Potentiation of thrombus instability: a contributory mechanism to the effectiveness of antithrombotic medications

© The Author(s) 2018The stability of an arterial thrombus, determined by its structure and ability to resist endogenous fibrinolysis, is a major determinant of the extent of infarction that results from coronary or cerebrovascular thrombosis. There is ample evidence from both laboratory and clinical studies to suggest that in addition to inhibiting platelet aggregation, antithrombotic medications have shear-dependent effects, potentiating thrombus fragility and/or enhancing endogenous fibrinolysis. Such shear-dependent effects, potentiating the fragility of the growing thrombus and/or enhancing endogenous thrombolytic activity, likely contribute to the clinical effectiveness of such medications. It is not clear how much these effects relate to the measured inhibition of platelet aggregation in response to specific agonists. These effects are observable only with techniques that subject the growing thrombus to arterial flow and shear conditions. The effects of antithrombotic medications on thrombus stability and ways of assessing this are reviewed herein, and it is proposed that thrombus stability could become a new target for pharmacological intervention.Peer reviewedFinal Published versio

Cardiovascular Effects of Switching from Tobacco Cigarettes to Electronic Cigarettes

The VESUVIUS (Vascular Effects of Regular Cigarettes Versus Electronic Cigarette Use) trial was funded by the British Heart Foundation (grant PG/15/64/31681); and supported by Immunoassay Biomarker Core Laboratory, University of Dundee, the Tayside Medical Sciences Centre, and the NHS Tayside Smoking Cessation Service. The funder had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or in the decision to submit for publication. Dr. Donnan has received research grants from AbbVie, Shire, and Gilead Sciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.Peer reviewedPublisher PD

Biomarkers of oxidative stress and antioxidant status in children born small for gestational age: Evidence of lipid peroxidation

Children born small for gestational age are known to be at increased risk for adult diseases such as hypertension, diabetes, and coronary heart disease. Oxidative stress is a common feature of these pathogenic conditions and can be the key link between size at birth and increased morbidity later in life. the purpose of this study was to analyze the parameters of lipoperoxidation and changes in antioxidant defense system as well as assess their relationship to birth weight. Concentrations of thiobarbituric-acid-reactive-substances and F-2-isoprostanes, total antioxidant status, and the activity of both superoxide dismutase and glutathione peroxidase were measured in 65 children (33 boys, 32 girls; ages 8-13 y). Thiobarbituric-acid-reactive-substances and F-2-isoprostane levels were significantly elevated in children born small for gestational age. Nevertheless, superoxide dismutase activity was significantly elevated in these children and the levels of both glutathione peroxidase activity and total antioxidant status were unchanged. Moreover, we found that systolic blood pressure was positively associated with thiobarbituric-acid-reactive-substances levels in race- and gender-adjusted models but not in a multivariable regression model. in conclusion, the current study revealed that there is evidence of oxidative stress in children born small for gestational age as supported by increased lipid peroxidation.Universidade Federal de São Paulo, Sch Med, Dept Physiol, Div Nephrol, BR-04023900 São Paulo, BrazilUniv São Paulo, Sch Med, Inst Biomed Sci, BR-00508070 São Paulo, BrazilUniversidade Federal de São Paulo, Sch Med, Dept Physiol, Div Nephrol, BR-04023900 São Paulo, BrazilWeb of Scienc

The evidence base for circulating tumour DNA blood-based biomarkers for the early detection of cancer: a systematic mapping review

Background: The presence of circulating cell-free DNA from tumours in blood (ctDNA) is of major importance to those interested in early cancer detection, as well as to those wishing to monitor tumour progression or diagnose the presence of activating mutations to guide treatment. In 2014, the UK Early Cancer Detection Consortium undertook a systematic mapping review of the literature to identify blood-based biomarkers with potential for the development of a non-invasive blood test for cancer screening, and which identified this as a major area of interest. This review builds on the mapping review to expand the ctDNA dataset to examine the best options for the detection of multiple cancer types. Methods: The original mapping review was based on comprehensive searches of the electronic databases Medline, Embase, CINAHL, the Cochrane library, and Biosis to obtain relevant literature on blood-based biomarkers for cancer detection in humans (PROSPERO no. CRD42014010827). The abstracts for each paper were reviewed to determine whether validation data were reported, and then examined in full. Publications concentrating on monitoring of disease burden or mutations were excluded. Results: The search identified 94 ctDNA studies meeting the criteria for review. All but 5 studies examined one cancer type, with breast, colorectal and lung cancers representing 60% of studies. The size and design of the studies varied widely. Controls were included in 77% of publications. The largest study included 640 patients, but the median study size was 65 cases and 35 controls, and the bulk of studies (71%) included less than 100 patients. Studies either estimated cfDNA levels non-specifically or tested for cancer-specific mutations or methylation changes (the majority using PCR-based methods). Conclusion: We have systematically reviewed ctDNA blood biomarkers for the early detection of cancer. Pre-analytical, analytical, and post-analytical considerations were identified which need to be addressed before such biomarkers enter clinical practice. The value of small studies with no comparison between methods, or even the inclusion of controls is highly questionable, and larger validation studies will be required before such methods can be considered for early cancer detection

