RNA interference screening identifies a novel role for PCTK1/CDK16 in medulloblastoma with c-Myc amplification.

Medulloblastoma (MB) is the most common malignant brain tumor in children and is associated with a poor outcome. cMYC amplification characterizes a subgroup of MB with very poor prognosis. However, there exist so far no targeted therapies for the subgroup of MB with cMYC amplification. Here we used kinome-wide RNA interference screening to identify novel kinases that may be targeted to inhibit the proliferation of c-Myc-overexpressing MB. The RNAi screen identified a set of 5 genes that could be targeted to selectively impair the proliferation of c-Myc-overexpressing MB cell lines: AKAP12 (A-kinase anchor protein), CSNK1α1 (casein kinase 1, alpha 1), EPHA7 (EPH receptor A7) and PCTK1 (PCTAIRE protein kinase 1). When using RNAi and a pharmacological inhibitor selective for PCTK1, we could show that this kinase plays a crucial role in the proliferation of MB cell lines and the activation of the mammalian target of rapamycin (mTOR) pathway. In addition, pharmacological PCTK1 inhibition reduced the expression levels of c-Myc. Finally, targeting PCTK1 selectively impaired the tumor growth of c-Myc-overexpressing MB cells in vivo. Together our data uncover a novel and crucial role for PCTK1 in the proliferation and survival of MB characterized by cMYC amplification.

3B.01: Performance of targeted screening for the identification of hypertension in children

OBJECTIVE: As universal screening of hypertension performs poorly in childhood, targeted screening to children at higher risk of hypertension has been proposed. Our goal was to assess the performance of combined parental history of hypertension and overweight/obesity to identify children with hypertension. We estimated the sensitivity, specificity, negative and positive predictive values of overweight/obesity and parental history of hypertension for the identification of hypertension in children. DESIGN AND METHOD: We analyzed data from a school-based cross-sectional study including 5207 children aged 10 to 14 years from all public 6th grade classes in the canton of Vaud, Switzerland. Blood pressure was measured with a clinically validated oscillometric automated device over up to three visits separated by one week. Children had hypertension if they had sustained elevated blood pressure over the three visits. Parents were interviewed about their history of hypertension. RESULTS: The prevalence of hypertension was 2.2%. 14% of children were overweight or obese and 20% had a positive history of hypertension in either or both parents. 30% of children had either or both conditions. After accounting for several potential confounding factors, parental history of hypertension (odds ratio (OR): 2.6; 95% confidence interval (CI): 1.8-4.0), overweight excluding obesity (OR: 2.5; 95% CI: 1.5-4.2) and obesity (OR: 10.1; 95% CI: 6.0-17.0) were associated with hypertension in children. Considered in isolation, the sensitivity and positive predictive values of parental history of hypertension (respectively 41% and 5%) or overweight/obesity (respectively 43% and 7%) were relatively low. Nevertheless, considered together, the sensitivity of targeted screening in children with either overweight/obesity or paternal history of hypertension was higher (65%) but the positive predictive value remained low (5%). The negative predictive value was systematically high. CONCLUSIONS: Restricting screening of hypertension to children with either overweight/obesity or with hypertensive parents would substantially limit the proportion of children to screen (30%) and allow the identification of a relatively large proportion (65%) of hypertensive cases. That could be a valuable alternative to universal screening.

Screening for ALK in non-small cell lung carcinomas: 5A4 and D5F3 antibodies perform equally well, but combined use with FISH is recommended.

