Fine-mapping the HOXB region detects common variants tagging a rare coding allele : evidence for synthetic association in prostate cancer

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

Flupirtine enhances the anti-hyperalgesic effects of morphine in a rat model of prostate bone metastasis

Objective Current treatments for cancer pain are often inadequate, particularly when metastasis to bone is involved. The addition to the treatment regimen of another drug that has a complementary analgesic effect may increase the overall analgesia without the necessity to increase doses, thus avoiding dose-related side effects. This project investigated the synergistic effect of the addition of the potassium channel (KCNQ2–3) modulator flupirtine to morphine treatment in a rat model of prostate cancer-induced bone pain. Design Syngeneic prostate cancer cells were injected into the right tibia of male Wistar rats under anesthesia. This led to expanding tumor within the bone in 2 weeks, together with the concurrent development of hyperalgesia to noxious heat. Paw withdrawal thresholds from noxious heat were measured before and after the maximum non-sedating doses of morphine and flupirtine given alone and in combinations. Dose-response curves for morphine (0.13–5.0 mg/kg ip) and flupirtine (1.25–10.0 mg/kg ip) given alone and in fixed-dose combinations were plotted and subjected to an isobolographic analysis. Results Both morphine (ED50 = 0.74 mg/kg) and flupirtine (ED50 = 3.32 mg/kg) caused dose-related anti-hyperalgesia at doses that did not cause sedation. Isobolographic analysis revealed that there was a synergistic interaction between flupirtine and morphine. Addition of flupirtine to morphine treatment improved morphine anti-hyperalgesia, and resulted in the reversal of cancer-induced heat hyperalgesia. Conclusions These results suggest that flupirtine in combination with morphine may be useful clinically to provide better analgesia at lower morphine doses in the management of pain caused by tumors growing in bone.

Intravenous injection of leconotide, an omega conotoxin : synergistic antihyperalgesic effects with morphine in a rat model of bone cancer pain

Objective.  Leconotide (CVID, AM336, CNSB004) is an omega conopeptide similar to ziconotide, which blocks voltage sensitive calcium channels. However, unlike ziconotide, which must be administered intrathecally, leconotide can be given intravenously because it is less toxic. This study investigated the antihyperalgesic potency of leconotide given intravenously alone and in combinations with morphine-administered intraperitoneally, in a rat model of bone cancer pain. Design.  Syngeneic rat prostate cancer cells AT3B-1 were injected into one tibia of male Wistar rats. The tumor expanded within the bone causing hyperalgesia to heat applied to the ipsilateral hind paw. Measurements were made of the maximum dose (MD) of morphine and leconotide given alone and in combinations that caused no effect in an open-field activity monitor, rotarod, and blood pressure and heart rate measurements. Paw withdrawal thresholds from noxious heat were measured. Dose response curves for morphine (0.312–5.0 mg/kg intraperitoneal) and leconotide (0.002–200 µg/kg intravenous) given alone were plotted and responses compared with those caused by morphine and leconotide in combinations. Results.  Leconotide caused minimal antihyperalgesic effects when administered alone. Morphine given alone intraperitoneally caused dose-related antihyperalgesic effects (ED50 = 2.40 ± 1.24 mg/kg), which were increased by coadministration of leconotide 20 µg/kg (morphine ED50 = 0.16 ± 1.30 mg/kg); 0.2 µg/kg (morphine ED50 = 0.39 ± 1.27 mg/kg); and 0.02 µg/kg (morphine ED50 = 1.24 ± 1.30 mg/kg). Conclusions.  Leconotide caused a significant increase in reversal by morphine of the bone cancer-induced hyperalgesia without increasing the side effect profile of either drug. Clinical Implication.  Translation into clinical practice of the method of analgesia described here will improve the quantity and quality of analgesia in patients with bone metastases. The use of an ordinary parenteral route for administration of the calcium channel blocker (leconotide) at low dose opens up the technique to large numbers of patients who could not have an intrathecal catheter for drug administration. Furthermore, the potentiating synergistic effect with morphine on hyperalgesia without increased side effects will lead to greater analgesia with improved quality of life.

