NAD(P)H:quinone oxidoreductase 1 (NQO1) P187S polymorphism and prostate cancer risk in Caucasians

NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyses the reduction of quinoid compounds to hydroquinones, preventing the generation of free radicals and reactive oxygen. A “C” to “T” transversion at position 609 of NQO1, leading to a nonsynonymous amino acid change (Pro187Ser, P187S), results in an altered enzyme activity. No NQO1 protein activity was detected in NQO1 609TT genotype, and low to intermediate activity was detected in NQO1 609CT genotype compared with 609CC genotype. Thus, this polymorphism may result in altered cancer predisposition. For prostate cancer, only sparse data are available. We therefore analyzed the distribution of the NQO1 P187S SNP (single nucleotide polymorphism) in prostate cancer patients and a healthy control group. Allelic variants were determined using RFLP analysis. Overall, 232 patients without any malignancy and 119 consecutive prostate cancer patients were investigated. The genotype distribution in our cohorts followed the Hardy–Weinberg equilibrium in cases and controls. The distribution of the NQO1 codon 187 SNP did not differ significantly between prostate cancer patients and the control group (p = 0.242). There was also no association between the allelic variants and stage or Gleason score of the tumors. The NQO1 P187S SNP was not significantly associated with an increased prostate cancer risk in our cohorts. The SNP has also no influence on histopathological characteristics of the tumors. A combined analysis of all available data from published European studies also showed no significant differences in the genotype distribution between controls and prostate cancer patients. Our data suggest a minor role of the NQO1 nucleotide 609 polymorphism in prostate carcinogenesis

Роль организаций общественного здравоохранения в решении проблем общественного здоровья в Европе

Рост числа случаев избыточного веса и ожирения, неизменно высокие показатели вредного потребления алкоголя и растущая угроза УПП – это лишь часть тех факторов, которые представляют собой наибольшую опасность для здоровья жителей Европы. И хотя масштаб этих проблем в разных государствах различается, в Европе сегодня нет ни одной страны, которую бы они не затрагивали. Совершенно очевидно, что учреждения и организации общественного здравоохранения должны принимать участие в решении каждой из перечисленных проблем, для урегулирования которых требуется принятие мер не только на уровне системы здравоохранения, но и со стороны других секторов. Однако при этом остаются вопросы относительно той роли, которую организации общественного здравоохранения играют в решении этих проблем в настоящий момент. Данная работа призвана восполнить именно этот пробел. В ее основу легли страновые отчеты восьми стран Европы (Англия, Германия, Италия, Республика Молдова, Нидерланды, Польша, Франция и Швеция), посвященные усилиям организаций общественного здравоохранения по решению проблем ожирения и потребления алкоголя, и страновые отчеты девяти европейских стран (Англия, Германия, Италия, Республика Молдова, Нидерланды, Польша, Словения, Франция и Швеция) о работе по борьбе с устойчивостью к противомикробным препаратам

MiRNA-21 Expression Decreases from Primary Tumors to Liver Metastases in Colorectal Carcinoma.

OBJECTIVE Metastasis is the major cause of death in colorectal cancer patients. Expression of certain miRNAs in the primary tumors has been shown to be associated with progression of colorectal cancer and the initiation of metastasis. In this study, we compared miRNA expression in primary colorectal cancer and corresponding liver metastases in order to get an idea of the oncogenic importance of the miRNAs in established metastases. METHODS We analyzed the expression of miRNA-21, miRNA-31 and miRNA-373 in corresponding formalin-fixed paraffin-embedded (FFPE) tissue samples of primary colorectal cancer, liver metastasis and healthy tissues of 29 patients by quantitative real-time PCR. RESULTS All three miRNAs were significantly up-regulated in the primary tumor tissues as compared to healthy colon mucosa of the respective patients (p < 0.01). MiRNA-21 and miRNA-31 were also higher expressed in liver metastases as compared to healthy liver tissues (p < 0.01). No significant difference of expression of miRNA-31 and miRNA-373 was observed between primary tumors and metastases. Of note, miRNA-21 expression was significantly reduced in liver metastases as compared to the primary colorectal tumors (p < 0.01). CONCLUSION In the context of previous studies demonstrating increased miRNA-21 expression in metastatic primary tumors, our findings raise the question whether miRNA-21 might be involved in the initiation but not in the perpetuation and growth of metastases