OBJECTIVES: Immunohistochemistry (IHC) has become a promising method for pre-screening ALK-rearrangements in non-small cell lung carcinomas (NSCLC). Various ALK antibodies, detection systems and automated immunostainers are available. We therefore aimed to compare the performance of the monoclonal 5A4 (Novocastra, Leica) and D5F3 (Cell Signaling, Ventana) antibodies using two different immunostainers. Additionally we analyzed the accuracy of prospective ALK IHC-testing in routine diagnostics. MATERIALS AND METHODS: Seventy-two NSCLC with available ALK FISH results and enriched for FISH-positive carcinomas were retrospectively analyzed. IHC was performed on BenchMarkXT (Ventana) using 5A4 and D5F3, respectively, and additionally with 5A4 on Bond-MAX (Leica). Data from our routine diagnostics on prospective ALK-testing with parallel IHC, using 5A4, and FISH were available from 303 NSCLC. RESULTS: All three IHC protocols showed congruent results. Only 1/25 FISH-positive NSCLC (4%) was false negative by IHC. For all three IHC protocols the sensitivity, specificity, positive (PPV) and negative predictive values (NPV) compared to FISH were 96%, 100%, 100% and 97.8%, respectively. In the prospective cohort 3/32 FISH-positive (9.4%) and 2/271 FISH-negative (0.7%) NSCLC were false negative and false positive by IHC, respectively. In routine diagnostics the sensitivity, specificity, PPV and NPV of IHC compared to FISH were 90.6%, 99.3%, 93.5% and 98.9%, respectively. CONCLUSIONS: 5A4 and D5F3 are equally well suited for detecting ALK-rearranged NSCLC. BenchMark and BOND-MAX immunostainers can be used for IHC with 5A4. True discrepancies between IHC and FISH results do exist and need to be addressed when implementing IHC in an ALK-testing algorithm.

Training primary care physicians in shared decision making for colorectal cancer screening : Insights from the first statewide colorectal cancer screening program in Switzerland

Background: The State of Vaud has launched the first population-based, organized, colorectal cancer screening program in Switzerland for the population aged 50 to 69. Each primary care physician (PCP) has been invited to participate in an interactive session preparing them to enroll patients in the screening program. We aimed at testing the impact of an interactive seminar for PCPs on their intention to discuss the options of no screening, screening with the fecal-immunological test (FIT) and colonoscopy. We measured attitude, intentions and knowledge through questionnaires filled by PCPs before and after a 2.5 hour-long interactive seminar. The main outcome was the proportion of physicians foreseeing to offer coloscopy vs FIT on an equal basis. Physicians estimated the proportion of their patients prescribed a fecal occult blood test (FOBT) vs coloscopy over the months before the seminar and after the interactive seminar. We used a clinical vignette to test for knowledge about screening indications. The interactive seminar included powerpoint presentations with quizzes and clickers, an 8-minute video presenting a shared decision making (SDM) consultation around CRC screening and distribution of educational materials such as a SDM decision aid and background epidemiological information.

Colorectal Cancer Screening in Switzerland: Cross-Sectional Trends (2007-2012) in Socioeconomic Disparities.

BACKGROUND: Despite universal health care coverage, disparities in colorectal cancer (CRC) screening by income in Switzerland have been reported. However, it is not known if these disparities have changed over time. This study examines the association between socioeconomic position and CRC screening in Switzerland between 2007 and 2012. METHODS: Data from the 2007 (n = 5,946) and 2012 (n = 7,224) population-based Swiss Health Interview Survey data (SHIS) were used to evaluate the association between monthly household income, education, and employment with CRC screening, defined as endoscopy in the past 10 years or fecal occult blood test (FOBT) in the past 2 years. Multivariable Poisson regression was used to estimate prevalence ratios (PR) and 95% Confidence Intervals (CI) adjusting for demographics, health status, and health utilization. RESULTS: CRC screening increased from 18.9% in 2007 to 22.2% in 2012 (padjusted: = 0.036). During the corresponding time period, endoscopy increased (8.2% vs. 15.0%, padjusted:<0.001) and FOBT decreased (13.0% vs. 9.8%, padjusted:0.002). CRC screening prevalence was greater in the highest income (>$6,000) vs. lowest income (≤$2,000) group in 2007 (24.5% vs. 10.5%, PR:1.37, 95%CI: 0.96-1.96) and in 2012 (28.6% vs. 16.0%, PR:1.45, 95%CI: 1.09-1.92); this disparity did not significantly change over time. CONCLUSIONS: While CRC screening prevalence in Switzerland increased from 2007 to 2012, CRC screening coverage remains low and disparities in CRC screening by income persisted over time. These findings highlight the need for increased access to CRC screening as well as enhanced awareness of the benefits of CRC screening in the Swiss population, particularly among low-income residents.

