(In)finite extent of stationary perfect fluids in Newtonian theory

For stationary, barotropic fluids in Newtonian gravity we give simple criteria on the equation of state and the "law of motion" which guarantee finite or infinite extent of the fluid region (providing a priori estimates for the corresponding stationary Newton-Euler system). Under more restrictive conditions, we can also exclude the presence of "hollow" configurations. Our main result, which does not assume axial symmetry, uses the virial theorem as the key ingredient and generalises a known result in the static case. In the axially symmetric case stronger results are obtained and examples are discussed.Comment: Corrections according to the version accepted by Ann. Henri Poincar

Development of Pancreatic Cancer: Targets for Early Detection and Treatment

Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death worldwide and compared to other malignancies its share in cancer mortality is expected to rise further. This is due to a lack of sensitive diagnostic tools that would permit earlier detection in a potentially curable stage and the very slow progress in finding effective drug treatments for pancreatic cancer. Key Messages: Aside from genetic predispositions and environmental agents, chronic pancreatitis is by far the greatest risk factor for PDAC. It also shares several etiological factors with pancreatic cancer and represents its most challenging differential diagnosis. Biomarkers that can distinguish between chronic pancreatitis and PDAC may therefore be suitable for the latter's early detection. Moreover, targeting the natural history of chronic pancreatitis would be one approach to prevent PDAC. Targeting tumor-cell signaling directly by interfering with receptor tyrosine kinases has shown some efficacy, although the results in clinical trials were less encouraging than for other cancers. Other compounds developed have targeted the formation of extracellular matrix around the tumor, the proteolytic activity in the tumor environment, histone deacetylases, hedgehog signaling and heat shock proteins, but none has yet found its way into routine patient care. Attempts to individualize treatment according to the tumor's somatic mutation profile are novel but so far impractical. Conclusions: Progress in the treatment of pancreatic cancer has been exceedingly slow and mostly dependent on improved pharmaceutical preparations or combinations of established chemotherapeutic agents. The promise of major breakthroughs implied in targeting tumor signal transduction events has so far not materialized

Co-operatively Developing Research Data Management – An Inside View of the FDNext Project

Im DFG-Forschungsprojekt FDNext arbeiten sechs Universitäten aus Berlin und Brandenburg zusammen, um im Verbund ein nachhaltiges institutionelles Forschungsdatenmanagement mit der Entwicklung verschiedener Tools für Fachbereiche, Rechtsberatung, Policies und Service Management auszubauen. In der dreijährigen Förderphase werden Werkzeuge und Konzepte für Fachbereiche, Rechtsberatung, Policies und Service-Management im engen Austausch mit Projektpartner*innen aus Fakultäten, Fachbereichen und der Forschung erarbeitet, (weiter-)entwickelt und abschließend mit Akteur*innen der bundesweiten FDM-Community evaluiert. In dem Artikel werden die sechs Arbeitsschwerpunkte und ihre Zwischenergebnisse nach Ablauf der ersten Hälfte der Projektlaufzeit vorgestellt.The DFG-funded research project “FDNext” is a regional network comprising six universities in Berlin and Brandenburg focusing on jointly developing different tools for academic departments, legal advice offices, policies and service areas to ensure sustainable institutional research data management. During the three-year funding phase, tools and concepts to address the special needs of different disciplines, legal advice services, policies and service management will be further advanced in close cooperation with partners from different faculties, disciplines and research groups, followed by an in-depth evaluation by the RDM community across Germany. The article presents the six special focus areas and preliminary results at the end of the first half of the current funding phase.Peer Reviewe

PROTECT: pervasive and useR fOcused biomeTrics bordEr projeCT. A Case Study

PROTECT: Pervasive and useR fOcused biomeTrics bordEr projeCT is an EU project funded by the Horizon 2020 research and Innovation Programme. The main aim of PROTECT was to build an advanced biometric-based person identification system that works robustly across a range of border crossing types and that has strong user-centric features. This work presents the case study of the multibiometric verification system developed within PROTECT. The system has been developed to be suitable for different borders such as air, sea, and land borders. The system covers two use cases: the walk-through scenario, in which the traveller is on foot; the drive-through scenario, in which the traveller is in a vehicle. Each deployment includes a different set of biometric traits and this paper illustrates how to evaluate such multibiometric system in accordance with international standards and, in particular, how to overcome practical problems that may be encountered when dealing with multibiometric evaluation, such as different score distributions and missing scores

