Incidental Detection of Internal Jugular Vein Thrombosis Secondary to Undiagnosed Benign Substernal Goiter

Internal jugular vein thrombosis is a serious event with potentially fatal outcome, where the clinical symptoms may be vague or absent. This paper refers to a rare case where routine carotid Doppler ultrasound prior to coronary artery bypass grafting (CABG) and aortic valve replacement (AVR) in a 76-year-old man, incidentally revealed thrombosis of the right internal jugular vein. Thoracic CT demonstrated an underlying, large, benign substernal multinodular goiter, mainly involving the right lobe, causing compression and displacement of the great vessels. A successful, one-stage operation including ligation of the internal jugular vein to avoid pulmonary embolism and hemithyroidectomy, combined with the scheduled CABG and AVR, was performed. This case illustrates that benign substernal goiter may be associated with asymptomatic internal jugular vein thrombosis. Carotid Doppler ultrasound should involve evaluation of the internal jugular vein concerning thrombosis as its presence may reveal space-occupying lesions in the thorax

Composition and biological significance of the human Nα-terminal acetyltransferases

Protein Nα-terminal acetylation is one of the most common protein modifications in eukaryotic cells, occurring on approximately 80% of soluble human proteins. An increasing number of studies links Nα-terminal acetylation to cell differentiation, cell cycle, cell survival, and cancer. Thus, Nα-terminal acetylation is an essential modification for normal cell function in humans. Still, little is known about the functional role of Nα-terminal acetylation. Recently, the three major human N-acetyltransferase complexes, hNatA, hNatB and hNatC, were identified and characterized. We here summarize the identified N-terminal acetyltransferase complexes in humans, and we review the biological studies on Nα-terminal acetylation in humans and other higher eukaryotes

A role for human N-alpha acetyltransferase 30 (Naa30) in maintaining mitochondrial integrity

N-terminal acetylation (Nt-acetylation) by N-terminal acetyltransferases (NATs) is one of the most common protein modifications in eukaryotes. The NatC complex represents one of three major NATs of which the substrate profile remains largely unexplored. Here, we defined the in vivo human NatC Nt-acetylome on a proteome-wide scale by combining knockdown of its catalytic subunit Naa30 with positional proteomics. We identified 46 human NatC substrates, expanding our current knowledge on the substrate repertoire of NatC which now includes proteins harboring Met-Leu, Met-Ile, Met-Phe, Met-Trp, Met-Val, Met-Met, Met-His and Met-Lys N termini. Upon Naa30 depletion the expression levels of several organellar proteins were found reduced, in particular mitochondrial proteins, some of which were found to be NatC substrates. Interestingly, knockdown of Naa30 induced the loss of mitochondrial membrane potential and fragmentation of mitochondria. In conclusion, NatC N-tacetylates a large variety of proteins and is essential for mitochondrial integrity and function

Inverse correlation between PDGFC expression and lymphocyte infiltration in human papillary thyroid carcinoma

Background: Members of the PDGF family have been suggested as potential biomarkers for papillary thyroid carcinomas (PTC). However, it is known that both expression and stimulatory effect of PDGF ligands can be affected by inflammatory cytokines. We have performed a microarray study in a collection of PTCs, of which about half the biopsies contained tumour-infiltrating lymphocytes or thyroiditis. To investigate the expression level of PDGF ligands and receptors in PTC we measured the relative mRNA expression of all members of the PDGF family by qRT-PCR in 10 classical PTC, eight clinically aggressive PTC, and five non-neoplastic thyroid specimens, and integrated qRT-PCR data with microarray data to enable us to link PDGF-associated gene expression profiles into networks based on recognized interactions. Finally, we investigated potential influence on PDGF mRNA levels by the presence of tumour-infiltrating lymphocytes. Methods: qRT-PCR was performed on PDGFA, PDGFB, PDGFC, PDGFD, PDGFRA PDGFRB and a selection of lymphocyte specific mRNA transcripts. Semiquantitative assessment of tumourinfiltrating lymphocytes was performed on the adjacent part of the biopsy used for RNA extraction for all biopsies, while direct quantitation by qRT-PCR of lymphocyte-specific mRNA transcripts were performed on RNA also subjected to expression analysis. Relative expression values of PDGF family members were combined with a cDNA microarray dataset and analyzed based on clinical findings and PDGF expression patterns. Ingenuity Pathway Analysis (IPA) was used to elucidate potential molecular interactions and networks. Results: PDGF family members were differentially regulated at the mRNA level in PTC as compared to normal thyroid specimens. Expression of PDGFA (p = 0.003), PDGFB (p = 0.01) and PDGFC (p = 0.006) were significantly up-regulated in PTCs compared to non-neoplastic thyroid tissue. In addition, expression of PDGFC was significantly up-regulated in classical PTCs as compared to clinically aggressive PTCs (p = 0.006), and PDGFRB were significantly up-regulated in clinically aggressive PTCs (p = 0.01) as compared to non-neoplastic tissue. Semiquantitative assessment of lymphocytes correlated well with quantitation of lymphocyte-specific gene expression. Further more, by combining TaqMan and microarray data we found a strong inverse correlation between PDGFC expression and the expression of lymphocyte specific mRNAs. Conclusion: At the mRNA level, several members of the PDGF family are differentially expressed in PTCs as compared to normal thyroid tissue. Of these, only the PDGFC mRNA expression level initially seemed to distinguish classical PTCs from the more aggressive PTCs. However, further investigation showed that PDGFC expression level correlated inversely to the expression of several lymphocyte specific genes, and to the presence of lymphocytes in the biopsies. Thus, we find that PDGFC mRNA expression were down-regulated in biopsies containing infiltrated lymphocytes or thyroiditis. No other PDGF family member could be linked to lymphocyte specific gene expression in our collection of PTCs biopsies