Prevalence and clinical outcomes for patients with ALK-positive resected stage I to III adenocarcinoma : results from the European Thoracic Oncology Platform Lungscape Project

PURPOSE: The prevalence of anaplastic lymphoma kinase (ALK) gene fusion (ALK positivity) in early-stage non-small-cell lung cancer (NSCLC) varies by population examined and detection method used. The Lungscape ALK project was designed to address the prevalence and prognostic impact of ALK positivity in resected lung adenocarcinoma in a primarily European population. METHODS: Analysis of ALK status was performed by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) in tissue sections of 1,281 patients with adenocarcinoma in the European Thoracic Oncology Platform Lungscape iBiobank. Positive patients were matched with negative patients in a 1:2 ratio, both for IHC and for FISH testing. Testing was performed in 16 participating centers, using the same protocol after passing external quality assessment. RESULTS: Positive ALK IHC staining was present in 80 patients (prevalence of 6.2%; 95% CI, 4.9% to 7.6%). Of these, 28 patients were ALK FISH positive, corresponding to a lower bound for the prevalence of FISH positivity of 2.2%. FISH specificity was 100%, and FISH sensitivity was 35.0% (95% CI, 24.7% to 46.5%), with a sensitivity value of 81.3% (95% CI, 63.6% to 92.8%) for IHC 2+/3+ patients. The hazard of death for FISH-positive patients was lower than for IHC-negative patients (P = .022). Multivariable models, adjusted for patient, tumor, and treatment characteristics, and matched cohort analysis confirmed that ALK FISH positivity is a predictor for better overall survival (OS). CONCLUSION: In this large cohort of surgically resected lung adenocarcinomas, the prevalence of ALK positivity was 6.2% using IHC and at least 2.2% using FISH. A screening strategy based on IHC or H-score could be envisaged. ALK positivity (by either IHC or FISH) was related to better OS.

Risk factors associated with an outbreak of dengue fever/dengue haemorrhagic fever in Hanoi, Vietnam

Dengue fever/dengue haemorrhagic fever (DF/DHF) appears to be emerging in Hanoi in recent years. A case-control study was performed to investigate risk factors for the development of DF/DHF in Hanoi. A total of 73 patients with DF/DHF and 73 control patients were included in the study. The risk factor analysis indicated that living in rented housing, living near uncovered sewers, and living in a house discharging sewage directly into to ponds were all significantly associated with DF/DHF. People living in rented houses were 2·2 times more at risk of DF/DHF than those living in their own homes [adjusted odds ratio (aOR) 2·2, 95% confidence interval (CI) 1·1–4·6]. People living in an unhygienic house, or in a house discharging sewage directly to the ponds were 3·4 times and 4·3 times, respectively, more likely to be associated with DF/DHF (aOR 3·4, 95% CI 1–11·7; aOR 4·3, 95% CI 1·1–16·9). These results contribute to the understanding of the dynamics of dengue transmission in Hanoi, which is needed to implement dengue prevention and control programmes effectively and efficiently.

A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer

Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.

A large-scale analysis of genetic variants within putative miRNA binding sites in prostate cancer

Prostate cancer is the second most common malignancy among men worldwide. Genome-wide association studies have identified 100 risk variants for prostate cancer, which can explain approximately 33% of the familial risk of the disease. We hypothesized that a comprehensive analysis of genetic variations found within the 3' untranslated region of genes predicted to affect miRNA binding (miRSNP) can identify additional prostate cancer risk variants. We investigated the association between 2,169 miRSNPs and prostate cancer risk in a large-scale analysis of 22,301 cases and 22,320 controls of European ancestry from 23 participating studies. Twenty-two miRSNPs were associated (P<2.3×10(-5)) with risk of prostate cancer, 10 of which were within 7 genes previously not mapped by GWAS studies. Further, using miRNA mimics and reporter gene assays, we showed that miR-3162-5p has specific affinity for the KLK3 rs1058205 miRSNP T-allele, whereas miR-370 has greater affinity for the VAMP8 rs1010 miRSNP A-allele, validating their functional role. SIGNIFICANCE Findings from this large association study suggest that a focus on miRSNPs, including functional evaluation, can identify candidate risk loci below currently accepted statistical levels of genome-wide significance. Studies of miRNAs and their interactions with SNPs could provide further insights into the mechanisms of prostate cancer risk.