Idea Screening in Telecom Business

Diplomityö on tehty Telecom Business Research Centerissä Lappeenrannassa. Toimialalle tyypillistä on tekniikan ja globaalien markkinoiden nopea kehitys, mikä edellyttää alan tuotekehitykseltä panostamista oikeisiin ideoihin, sekä niiden nopeaa ja joustavaa kehittämistä tuotteiksi. Tuotekehityksen alkuvaihe on johtamisen kannalta erityisen suuri haaste, koska ideoita on runsaasti, mutta resurssit tehdä niihin liittyviä selvityksiä ovat rajalliset. Diplomityön tavoitteena oli tuotekehityksen alkuvaiheen ymmärtäminen ja tutkia kuinka ideoita pystytään seulomaan. Tutkimus perustuu tuotekehityskirjallisuuteen ja haastatteluihin Telecom-teollisuudessa. Työn tuloksena ideoiden seulontaa kirjallisuudessa ja Telecom-teollisuudessa kuvataan ja niiden perusteella esitetään toimivia käytäntöjä tuotekehitysideoiden seulontaan toimialalla. Ehdotettujen käytäntöjen tavoitteena on saada parempia ideoita tehokkaammin tuotekehityksen alkuvaiheesta varsinaiseksi tuotekehitysprojektiksi.

Development of e-Service tools for customer services and processes, Case: KONE Oyj Finland

Tutkimuksen tavoitteena oli selvittää miten kehittää yrityksen nykyistä e-palvelujärjestelmää, Internet -teknologiaan perustuvaa sähköisiä kommunikaatio- ja tiedonjakojärjestelmää, yrityksen business-to-business asiakkuuksien johtamisessa. Tavoitteena oli myös luoda ehdotukset uusista e-palvelusopimusmalleista. Tutkimuksen teoriaosuudessa pyrittiin kehittämään aikaisempiin tutkimuksiin, tietokirjallisuuteen ja asiantuntijoihin perustuva viitekehysmalli. Empiirisessä osassa tutkimuksen tavoitteisiin pyrittiin haastattelemalla yrityksen asiakkaita ja henkilöstöä, sekä tarkastelemalla asiakaskontaktien nykyistä tilaa ja kehittymistä. Näiden tietojen perusteella selvitettiin e-palvelun käyttäjien tarpeita, profiilia ja valmiuksia palvelun käyttöön sekä palvelun nykyistä houkuttelevuutta. Tutkimuksen teoriaosan lähdeaineistona käytettiin kirjallisuutta, artikkeleita ja tilastoja asiakashallinnasta sekä e-palveluiden, erityisesti Internet ja verkkopalveluiden markkinoinnista, nykytilasta sekä palveluiden kehittämisestä. Lisäksi tutkittiin kirjallisuutta arvoverkostoanalyysistä, asiakkaan arvosta, informaatioteknologiasta, palvelun laadusta ja asiakastyytyväisyydestä. Tutkimuksen empiirinen osa perustuu yrityksen henkilöstöltä sekä asiakkailta haastatteluissa kerättyihin tietoihin, yrityksen ennalta keräämiin materiaaleihin sekä Taloustutkimuksen keräämiin tietoihin. Tutkimuksessa käytettiin case -menetelmää, joka oli yhdistelmä sekä kvalitatiivista että kvantitatiivista tutkimusta. Casen tarkoituksena oli testata mallin paikkansapitävyyttä ja käyttökelpoisuutta, sekä selvittää onko olemassa vielä muita tekijöitä, jotka vaikuttavat asiakkaan saamaan arvoon. Kvalitatiivinen aineisto perustuu teemahaastattelumenetelmää soveltaen haastateltuihin asiakkaisiin ja yrityksen työntekijöihin. Kvantitatiivinen tutkimus perustuu Taloustutkimuksen tutkimukseen ja yrityksen asiakaskontakteista kerättyyn tietoon. Haastatteluiden perusteella e-palvelut nähtiin hyödyllisinä ja tulevaisuudessa erittäin tärkeinä. E-palvelut nähdään yhtenä tärkeänä kanavana, perinteisten kanavien rinnalla, tehostaa business-to-business -asiakkuuksien johtamista. Tutkimuksen antamien tulosten mukaan asiakkaiden palveluun liittyvän tieto-, taito-, tarpeellisuus- ja kiinnostavuustasojen vaihtelevaisuus osoittaa selvän tarpeen eritasoisille e-palvelupaketti ratkaisuille. Tuloksista muodostettu ratkaisuehdotus käsittää neljän eri e-palvelupaketin rakentamisen asiakkaiden eri tarpeita mukaillen.