Interaction between HIF-1α (ODD) and hARD1 does not induce acetylation and destabilization of HIF-1α

AbstractHypoxia inducible factor-1α (HIF-1α) is a central component of the cellular responses to hypoxia. Hypoxic conditions result in stabilization of HIF-1α and formation of the transcriptionally active HIF-1 complex. It was suggested that mammalian ARD1 acetylates HIF-1α and thereby enhances HIF-1α ubiquitination and degradation. Furthermore, ARD1 was proposed to be downregulated in hypoxia thus facilitating the stabilization of HIF-1α. Here we demonstrate that the level of human ARD1 (hARD1) protein is not decreased in hypoxia. Moreover, hARD1 does not acetylate and destabilize HIF-1α. However, we find that hARD1 specifically binds HIF-1α, suggesting a putative, still unclear, connection between these proteins

A novel human NatA Nα-terminal acetyltransferase complex: hNaa16p-hNaa10p (hNat2-hArd1)

<p>Abstract</p> <p>Background</p> <p>Protein acetylation is among the most common protein modifications. The two major types are post-translational N^ε-lysine acetylation catalyzed by KATs (Lysine acetyltransferases, previously named HATs (histone acetyltransferases) and co-translational N^α-terminal acetylation catalyzed by NATs (N-terminal acetyltransferases). The major NAT complex in yeast, NatA, is composed of the catalytic subunit Naa10p (<b>N a</b>lpha <b>a</b>cetyltransferase <b>10 p</b>rotein) (Ard1p) and the auxiliary subunit Naa15p (Nat1p). The NatA complex potentially acetylates Ser-, Ala-, Thr-, Gly-, Val- and Cys- N-termini after Met-cleavage. In humans, the homologues hNaa15p (hNat1) and hNaa10p (hArd1) were demonstrated to form a stable ribosome associated NAT complex acetylating NatA type N-termini <it>in vitro </it>and <it>in vivo</it>.</p> <p>Results</p> <p>We here describe a novel human protein, hNaa16p (hNat2), with 70% sequence identity to hNaa15p (hNat1). The gene encoding hNaa16p originates from an early vertebrate duplication event from the common ancestor of h<it>NAA15 </it>and h<it>NAA16</it>. Immunoprecipitation coupled to mass spectrometry identified both endogenous hNaa15p and hNaa16p as distinct interaction partners of hNaa10p in HEK293 cells, thus demonstrating the presence of both hNaa15p-hNaa10p and hNaa16p-hNaa10p complexes. The hNaa16p-hNaa10p complex acetylates NatA type N-termini <it>in vitro</it>. hNaa16p is ribosome associated, supporting its potential role in cotranslational N^α-terminal acetylation. h<it>NAA16 </it>is expressed in a variety of human cell lines, but is generally less abundant as compared to h<it>NAA15</it>. Specific knockdown of h<it>NAA16 </it>induces cell death, suggesting an essential role for hNaa16p in human cells.</p> <p>Conclusion</p> <p>At least two distinct NatA protein N^α-terminal acetyltransferases coexist in human cells potentially creating a more complex and flexible system for N^α-terminal acetylation as compared to lower eukaryotes.</p

Primary Hyperparathyroidism Influences the Expression of Inflammatory and Metabolic Genes in Adipose Tissue

Background: Primary hyperparathyroidism (PHPT) is characterised by increased production of parathyroid hormone (PTH) resulting in elevated serum calcium levels. The influence on bone metabolism with altered bone resorption is the most studied clinical condition in PHPT. In addition to this, patients with PHPT are at increased risk of non-skeletal diseases, such as impaired insulin sensitivity, arterial hypertension and increased risk of death by cardiovascular diseases (CVD), possibly mediated by a chronic low-grade inflammation. The aim of this study was to investigate whether adipose tissue reflects the low-grade inflammation observed in PHPT patients. Methodology/Principal Findings: Subcutaneous fat tissue from the neck was sampled from 16 non-obese patients with PHPT and from 16 patients operated for benign thyroid diseases, serving as weight-matched controls. RNA was extracted and global gene expression was analysed with Illumina BeadArray Technology. We found 608 differentially expressed genes (q-value,0.05), of which 347 were up-regulated and 261 were down-regulated. Gene ontology analysis showed that PHPT patients expressed increased levels of genes involved in immunity and defense (e.g. matrix metallopeptidase 9, S100 calcium binding protein A8 and A9, CD14, folate receptor 2), and reduced levels of genes involved in metabolic processes. Analysis of transcription factor binding sites present in the differentially expressed genes corroborated the up-regulation of inflammatory processes. Conclusions/Significance: Our findings demonstrate that PHPT strongly influences gene regulation in fat tissue, which may result in altered adipose tissue function and release of pathogenic factors that increase the risk of CVD