A genome-wide association study of Hodgkin Lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21, and 10p14 (GATA3)

To identify predisposition loci for classical Hodgkin Lymphoma (cHL) we conducted a genome-wide association study of 589 cHL cases and 5,199 controls with validation in 4 independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL; odds ratio [OR]=1.22, Pcombined=1.91×10−8), 8q24.21 (rs2019960, PVT1; OR=1.33, Pcombined=1.26×10−13) and 10p14 (rs501764, GATA3; OR=1.25, Pcombined=7.05×10−8). Furthermore, we confirmed the role of the MHC in disease etiology by revealing a strong HLA association (rs6903608; OR=1.70, Pcombined=2.84×10−50). These data provide new insight into the pathogenesis of cHL

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: A systematic analysis from the Global Burden of Disease Study 2016

Background: A key component of achieving universal health coverage is ensuring that all populations have access to quality health care. Examining where gains have occurred or progress has faltered across and within countries is crucial to guiding decisions and strategies for future improvement. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to assess personal health-care access and quality with the Healthcare Access and Quality (HAQ) Index for 195 countries and territories, as well as subnational locations in seven countries, from 1990 to 2016. Methods Drawing from established methods and updated estimates from GBD 2016, we used 32 causes from which death should not occur in the presence of effective care to approximate personal health-care access and quality by location and over time. To better isolate potential effects of personal health-care access and quality from underlying risk factor patterns, we risk-standardised cause-specific deaths due to non-cancers by location-year, replacing the local joint exposure of environmental and behavioural risks with the global level of exposure. Supported by the expansion of cancer registry data in GBD 2016, we used mortality-to-incidence ratios for cancers instead of risk-standardised death rates to provide a stronger signal of the effects of personal health care and access on cancer survival. We transformed each cause to a scale of 0-100, with 0 as the first percentile (worst) observed between 1990 and 2016, and 100 as the 99th percentile (best); we set these thresholds at the country level, and then applied them to subnational locations. We applied a principal components analysis to construct the HAQ Index using all scaled cause values, providing an overall score of 0-100 of personal health-care access and quality by location over time. We then compared HAQ Index levels and trends by quintiles on the Socio-demographic Index (SDI), a summary measure of overall development. As derived from the broader GBD study and other data sources, we examined relationships between national HAQ Index scores and potential correlates of performance, such as total health spending per capita. Findings In 2016, HAQ Index performance spanned from a high of 97\ub71 (95% UI 95\ub78-98\ub71) in Iceland, followed by 96\ub76 (94\ub79-97\ub79) in Norway and 96\ub71 (94\ub75-97\ub73) in the Netherlands, to values as low as 18\ub76 (13\ub71-24\ub74) in the Central African Republic, 19\ub70 (14\ub73-23\ub77) in Somalia, and 23\ub74 (20\ub72-26\ub78) in Guinea-Bissau. The pace of progress achieved between 1990 and 2016 varied, with markedly faster improvements occurring between 2000 and 2016 for many countries in sub-Saharan Africa and southeast Asia, whereas several countries in Latin America and elsewhere saw progress stagnate after experiencing considerable advances in the HAQ Index between 1990 and 2000. Striking subnational disparities emerged in personal health-care access and quality, with China and India having particularly large gaps between locations with the highest and lowest scores in 2016. In China, performance ranged from 91\ub75 (89\ub71-93\ub76) in Beijing to 48\ub70 (43\ub74-53\ub72) in Tibet (a 43\ub75-point difference), while India saw a 30\ub78-point disparity, from 64\ub78 (59\ub76-68\ub78) in Goa to 34\ub70 (30\ub73-38\ub71) in Assam. Japan recorded the smallest range in subnational HAQ performance in 2016 (a 4\ub78-point difference), whereas differences between subnational locations with the highest and lowest HAQ Index values were more than two times as high for the USA and three times as high for England. State-level gaps in the HAQ Index in Mexico somewhat narrowed from 1990 to 2016 (from a 20\ub79-point to 17\ub70-point difference), whereas in Brazil, disparities slightly increased across states during this time (a 17\ub72-point to 20\ub74-point difference). Performance on the HAQ Index showed strong linkages to overall development, with high and high-middle SDI countries generally having higher scores and faster gains for non-communicable diseases. Nonetheless, countries across the development spectrum saw substantial gains in some key health service areas from 2000 to 2016, most notably vaccine-preventable diseases. Overall, national performance on the HAQ Index was positively associated with higher levels of total health spending per capita, as well as health systems inputs, but these relationships were quite heterogeneous, particularly among low-to-middle SDI countries. Interpretation GBD 2016 provides a more detailed understanding of past success and current challenges in improving personal health-care access and quality worldwide. Despite substantial gains since 2000, many low-SDI and middle- SDI countries face considerable challenges unless heightened policy action and investments focus on advancing access to and quality of health care across key health services, especially non-communicable diseases. Stagnating or minimal improvements experienced by several low-middle to high-middle SDI countries could reflect the complexities of re-orienting both primary and secondary health-care services beyond the more limited foci of the Millennium Development Goals. Alongside initiatives to strengthen public health programmes, the pursuit of universal health coverage hinges upon improving both access and quality worldwide, and thus requires adopting a more comprehensive view-and subsequent provision-of quality health care for all populations

Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: A systematic analysis from the Global Burden of Disease Study 2016

Copyright © 2018 The Author(s). Published by Elsevier Ltd. Background A key component of achieving universal health coverage is ensuring that all populations have access to quality health care. Examining where gains have occurred or progress has faltered across and within countries is crucial to guiding decisions and strategies for future improvement. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to assess personal health-care access and quality with the Healthcare Access and Quality (HAQ) Index for 195 countries and territories, as well as subnational locations in seven countries, from 1990 to 2016. Methods Drawing from established methods and updated estimates from GBD 2016, we used 32 causes from which death should not occur in the presence of effective care to approximate personal health-care access and quality by location and over time. To better isolate potential effects of personal health-care access and quality from underlying risk factor patterns, we risk-standardised cause-specific deaths due to non-cancers by location-year, replacing the local joint exposure of environmental and behavioural risks with the global level of exposure. Supported by the expansion of cancer registry data in GBD 2016, we used mortality-to-incidence ratios for cancers instead of risk-standardised death rates to provide a stronger signal of the effects of personal health care and access on cancer survival. We transformed each cause to a scale of 0-100, with 0 as the first percentile (worst) observed between 1990 and 2016, and 100 as the 99th percentile (best); we set these thresholds at the country level, and then applied them to subnational locations. We applied a principal components analysis to construct the HAQ Index using all scaled cause values, providing an overall score of 0-100 of personal health-care access and quality by location over time. We then compared HAQ Index levels and trends by quintiles on the Socio-demographic Index (SDI), a summary measure of overall development. As derived from the broader GBD study and other data sources, we examined relationships between national HAQ Index scores and potential correlates of performance, such as total health spending per capita. Findings In 2016, HAQ Index performance spanned from a high of 97·1 (95% UI 95·8-98·1) in Iceland, followed by 96·6 (94·9-97·9) in Norway and 96·1 (94·5-97·3) in the Netherlands, to values as low as 18·6 (13·1-24·4) in the Central African Republic, 19·0 (14·3-23·7) in Somalia, and 23·4 (20·2-26·8) in Guinea-Bissau. The pace of progress achieved between 1990 and 2016 varied, with markedly faster improvements occurring between 2000 and 2016 for many countries in sub-Saharan Africa and southeast Asia, whereas several countries in Latin America and elsewhere saw progress stagnate after experiencing considerable advances in the HAQ Index between 1990 and 2000. Striking subnational disparities emerged in personal health-care access and quality, with China and India having particularly large gaps between locations with the highest and lowest scores in 2016. In China, performance ranged from 91·5 (89·1-93·6) in Beijing to 48·0 (43·4-53·2) in Tibet (a 43·5-point difference), while India saw a 30·8-point disparity, from 64·8 (59·6-68·8) in Goa to 34·0 (30·3-38·1) in Assam. Japan recorded the smallest range in subnational HAQ performance in 2016 (a 4·8-point difference), whereas differences between subnational locations with the highest and lowest HAQ Index values were more than two times as high for the USA and three times as high for England. State-level gaps in the HAQ Index in Mexico somewhat narrowed from 1990 to 2016 (from a 20·9-point to 17·0-point difference), whereas in Brazil, disparities slightly increased across states during this time (a 17·2-point to 20·4-point