Upgrading the SPS Operational Software for the LHC Era: The SPS-2001 Software Project

In December 1996, it was decided to set up a project to re-engineer the CERN SPS Accelerator application software to improve the operational efficiency and to cover the specific needs of the SPS as LHC injector. The mandate of this project is to provide a first working version of the software in June 2001 and a final version in July 2003. It will make use of the emerging CERN accelerator control infrastructure amongst which the new Java Application Programming Interface (this conference). This presentation reviews the reasons why the project was launched, its scope and objectives, the project planning and the methods used to run the analysis. The first results of the analysis phase and their implications for the application software, for the control infrastructure and for the accelerator equipment software services will be presented

The VEGF pathway and the AKT/mTOR/p70S6K1 signalling pathway in human epithelial ovarian cancer

Vascular endothelial growth factor (VEGF)-A inhibitors exhibit unseen high responses and toxicity in recurrent epithelial ovarian cancer suggesting an important role for the VEGF/VEGFR pathway. We studied the correlation of VEGF signalling and AKT/mTOR signalling. Using a tissue microarray of clinical samples (N=86), tumour cell immunohistochemical staining of AKT/mTOR downstream targets, pS6 and p4E-BP1, together with tumour cell staining of VEGF-A and pVEGFR2 were semi-quantified. A correlation was found between the marker for VEGFR2 activation (pVEGFR2) and a downstream target of AKT/mTOR signalling (pS6) (R=0.29; P=0.002). Additional gene expression analysis in an independent cDNA microarray dataset (N=24) showed a negative correlation (R=−0.73, P<0.0001) between the RPS6 and the VEGFR2 gene, which is consistent as the gene expression and phosphorylation of S6 is inversely regulated. An activated tumour cell VEGFR2/AKT/mTOR pathway was associated with increased incidence of ascites (χ2, P=0.002) and reduced overall survival of cisplatin–taxane-based patients with serous histology (N=32, log-rank test, P=0.04). These data propose that VEGF-A signalling acts on tumour cells as a stimulator of the AKT/mTOR pathway. Although VEGF-A inhibitors are classified as anti-angiogenic drugs, these data suggest that the working mechanism has an important additional modality of targeting the tumour cells directly

Induction of lymphangiogenesis in and around axillary lymph node metastases of patients with breast cancer

We studied the presence of lymphangiogenesis in lymph node (LN) metastases of breast cancer. Lymph vessels were present in 52 of 61 (85.2%) metastatically involved LNs vs 26 of 104 (25.0%) uninvolved LNs (P<0.001). Furthermore, median intra- and perinodal lymphatic endothelial cell proliferation fractions were higher in metastatically involved LNs (P<0.001). This is the first report demonstrating lymphangiogenesis in LN metastases of cancer in general and breast cancer in particular

Open Science in Software Engineering

Open science describes the movement of making any research artefact available to the public and includes, but is not limited to, open access, open data, and open source. While open science is becoming generally accepted as a norm in other scientific disciplines, in software engineering, we are still struggling in adapting open science to the particularities of our discipline, rendering progress in our scientific community cumbersome. In this chapter, we reflect upon the essentials in open science for software engineering including what open science is, why we should engage in it, and how we should do it. We particularly draw from our experiences made as conference chairs implementing open science initiatives and as researchers actively engaging in open science to critically discuss challenges and pitfalls, and to address more advanced topics such as how and under which conditions to share preprints, what infrastructure and licence model to cover, or how do it within the limitations of different reviewing models, such as double-blind reviewing. Our hope is to help establishing a common ground and to contribute to make open science a norm also in software engineering.Comment: Camera-Ready Version of a Chapter published in the book on Contemporary Empirical Methods in Software Engineering; fixed layout issue with side-note

Where do the elderly die? The impact of nursing home utilisation on the place of death. Observations from a mortality cohort study in Flanders

BACKGROUND: Most of the research concerning place of death focuses on terminally ill patients (cancer patients) while the determinants of place of death of the elderly of the general population are not intensively studied. Studies showed the influence of gender, age, social-economical status and living arrangements on the place of death, but a facet not taken into account so far is the influence of the availability of nursing homes. METHODS: We conducted a survey of deaths, between January 1999 and December 2000 in a small densely populated area in Belgium, with a high availability of nursing homes (within 5 to 10 km of the place of residence of every elderly). We determined the incidence of total mortality (of subjects >60 years) from local official death registers that we consulted via the priest or the mortician of the local parish, to ask where the decedent had died and whether the deceased had lived in a nursing home. We compared the distribution of the places of death between parishes with a nursing home and with parishes without nursing home. RESULTS: 240 women and 217 men died during the two years study period. Only 22% died at home, while the majority (78%) died in an institutional setting, either a hospital (50%) or a nursing home (28%). Place of death was influenced by individual factors (age and gender) and the availability of a nursing home in the 'own' parish. The chance of in-hospital death was 65% higher for men (95% Confidence Interval [CI]: 14 to 138%; p = 0.008) and decreased by 4% (CI: -5.1% to -2.5%; p < 0.0001) for each year increase in age. Independent of gender and age, the chance of in-hospital death was 41% (CI: -60% to -13%; p = 0.008) lower in locations with a nursing home. CONCLUSION: Demographic, but especially social-contextual factors determine where elderly will end their life. The majority of elderly in Flanders die in an institution. Age, gender and living situation are predictors of the place of death but the embedment of a nursing home in the local community seems to be a key predictor

Lack of detectable neoantigen depletion signals in the untreated cancer genome.

