Abnormal plasma DNA profiles in early ovarian cancer using a non-invasive prenatal testing platform: Implications for cancer screening

Background: Non-invasive prenatal testing (NIPT) identifies fetal aneuploidy by sequencing cell-free DNA in the maternal plasma. Pre-symptomatic maternal malignancies have been incidentally detected during NIPT based on abnormal genomic profiles. This low coverage sequencing approach could have potential for ovarian cancer screening in the non-pregnant population. Our objective was to investigate whether plasma DNA sequencing with a clinical whole genome NIPT platform can detect early- and late-stage high-grade serous ovarian carcinomas (HGSOC). Methods: This is a case control study of prospectively-collected biobank samples comprising preoperative plasma from 32 women with HGSOC (16 ‘early cancer’ (FIGO I–II) and 16 ‘advanced cancer’ (FIGO III–IV)) and 32 benign controls. Plasma DNA from cases and controls were sequenced using a commercial NIPT platform and chromosome dosage measured. Sequencing data were blindly analyzed with two methods: (1) Subchromosomal changes were called using an open source algorithm WISECONDOR (WIthin-SamplE COpy Number aberration DetectOR). Genomic gains or losses ≥ 15 Mb were prespecified as “screen positive” calls, and mapped to recurrent copy number variations reported in an ovarian cancer genome atlas. (2) Selected whole chromosome gains or losses were reported using the routine NIPT pipeline for fetal aneuploidy. Results: We detected 13/32 cancer cases using the subchromosomal analysis (sensitivity 40.6 %, 95 % CI, 23.7–59.4 %), including 6/16 early and 7/16 advanced HGSOC cases. Two of 32 benign controls had subchromosomal gains ≥ 15 Mb (specificity 93.8 %, 95 % CI, 79.2–99.2 %). Twelve of the 13 true positive cancer cases exhibited specific recurrent changes reported in HGSOC tumors. The NIPT pipeline resulted in one “monosomy 18” call from the cancer group, and two “monosomy X” calls in the controls. Conclusions: Low coverage plasma DNA sequencing used for prenatal testing detected 40.6 % of all HGSOC, including 38 % of early stage cases. Our findings demonstrate the potential of a high throughput sequencing platform to screen for early HGSOC in plasma based on characteristic multiple segmental chromosome gains and losses. The performance of this approach may be further improved by refining bioinformatics algorithms and targeting selected cancer copy number variations. Abbreviations: CNV, copy number variation; HGSOC, high grade serous ovarian carcinoma; NIPT, non-invasive prenatal testing; WISECONDOR, within sample copy number aberration detecto

The retinoic acid receptor alpha (RARA) gene is not associated with myopia, hypermetropia, and ocular biometric measures

Purpose: The Retinoic Acid Receptor Alpha (RARA) gene is a potential candidate gene for myopia due to its differential expression in animal models during experimentally induced myopia. To test for whether RARA is associated with myopia we have undertaken a case-control study assessing for associations between RARA and myopia, hypermetropia, and ocular biometric measures. Methods: A total of 802 Anglo-Celtic individuals were genotyped. Five tag single nucleotide polymorphisms (tSNPs) in RARA with an r2 of 0.8 and a minor allele frequency greater than 5% were selected for genotyping. Genotype frequencies of these 5 tSNPs were compared between individuals with emmetropia and those with myopia or hypermetropia. A quantitative analysis was also performed to assess associations with ocular biometric measures including axial length, corneal curvature and anterior chamber depth. Results: We did not identify any significant association between tSNPs in RARA with either myopia or hypermetropia as qualitative traits. Neither did we identify any significant associations of these tSNPs with the quantitative traits of axial length, corneal curvature and anterior chamber depth. Conclusions: This is the first study to assess for associations between RARA and myopia, hypermetropia, and ocular biometric measures. Our findings suggest that variations in the nucleotide sequence of RARA are not associated with myopia, hypermetropia, or ocular biometric measures in our population

Vitamin D regulates tyrosine hydroxylase expression: N-cadherin a possible mediator

