Blue luminous stars in nearby galaxies - UIT005: a possible link to the luminous blue variable stage

(abridged) A detailed study of the blue supergiant UIT005 (B2-2.5Ia+) in M33 is presented. The results of our quantitative spectral analysis indicate that the star is a very luminous, log(L/Lsun)~5.9 dex, and massive, M~50 Msun, object, showing a very high nitrogen-to-oxygen ratio in its surface (N/O~8, by mass). Based on the derived Mg and Si abundances, we argue that this high N/O ratio cannot be the result of an initial low O content due to its location on the disk of M33, known to present a steep metallicity gradient. In combination with the He abundance, the most plausible interpretation is that UIT005 is in an advanced stage of evolution, showing in its surface N enrichment and O depletion resulting from mixing with CNO processed material from the stellar interior. A comparison with the predictions of current stellar evolutionary models indicates that there are significant discrepancies, in particular with regard to the degree of chemical processing, with the models predicting a much lower degree of O depletion than observed. At the same time, the mass-loss rate derived in our analysis is an order of magnitude lower than the values considered in the evolutionary calculations. Based on a study of the surrounding stellar population and the nearby cluster NGC588, using WFPC2 photometry, we suggest that UIT005 could be in fact a runaway star from this cluster.Comment: Accepted for publication by ApJ, 11 figures, 45 page

A target-disease network model of second-generation BCR-ABL inhibitor action in Ph+ ALL

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is in part driven by the tyrosine kinase bcr-abl, but imatinib does not produce long-term remission. Therefore, second-generation ABL inhibitors are currently in clinical investigation. Considering different target specificities and the pronounced genetic heterogeneity of Ph+ ALL, which contributes to the aggressiveness of the disease, drug candidates should be evaluated with regard to their effects on the entire Ph+ ALL-specific signaling network. Here, we applied an integrated experimental and computational approach that allowed us to estimate the differential impact of the bcr-abl inhibitors nilotinib, dasatinib, Bosutinib and Bafetinib. First, we determined drug-protein interactions in Ph+ ALL cell lines by chemical proteomics. We then mapped those interactions along with known genetic lesions onto public protein-protein interactions. Computation of global scores through correlation of target affinity, network topology, and distance to disease-relevant nodes assigned the highest impact to dasatinib, which was subsequently confirmed by proliferation assays. In future, combination of patient-specific genomic information with detailed drug target knowledge and network-based computational analysis should allow for an accurate and individualized prediction of therapy.Uwe Rix, a, Jacques Colinge, Katharina Blatt, Manuela Gridling, Lily L. Remsing Rix, a, Katja Parapatics, Sabine Cerny-Reiterer, Thomas R. Burkard, Ulrich Jäger, Junia V. Melo, Keiryn L. Bennett, Peter Valent, Giulio Superti-Furg

Role of Renal Biopsy in the Management of Renal Cancer: Concordance between Ultrasound/CT-Guided Biopsy Results and Definitive Pathology, Adverse Events, and Complication Rate

\ua9 2023 by the authors.(1) Background: In the last decade, the number of detected renal cancer cases has increased, with the highest incidence in Western countries. Although renal biopsy is reported as a safe procedure, it is not adopted in all centres. As it is not possible to accurately distinguish benign tumours using imaging, this may lead to overtreatment. Most of the cancer detected on imaging is treated by surgery, radiofrequency ablation (RFA), or cryotherapy. (2) Methods: This was a single-centre retrospective study of 225 patients studied preoperatively with ultrasound (US)/CT-guided renal biopsy, with the aim of supporting clinical management. Decisions regarding the biopsy were based on either MDT indication or physician preference. US-guided renal biopsy was the first option for all patients; CT-guided biopsy was used when US-guided biopsy was not feasible. The efficacy of renal biopsy in terms of diagnostic performance and the concordance between biopsy results and definitive pathology were investigated. Additionally, adverse events related to the biopsy were recorded and analysed. Data collected throughout the study were analysed using binary logistic regression, Fisher’s exact test, and Pearson’s chi-square test to investigate possible correlations between post-procedural complications and the size of the lesion. (3) Results: Renal biopsy was not diagnostic in 23/225 (10.2%) patients. A CT-guided approach was necessary in 20/225 patients after failure of US-guided biopsy. The complication rate of renal biopsy was 4.8% overall—all Clavien grade I and without any serious sequelae. Interestingly, complications occurred in patients with very different sizes of renal cell carcinoma. No correlation between complications and anticoagulant/antiplatelet drugs was found. No seeding was reported among the patients who underwent partial/radical nephrectomy. (4) Conclusions: Renal biopsy was shown to be safe and effective, with a high concordance between biopsy results and definitive pathology and a low rate of complications. The use of a CT-guided approach whenever the US-guided approach failed improved the diagnostic performance of renal biopsy