difference). Performance on the HAQ Index showed strong linkages to overall development, with high and high-middle SDI countries generally having higher scores and faster gains for non-communicable diseases. Nonetheless, countries across the development spectrum saw substantial gains in some key health service areas from 2000 to 2016, most notably vaccine-preventable diseases. Overall, national performance on the HAQ Index was positively associated with higher levels of total health spending per capita, as well as health systems inputs, but these relationships were quite heterogeneous, particularly among low-to-middle SDI countries. Interpretation GBD 2016 provides a more detailed understanding of past success and current challenges in improving personal health-care access and quality worldwide. Despite substantial gains since 2000, many low-SDI and middle- SDI countries face considerable challenges unless heightened policy action and investments focus on advancing access to and quality of health care across key health services, especially non-communicable diseases. Stagnating or minimal improvements experienced by several low-middle to high-middle SDI countries could reflect the complexities of re-orienting both primary and secondary health-care services beyond the more limited foci of the Millennium Development Goals. Alongside initiatives to strengthen public health programmes, the pursuit of universal health coverage hinges upon improving both access and quality worldwide, and thus requires adopting a more comprehensive view - and subsequent provision - of quality health care for all populations

Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: a systematic analysis from the Global Burden of Disease Study 2016.

BACKGROUND: A key component of achieving universal health coverage is ensuring that all populations have access to quality health care. Examining where gains have occurred or progress has faltered across and within countries is crucial to guiding decisions and strategies for future improvement. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to assess personal health-care access and quality with the Healthcare Access and Quality (HAQ) Index for 195 countries and territories, as well as subnational locations in seven countries, from 1990 to 2016. METHODS: Drawing from established methods and updated estimates from GBD 2016, we used 32 causes from which death should not occur in the presence of effective care to approximate personal health-care access and quality by location and over time. To better isolate potential effects of personal health-care access and quality from underlying risk factor patterns, we risk-standardised cause-specific deaths due to non-cancers by location-year, replacing the local joint exposure of environmental and behavioural risks with the global level of exposure. Supported by the expansion of cancer registry data in GBD 2016, we used mortality-to-incidence ratios for cancers instead of risk-standardised death rates to provide a stronger signal of the effects of personal health care and access on cancer survival. We transformed each cause to a scale of 0-100, with 0 as the first percentile (worst) observed between 1990 and 2016, and 100 as the 99th percentile (best); we set these thresholds at the country level, and then applied them to subnational locations. We applied a principal components analysis to construct the HAQ Index using all scaled cause values, providing an overall score of 0-100 of personal health-care access and quality by location over time. We then compared HAQ Index levels and trends by quintiles on the Socio-demographic Index (SDI), a summary measure of overall development. As derived from the broader GBD study and other data sources, we examined relationships between national HAQ Index scores and potential correlates of performance, such as total health spending per capita

The role of microRNAs in prostate cancer.