Vitamin D is a neuroactive steroid. Its genomic actions are mediated via the active form of vitamin D, 1,25(OH)2D3, binding to the vitamin D receptor (VDR). The VDR emerges in the rat mesencephalon at embryonic day 12, representing the peak period of dopaminergic cell birth. Our prior studies reveal that developmental vitamin D (DVD)-deficiency alters the ontogeny of dopaminergic neurons in the developing mesencephalon. There is also consistent evidence from others that 1,25(OH)2D3 promotes the survival of dopaminergic neurons in models of dopaminergic toxicity. In both developmental and toxicological studies it has been proposed that 1,25(OH)2D3 may modulate the differentiation and maturation of dopaminergic neurons; however, to date there is lack of direct evidence. The aim of the current study is to investigate this both in vitro using a human SH-SY5Y cell line transfected with rodent VDR and in vivo using a DVD-deficient model. Here we show that in VDR-expressing SH-SY5Y cells, 1,25(OH)2D3 significantly increased production of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. This effect was dose- and time-dependent, but was not due to an increase in TH-positive cell number, nor was it due to the production of trophic survival factors for dopamine neurons such as glial-derived neurotrophic factor (GDNF). In accordance with 1,25(OH)2D3's anti-proliferative actions in the brain, 1,25(OH)2D3 reduced the percentage of dividing cells from approximately 15-10%. Given the recently reported role of N-cadherin in the direct differentiation of dopaminergic neurons, we examined here whether it may be elevated by 1,25(OH)2D3. We confirmed this in vitro and more importantly, we showed DVD-deficiency decreases N-cadherin expression in the embryonic mesencephalon. In summary, in our in vitro model we have shown 1,25(OH)2D3 increases TH expression, decreases proliferation and elevates N-cadherin, a potential factor that mediates these processes. Accordingly all of these findings are reversed in the developing brain in our DVD-deficiency model. Remarkably our findings in the DVD-deficiency model phenocopy those found in a recent model where N-cadherin was regionally ablated from the mesencephalon. This study has, for the first time, shown that vitamin D directly modulates TH expression and strongly suggests N-cadherin may be a plausible mediator of this process both in vitro and in vivo. Our findings may help to explain epidemiological data linking DVD deficiency with schizophrenia