Translation of Allusions in the Animated Cartoon The Simpsons

Tässä tutkielmassa tarkastellaan The Simpsons (Simpsonit) animaatiosarjassa esiintyvien sanallisten alluusioiden kääntymistä suomenkielisiksi tekstityksiksi. Tarkoituksena on selvittää kvantitatiivisen analyysin keinoin, miten kääntäjä Sari Luhtanen käyttää eri käännösstrategioita hyväkseen. Tutkimusaineisto on kerätty kuudesta Simpsonit-sarjan jaksosta esityskausilta 7-11. Työn teoriaosiossa määritellään aluksi intertekstuaalisuuden sekä alluusion käsitteet, jonka jälkeen käsitellään alluusiota huumorin välineenä. Mahdollisten käännösstrategioiden määrittely tukeutuu Ritva Leppihalmeen alluusioiden kääntämistä käsittelevään tutkimukseen. Leppihalmeen terminologiaa mukaillen alluusiot jaetaan erisnimialluusioihin ja suoriin tekstilainoihin. Simpsonit-sarjan olemusta ja tekijöiden tarkoitusperiä pohtii oma lukunsa, joka sisältää myös kääntäjä Luhtasen ajatuksia käännöstyöstä, sekä haastattelussa esiintulleita yksityiskohtia käännösprosessista. Tekstittämisen erityispiirteitä kääntämisen alalajina käsitellään Henrik Gottliebin sekä Jan Ivarssonin määritelmien kautta. Gottliebin määritelmää elokuvasta polysemioottisena, neljästä eri viestintäkanavasta koostuvana kokonaisuutena sovelletaan myös tutkimuksen empiirisessä osuudessa. Tekstittämiseen todetaan kohdistuvan merkittäviä teknisiä rajoituksia, jotka tehokkaasti estävät kääntäjää pyrkimästä muodolliseen vastaavuuteen lähdetekstin kanssa. Koska tekstitys kuitenkin esitetään aina alkuperäisen materiaalin yhteydessä, sen voi mieltää ylimääräiseksi viestintäkanavaksi jonka avulla kääntäjä auttaa kohdeyleisöä kokemaan tekstitetyn ohjelman alkuperäisen yleisön kokemusta vastaavalla tavalla (dynaaminen vastaavuus). Tutkimuksen empiirinen osuus tarkastelee materiaalissa esiintyviä alluusioiden käännöksiä kvantitatiivisen analyysin muodossa, jonka jälkeen Luhtasen tekemiä käännösvalintoja käsitellään yksityiskohtaisemmin esimerkkien avulla. Luhtasen todetaan sisällyttävän dialogissa esiintyvät alluusiot tekstityksiin lähes aina, mutta useimmiten jättävän tekstityksistä pois pelkästään visuaalisella kanavalla esiintyvät sanallisen alluusiot. Erisnimialluusiot Luhtanen kääntää tyypillisesti muuttumattomina, mutta harkintansa mukaan saattaa Suomessa täysin tuntemattomien nimien kohdalla tarjota myös selittävän käännöksen. Suoria tekstilainoja kääntäessään hän ei näytä suosivan mitään tiettyä strategiaa. Erillisiä selityksiä sisältäviä strategioita Luhtanen ei käytä. Yleisen alluusioiden runsauden lisäksi Simpsonit-sarjan erityispiirteenä näyttävät olevan visuaalisella kanavalla ajoittain esiintyvät, nopeasti ohi menevät sanallisten alluusioiden keskittymät. Näiden alluusiokeskittymien edessä kääntäjä on usein voimaton, ja Luhtanen onkin lähes aina jättänyt tällaiset alluusiokeskittymät kokonaan suomentamatta.

Studies in Nonlinear Optical Materials: Structure of Methyl 2-(4-Ethyl-5-methyl- 2-thioxo-2,3-dihydro-l,3-thiazol- 3-yl) propionate

CIoH15NO282, Mr=245"0, orthorhombic, P21212 ~, a = 6.639 (2), b = 8.205 (2), c = 22.528(6)A, V= I227.2(6)A 3, z=4, Dm= 1.315, Dx= 1.326gem -3, MoKa, 2=0.7107A, 12= 3.63 cm -1, F(000) = 520, T= 293 K, R = 0.037 for 1115 significant reflections. The second-harmonicgeneration (SHG) efficiency of this compound is only 1/10th of the urea standard. The observed low second-order nonlinear response may be attributed to the unfavourable packing of the molecules in the crystal lattice.