Das Prostatakarzinom ist in Deutschland die am häufigsten vorkommende Krebserkrankung beim Mann. Die Ursachen dieser Erkrankung sind weitestgehend unbekannt, wobei neben dem Alter auch eine genetische Prädisposition sowie Faktoren wie Ernährung diskutiert werden. Die Diagnostik des Prostatakarzinoms findet bislang zum einen mittels digital rektaler Tastuntersuchung statt, wobei hier nur etwa 2-5% der Tumore entdeckt werden und zum anderen über die Messung des prostataspezifischen Antigens (PSA). Der PSA Level wird jedoch von patientenabhängigen Größen wie z.B. Prostatagröße, Harnwegsinfekte und therapeutische oder diagnostische Eingriffe am unteren Harntrakt beeinflusst, sodass eine Erhöhung des PSA-Wertes nicht unbedingt mit einer bösartigen Veränderung der Prostata zusammenhängt. Das Ziel ist, genauere Marker für die Diagnose und Prognose zu finden. MicroRNAs (miRNA) sind kleine RNAs von 19-22 Nukleotiden Länge, welche etwa 30% aller menschlichen Gene regulieren. In mehreren Arbeiten wurde bereits gezeigt, dass miRNAs eine zentrale Rolle bei physiologischen und pathologischen Prozessen, wie bei der Zelldifferenzierung, Zellzykluskontrolle, Proliferation, Apoptose und über die Regulation dieser Prozesse auch bei der Entstehung von Krebs spielen. Das erste Ziel dieser Arbeit war die Erstellung eines globalen miRNA Expressionsprofiles im Prostatakarzinom. Hierzu wurden Sequenzierungs- und miRNA microArray-Analysen durchgeführt. Mit beiden Ansätzen wurden sieben miRNAs (miR-375, miR-200c, miR-106a, miR-106b, let-7a, miR-21, miR-20a) hochreguliert und zwei miRNAs (miR-145, miR-221) herunterreguliert gefunden. Die Expression der am stärksten dereguliert exprimierten miRNAs (miR-375, miR-200c, miR-145) und zusätzlich miR-143 wurde mittels quantitativer real-time Polymerasekettenreaktion (qRT-PCR) in Prostatazelllinien und zwei Kollektiven von Primärgeweben untersucht und die Art der Deregulation (hoch- bzw. herunterreguliert im Tumor) konnte für alle bestätigt werden. Mittels bioinformatischer Recherche wurden für alle vier miRNAs Zielgene (MYO6, SEC23A, ERG) identifiziert. Deren Expression wurde ebenfalls mittels qRT-PCR in Prostatazelllinien und einem Kollektiv von Primärgeweben analysiert und für alle drei Zielgene konnte eine inverse Expression zu der jeweiligen miRNA gefunden werden. Außerdem wurde der Einfluss der Deregulation der miRNAs miR-375, miR-200c und miR-145, sowie von Sec23A und ERG in vitro untersucht. Knockdown von miR-375 und miR-200c führte zu einer Veränderung der zellbiologischen Paramter Proliferation, Viabilität, Zytotoxizität, Apoptose und Wundheilung. Ebenso konnte ein Einfluss der Deregulation von Sec23A auf die untersuchten zellbiologischen Parameter festgestellt werden. Für ERG wurde sowohl die Gesamt-ERG Expression als auch die Expression einzelner Spleißvarianten untersucht. Die Expression von Gesamt-ERG und für die ERG-2 Spleißvariante wurde im Tumor hochreguliert gefunden. Nach ERG-2 Knockdown und ektoper Expression von miR-145 wurden ebenfalls reziproke Auswirkungen auf Proliferation und Invasionsverhalten festgestellt. Auf Proteinebene wurde sowohl für die Gesamt-ERG-Proteinmenge als auch für ERG-2 eine Korrelation mit der miR-145 Expression gefunden. Da die miRNA Expression ein differenzielles Muster zwischen Tumor- und Normalgewebe zeigte, wurde das diagnostische Potential der miRNAs mittels binärer logistischer Regressionsanalysen untersucht. Eine Kombination der miRNAs miR-375, miR-145 und miR-143 zeigte hierbei den besten prädiktiven Wert zur Unterscheidung von Tumor- und Normalgewebe. Diese Befunde unterstreichen die Funktion von miRNAs als vielversprechende diagnostische Marker für das Prostatakarzinom, sowie als Wegbereiter zur Identifizierung von neuen tumorrelevanten