Associations between tamoxifen, estrogens, and FSH serum levels during steady state tamoxifen treatment of postmenopausal women with breast cancer

<p>Abstract</p> <p>Background</p> <p>The cytochrome P450 (CYP) enzymes 2C19, 2D6, and 3A5 are responsible for converting the selective estrogen receptor modulator (SERM), tamoxifen to its active metabolites 4-hydroxy-tamoxifen (4OHtam) and 4-hydroxy-<it>N</it>-demethyltamoxifen (4OHNDtam, endoxifen). Inter-individual variations of the activity of these enzymes due to polymorphisms may be predictors of outcome of breast cancer patients during tamoxifen treatment. Since tamoxifen and estrogens are both partly metabolized by these enzymes we hypothesize that a correlation between serum tamoxifen and estrogen levels exists, which in turn may interact with tamoxifen on treatment outcome. Here we examined relationships between the serum levels of tamoxifen, estrogens, follicle-stimulating hormone (FSH), and also determined the genotypes of CYP2C19, 2D6, 3A5, and SULT1A1 in 90 postmenopausal breast cancer patients.</p> <p>Methods</p> <p>Tamoxifen and its metabolites were measured by liquid chromatography-tandem mass spectrometry. Estrogen and FSH levels were determined using a sensitive radio- and chemiluminescent immunoassay, respectively.</p> <p>Results</p> <p>We observed significant correlations between the serum concentrations of tamoxifen, <it>N</it>-dedimethyltamoxifen, and tamoxifen-<it>N</it>-oxide and estrogens (p < 0.05). The genotype predicted CYP2C19 activity influenced the levels of both tamoxifen metabolites and E1.</p> <p>Conclusions</p> <p>We have shown an association between tamoxifen and its metabolites and estrogen serum levels. An impact of CYP2C19 predicted activity on tamoxifen, as well as estrogen kinetics may partly explain the observed association between tamoxifen and its metabolites and estrogen serum levels. Since the role of estrogen levels during tamoxifen therapy is still a matter of debate further prospective studies to examine the effect of tamoxifen and estrogen kinetics on treatment outcome are warranted.</p

Norwegian Air Shuttle ASA : strategisk regnskapsanalyse og verdsettelse

Denne masteroppgaven er en fundamental verdsettelse av Norwegian Air Shuttle ASA, heretter kalt Norwegian. Oppgavens mål er å vurdere om selskapets aksjekurs per 16.02.2015 på NOK 228,70 kan rettferdiggjøres basert på selskapets underliggende økonomiske forhold. Den fundamentale verdsettelsen vil suppleres av en komparativ verdsettelse for å kunne sammenligne og vurdere rimeligheten av verdsettelsesanslagene. Oppgaven starter med en kort introduksjon av flybransjen før Norwegian og selskapene i vår komparative bransje presenteres. Norwegians strategiske og økonomiske posisjon undersøkes så gjennom en strategisk regnskapsanalyse. Sammen med våre forventninger til fremtiden danner resultatene fra den strategiske regnskapsanalysen grunnlaget for utarbeidelsen av Norwegians fremtidige budsjett og avkastningskrav. Kontantstrømmene fra fremtidsbudsjettet diskonteres med avkastnings-kravene i forskjellige egenkapital- og selskapskapitalmodeller for å regne ut verdiestimater på Norwegians egenkapital. Gjennom en konvergeringsprosess hvor avkastningskravene sekvensielt vektes med verdibaserte vekter, konvergerer så verdiestimatene til ett felles verdiestimat på Norwegians egenkapital. Denne summen divideres på Norwegians utestående aksjer for å stå igjen med et verdiestimat per aksje. Den fundamentale verdsettelsen kom frem til et verdiestimat på Norwegian-aksjen på NOK 182,92. Det er omtrent 20 % lavere enn aksjekursen per 16.02.2015 på NOK 228,70. Den komparative verdsettelsen kom frem til et verdiestimat på Norwegian-aksjen på NOK 226. Dette estimatet er i tråd med aksjekursen på NOK 228,70, og viste at selskapene i vår komparative bransje var relativt likt priset av markedene. Dette resultatet ble tolket som at markedene var relativt positivt innstilt til flyselskapssektoren, og at dette kunne bidra til å forklare Norwegians høye aksjekurs i forhold til aksjekursen vår fundamentale verdsettelse skulle tilsi. På bakgrunn av den fundamentale verdsettelsen konkluderer oppgaven med en salgsanbefaling av Norwegian-aksjen.nhhma