Intra-organizational use of communication tools in value nets - Cases from the ICT industry

Tutkimuksen tavoitteena oli selvittää sisäisen kommunikoinnin tilannetta case-yrityksissä. Yritykset kuuluvat kahteen case-arvoverkostoon, jotka toimivat informaatio- ja kommunikaatioteknologian alalla. Sisäinen kommunikointi valittiin tutkimusalueeksi, koska se muodostaa perustan ulkoiselle, yritysten väliselle kommunikoinnille. Tutkimuksen painopiste oli web-pohjaisessa kommunikoinnissa ja webin ominaisuuksissa arvoverkoston näkökulmasta. Tutkimusprosessissa käytettiin sekä kvalitatiivisia että kvantitatiivisia menetelmiä. Tutkimuksen kvantitatiivinen osa toteutettiin web-kyselynä, jonka tulokset osoittivat, että case-yritysten sisäinen kommunikointi perustuu pääasiassa perinteisten kommunikointivälineiden käyttöön. Toisin sanoen, webin hyödyntäminen on vähäistä, mihin vaikuttavat monet eri tekijät. Webissä on kuitenkin useita ominaisuuksia, jotka parantavat kommunikointia arvoverkostossa ja siksi nämä web-pohjaiset välineet tulisi huomioida, kun suunnitellaan yleistä kommunikointijärjestelmää. Tutkimuksen teoreettisessa osassa määriteltiin vuorovaikutteisuus-ominaisuuteen perustuva kommunikointivälineiden luokittelu. Tämän lisäksi määriteltiin myös arvoverkoston käsite. Empiirinen osa koostui web-kyselyn toteutuksen ja tulosten raportoinnista, jonka jälkeen yhteenvetokappale koosti merkittävimmät havainnot sekä mahdolliset jatkotutkimusaiheet.

Participation rates for organized colorectal cancer screening programmes: an international comparison.

OBJECTIVE: Participation, an indicator of screening programme acceptance and effectiveness, varies widely in clinical trials and population-based colorectal cancer (CRC) screening programmes. We aimed to assess whether CRC screening participation rates can be compared across organized guaiac fecal occult blood test (G-FOBT)/fecal immunochemical test (FIT)-based programmes, and what factors influence these rates. METHODS: Programme representatives from countries participating in the International Cancer Screening Network were surveyed to describe their G-FOBT/FIT-based CRC screening programmes, how screening participation is defined and measured, and to provide participation data for their most recent completed screening round. RESULTS: Information was obtained from 15 programmes in 12 countries. Programmes varied in size, reach, maturity, target age groups, exclusions, type of test kit, method of providing test kits and use, and frequency of reminders. Coverage by invitation ranged from 30-100%, coverage by the screening programme from 7-67.7%, overall uptake/participation rate from 7-67.7%, and first invitation participation from 7-64.3%. Participation rates generally increased with age and were higher among women than men and for subsequent compared with first invitation participation. CONCLUSION: Comparisons among CRC screening programmes should be made cautiously, given differences in organization, target populations, and interpretation of indicators. More meaningful comparisons are possible if rates are calculated across a uniform age range, by gender, and separately for people invited for the first time vs. previously.

