The positive impact of agile retrospectives on the collaboration of distributed development teams – A practical approach on the example of Bosch engineering GmbH

To counteract competitive pressure, increasing customer requirements and growing product complexity successful distributed collaboration in product development is vital. Companies have to face new challenges, such as efficiency losses in communication. To overcome these challenges agile working practices, such as agile retrospectives, could be beneficial. The objective of this scientific work is to evaluate the benefit of agile working practices on the example of agile retrospectives, for the improvement of collaboration in distributed development teams. Based on literature analysis, qualitative and quantitative expert interviews following the DRM by Blessing and Chakrabarti, this scientific work shows that agile working practices have a high potential to improve distributed collaboration. To address this potential, several virtual agile retrospectives are developed and conducted within a distributed team at Bosch Engineering GmbH. The evaluation of this approach results in a high potential of agile retrospectives indicating an improvement tendency. Especially iteratively implemented virtual agile retrospectives have a positive impact on successful distributed collaboration

Th-MYCN Mice with Caspase-8 Deficiency Develop Advanced Neuroblastoma with Bone Marrow Metastasis

Neuroblastoma, the most common extracranial pediatric solid tumor, is responsible for 15% of all childhood cancer deaths. Patients frequently present at diagnosis with metastatic disease, particularly to the bone marrow (BM). Advances in therapy and understanding of the metastatic process have been limited due in part, to the lack of animal models harboring BM disease. The widely employed transgenic model, the Th-MYCN mouse, exhibits limited metastasis to this site. Here we establish the first genetic immunocompetent mouse model for metastatic neuroblastoma with enhanced secondary tumors in the BM. This model recapitulates two frequent alterations in metastatic neuroblasoma, over-expression of MYCN and loss of caspase-8 expression. Mouse caspase-8 gene was deleted in neural crest lineage cells by crossing a Th-Cre transgenic mouse with a caspase-8 conditional knockout mouse. This mouse was then crossed with the neuroblastoma prone Th-MYCN mouse. While over-expression of MYCN by itself rarely caused bone marrow metastasis, combining MYCN overexpression and caspase-8 deletion significantly enhanced BM metastasis (37% incidence). Microarray expression studies of the primary tumors mRNAs and microRNAs revealed extracellular matrix (ECM) structural changes, increased expression of genes involved in epithelial to mesenchymal transition, inflammation and down-regulation of miR-7a and miR-29b. These molecular changes have been shown to be associated with tumor progression and activation of the cytokine transforming growth factor beta (TGF-β) pathway in various tumor models. Cytokine TGF-β can preferentially promote single cell motility and blood borne metastasis and therefore activation of this pathway may explain the enhanced BM metastasis observed in this animal model.Fil: Teitz, Tal. St. Jude Children’s Research Hospital. Department of Tumor Cell Biology; Estados UnidosFil: Inoue, Madoka. St. Jude Children’s Research Hospital. Department of Tumor Cell Biology; Estados UnidosFil: Valentine, Marcus B.. St. Jude Children’s Research Hospital. Department of Tumor Cell Biology; Estados UnidosFil: Zhu, Kejin. St. Jude Children’s Research Hospital. Department of Tumor Cell Biology; Estados UnidosFil: Rehg, Jerold E.. St. Jude Children’s Research Hospital. Department of Pathology; Estados UnidosFil: Zhao, Wei. St. Jude Children’s Research Hospital. Department of Biostatistics; Estados UnidosFil: Finkelstein, David. St. Jude Children’s Research Hospital. Department of Computational Biology; Estados UnidosFil: Wang, Yong-Dong. St. Jude Children’s Research Hospital. Hartwell Center for Bioinformatics and Biotechnology; Estados UnidosFil: Johnson, Melissa D.. St. Jude Children’s Research Hospital. Animal Imaging Center; Estados UnidosFil: Calabrese, Christopher. St. Jude Children’s Research Hospital. Animal Imaging Center; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Hakem, Razqallah. University of Toronto. Ontario Cancer Institute. Department of Medical Biophysics; CanadáFil: Weiss, William A.. University of California. Departments of Neurology, Pediatrics and Neurological Surgery; Estados UnidosFil: Lahti, Jill M.. St. Jude Children’s Research Hospital. Department of Tumor Cell Biology; Estados Unido

