classification of tumour origin using the GEM method confirmed the clinicians' suspicion in 16 out of 21 cases. There was a clinical/GEM inconsistency in 4 out of 21 patients and a pathological/GEM inconsistency in 1 patient. The improved diagnoses by the GEM method would have influenced the management in 12 out of 21 cases. Genomic profiling and cancer classification tools represent a promising analytical approach to assist with the management of CUP patients. We propose that GEM diagnosis be considered when the primary clinical algorithm has failed to provide a diagnosis

Acute kidney disease and renal recovery : consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of > 90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD

Prediction of pre-eclampsia: a protocol for systematic reviews of test accuracy

BACKGROUND: Pre-eclampsia, a syndrome of hypertension and proteinuria, is a major cause of maternal and perinatal morbidity and mortality. Accurate prediction of pre-eclampsia is important, since high risk women could benefit from intensive monitoring and preventive treatment. However, decision making is currently hampered due to lack of precise and up to date comprehensive evidence summaries on estimates of risk of developing pre-eclampsia. METHODS/DESIGN: A series of systematic reviews and meta-analyses will be undertaken to determine, among women in early pregnancy, the accuracy of various tests (history, examinations and investigations) for predicting pre-eclampsia. We will search Medline, Embase, Cochrane Library, MEDION, citation lists of review articles and eligible primary articles and will contact experts in the field. Reviewers working independently will select studies, extract data, and assess study validity according to established criteria. Language restrictions will not be applied. Bivariate meta-analysis of sensitivity and specificity will be considered for tests whose studies allow generation of 2 × 2 tables. DISCUSSION: The results of the test accuracy reviews will be integrated with results of effectiveness reviews of preventive interventions to assess the impact of test-intervention combinations for prevention of pre-eclampsia