Long-term vs. Short-term Contracts; A European perspective on natural gas

This paper analyses the economics of long-term gas contracts under changing institutional conditions, mainly gas sector liberalisation. The paper is motivated by the increasingly tense debate in continental Europe, UK and the US on the security of long-term gas supply. We discuss the main issues regarding long-term contracts, i.e. the changing role of the flexibility clause, the effect of abandoning the destination clause, and the strategic behaviour of producers between long-term sales and spot-sales. The literature suggests consumers and producers benefit from risk hedging through long-term contracts. Furthermore long-term contracts may reduce exercise of market power. This was argued to benefit consumers at the ‘expense’ of producers’ profits. Our analysis shows if the long-run demand elasticity is significantly lower than the short-run elasticity, both strategic producers and consumers benefit from lower prices and larger market volume. Some policy implications of the findings are also discussed

The differentiation/retrodifferentiation program of human U937 leukemia cells is accompanied by changes of VCP/p97

<p>Abstract</p> <p>Background</p> <p>Retrodifferentiation and regained proliferative capacity of growth-arrested human leukemic cells after monocyte-like differentiation requires proteolytic activities together with distinct regulatory factors. The AAA ATPase valosin-containing protein (VCP/p97) contributes to protein degradation and cell cycle regulation, respectively, and it was of interest to study a possible role of VCP/p97 during this myelomonocytic differentiation and retrodifferentiation.</p> <p>Results</p> <p>Separation of autonomously proliferating human U937 myeloid leukemia cells by centrifugal elutriation demonstrated unaltered VCP/p97 expression levels throughout distinct phases of the cell cycle. However, phorbol ester-induced G₀/G₁cell cycle arrest in differentiating human U937 leukemia cells was associated with a significantly increased protein and mRNA amount of this AAA ATPase. These elevated VCP/p97 levels progressively decreased again when growth-arrested U937 cells entered a retrodifferentiation program and returned to the tumorigenic phenotype. Whereas VCP/p97 was observed predominantly in the cytosol of U937 tumor and retrodifferentiated cells, a significant nuclear accumulation appeared during differentiation and G₀/G₁ growth arrest. Analysis of subcellular compartments by immunoprecipitations and 2D Western blots substantiated these findings and revealed furthermore a tyrosine-specific phosphorylation of VCP/p97 in the cytosolic but not in the nuclear fractions. These altered tyrosine phosphorylation levels, according to distinct subcellular distributions, indicated a possible functional involvement of VCP/p97 in the leukemic differentiation process. Indeed, a down-modulation of VCP/p97 protein by siRNA revealed a reduced expression of differentiation-associated genes in subsequent DNA microarray analysis. Moreover, DNA-binding and proliferation-associated genes, which are down-regulated during differentiation of the leukemic cells, demonstrated elevated levels in the VCP/p97 siRNA transfectants.</p> <p>Conclusion</p> <p>The findings demonstrated that monocytic differentiation and G₀/G₁growth arrest in human U937 leukemia cells was accompanied by an increase in VCP/p97 expression and a distinct subcellular distribution to be reverted during retrodifferentiation. Together with a down-modulation of VCP/p97 by siRNA, these results suggested an association of this AAA ATPase in the differentiation/retrodifferentiation program.</p

The homeobox gene HLXB9 is upregulated in a morphological subset of poorly differentiated hepatocellular carcinoma

The prognostic outcome for hepatocellular carcinoma (HCC) remains poor. Disease progression is accompanied by dedifferentiation of the carcinoma, a process that is not well understood. The aim of this study was to get more insight into the molecular characteristics of dedifferentiated carcinomas using high throughput techniques. Microarray-based global gene expression analysis was performed on five poorly differentiated HCC cell lines compared with non-neoplastic hepatic controls and a set of three cholangiolar carcinoma (CC) cell lines. The gene with the highest upregulation was HLXB9. HLXB9 is a gene of the homeobox genfamily important for the development of the pancreas. RT-PCR confirmed the upregulation of HLXB9 in surgical specimens of carcinoma tissue, suggesting its biological significance. Interestingly, HLXB9 upregulation was primary observed in poorly differentiated HCC with a pseudoglandular pattern compared with a solid pattern HCC or in moderate or well-differentiated HCC. Additional the expression of translated HLXB9, the protein HB9 (NCBI: NP_001158727), was analyzed by western blotting. Expression of HB9 was only detected in the cytoplasm but not in the nuclei of the HCC cells. For validation CC were also investigated. Again, we found an upregulation of HLXB9 in CC cells accompanied by an expression of HB9 in the cytoplasms of these tumor cells, respectively. In conclusion, homeobox HLXB9 is upregulated in poorly differentiated HCC with a pseudoglandular pattern. The translated HB9 protein is found in the cytoplasm of these HCC and CC. We therefore assume HLXB9 as a possible link in the understanding of the development of HCC and CC, respectivel