Calculation analysis of energy saving tools for fan and pump applications

This thesis analyses the calculation of FanSave and PumpSave energy saving tools calculation. With these programs energy consumption of variable speed drive control for fans and pumps can be compared to other control methods. With FanSave centrifugal and axial fans can be examined and PumpSave deals with centrifugal pumps. By means of these programs also suitable frequency converter can be chosen from the ABB collection. Programs need as initial values information about the appliances like amount of flow and efficiencies. Operation time is important factor when calculating the annual energy consumption and information about it are the length and profile. Basic theory related to fans and pumps is introduced without more precise instructions for dimensioning. FanSave and PumpSave contain various methods for flow control. These control methods are introduced in the thesis based on their operational principles and suitability. Also squirrel cage motor and frequency converter are introduced because of their close involvement to fans and pumps. Second part of the thesis contains comparison between results of FanSave’s and PumpSave’s calculation and performance curve based calculation. Also laboratory tests were made with centrifugal and axial fan and also with centrifugal pump. With the results from this thesis the calculation of these programs can be adjusted to be more accurate and also some new features can be added.

Dépistage du risque d'allergie et prévention en maternité : enquête des pratiques AllerNaiss [Screening for the risk of allergy and prevention in French maternity units: A survey].

Allergy has been on the rise for half a century and concerns nearly 30% of children; it has now become a real public health problem. The guidelines on prevention of allergy set up by the French Society of Paediatrics (SFP) and the European Society of Paediatric Allergology and Clinical Immunology (ESPACI) are based on screening children at risk through a systematic search of the family history and recommend, for children at risk, exclusive breastfeeding whenever possible or otherwise utilization of hypoallergenic infant formula, which has demonstrated efficacy. The AllerNaiss practice survey assessed the modes of screening and prevention of allergy in French maternity units in 2012. The SFP guidelines are known by 82% of the maternity units that took part in the survey, and the ESPACI guidelines by 55% of them. A screening strategy is in place in 59% of the participating maternity wards, based on local consensus for 36% of them, 13% of the units having a written screening procedure. Screening is based on the search for a history of allergy in first-degree relatives (99%) during pregnancy (51%), in the delivery room (50%), and after delivery (89%). A mode of prevention of the risk of allergy exists in 62% of the maternity units, most often in writing (49%). A hypoallergenic infant formula is prescribed for non-breastfed children in 90% of the units. The survey shows that there is a real need for formalization of allergy risk screening and prevention of allergy in newborns in French maternity units.

Abdominal Aortic Aneurysm: What About Screening?

The prevalence of abdominal aortic aneurysm (AAA) in general population is 4-9% with a high mortality rate when ruptured. Therefore, screening programs were developed in many countries to detect small and large AAA in selected patients. Indeed, prevalence of AAA increases in patients over 65 years old with cigarette smoking history. This paper reviews recent literature related to AAA screening focusing on epidemiology, screening tests and evidence based medicine to highlight not only advantages but also disadvantages of screening programs among population.

Analysis of SKI-1/S1P prodomain provides insight on maturation and activation of SKI-1/S1P zymogen