Counting co-occurrences in citations to identify plagiarised text fragments

The final publication is available at Springer via http://dx.doi.org/10.1007/978-3-642-40802-1_19Research in external plagiarism detection is mainly concerned with the comparison of the textual contents of a suspicious document against the contents of a collection of original documents. More recently, methods that try to detect plagiarism based on citation patterns have been proposed. These methods are particularly useful for detecting plagiarism in scientific publications. In this work, we assess the value of identifying co-occurrences in citations by checking whether this method can identify cases of plagiarism in a dataset of scientific papers. Our results show that most the cases in which co-occurrences were found indeed correspond to plagiarised passagesThis work was partially funded by CNPq (478979/2012-6). Solange Pertile’s 5-month internship at NLE Lab of Universitat Polit`ecnica de Val`encia was funded by CAPES. P.Rosso’s work was carried out in the framework of the the VLC/CAMPUS Microcluster on Multimodal Interaction in Intelligent Systems and the European Commission WIQ-EI IRSES (no. 269180) and DIANA-APPLICATIONSFinding Hidden Knowledge in Texts: Applications (TIN2012-38603-C02-01) research projects. We thank the authors of [5] for sharing their dataset with us and Enrique Flores for the preliminary brainstorming on how to identify co-occurrences in citationsPertile, SDL.; Rosso, P.; Moreira, VP. (2013). Counting co-occurrences in citations to identify plagiarised text fragments. En Information Access Evaluation. Multilinguality, Multimodality, and Visualization. Springer Verlag (Germany). 150-154. https://doi.org/10.1007/978-3-642-40802-1_19S150154CrossCheck, http://www.crossref.org/crosscheck/Journal of Zhejiang University-Science, http://www.zju.edu.cn/jzus/PAN, http://www.pan.webis.dePlagiarism corpus, http://www.c2learn.com/plagiarism/corpus/v1/Alzahrani, S., Palade, V., Salim, N., Abraham, A.: Using structural information and citation evidence to detect significant plagiarism cases in scientific publications. JASIST 63(2), 286–312 (2012)Barrón-Cedeño, A., Vila, M., Marti, A., Rosso, P.: Plagiarism meets paraphrasing: Insights for the next generation in automatic plagiarism detection. Computational Linguistics 39(4) (2013)Cortez, E., da Silva, A.S., Gonçalves, M.A., de Moura, E.S.: Ondux: on-demand unsupervised learning for information extraction. In: SIGMOD, pp. 807–818 (2010)Gipp, B., Meuschke, N.: Citation pattern matching algorithms for citation-based plagiarism detection: greedy citation tiling, citation chunking and longest common citation sequence. In: DocEng, pp. 249–258 (2011)Gupta, P., Rosso, P.: Text reuse with ACL (upward) trends. In: ACL 2012 Special Workshop on Rediscovering 50 Years of Discoveries, pp. 76–82 (2012)Mccabe, D.L.: Cheating among college and university students: A north american perspective. International Journal for Educational Integrity 1 (2005)Potthast, M., Barrón-Cedeño, A., Stein, B., Rosso, P.: Cross-language plagiarism detection. Language Resources and Evaluation 45(1), 45–62 (2011)Potthast, M., Gollub, T., Hagen, M., Tippmann, M., Kiesel, J., Stamatatos, E., Rosso, P., Stein, B.: Overview of the 5th International Competition on Plagiarism Detection. In: CLEF 2013 - Working Notes (September 2013)Ritt, M., Costa, A.M., Mergen, S., Orengo, V.M.: An integer linear programming approach for approximate string comparison. European Journal of Operational Research 198(3), 706–714 (2009)Zhang, Y.: Crosscheck: an effective tool for detecting plagiarism. Learned Publishing 23, 9–14 (2010

Systemic perturbations of the kynurenine pathway precede progression to dementia independently of amyloid-β

Increasing evidence suggests that kynurenine pathway (KP) dyshomeostasis may promote disease progression in dementia. Studies in Alzheimer's disease (AD) patients confirm KP dyshomeostasis in plasma and cerebrospinal fluid (CSF) which correlates with amyloid-β and tau pathology. Herein, we performed the first comprehensive study assessing baseline levels of KP metabolites in participants enrolling in the Australian Imaging Biomarkers Flagship Study of Aging. Our purpose was to test the hypothesis that changes in KP metabolites may be biomarkers of dementia processes that are largely silent. We used a cross-sectional analytical approach to assess non-progressors (N = 73); cognitively normal (CN) or mild cognitive impairment (MCI) participants at baseline and throughout the study, and progressors (N = 166); CN or MCI at baseline but progressing to either MCI or AD during the study. Significant KP changes in progressors included increased 3-hydroxyanthranilic acid (3-HAA) and 3-hydroxyanthranilic acid/anthranilic acid (3-HAA/AA) ratio, the latter having the largest effect on the odds of an individual being a progressor (OR 35.3; 95% CI between 14 and 104). 3-HAA levels were hence surprisingly bi-phasic, high in progressors but low in non-progressors or participants who had already transitioned to MCI or dementia. This is a new, unexpected and interesting result, as most studies of the KP in neurodegenerative disease show reduced 3-HAA/AA ratio after diagnosis. The neuroprotective metabolite picolinic acid was also significantly decreased while the neurotoxic metabolite 3-hydroxykynurenine increased in progressors. These results were significant even after adjustment for confounders. Considering the magnitude of the OR to predict change in cognition, it is important that these findings are replicated in other populations. Independent validation of our findings may confirm the utility of 3-HAA/AA ratio to predict change in cognition leading to dementia in clinical settings

Does police size matter?:A review of the evidence regarding restructuring police organisations