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. Homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC), in contrast to patients with two predicted protein truncating mutations (PPTM). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n=31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n=30), and with two PPTMs (BSEP3/3; n=77). We compared presentation, native liver survival (NLS), and effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (P<0.001). Without siEHC in their follow-up, NLS of BSEP1/3 was similar to BSEP3/3 patients, but considerably lower than BSEP1/1 patients (at age 10 years: 38%, 30%, and 71%, resp; P=0.003). After siEHC, BSEP1/3 and BSEP3/3 patients had similarly low NLS, while this was much higher in BSEP1/1 patients (10 years after siEHC, 27%, 14%, and 92%, resp.; P<0.001). Conclusions: BSEP deficiency patients with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as patients with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment

Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol

Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; p&lt;0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9–81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3–59·0) in the standard of care group (HR 0·65 [0·55–0·77]; p&lt;0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83–1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (&lt;1%) with standard of care in the abiraterone trial). Interpretation: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas

RRAD, IL4I1, CDKN1A, and SERPINE1 genes are potentially co-regulated by NF-κB and p53 transcription factors in cells exposed to high doses of ionizing radiation

Abstract Background The cellular response to ionizing radiation involves activation of p53-dependent pathways and activation of the atypical NF-κB pathway. The crosstalk between these two transcriptional networks include (co)regulation of common gene targets. Here we looked for novel genes potentially (co)regulated by p53 and NF-κB using integrative genomics screening in human osteosarcoma U2-OS cells irradiated with a high dose (4 and 10 Gy). Radiation-induced expression in cells with silenced TP53 or RELA (coding the p65 NF-κB subunit) genes was analyzed by RNA-Seq while radiation-enhanced binding of p53 and RelA in putative regulatory regions was analyzed by ChIP-Seq, then selected candidates were validated by qPCR. Results We identified a subset of radiation-modulated genes whose expression was affected by silencing of both TP53 and RELA, and a subset of radiation-upregulated genes where radiation stimulated binding of both p53 and RelA. For three genes, namely IL4I1, SERPINE1, and CDKN1A, an antagonistic effect of the TP53 and RELA silencing was consistent with radiation-enhanced binding of both p53 and RelA. This suggested the possibility of a direct antagonistic (co)regulation by both factors: activation by NF-κB and inhibition by p53 of IL4I1, and activation by p53 and inhibition by NF-κB of CDKN1A and SERPINE1. On the other hand, radiation-enhanced binding of both p53 and RelA was observed in a putative regulatory region of the RRAD gene whose expression was downregulated both by TP53 and RELA silencing, which suggested a possibility of direct (co)activation by both factors. Conclusions Four new candidates for genes directly co-regulated by NF-κB and p53 were revealed

Comparability of size measurements of the pancreas in magnetic resonance imaging and transabdominal ultrasound

Abstract Introduction Transabdominal ultrasound (US) and magnetic resonance imaging (MRI) are commonly used for the examination of the pancreas in clinical routine. We therefore were interested in the concordance of these two imaging methods for the size measurement of the pancreas and how age, gender, and body mass index (BMI) affect the organ size. Methods A total of 342 participants from the Study of Health in Pomerania underwent whole‐body MRI and transabdominal US on the same day, and the diameter of the pancreatic head, body, and tail were measured. The agreement between US and MRI measurements was assessed by Bland and Altman plots. Intraclass correlation coefficients were used to compare observers. A multivariable regression model was applied using the independent variables age, gender, and body mass index. Results Compared to MRI, abdominal US returned smaller values for each segment of the pancreas, with a high level of inconsistency between these two methods. The mean difference was 0.39, 0.18, and 0.54 cm for the head, body, and tail, respectively. A high interobserver variability was detected for US. Multivariable analysis showed that pancreatic size in all three segments increased with BMI in both genders whereas pancreatic head and tail size decreased with age, an effect more marked in women. Conclusions Agreement of pancreatic size measurements is poor between US and MRI. These limitations should be considered when evaluating morphologic features for pathologic conditions or setting limits of normal size. Adjustments for BMI, gender, and age may also be warranted