CUT-PCR: CRISPR-mediated, ultrasensitive detection of target DNA using PCR

Circulating tumor DNA (ctDNA) has emerged as a tumor-specific biomarker for the early detection of various cancers. To date, several techniques have been devised to enrich the extremely small amounts of ctDNA present in plasma, but they are still insufficient for cancer diagnosis, especially at the early stage. Here, we developed a novel method, CUT (CRISPR-mediated, Ultrasensitive detection of Target DNA)-PCR, which uses CRISPR endonucleases to enrich and detect the extremely small amounts of tumor DNA fragments among the much more abundant wild-type DNA fragments by specifically eliminating the wild-type sequences. We computed that by using various orthologonal CRISPR endonucleases such as SpCas9 and FnCpf1, the CUT-PCR method would be applicable to 80% of known cancer-linked substitution mutations registered in the COSMIC database. We further verified that CUT-PCR together with targeted deep sequencing enables detection of a broad range of oncogenes with high sensitivity (<0.01%) and accuracy, which is superior to conventional targeted deep sequencing. In the end, we successfully applied CUT-PCR to detect sequences with oncogenic mutations in the ctDNA of colorectal cancer patients' blood, suggesting that our technique could be adopted for diagnosing various types of cancer at early stages

Влияние облучения протонами на структуру наноразмерного металлического многослойного покрытия Zr/Nb

Образцы наноразмерного многослойного Zr/Nb покрытия, полученные путем магнетронного распыления, были подвергнуты облучению пучком протонов с током 2 и 4 мкА на линейном ускорителе ЭСГ-2,5. Анализ распределения протонов и дефектов по глубине был проведен в программном пакете SRIM. Методом рентгеноструктурного анализа определены размер кристаллитов и микронапряжения после облучения. Присутствие дефектной структуры в покрытии было определено по результатам измерения электросопротивления. Была установлена корреляционная зависимость данных электросопротивления и рентгеноструктурного анализа свидетельствующая о формировании дефектной структуры в покрытиях после облучения. Механические характеристики, такие как твердость и модуль Юнга были рассчитаны из данных по наноиндентированию.Nanoscale multilayer Zr/Nb coatings, received by magnetron sputtering, were been irradiated by proton beam with electrostatic Van De Graaff ion accelerator, ion current was 2 and 4 ?A. The penetration depth and distribution of defects was determined with SRIM simulation code. X–ray analyses before and after irradiation were performed to observe changes in crystalline sizes and microstrain values. Presence of defect structure in the coating was determined by electrical resistance measurements . There was observed correlation dependence between changes in electrical resistance and results of X-ray diffraction analyses. Mechanical properties, like hardness and Young’s modulus, were determined from nanoindentation tests

Nutraceutical therapies for atherosclerosis

Atherosclerosis is a chronic inflammatory disease affecting large and medium arteries and is considered to be a major underlying cause of cardiovascular disease (CVD). Although the development of pharmacotherapies to treat CVD has contributed to a decline in cardiac mortality in the past few decades, CVD is estimated to be the cause of one-third of deaths globally. Nutraceuticals are natural nutritional compounds that are beneficial for the prevention or treatment of disease and, therefore, are a possible therapeutic avenue for the treatment of atherosclerosis. The purpose of this Review is to highlight potential nutraceuticals for use as antiatherogenic therapies with evidence from in vitro and in vivo studies. Furthermore, the current evidence from observational and randomized clinical studies into the role of nutraceuticals in preventing atherosclerosis in humans will also be discussed

Prognostic DNA methylation markers for sporadic colorectal cancer: a systematic review

Background Biomarkers that can predict the prognosis of colorectal cancer (CRC) patients and that can stratify high-risk early stage patients from low-risk early stage patients are urgently needed for better management of CRC. During the last decades, a large variety of prognostic DNA methylation markers has been published in the literature. However, to date, none of these markers are used in clinical practice. Methods To obtain an overview of the number of published prognostic methylation markers for CRC, the number of markers that was validated independently, and the current level of evidence (LoE), we conducted a systematic review of PubMed, EMBASE, and MEDLINE. In addition, we scored studies based on the REMARK guidelines that were established in order to attain more transparency and complete reporting of prognostic biomarker studies. Eighty-three studies reporting on 123 methylation markers fulfilled the study entry criteria and were scored according to REMARK. Results Sixty-three studies investigated single methylation markers, whereas 20 studies reported combinations of methylation markers. We observed substantial variation regarding the reporting of sample sizes and patient characteristics, statistical analyses, and methodology. The median (range) REMARK score for the studies was 10.7 points (4.5 to 17.5) out of a maximum of 20 possible points. The median REMARK score was lower in studies, which reported a p value below 0.05 versus those, which did not (p = 0.005). A borderline statistically significant association was observed between the reported p value of the survival analysis and the size of the study population (p = 0.051). Only 23 out of 123 markers (17%) were investigated in two or more study series. For 12 markers, and two multimarker panels, consistent results were reported in two or more study series. For four markers, the current LoE is level II, for all other markers, the LoE is lower. Conclusion This systematic review reflects that adequate reporting according to REMARK and validation of prognostic methylation markers is absent in the majority of CRC methylation marker studies. However, this systematic review provides a comprehensive overview of published prognostic methylation markers for CRC and highlights the most promising markers that have been published in the last two decades