Restructuring and merging public sector organisations is often seen as a way to enhance efficiency and efficacy. There is ongoing debate about the impact of police force sizes, structures and mergers as police organisations attempt to adapt to reductions in their budgets and changes in patterns of criminality. The article reviews the evidence regarding key aspects of police reform: finding mixed evidence regarding the links between size and performance, while noting risks that mergers may impair local policing. The article discusses the impact of mergers on protective services, governance and accountability, while also discussing potential risks and opportunities associated with the merger process itself. The review finds significant gaps in the available evidence, and significant opportunities to expand the evidence base on this topic. Given current gaps in the evidence regarding size, efficacy and efficiency, it is important to give due consideration to symbolic and rhetorical aspects of mergers

From bench to bedside: in vitro and in vivo evaluation of a neonate-focused nebulized surfactant delivery strategy.

BACKGROUND: Non-invasive delivery of nebulized surfactant has been a neonatology long-pursued goal. Nevertheless, the clinical efficacy of nebulized surfactant remains inconclusive, in part, due to the great technical challenges of depositing nebulized drugs in the lungs of preterm infants. The aim of this study was to investigate the feasibility of delivering nebulized surfactant (poractant alfa) in vitro and in vivo with an adapted, neonate-tailored aerosol delivery strategy. METHODS: Particle size distribution of undiluted poractant alfa aerosols generated by a customized eFlow-Neos nebulizer system was determined by laser diffraction. The theoretical nebulized surfactant lung dose was estimated in vitro in a clinical setting replica including a neonatal continuous positive airway pressure (CPAP) circuit, a cast of the upper airways of a preterm neonate, and a breath simulator programmed with the tidal breathing pattern of an infant with mild respiratory distress syndrome (RDS). A dose-response study with nebulized surfactant covering the 100-600\u2009mg/kg nominal dose-range was conducted in RDS-modelling, lung-lavaged spontaneously-breathing rabbits managed with nasal CPAP. The effects of nebulized poractant alfa on arterial gas exchange and lung mechanics were assessed. Exogenous alveolar disaturated-phosphatidylcholine (DSPC) in the lungs was measured as a proxy of surfactant deposition efficacy. RESULTS: Laser diffraction studies demonstrated suitable aerosol characteristics for inhalation (mass median diameter, MMD\u2009=\u20093\u2009\u3bcm). The mean surfactant lung dose determined in vitro was 13.7%\u2009\ub1\u20094.0 of the 200\u2009mg/kg nominal dose. Nebulized surfactant delivered to spontaneously-breathing rabbits during nasal CPAP significantly improved arterial oxygenation compared to animals receiving CPAP only. Particularly, the groups of animals treated with 200\u2009mg/kg and 400\u2009mg/kg of nebulized poractant alfa achieved an equivalent pulmonary response in terms of oxygenation and lung mechanics as the group of animals treated with instilled surfactant (200\u2009mg/kg). CONCLUSIONS: The customized eFlow-Neos vibrating-membrane nebulizer system efficiently generated respirable aerosols of undiluted poractant alfa. Nebulized surfactant delivered at doses of 200\u2009mg/kg and 400\u2009mg/kg elicited a pulmonary response equivalent to that observed after treatment with an intratracheal surfactant bolus of 200\u2009mg/kg. This bench-characterized nebulized surfactant delivery strategy is now under evaluation in Phase II clinical trial (EUDRACT No.:2016-004547-36)

From bench to bedside: In vitro and in vivo evaluation of a neonate-focused nebulized surfactant delivery strategy