SKI-l/SlP protease is a member of the proprotein convertase family, with several functions in cellular metabolism and homeostasis. It is responsible for the processing of several cellular substrates, including ATF6, SREBPs, and GlcNAc-1- phosphotranspherase. Furthermore, SKI-1/SlP is also responsible for maturation of arenavirus surface glycoprotein into GP1 and GP2 subunits. This processing is a strict requirement in order to achieve fully mature and fusion-competent virions. Furthermore, SKI-1/SlP itself is synthesized as an inactive zymogen, requiring sequential autocatalytic processing at several sites (B'/B and C) in its prodomain in order to mature and become fully active. Our project focused on the analysis of SKI- 1/S1P prodomain in the biogenesis of the active enzyme. In this context we have additionally developed and characterized a novel cell-based sensor for assessment of cellular activity of the enzyme, with a potential application in screening for novel SKI- 1/S1P inhibitors. In a first aim we have analysed the relevance of cleavage motifs found in the enzyme prodomain. Using molecular and biochemistry tools we have identified and characterized a novel C' maturation site. Furthermore, we found that SKI-1/SlP autoprocessing results in intermediates whose catalytic domain remains associated with prodomain fragments of different lengths. Contrasting with other proprotein convertases, incompletely matured intermediates of SKI-1/SlP exhibit full catalytic activity toward selected substrates. In a second aim, we turned our attention to the structural basis of SKI-1/SlP N- terminus assisted folding. Studying the folding and activity of prodomain-truncated forms of the enzyme we found that a minimal folding unit is contained in the AB region. Deletion of the BC sequence affected auto-maturation but not folding, and partial activity was retained. However, the BC region seemed required for complete and full activity. Phylogenetic analyses showed that the AB sequence is highly conserved, while the BC fragment is variable in sequence and length. Specifically, replacement of the human prodomain with that of Drosophila, resulted in a fully mature and active chimeric enzyme, suggesting an evolution process of SKI-1/SlP prodomain towards a more complex arrangement and steps of activation. Overall, the additional data we have produced might provide fundamental knowledge crucial for the development of novel SKI-1/SlP inhibitors while also providing new SKI- 1/S1P variants with potential use in crystallization purpose. -- SKI-l/SlP est une protéase membre de la famille des proprotéines convertases (PCs), avec plusieurs fonctions dans le métabolisme cellulaire et de l'homéostasie. Il est responsable pour la maturation de plusieurs substrats cellulaires, y compris ATF6, SREBPs et GlcNAc-1-phosphotranspherase. SKI-l/SlP est également responsable pour la maturation de la glycoprotéine des arénavirus, une exigence stricte pour atteindre des virions infectieuse. Synthétisé comme un zymogène inactif, SKI-l/SlP nécessite d'un traitement autocatalytique séquentiel sur plusieurs sites (B'/B et C) de son prodomaine afin de devenir pleinement active. Notre projet était axé sur l'analyse de SKI-l/SlP prodomaine dans la biogenèse de l'enzyme. Dans ce contexte, nous avons développé un nouveau senseur-cellulaire pour l'évaluation de l'activité de l'enzyme. Ce dernier pourrait avoir une potentielle application dans l'identification de nouveaux inhibiteurs de SKI-l/SlP. Premièrement, nous avons analysé la pertinence des motifs de clivage trouvés dans le prodomaine de l'enzyme. En utilisant des outils moléculaires et biochimiques, nous avons identifié et caractérisé un nouveau site de maturation (C'). Aussi, nous avons constaté que la maturation de SKI-l/SlP a des intermédiaires dont le domaine catalytique reste associé à des fragments du prodomaine de différentes longueurs. Contrastant avec d'autres PCs, les intermédiaires partiellement matures de SKI-1 / SIP présentent une activité catalytique complète envers des substrats spécifiques. Dans un deuxième but nous avons tourné notre attention sur la base structurelle du pliage de SKI-l/SlP assisté par son N-terminus: En étudiant l'activité et pliage des formes tronquées dans le prodomaine de l'enzyme, nous avons constaté qu'une unité de pliage minimale est contenue dans la région de l'AB. La suppression de la séquence d'auto-BC affecte la maturation mais pas le pliage, et l'activité partielle est maintenue. Cependant, la région BC semble nécessaire pour une activité complète. Les analyses phylogénétiques ont montré que la séquence AB est fortement conservée, tandis que le fragment de BC est variable en longueur et en séquence. En particulier, le remplacement du prodomaine humain avec celui de la drosophile, a donné lieu à une enzyme chimérique complètement mature et active. Suggérant un processus d'évolution du prodomaine vers un arrangement et des mesures d'activation plus complexe. Globalement, ces donnees supplémentaires augment les connaissances fondamentales cruciales pour le développement de nouveaux inhibiteurs de SKI-1/ SIP, tout en offrant de nouvelles variantes SKI-1 / SIP dans le but d'obtenir la structure cristallographique de l'enzyme.