Somatic mutations can result in the formation of neoantigens, immunogenic peptides that are presented on the tumor cell surface by HLA molecules. These mutations are expected to be under negative selection pressure, but the extent of the resulting neoantigen depletion remains unclear. On the basis of HLA affinity predictions, we annotated the human genome for its translatability to HLA binding peptides and screened for reduced single nucleotide substitution rates in large genomic data sets from untreated cancers. Apparent neoantigen depletion signals become negligible when taking into consideration trinucleotide-based mutational signatures, owing to lack of power or to efficient immune evasion mechanisms that are active early during tumor evolution

Semiautomated isolation and molecular characterisation of single or highly purified tumour cells from CellSearch enriched blood samples using dielectrophoretic cell sorting

Background: Molecular characterisation of single circulating tumour cells (CTCs) holds considerable promise for predictive biomarker assessment and to explore CTC heterogeneity. We evaluate a new method, the DEPArray system, that allows the dielectrophoretic manipulation and isolation of single and 100% purified groups of CTCs from pre-enriched blood samples and explore the feasibility of their molecular characterisation.Methods:Samples containing known numbers of two cell populations were used to assess cell loss during sample loading. Cultured breast cancer cells were isolated from spiked blood samples using CellSearch CTC and Profile kits. Single tumour cells and groups of up to 10 tumour cells were recovered with the DEPArray system and subjected to transcriptional and mutation analysis.Results:On average, 40% cell loss was observed when loading samples to the DEPArray system. Expected mutations in clinically relevant markers could be obtained for 60% of single recovered tumour cells and all groups of tumour cells. Reliable gene expression profiles were obtained from single cells and groups of up to 10 cells for 2 out of 3 spiked breast cancer cell lines.Conclusion:We describe a semiautomated workflow for the isolation of small groups of 1 to 10 tumour cells from whole blood samples and provide proof of principle for the feasibility of their comprehensive molecular characterisation

NF-κB activation in inflammatory breast cancer is associated with oestrogen receptor downregulation, secondary to EGFR and/or ErbB2 overexpression and MAPK hyperactivation

Activation of NF-κB in inflammatory breast cancer (IBC) is associated with loss of estrogen receptor (ER) expression, indicating a potential crosstalk between NF-κB and ER. In this study, we examined the activation of NF-κB in IBC and non-IBC with respect to ER and EGFR and/or ErbB2 expression and MAPK hyperactivation. A qRT–PCR based ER signature was evaluated in tumours with and without transcriptionally active NF-κB, as well as correlated with the expression of eight NF-κB target genes. Using a combined ER/NF-κB signature, hierarchical clustering was executed. Hyperactivation of MAPK was investigated using a recently described MAPK signature (Creighton et al, 2006), and was linked to tumour phenotype, ER and EGFR and/or ErbB2 overexpression. The expression of most ER-modulated genes was significantly elevated in breast tumours without transcriptionally active NF-κB. In addition, the expression of most ER-modulated genes was significantly anticorrelated with the expression of most NF-κB target genes, indicating an inverse correlation between ER and NF-κB activation. Clustering using the combined ER and NF-κB signature revealed one cluster mainly characterised by low NF-κB target gene expression and a second one with elevated NF-κB target gene expression. The first cluster was mainly characterised by non-IBC specimens and IHC ER+ breast tumours (13 out of 18 and 15 out of 18 respectively), whereas the second cluster was mainly characterised by IBC specimens and IHC ER− breast tumours (12 out of 19 and 15 out of 19 respectively) (Pearson χ2, P<0.0001 and P<0.0001 respectively). Hyperactivation of MAPK was associated with both ER status and tumour phenotype by unsupervised hierarchical clustering using the MAPK signature and was significantly reflected by overexpression of EGFR and/or ErbB2. NF-κB activation is linked to loss of ER expression and activation in IBC and in breast cancer in general. The inverse correlation between NF-κB activation and ER activation is due to EGFR and/or ErbB2 overexpression, resulting in NF-κB activation and ER downregulation

Validation of a Tissue Microarray to Study Differential Protein Expression in Inflammatory and Non-Inflammatory Breast Cancer

Aims. Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer with poor prognosis. The mechanisms responsible for the aggressive clinical evolution are incompletely understood. We constructed a tissue microarray (TMA) and validated its use in translational IBC research. Differential expression of proteins that might play a role in causing the IBC phenotype was studied.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44222/1/10549_2004_Article_5256693.pd

Practical Guidance for Integrating Data Management into Long-Term Ecological Monitoring Projects

Long-term monitoring and research projects are essential to understand ecological change and the effectiveness of management activities. An inherent characteristic of long-term projects is the need for consistent data collection over time, requiring rigorous attention to data management and quality assurance. Recent papers have provided broad recommendations for data management; however, practitioners need more detailed guidance and examples. We present general yet detailed guidance for the development of comprehensive, concise, and effective data management for monitoring projects. The guidance is presented as a graded approach, matching the scale of data management to the needs of the organization and the complexity of the project. We address the following topics: roles and responsibilities; consistent and precise data collection; calibration of field crews and instrumentation; management of tabular, photographic, video, and sound data; data completeness and quality; development of metadata; archiving data; and evaluation of existing data from other sources. This guidance will help practitioners execute effective data management, thereby, improving the quality and usability of data for meeting project objectives as well as broader meta-analysis and macrosystem ecology research