Background: Non-invasive delivery of nebulized surfactant has been a neonatology long-pursued goal. Nevertheless, the clinical efficacy of nebulized surfactant remains inconclusive, in part, due to the great technical challenges of depositing nebulized drugs in the lungs of preterm infants. The aim of this study was to investigate the feasibility of delivering nebulized surfactant (poractant alfa) in vitro and in vivo with an adapted, neonate- tailored aerosol delivery strategy. Methods: Particle size distribution of undiluted poractant alfa aerosols generated by a customized eFlow-Neos nebulizer system was determined by laser diffraction. The theoretical nebulized surfactant lung dose was estimated in vitro in a clinical setting replica including a neonatal continuous positive airway pressure (CPAP) circuit, a cast of the upper airways of a preterm neonate, and a breath simulator programmed with the tidal breathing pattern of an infant with mild respiratory distress syndrome (RDS). A dose-response study with nebulized surfactant covering the 100\u2013600 mg/kg nominal dose-range was conducted in RDS-modelling, lung-lavaged spontaneously-breathing rabbits managed with nasal CPAP. The effects of nebulized poractant alfa on arterial gas exchange and lung mechanics were assessed. Exogenous alveolar disaturated-phosphatidylcholine (DSPC) in the lungs was measured as a proxy of surfactant deposition efficacy. Results: Laser diffraction studies demonstrated suitable aerosol characteristics for inhalation (mass median diameter, MMD = 3 \u3bcm). The mean surfactant lung dose determined in vitro was 13.7% \ub1 4.0 of the 200 mg/kg nominal dose. Nebulized surfactant delivered to spontaneously-breathing rabbits during nasal CPAP significantly improved arterial oxygenation compared to animals receiving CPAP only. Particularly, the groups of animals treated with 200 mg/kg and 400 mg/kg of nebulized poractant alfa achieved an equivalent pulmonary response in terms of oxygenation and lung mechanics as the group of animals treated with instilled surfactant (200 mg/kg). Conclusions: The customized eFlow-Neos vibrating-membrane nebulizer system efficiently generated respirable aerosols of undiluted poractant alfa. Nebulized surfactant delivered at doses of 200 mg/kg and 400 mg/kg elicited a pulmonary response equivalent to that observed after treatment with an intratracheal surfactant bolus of 200 mg/kg. This bench-characterized nebulized surfactant delivery strategy is now under evaluation in Phase II clinical trial (EUDRACT No.:2016\u2013004547-36)

Profile of Lipid and Protein Autacoids in Diabetic Vitreous Correlates With the Progression of Diabetic Retinopathy

OBJECTIVE: This study was aimed at obtaining a profile of lipids and proteins with a paracrine function in normal and diabetic vitreous and exploring whether the profile correlates with retinal pathology. RESEARCH DESIGN AND METHODS: Vitreous was recovered from 47 individuals undergoing vitreoretinal surgery: 16 had nonproliferative diabetic retinopathy (NPDR), 15 had proliferative diabetic retinopathy, 7 had retinal detachments, and 9 had epiretinal membranes. Protein and lipid autacoid profiles were determined by protein arrays and mass spectrometry-based lipidomics. RESULTS: Vitreous lipids included lipoxygenase (LO)- and cytochrome P450 epoxygenase (CYP)-derived eicosanoids. The most prominent LO-derived eicosanoid was 5-hydroxyeicosate traenoic acid (HETE), which demonstrated a diabetes-specific increase (P = 0.027) with the highest increase in NPDR vitreous. Vitreous also contained CYP-derived epoxyeicosatrienoic acids; their levels were higher in nondiabetic than diabetic vitreous (P < 0.05). Among inflammatory, angiogenic, and angiostatic cytokines and chemokines, only vascular endothelial growth factor (VEGF) showed a significant diabetes-specific profile (P < 0.05), although a similar trend was noted for tumor necrosis factor (TNF)-alpha. Soluble VEGF receptors R1 and R2 were detected in all samples with lowest VEGF-R2 levels (P < 0.05) and higher ratio of VEGF to its receptors in NPDR and PDR vitreous. CONCLUSIONS: This study is the first to demonstrate diabetes-specific changes in vitreous lipid autacoids including arachidonate and docosahexanoate-derived metabolites indicating an increase in inflammatory versus anti-inflammatory lipid mediators that correlated with increased levels of inflammatory and angiogenic proteins, further supporting the notion that inflammation plays a role the pathogenesis of this disease