Herätys kylässä ja tuvissa : Rääkkylän Oravisalon kylä ja renqvistiläinen herätys 1820-luvulla

A Revival in a Village and its Households. The Village of Oravisalo in Rääkkylä Parish and the Renqvistist Revivalism in the 1820s. My purpose is to apply the science of religion and the study of past communities to the study of religious revivalism. Revivalism will be considered a religious phenomenon as well as a cultural and social phenomenon. What makes this study unique is the possibility to reconstruct a list of participating revivalists based on entries in the communion book of the time. The conflict between the revivalists and the chaplain of Rääkkylä also generated other documentary material. The community in Oravisalo was relatively stratified. People lived in complex and varying forms of households. They also had plentiful contacts both with unrelated inhabitants of Oravisalo and with the neighbouring villages. Through these contacts the inhabitants of Oravisalo were introduced to revivalism. In Oravisalo, the revival for the most part fell into a certain social stratum and did not severely damage existing relationships within families or among acquaintances. The revivalists formed a new community within the village but the community was neither very tightly-knit nor was it closed. The revival was an individual phenomenon affected by general factors. First, there were factors that brought about a quest for an applicable system of meanings. These factors included at least three important issues: the Great Partition of land, the crisis of slash-and-burn cultivation, and a population growth that increased the proportion of the landless in the village. As a result, many of the revivalists had low status and poor expectations for the future. Second, there were factors that appealed to the people in the message and character of the preacher, Henrik Renqvist. Third, the proximity of the village to Liperi, where the revival got its start, was crucial to revivalism s spread to Oravisalo. Culturally, the revival meant a change in the system of symbols or meanings, so it was not solely a matter of intensified religious fervour. For instance, Communion, prayer, reading, and perhaps baptism symbolised different things to the revivalists than to other villagers. However, the revivalists do not seem to have started any moral revolution in their village. The religious aspect defined the limits of the protest and the resistance towards authorities. The revivalists wanted only to have the right to follow their conscience. The freedom granted the female members was limited to the religious sphere. No social or economic claims were made. The revival altered the situation of its members only on a symbolic level, yet it also offered them status within their own group.

Teollisuuden ja yhteiskunnan palveluksessa : Arkkitehti Bertel Liljequist (1885 - 1954) tuotantolaitosten suunnittelijana maailmansotien välisenä aikana

My thesis concerns the plans drawn up by architect Bertel Liljequist (1885 1954) for an industrial corporation and a city in Finland during the interwar years. These were two quite different clients: the Kymi Company operating in Kuusankoski and the City of Helsinki. My study includes the micro-examination of the wider social issues involved. That the industrial community and factories in Kuusankoski be constructed correctly in a way supporting corporate strategy was of primary importance for the company s operations. Through the planning process for Helsinki s abattoirs, I show how a city dealt with the twin problems of hygiene and increasing demand for food resulting from a growth in population. I clarify how society and its economic, political and class structures affected the practice of architecture and its expression in the built environment. I analyse how the different backgrounds and starting points of the clients affected the construction projects under study and architect Bertel Liljequist s work. In studying Liljequist as an industrial designer, I have considered it vital to ascertain the client s intentions and objectives within the framework of the prevailing social situation. I examine the meanings the client wished the architecture to express and also to communicate to those working in the factory and the area as well as to the workers living on company land. The social outlook of the owners and management of Kymi Company implicitly affected the appearance of the factory. A brick fairface for the factories was a safe and natural material at the beginning of the 1920s when taking into consideration the events of the 1918 Civil War. To have built a White factory in the style of a defence building would have been provocative. Outside the factory gates, however, the company supported White architecture. The company used the factory buildings to manifest its power and the dwellings to bind the workers and make them loyal to the company. Architecture was thus one way in which the company manifested its position as the higher and undisputed authority. The role of the City of Helsinki within the planning process was for its officials to provide expert opinions but also to arrange study trips for the architect and the abattoir s general manager. The city also decided on the standard of the design. The city s responsibility for the health of its inhabitants and the requirements of modern meat production can be seen in the minimal architecture and clear functionality of the plant. The architecture left no doubt about the trustworthiness of the modern city. Translation: Michael Wynne-Ellis

