High expression of focal adhesion kinase (p125(FAK)) in node-negative breast cancer is related to overexpression of HER-2/neu and activated Akt kinase but does not predict outcome

INTRODUCTION: Focal adhesion kinase (FAK) regulates multiple cellular processes including growth, differentiation, adhesion, motility and apoptosis. In breast carcinoma, FAK overexpression has been linked to cancer progression but the prognostic relevance remains unknown. In particular, with regard to lymph node-negative breast cancer it is important to identify high-risk patients who would benefit from further adjuvant therapy. METHODS: We analyzed 162 node-negative breast cancer cases to determine the prognostic relevance of FAK expression, and we investigated the relationship of FAK with major associated signaling pathways (HER2, Src, Akt and extracellular regulated kinases) by immunohistochemistry and western blot analysis. RESULTS: Elevated FAK expression did not predict patient outcome, in contrast to tumor grading (P = 0.005), Akt activation (P = 0.0383) and estrogen receptor status (P = 0.0033). Significant positive correlations were observed between elevated FAK expression and HER2 overexpression (P = 0.001), as well as phospho-Src Tyr-215 (P = 0.021) and phospho-Akt (P < 0.001), but not with phospho-ERK1/2 (P = 0.108). Western blot analysis showed a significant correlation of FAK Tyr-861 activation and HER2 overexpression (P = 0.01). CONCLUSIONS: Immunohistochemical detection of FAK expression is of no prognostic significance in node-negative breast cancer but provides evidence that HER2 is involved in tumor malignancy and metastatic ability of breast cancer through a novel signaling pathway participating FAK and Src

Ice-confined construction of a large basaltic volcano—Austurfjöll massif, Askja, Iceland

Austurfjöll is the largest basaltic glaciovolcanic massif at Askja volcano (Central Iceland), and through detailed studies of its volcanological and geochemical characteristics, we provide a detailed account of the sequence and structure of the ice-confined construction of a large Icelandic basaltic volcano. In particular, Austurfjöll represents a geometry of vents, and resulting glaciovolcanic morphology, not previously documented in ice-confined basaltic volcanoes. Austurfjöll was constructed during two major phases of basaltic volcanism, via seven eruptive episodes through disperse fissure-dominated eruptions. The earliest episode involved a rare and poorly exposed example of subaerial activity, and this was succeeded by six episodes involving the eruption of ice-confined pillow lavas and numerous overlapping fissure eruptions of phreatomagmatic tephra. Evidence of local subaerial lavas and tephras indicates the local growth of eruptive centers above englacial lake levels, and subsequent flooding, but no prolonged subaerial activity. Localized ice-contact facies, paleowater levels, and diamictons indicate the position and thickness of the ice was variable during the construction of Austurfjöll, and eruptive activity likely occurred in multiple and variable level meltwater lakes during the last glacial period. Lithofacies evidence including gradational transitions from effusive to explosive deposits, superposition of fragmental facies above coherent facies, and drainage channels suggest that changes in eruptive style were driven largely by external factors such as drainage and the increasing elevation of the massif. This study emphasizes the unique character of Austurfjöll, being composed of large pillow lava sheets, numerous (> 40) overlapping glaciovolcanic tindars, and only localized emergent deposits, as a product of its prolonged ice-confined eruptive history, contrasts with previous descriptions of tuyas and tindars

Gravitational Waves from Gravitational Collapse

Gravitational wave emission from the gravitational collapse of massive stars has been studied for more than three decades. Current state of the art numerical investigations of collapse include those that use progenitors with realistic angular momentum profiles, properly treat microphysics issues, account for general relativity, and examine non--axisymmetric effects in three dimensions. Such simulations predict that gravitational waves from various phenomena associated with gravitational collapse could be detectable with advanced ground--based and future space--based interferometric observatories.Comment: 68 pages including 13 figures; revised version accepted for publication in Living Reviews in Relativity (http://www.livingreviews.org