Preclinical Models for Neuroblastoma: Establishing a Baseline for Treatment

Preclinical models of pediatric cancers are essential for testing new chemotherapeutic combinations for clinical trials. The most widely used genetic model for preclinical testing of neuroblastoma is the TH-MYCN mouse. This neuroblastoma-prone mouse recapitulates many of the features of human neuroblastoma. Limitations of this model include the low frequency of bone marrow metastasis, the lack of information on whether the gene expression patterns in this system parallels human neuroblastomas, the relatively slow rate of tumor formation and variability in tumor penetrance on different genetic backgrounds. As an alternative, preclinical studies are frequently performed using human cell lines xenografted into immunocompromised mice, either as flank implant or orthtotopically. Drawbacks of this system include the use of cell lines that have been in culture for years, the inappropriate microenvironment of the flank or difficult, time consuming surgery for orthotopic transplants and the absence of an intact immune system.Here we characterize and optimize both systems to increase their utility for preclinical studies. We show that TH-MYCN mice develop tumors in the paraspinal ganglia, but not in the adrenal, with cellular and gene expression patterns similar to human NB. In addition, we present a new ultrasound guided, minimally invasive orthotopic xenograft method. This injection technique is rapid, provides accurate targeting of the injected cells and leads to efficient engraftment. We also demonstrate that tumors can be detected, monitored and quantified prior to visualization using ultrasound, MRI and bioluminescence. Finally we develop and test a "standard of care" chemotherapy regimen. This protocol, which is based on current treatments for neuroblastoma, provides a baseline for comparison of new therapeutic agents.The studies suggest that use of both the TH-NMYC model of neuroblastoma and the orthotopic xenograft model provide the optimal combination for testing new chemotherapies for this devastating childhood cancer

Immunosuppressive effects of radiation on human dendritic cells: reduced IL-12 production on activation and impairment of naïve T-cell priming

Dendritic cells (DC) are professional antigen-presenting cells (APC) of the immune system, uniquely able to prime naïve T-cell responses. They are the focus of a range of novel strategies for the immunotherapy of cancer, a proportion of which include treating DC with ionising radiation to high dose. The effects of radiation on DC have not, however, been fully characterised. We therefore cultured human myeloid DC from CD14+ precursors, and studied the effects of ionising radiation on their phenotype and function. Dendritic cells were remarkably resistant against radiation-induced apoptosis, showed limited changes in surface phenotype, and mostly maintained their endocytic, phagocytic and migratory capacity. However, irradiated DC were less effective in a mixed lymphocyte reaction, and on maturation produced significantly less IL-12 than unirradiated controls, while IL-10 secretion was maintained. Furthermore, peptide-pulsed irradiated mature DC were less effective at naïve T-cell priming, stimulating fewer effector cells with lower cytotoxicity against antigen-specific targets. Hence irradiation of DC in vitro, and potentially in vivo, has a significant impact on their function, and may shift the balance between T-cell activation and tolerisation in DC-mediated immune responses

Epidemiological Evidence for Work Load as a Risk Factor for Osteoarthritis of the Hip: A Systematic Review

Osteoarthritis of the hip (OA) is a common degenerative disorder of the joint cartilage that presents a major public health problem worldwide. While intrinsic risk factors (e.g, body mass and morphology) have been identified, external risk factors are not well understood. In this systematic review, the evidence for workload as a risk factor for hip OA is summarized and used to derive recommendations for prevention and further research.Epidemiological studies on workload or occupation and osteoarthritis of the hip were identified through database and bibliography searches. Using pre-defined quality criteria, 30 studies were selected for critical evaluation; six of these provided quantitative exposure data.Study results were too heterogeneous to develop pooled risk estimates by specific work activities. The weight of evidence favors a graded association between long-term exposure to heavy lifting and risk of hip OA. Long-term exposure to standing at work might also increase the risk of hip OA.It is not possible to estimate a quantitative dose-response relationship between workload and hip OA using existing data, but there is enough evidence available to identify job-related heavy lifting and standing as hazards, and thus to begin developing recommendations for preventing hip OA by limiting the amount and duration of these activities. Future research to identify specific risk factors for work-related hip OA should focus on implementing rigorous study methods with quantitative exposure measures and objective diagnostic criteria