Renewable Electric Energy Integration: Quantifying the Value of Design of Markets for International Transmission Capacity

Integrating large quantities of supply-driven renewable electricity generation remains a political and operational challenge. One of the main obstacles in Europe to installing at least 200 GWs of power from variable renewable sources is how to deal with the insufficient network capacity and the congestion that will result from new flow patterns. We model the current methodology for controlling congestion at international borders and compare its results, under varying penetrations of wind power, with a model that simulates an integrated European network that utilises nodal/localised marginal pricing. The nodal pricing simulations illustrate that congestion - and price - patterns vary considerably between wind scenarios and within countries, and that a nodal price regime could make fuller use of existing EU network capacity, introducing substantial operational cost savings and reducing marginal power prices in the majority of European countries.Power market design, renewable power integration, congestion management, transmission economics

Circulation and Oxygen Distribution in the Tropical Atlantic Cruise No. 80, Leg 1; October 26 to November 23, 2009 Mindelo (Cape Verde) to Mindelo (Cape Verde)

METEOR cruise 80/1 was a contribution to the SFB 754 “Climate-Biogeochemistry Interactions in the Tropical Ocean”. Shipboard, glider and moored observations are used to study the temporal and spatial variability of physical and biogeochemical parameters within the oxygen minimum zone (OMZ) of the tropical North Atlantic. As part of the BMBF “Nordatlantik” project, it further focuses on the equatorial current system including the Equatorial Undercurrent (EUC) and intermediate currents below. During the cruise, hydrographic station observations were performed using a CTD/O2 rosette, including water sampling for salinity, oxygen, nutrients and other biogeochemical tracers. Underway current measurements were successfully carried out with the 75 kHz ADCP borrowed from R/V POSEIDON during the first part of the cruise, and R/V METEOR’s 38 kHz ADCP during the second part. During M80/1, an intensive mooring program was carried out with 8 mooring recoveries and 8 mooring deployments. Right at the beginning of the cruise, a multidisciplinary mooring near the Cape Verde Islands was recovered and redeployed. Within the framework of SFB 754, two moorings with CTD/O2 profilers were recovered and redeployed with other instrumentation in the center and at the southern rim of the OMZ of the tropical North Atlantic. The equatorial mooring array as part of BMBF “North Atlantic” project consists of 5 current meter moorings along 23°W between 2°S and 2°N. It is aimed at quantifying the variability of the thermocline water supply toward the equatorial cold tongue which develops east of 10°W during boreal summer. Several glider missions were performed during the cruise. One glider was recovered that was deployed two months earlier. Another glider was deployed for two short term missions, near the equator for about 8 days and near 8°N for one day. This glider was equipped with a new microstructure probe in addition to standard sensors, i.e. CTD/O2, chlorophyll and turbidity

Efficient Small Extracellular Vesicles (EV) Isolation Method and Evaluation of EV-Associated DNA Role in Cell-Cell Communication in Cancer

SIMPLE SUMMARY: Small extracellular vesicles (sEVs) released by all cell types function as a mediator in intercellular communication that can promote cell division and survival to remodel the tumor microenvironment to develop tumor invasion and metastasis. Even though dsDNA baggage is associated with all small EV populations, the functional role of EV-DNA in cancer remains poorly understood. This is due to a lack of methods allowing the efficient separation of small EVs (sEVs) from other non-sEV components. The main aim of our study was to develop an efficient sEV isolation method along with EV-associated DNA (EV-DNA) monitoring tool to evaluate the role of EV-DNA as a mediator of cell–cell communication in cancer. Our detailed small EV-DNA characterization confirmed that isolated sEVs using the TSU method (Tangential flow filtration + Size exclusion chromatography + Ultrafiltration) are free from contaminants such as cell-free and apoptotic bodies DNA, making TSU ideal for performing EV-DNA functional studies. Next, we revealed the exact EV-DNA distribution in the recipient cells using 3D image analysis and the association of EV-DNA with key cellular proteins, which may have an essential role in cancer. In the leukemia model, EV-DNA isolated from leukemia cell lines associated with mesenchymal stromal cells (MSCs), a crucial factor in the bone marrow (BM) microenvironment. ABSTRACT: Small extracellular vesicles (sEVs) play essential roles in intercellular signaling both in normal and pathophysiological conditions. Comprehensive studies of dsDNA associated with sEVs are hampered by a lack of methods, allowing efficient separation of sEVs from free-circulating DNA and apoptotic bodies. In this work, using controlled culture conditions, we enriched the reproducible separation of sEVs from free-circulated components by combining tangential flow filtration, size-exclusion chromatography, and ultrafiltration (TSU). EV-enriched fractions (F2 and F3) obtained using TSU also contained more dsDNA derived from the host genome and mitochondria, predominantly localized inside the vesicles. Three-dimensional reconstruction of high-resolution imaging showed that the recipient cell membrane barrier restricts a portion of EV-DNA. Simultaneously, the remaining EV-DNA overcomes it and enters the cytoplasm and nucleus. In the cytoplasm, EV-DNA associates with dsDNA-inflammatory sensors (cGAS/STING) and endosomal proteins (Rab5/Rab7). Relevant to cancer, we found that EV-DNA isolated from leukemia cell lines communicates with mesenchymal stromal cells (MSCs), a critical component in the BM microenvironment. Furthermore, we illustrated the arrangement of sEVs and EV-DNA at a single vesicle level using super-resolution microscopy. Altogether, employing TSU isolation, we demonstrated EV-DNA distribution and a tool to evaluate the exact EV-DNA role of cell–cell communication in cancer

Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial

Children with myeloid leukemia associated with Down syndrome (ML-DS) have superior outcome compared with non-DS patients, but suffer from higher constitutional cytotoxic drug susceptibility. We analyzed the outcome of 170 pediatric patients with ML-DS enrolled in the prospective, multicenter, open-label, nonrandomized ML-DS 2006 trial by Nordic Society for Pediatric Hematology and Oncology (NOPHO), Dutch Childhood Oncology Group (DCOG), and Acute Myeloid Leukemia–Berlin-Frankfurt-Münster (AML-BFM) study group. Compared with the historical control arm (reduced-intensity protocol for ML-DS patients from the AML-BFM 98 trial), treatment intensity was reduced by lowering the cumulative dose of etoposide (950 to 450 mg/m2) and intrathecal central nervous system prophylaxis while omitting maintenance therapy. Still, 5-year overall survival (89% 6 3% vs 90% 6 4%; Plog-rank 5 .64), event-free survival (EFS; 87% 6 3% vs 89% 6 4%; Plog-rank 5 .71), and cumulative incidence of relapse/ nonresponse (CIR/NR; 6% 6 3% vs 6% 6 2%; PGray 5 .03) did not significantly differ between the ML-DS 2006 trial and the historical control arm. Poor early treatment response (5-year EFS, 58% 6 16% vs 88% 6 3%; Plog rank 5 .0008) and gain of chromosome 8 (CIR/NR, 16% 6 7% vs 3% 6 2%, PGray 5 .02; 5-year EFS, 73% 6 8% vs 91% 6 4%, Plog rank 5 .018) were identified as independent prognostic factors predicting a worse EFS. Five of 7 relapsed patients (71%) with cytogenetic data had trisomy 8. Our study reveals prognostic markers for children with ML-DS and illustrates that reducing therapy did not impair excellent outcome. The trial was registered at EudraCT as #2007-006219-2. (Blood. 2017;129(25): 3314-3321

Seminal plasma as a source of prostate cancer peptide biomarker candidates for detection of indolent and advanced disease

Background:Extensive prostate specific antigen screening for prostate cancer generates a high number of unnecessary biopsies and over-treatment due to insufficient differentiation between indolent and aggressive tumours. We hypothesized that seminal plasma is a robust source of novel prostate cancer (PCa) biomarkers with the potential to improve primary diagnosis of and to distinguish advanced from indolent disease. &lt;br&gt;Methodology/Principal Findings: In an open-label case/control study 125 patients (70 PCa, 21 benign prostate hyperplasia, 25 chronic prostatitis, 9 healthy controls) were enrolled in 3 centres. Biomarker panels a) for PCa diagnosis (comparison of PCa patients versus benign controls) and b) for advanced disease (comparison of patients with post surgery Gleason score &#60;7 versus Gleason score &#62;&gt;7) were sought. Independent cohorts were used for proteomic biomarker discovery and testing the performance of the identified biomarker profiles. Seminal plasma was profiled using capillary electrophoresis mass spectrometry. Pre-analytical stability and analytical precision of the proteome analysis were determined. Support vector machine learning was used for classification. Stepwise application of two biomarker signatures with 21 and 5 biomarkers provided 83% sensitivity and 67% specificity for PCa detection in a test set of samples. A panel of 11 biomarkers for advanced disease discriminated between patients with Gleason score 7 and organ-confined (&#60;pT3a) or advanced (&#8805;pT3a) disease with 80% sensitivity and 82% specificity in a preliminary validation setting. Seminal profiles showed excellent pre-analytical stability. Eight biomarkers were identified as fragments of N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase​,prostatic acid phosphatase, stabilin-2, GTPase IMAP family member 6, semenogelin-1 and -2. Restricted sample size was the major limitation of the study.&lt;/br&gt; &lt;br&gt;Conclusions/Significance: Seminal plasma represents a robust source of potential peptide makers for primary PCa diagnosis. Our findings warrant further prospective validation to confirm the diagnostic potential of identified seminal biomarker candidates.&lt;/br&gt