Phototriggered release of tetrapeptide AAPV from coumarinyl and pyrenyl cages

Ala-Ala-Pro-Val (AAPV) is a bioactive tetrapeptide that inhibits human neutrophil elastase (HNE), an enzyme involved in skin chronic inflammatory diseases like psoriasis. Caged derivatives of this peptide were prepared by proper N- and C-terminal derivatisation through a carbamate or ester linkage, respectively, with two photoactive moieties, namely 7-methoxycoumarin-2-ylmethyl and pyren-2-ylmethyl groups. These groups were chosen to assess the influence of the photosensitive group and the type of linkage in the controlled photorelease of the active molecule. The caged peptides were irradiated at selected wavelengths of irradiation (254, 300, and 350 nm), and the photolytic process was monitored by HPLC-UV. The results established the applicability of the tested photoactive groups for the release of AAPV, especially for the derivative bearing the carbamate-linked pyrenylmethyl group, which displayed the shortest irradiation times for the release at the various wavelengths of irradiation (ca. 4 min at 254 nm, 8 min at 300 nm and 46 min at 350 nm).Thanks are due to the Fundação para a Ciência e Tecnologia (FCT, Portugal) for financial support to the portuguese NMR network (PTNMR, Bruker Avance III 400- Univ. Minho), FCT and FEDER (European Fund for Regional Development)- COMPETE-QREN-EU for financial support through the Chemistry Research Centre of the University of Minho (Ref. UID/QUI/00686/2013 and UID/QUI/0686/2016). A PhD grant to A.M.S. (SFRH/BD/80813/2011) is also acknowledged.info:eu-repo/semantics/publishedVersio

Structure of Metaphase Chromosomes: A Role for Effects of Macromolecular Crowding

In metaphase chromosomes, chromatin is compacted to a concentration of several hundred mg/ml by mechanisms which remain elusive. Effects mediated by the ionic environment are considered most frequently because mono- and di-valent cations cause polynucleosome chains to form compact ∼30-nm diameter fibres in vitro, but this conformation is not detected in chromosomes in situ. A further unconsidered factor is predicted to influence the compaction of chromosomes, namely the forces which arise from crowding by macromolecules in the surrounding cytoplasm whose measured concentration is 100–200 mg/ml. To mimic these conditions, chromosomes were released from mitotic CHO cells in solutions containing an inert volume-occupying macromolecule (8 kDa polyethylene glycol, 10.5 kDa dextran, or 70 kDa Ficoll) in 100 µM K-Hepes buffer, with contaminating cations at only low micromolar concentrations. Optical and electron microscopy showed that these chromosomes conserved their characteristic structure and compaction, and their volume varied inversely with the concentration of a crowding macromolecule. They showed a canonical nucleosomal structure and contained the characteristic proteins topoisomerase IIα and the condensin subunit SMC2. These observations, together with evidence that the cytoplasm is crowded in vivo, suggest that macromolecular crowding effects should be considered a significant and perhaps major factor in compacting chromosomes. This model may explain why ∼30-nm fibres characteristic of cation-mediated compaction are not seen in chromosomes in situ. Considering that crowding by cytoplasmic macromolecules maintains the compaction of bacterial chromosomes and has been proposed to form the liquid crystalline chromosomes of dinoflagellates, a crowded environment may be an essential characteristic of all genomes

Lifecourse socioeconomic circumstances and multimorbidity among older adults

<p>Abstract</p> <p>Background</p> <p>Many older adults manage multiple chronic conditions (i.e. multimorbidity); and many of these chronic conditions share common risk factors such as low socioeconomic status (SES) in adulthood and low SES across the lifecourse. To better capture socioeconomic condition in childhood, recent research in lifecourse epidemiology has broadened the notion of SES to include the experience of specific hardships. In this study we investigate the association among childhood financial hardship, lifetime earnings, and multimorbidity.</p> <p>Methods</p> <p>Cross-sectional analysis of 7,305 participants age 50 and older from the 2004 Health and Retirement Study (HRS) who also gave permission for their HRS records to be linked to their Social Security Records in the United States. Zero-inflated Poisson regression models were used to simultaneously model the likelihood of the absence of morbidity and the expected number of chronic conditions.</p> <p>Results</p> <p>Childhood financial hardship and lifetime earnings were not associated with the absence of morbidity. However, childhood financial hardship was associated with an 8% higher number of chronic conditions; and, an increase in lifetime earnings, operationalized as average annual earnings during young and middle adulthood, was associated with a 5% lower number of chronic conditions reported. We also found a significant interaction between childhood financial hardship and lifetime earnings on multimorbidity.</p> <p>Conclusions</p> <p>This study shows that childhood financial hardship and lifetime earnings are associated with multimorbidity, but not associated with the absence of morbidity. Lifetime earnings modified the association between childhood financial hardship and multimorbidity suggesting that this association is differentially influential depending on earnings across young and middle adulthood. Further research is needed to elucidate lifecourse socioeconomic pathways associated with the absence of morbidity and the presence of multimorbidity among older adults.</p