Caspase-3 and caspase-8 expression in breast cancer: caspase-3 is associated with survival

Impaired apoptosis is one of the hallmarks of cancer. Caspase-3 and -8 are key regulators of the apoptotic response and have been shown to interact with the calpain family, a group of cysteine proteases, during tumorigenesis. The current study sought to investigate the prognostic potential of caspase-3 and -8 in breast cancer, as well as the prognostic value of combinatorial caspase and calpain expression. A large cohort (n = 1902) of early stage invasive breast cancer patients was used to explore the expression of caspase-3 and -8. Protein expression was examined using standard immunohistochemistry on tissue microarrays. High caspase-3 expression, but not caspase-8, is significantly associated with adverse breast cancer-specific survival (P = 0.008 and P = 0.056, respectively). Multivariate analysis showed that caspase-3 remained an independent factor when confounding factors were included (hazard ratio (HR) 1.347, 95% confidence interval (CI) 1.086–1.670; P = 0.007). The analyses in individual subgroups demonstrated the significance of caspase-3 expression in clinical outcomes in receptor positive (ER, PR or HER2) subgroups (P = 0.001) and in non-basal like subgroup (P = 0.029). Calpain expression had been previously assessed. Significant association was also found between high caspase-3/high calpain-1 and breast cancer-specific survival in the total patient cohort (P = 0.005) and basal-like subgroup (P = 0.034), as indicated by Kaplan–Meier analysis. Caspase-3 expression is associated with adverse breast cancer-specific survival in breast cancer patients, and provides additional prognostic values in distinct phenotypes. Combinatorial caspase and calpain expression can predict worse prognosis, especially in basal-like phenotypes. The findings warrant further validation studies in independent multi-centre patient cohorts

Drug-induced caspase 8 upregulation sensitises cisplatin-resistant ovarian carcinoma cells to rhTRAIL-induced apoptosis

BACKGROUND: Drug resistance is a major problem in ovarian cancer. Triggering apoptosis using death ligands such as tumour necrosis factor-related apoptosis inducing ligand (TRAIL) might overcome chemoresistance. METHODS: We investigated whether acquired cisplatin resistance affects sensitivity to recombinant human (rh) TRAIL alone or in combination with cisplatin in an ovarian cancer cell line model consisting of A2780 and its cisplatin-resistant subline CP70. RESULTS: Combining cisplatin and rhTRAIL strongly enhanced apoptosis in both cell lines. CP70 expressed less caspase 8 protein, whereas mRNA levels were similar compared with A2780. Pre-exposure of particularly CP70 to cisplatin resulted in strongly elevated caspase 8 protein and mRNA levels. Caspase 8 mRNA turnover and protein stability in the presence or absence of cisplatin did not differ between both cell lines. Cisplatin-induced caspase 8 protein levels were essential for the rhTRAIL-sensitising effect as demonstrated using caspase 8 small-interfering RNA (siRNA) and caspase-8 overexpressing constructs. Cellular FLICE-inhibitory protein (c-FLIP) and p53 siRNA experiments showed that neither an altered caspase 8/c-FLIP ratio nor a p53-dependent increase in DR5 membrane expression following cisplatin were involved in rhTRAIL sensitisation. CONCLUSION: Cisplatin enhances rhTRAIL-induced apoptosis in cisplatin-resistant ovarian cancer cells, and induction of caspase 8 protein expression is the key factor of rhTRAIL sensitisation. British Journal of Cancer (2011) 104, 1278-1287. doi:10.1038/bjc.2011.84 www.bjcancer.com (C) 2011 Cancer Research U