Expression analysis of imbalanced genes in prostate carcinoma using tissue microarrays

To identify candidate genes relevant for prostate tumour prognosis and progression, we performed an exhaustive gene search in seven previously described genomic-profiling studies of 161 prostate tumours, and four expression profiling studies of 61 tumours. From the resulting list of candidate genes, six were selected for protein-expression analysis based on the availability of antibodies applicable to paraffinised tissue: fatty acid synthase (FASN), MYC, β-adrenergic receptor kinase 1 (BARK1, GRK2) the catalytic subunits of protein phosphatases PP1α (PPP1CA) and PP2A (PPP2CB) and metastasis suppressor NM23-H1. These candidates were analysed by immunohistochemistry (IHC) on a tissue microarray containing 651 cores of primary prostate cancer samples and benign prostatic hyperplasias (BPH) from 175 patients. In univariate analysis, expression of PP1α (P=0.001) was found to strongly correlate with Gleason score. MYC immunostaining negatively correlated with both pT-stage and Gleason score (P<0.001 each) in univariate as well as in multivariate analysis. Furthermore, a subgroup of patients with high Gleason scores was characterised by a complete loss of BARK1 protein (P=0.023). In conclusion, our study revealed novel molecular markers of potential diagnostic and therapeutic relevance for prostate carcinoma

Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets

Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets

Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits

Igneous Rock Associations 29. The Nenana Magnetitite Lava Flow, Alaska Range, Alaska

Magnetitite deposits like El Laco (Chile) are rare and have controversial origins. An unusual magnetitite lava flow overlying a rhyolite unit occurs in the north-central Alaska Range and originally covered ~ 750 km2 of the Miocene Nenana basin. Dating of the rhyolite and relationships between the magnetitite and sedimentary rocks indicate that both are of Late Miocene age. The magnetitite flow is mainly magnetite with some post-eruptive alteration to hematite. Both the rhyolite flow and the magnetitite flow are vesicular, but the magnetitite flow also has small, millimetre-scale columnar jointing. The vesicular zones in the magnetitite flow grade into massive rock on the scale of a thin section, suggesting a degassing lava origin. Samples of the magnetitite flow contain between 12 and 26 wt.% SiO2 and between 45 and 75 wt.% FeO. Rare earth elements (REE) and trace elements from the magnetitite and rhyolite have similar patterns but with lesser abundance in the magnetitite. Both the rhyolite and the magnetitite have light-REE-enriched REE profiles with negative Eu anomalies. Electron microscopic analysis shows that most of the silica and trace element content of the magnetitite flow comes from very finely disseminated silicate minerals and glass in the magnetite. This suggests that the magnetitite was derived from a magma that had undergone unmixing into a silica-rich phase and an iron-rich phase prior to its eruption. Fractures and vesicles within the magnetitite flow contain minor rhyolitic glass and minerals suggesting that the rhyolite magma invaded columnar joints in the solidified magnetitite flow, and is a subvolcanic sill-like body at the studied locality. The magnetitite flow erupted prior to the emplacement of the rhyolite, which may be extrusive on a regional scale. The features of the Nenana magnetitite, and its geological relationships, are consistent with genetic models that invoke unmixing of magma into immiscible Fe-rich and Si-rich liquids during ascent.  Les gisements de magnétitite comme ceux de El Laco (Chili) sont rares et d’origines controversées. Une coulée de lave de magnétitite inhabituelle recouvrant une coulée de rhyolite se trouve dans le centre-nord de la chaîne de l'Alaska et couvrait environ 750 km2 du bassin miocène de Nénana. La datation de la rhyolite et les relations entre la magnétite et les roches sédimentaires indiquent que les deux sont d'âge Miocène supérieur. La coulée de magnétitite est principalement composée de magnétite avec quelques altérations post-éruptives en hématite. La coulée de rhyolite et la coulée de magnétitite sont toutes les deux vésiculaires, mais la coulée de magnétitite présente également de petits joints colonnaires d'échelle millimétrique. Les zones vésiculaires de la coulée de magnétitite se transforment en roche massive à l'échelle d'une lame mince, suggérant qu’elles proviennent d’une lave en dégazage. Les échantillons de la coulée de magnétitite contiennent entre 12 et 26 % en poids de SiO2 et entre 45 et 75 % en poids de FeO. Les éléments de terres rares (ETR) et les éléments traces de la magnétitite et de la rhyolite présentent des patrons similaires mais avec une moindre abondance dans la magnétitite. La rhyolite et de magnétitite présentent toutes deux un patron de terres rares enrichi en éléments de terres rares légers avec une anomalie négative en Eu. L'analyse au microscope électronique montre que la majeure partie de la silice et de la teneur en éléments traces de la coulée de magnétitite provient de minéraux silicatés et de verre finement disséminés dans la magnétite. Ceci suggère que la magnétitite provient d'un magma qui s’était décomposé en une phase riche en silice et une phase riche en fer avant son éruption. Les fractures et les vésicules dans la coulée de magnétitite contiennent du verre et des minéraux rhyolitiques comme constituant mineurs suggérant que le magma de rhyolite a envahi les joints colonnaires dans la coulée de magnétitite solidifiée et est un corps subvolcanique semblable à un filon-couche dans la localité étudiée. La coulée de magnétitite a fait éruption avant la mise en place de la rhyolite, qui peut être extrusive à l'échelle régionale. Les caractéristiques de la magnétitite de Nénana et ses relations géologiques sont cohérentes avec les modèles génétiques qui invoquent la séparation du magma en liquides non miscibles riches en fer et en silicium pendant l'ascension

A Paleomagnetic Reanalysis of the Auborus Formation, Namibia

Along the western margin of the Kalahari craton in southern Namibia, late Mesoproterozoic volcanic and sedimentary rocks of the Sinclair region are locally preserved at subgreenschist metamorphic grade [Hoal, 1993, Precambr. Res. 63, 143-162], thus amenable to paleomagnetic study. The youngest unit in the Sinclair succession is the Auborus Formation. comprising redbeds deposited after the cessation of Sinclair magmatism and during the waning stages of regional folding. A previous study of the Auborus Formation, utilizing data only from the natural remanent magnetization (NRM), found a well clustered, single-polarity direction differing from the present field at the sampling sites [Piper, 1975, Geophys. J. R. astr. Soc. 40, 313-344], suggesting that the Auborus Formation is likely to produce a high-quality paleomagnetic pole with proper demagnetization and field tests. We collected oriented samples through most of the Auborus stratigraphy in 2011 and 2012. Preliminary results from detailed thermal demagnetization exhibit broad agreement with Piper’s [1975] NRM data, and show a two-polarity hematite-borne characteristic remanence directed shallowly N-S. Directions are better grouped after correction for tectonic tilt, indicating a Proterozoic age of remanence because the Ediacaran-Cambrian Nama Group is flat-lying throughout the region. Present results are limited to the lower part of the Auborus Formation, in which a single reversal of the magnetic field has been documented. Analysis of the upper part of the formation is in progress, but we have already added three quality criteria (vector analysis, positive fold test, and reversals) to the Auborus pole of Piper [1975]. Along with a companion study of older units in the Sinclair terrane [Panzik et al., this meeting], our results will provide important constraints on regional tectonics of the western Kalahari craton, its role in Rodinia reconstructions, and late Mesoproterozoic geomagnetic reversal frequency