Genen, welche in der Zukunft als mögliche therapeutische Ziele oder prognostische Marker dienen können.Prostate cancer is the most frequent cancer in men in Germany. The causes of this disease are mostly unknown, however, besides the patient’s age a genetic predisposition as well as factors like nutrition are discussed. Methods for the diagnosis of prostate cancer are currently digital rectal examination and measurement of the prostate specific antigen (PSA). However, both methods have limitations as for the digital rectal examination only 2-5% of the tumors are found by this examination method and the PSA level differs due to patient dependent causes like the size of the prostate, urinary tract infections and therapeutic or diagnostic operations of the lower urinary tract, leading to an increased PSA level which is not necessarily correlated to a malignant lesion of the prostate. The goal is to find more precise markers for the diagnosis and later on the prognosis of prostate cancer. MicroRNAs (miRNA) are small regulatory RNAs of 19-22 nucleotides length, regulating the expression of approximately 30% of the human genes. Several publications already showed a central role for miRNAs in physiologic and pathologic processes like cell differentiation, cell cycle control, proliferation, apoptosis and via the regulation of these processes an important role in cancer development. The first aim of this study was to obtain a global miRNA expression profile of prostate cancer, therefore sequencing and miRNA microarray analyses were performed. With both techniques seven miRNAs (miR-375, miR-200c, miR-106a, miR-106b, let-7a, miR-21, miR-20a) where found to be upregulated and two miRNAs (miR-145, miR-221) were found to be downregulated. The expression of the most deregulated miRNAs (miR-375, miR-200c, miR-145) and additionally miR-143 was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) in prostate cell lines and two collectives of primary prostate tissue. The pattern of deregulation (up or down in tumor) predicted from sequencing and miRNA micorarray could be confirmed for all of the miRNAs. Using a bioinformatical approach, target genes (MYO6, SEC23A, ERG) for the four miRNAs were identified. The expression of the target genes was measured using qRT-PCR as well and an inverse expression of target gene and related miRNA was found. Moreover, the impact of the deregulated expression of miR-375, miR-200c and miR-145 as well as for Sec23A and ERG was examined in vitro. Knockdown of miR-375 and miR-200c led to changes in proliferation, viability, cytotoxicity, apoptosis and wound healing. The deregulation of Sec23A showed a similar impact on the examined cell biological parameter. For ERG the overall expression as well as the expression of different splice variants was examined. The overall ERG expression and the expression of the ERG-2 splice variant were found to be upregulated in prostate cancer. Knockdown of ERG-2 and ectopic expression of miR-145 led to reciprocal effects in proliferation and invasion. On protein level a correlation between the protein amount of ERG total and ERG-2 with the miR-145 expression was found. As the expression of miRNAs showed a specific pattern for tumor and normal tissue binary logistic regression was done to investigate the diagnostic potential of the miRNAs. A combination of the miRNAs miR-375, miR-145 and miR-143 showed the best predictive value to discriminate between normal and tumor tissue. These findings underline the promising role of miRNAs as diagnostic markers in prostate cancer. Moreover studying miRNAs and their target genes might lead to the identification of new tumorrelevant genes which might serve as therapeutic targets or prognostic markers in the future