Evolutionary relationships between bat coronaviruses and their hosts

Recent studies have suggested that bats are the natural reservoir of a range of coronaviruses (CoVs), and that rhinolophid bats harbor viruses closely related to the severe acute respiratory syndrome (SARS) CoV, which caused an outbreak of respiratory illness in humans during 2002-2003. We examined the evolutionary relationships between bat CoVs and their hosts by using sequence data of the virus RNA-dependent RNA polymerase gene and the bat cytochrome b gene. Phylogenetic analyses showed multiple incongruent associations between the phylogenies of rhinolophid bats and their CoVs, which suggested that host shifts have occurred in the recent evolutionary history of this group. These shifts may be due to either virus biologic traits or host behavioral traits. This finding has implications for the emergence of SARS and for the potential future emergence of SARS-CoVs or related viruses.

Approaches to selecting native plant replacements for fleshy-fruited invasive species

Invasive plants are a serious threat to biodiversity. Yet, in some cases, they may play an important ecological role in heavily modified landscapes, such as where fleshy-fruited invasive plants support populations of native frugivores. How can such conservation conflicts be managed? We advocate an approach in which native fleshy-fruited plants are ranked on their ability to provide the fruit food resources for native frugivores currently being provided by invasive plants. If these native taxa are preferentially used, where ecologically appropriate, in plantings for restoration and in park and garden settings, they could help support native frugivore populations in the event of extensive invasive plant control. We develop and critically examine six approaches to selecting candidate native plant taxa: a multivariate approach based on the frugivore assemblage, a scoring model, and several multivariate approaches (including trait combinations having the greatest correlation with the diet of the native frugivore assemblage) based on the functional traits of fruit morphology, phenology, conspicuousness, and accessibility. To illustrate these approaches, we use a case study with Bitou bush (Chrysanthemoides monilifera subsp. rotundata) (Asteraceae), an Australian Weed of National Significance. The model using a dissimilarity value generated from all available traits identified a set of species used by the frugivores of C. monilifera more than null models. A replacement approach using species ranked by either all traits available or the frugivore community appears best suited to guide selection of plants in restoration practice.

Predicting risk and benefit a priori in biological control of invasive plant species: a systems modelling approach

While the method using specialist herbivores in managing invasive plants (classical biological control) is regarded as relatively safe and cost-effective in comparison to other methods of management, the rarity of strict monophagy among insect herbivores illustrates that, like any management option, biological control is not risk-free. The challenge for classical biological control is therefore to predict risks and benefits a priori. In this study we develop a simulation model that may aid in this process. We use this model to predict the risks and benefits of introducing the chrysomelid beetle Charidotis auroguttata to manage the invasive liana Macfadyena unguis-cati in Australia. Preliminary host-specificity testing of this herbivore indicated that there was limited feeding on a non-target plant, although the non-target was only able to sustain some transitions of the life cycle of the herbivore. The model includes herbivore, target and non-target life history and incorporates spillover dynamics of populations of this herbivore from the target to the non-target under a variety of scenarios. Data from studies of this herbivore in the native range and under quarantine were used to parameterize the model and predict the relative risks and benefits of this herbivore when the target and non-target plants co-occur. Key model outputs include population dynamics on target (apparent benefit) and non-target (apparent risk) and fitness consequences to the target (actual benefit) and non-target plant (actual risk) of herbivore damage. The model predicted that risk to the non-target became unacceptable (i.e. significant negative effects on fitness) when the ratio of target to non-target in a given patch ranged from 1:1 to 3:2. By comparing the current known distribution of the non-target and the predicted distribution of the target we were able to identify regions in Australia where the agent may be pose an unacceptable risk. By considering risk and benefit simultaneously, we highlight how such a simulation modelling approach can assist scientists and regulators in making more objective decisions a priori, on the value of releasing specialist herbivores as biological control agents.