Resolving the complex structure of the dust torus in the active nucleus of the Circinus galaxy

To test the dust torus model for active galactic nuclei directly, we study the extent and morphology of the nuclear dust distribution in the Circinus galaxy using high resolution interferometric observations in the mid-infrared with the MIDI instrument at the Very Large Telescope Interferometer. We find that the dust distribution in the nucleus of Circinus can be explained by two components, a dense and warm disk-like component of 0.4 pc size and a slightly cooler, geometrically thick torus component with a size of 2.0 pc. The disk component is oriented perpendicular to the ionisation cone and outflow and seems to show the silicate feature at 10 micron in emission. It coincides with a nuclear maser disk in orientation and size. From the energy needed to heat the dust, we infer a luminosity of the accretion disk corresponding to 20% of the Eddington luminosity of the nuclear black hole. We find that the interferometric data are inconsistent with a simple, smooth and axisymmetric dust emission. The irregular behaviour of the visibilities and the shallow decrease of the dust temperature with radius provide strong evidence for a clumpy or filamentary dust structure. We see no evidence for dust reprocessing, as the silicate absorption profile is consistent with that of standard galactic dust. We argue that the collimation of the ionising radiation must originate in the geometrically thick torus component. Our findings confirm the presence of a geometrically thick, torus-like dust distribution in the nucleus of Circinus, as required in unified schemes of Seyfert galaxies. Several aspects of our data require that this torus is irregular, or "clumpy".Comment: 20 pages, 16 figures, accepted for publication by A&

A Computational Approach to Analyze the Mechanism of Action of the Kinase Inhibitor Bafetinib

Prediction of drug action in human cells is a major challenge in biomedical research. Additionally, there is strong interest in finding new applications for approved drugs and identifying potential side effects. We present a computational strategy to predict mechanisms, risks and potential new domains of drug treatment on the basis of target profiles acquired through chemical proteomics. Functional protein-protein interaction networks that share one biological function are constructed and their crosstalk with the drug is scored regarding function disruption. We apply this procedure to the target profile of the second-generation BCR-ABL inhibitor bafetinib which is in development for the treatment of imatinib-resistant chronic myeloid leukemia. Beside the well known effect on apoptosis, we propose potential treatment of lung cancer and IGF1R expressing blast crisis

Herschel/PACS far-infrared photometry of two z>4 quasars

We present Herschel far-infrared (FIR) observations of two sub-mm bright quasars at high redshift: SDSS J1148+5251 (z=6.42) and BR 1202-0725 (z=4.69) obtained with the PACS instrument. Both objects are detected in the PACS photometric bands. The Herschel measurements provide additional data points that constrain the FIR spectral energy distributions (SEDs) of both sources, and they emphasise a broad range of dust temperatures in these objects. For lambda_rest ~< 20mu, the two SEDs are very similar to the average SEDs of quasars at low redshift. In the FIR, however, both quasars show excess emission compared to low-z QSO templates, most likely from cold dust powered by vigorous star formation in the QSO host galaxies. For SDSS J1148+5251 we detect another object at 160mu with a distance of ~10 arcseconds from the QSO. Although no physical connection between the quasar and this object can be shown with the available data, it could potentially confuse low-resolution measurements, thus resulting in an overestimate of the FIR luminosity of the z=6.42 quasar.Comment: 4 pages, 3 figures, accepted for publication in the A&A special issue on Hersche