Global Health Governance and the Commercial Sector: A Documentary Analysis of Tobacco Company Strategies to Influence the WHO Framework Convention on Tobacco Control

Heide Weishaar and colleagues did an analysis of internal tobacco industry documents together with other data and describe the industry's strategic response to the proposed World Health Organization Framework Convention on Tobacco Control

Gaudin Models and Bending Flows: a Geometrical Point of View

In this paper we discuss the bihamiltonian formulation of the (rational XXX) Gaudin models of spin-spin interaction, generalized to the case of sl(r)-valued spins. In particular, we focus on the homogeneous models. We find a pencil of Poisson brackets that recursively define a complete set of integrals of the motion, alternative to the set of integrals associated with the 'standard' Lax representation of the Gaudin model. These integrals, in the case of su(2), coincide wih the Hamiltonians of the 'bending flows' in the moduli space of polygons in Euclidean space introduced by Kapovich and Millson. We finally address the problem of separability of these flows and explicitly find separation coordinates and separation relations for the r=2 case.Comment: 27 pages, LaTeX with amsmath and amssym

Successful new product development by optimizing development process effectiveness in highly regulated sectors: the case of the Spanish medical devices sector

Rapid development and commercialization of new products is of vital importance for small and medium sized enterprises (SME) in regulated sectors. Due to strict regulations, competitive advantage can hardly be achieved through the effectiveness of product concepts only. If an SME in a highly regulated sector wants to excell in new product development (NPD) performance, the company should focus on the flexibility, speed, and productivity of its NPD function: i.e. the development process effectiveness. Our main research goals are first to explore if SMEs should focus on their their development process effectiveness rather than on their product concept effectiveness to achieve high NPD performance; and second, to explore whether a shared pattern in the organization of the NPD function can be recognized to affect NPD performance positively. The medical devices sector in Spain is used as an example of a\ud highly regulated sector. A structured survey among 11 SMEs, of which 2 were studied also as in in-depth case studies, led to the following results. First of all, indeed the companies in the dataset which focused on the effectiveness of their development process, stood out in NPD performance. Further, the higher performing companies did have a number of commonalities in the organisation of their NPD function: 1) The majority of the higher performing firms had an NPD strategy characterized by a predominantly incremental project portfolio.\ud 2) a) Successful firms with an incremental project portfolio combined this with a functional team structure b) Successful firms with a radical project portfolio combined this with a heavyweight or autonomous team structure.\ud 3) A negative reciprocal relationship exists between formalization of the NPD processes and the climate of the NPD function, in that a formalized NPD process and an innovative climate do not seem to reinforce each other. Innovative climate combined with an informal NPD process does however contribute positively to NPD performance. This effect was stronger in combination with a radical project portfolio. The highest NPD performance was measured for companies focusing mainly on incremental innovation. It is argued that in highly regulated sectors, companies with an incremental product portfolio would benefit from employing a functional structure. Those companies who choose for a more radical project portfolio in highly regulated sectors should be aware\ud that they are likely to excell only in the longer term by focusing on strategic flexibility. In their NPD organization, they might be well advised to combine informal innovation processes with an innovative climate

Hsp90 orchestrates transcriptional regulation by Hsf1 and cell wall remodelling by MAPK signalling during thermal adaptation in a pathogenic yeast

Acknowledgments We thank Rebecca Shapiro for creating CaLC1819, CaLC1855 and CaLC1875, Gillian Milne for help with EM, Aaron Mitchell for generously providing the transposon insertion mutant library, Jesus Pla for generously providing the hog1 hst7 mutant, and Cathy Collins for technical assistance.Peer reviewedPublisher PD

Mapping the Hsp90 Genetic Interaction Network in Candida albicans Reveals Environmental Contingency and Rewired Circuitry

The molecular chaperone Hsp90 regulates the folding of diverse signal transducers in all eukaryotes, profoundly affecting cellular circuitry. In fungi, Hsp90 influences development, drug resistance, and evolution. Hsp90 interacts with ∼10% of the proteome in the model yeast Saccharomyces cerevisiae, while only two interactions have been identified in Candida albicans, the leading fungal pathogen of humans. Utilizing a chemical genomic approach, we mapped the C. albicans Hsp90 interaction network under diverse stress conditions. The chaperone network is environmentally contingent, and most of the 226 genetic interactors are important for growth only under specific conditions, suggesting that they operate downstream of Hsp90, as with the MAPK Hog1. Few interactors are important for growth in many environments, and these are poised to operate upstream of Hsp90, as with the protein kinase CK2 and the transcription factor Ahr1. We establish environmental contingency in the first chaperone network of a fungal pathogen, novel effectors upstream and downstream of Hsp90, and network rewiring over evolutionary time

Real-time PCR complements immunohistochemistry in the determination of HER-2/neu status in breast cancer

BACKGROUND: The clinical benefit of determining the status of HER-2/neu amplification in breast cancer patients is well accepted. Although immunohistochemistry (IHC) is the most frequently used method to assess the over-expression of HER-2 protein, fluorescent in-situ hybridization (FISH) is recognized as the "gold standard" for the determining of HER-2/neu status. The greatest discordance between the two methods occurs among breast tumors that receive an indeterminate IHC score of 2+. More recently, a real-time polymerase chain reaction (PCR) assay using the LightCycler(® )has been developed for quantifying HER-2/neu gene amplification. In this study, we evaluated the sensitivity and specificity of a commercially available LightCycler assay as it compares to FISH. To determine whether this assay provides an accurate alternative for the determination of HER-2/neu status, we focused primarily on tumors that were deemed indeterminate or borderline status by IHC. METHODS: Thirty-nine breast tumors receiving an IHC score of 2+ were evaluated by both FISH and LightCycler(® )technologies in order to determine whether quantitative real-time PCR provides an accurate alternative for the determination of HER-2/neu status. RESULTS: We found a high concordance (92%) between FISH and real-time PCR results. We also observed that 10% of these tumors were positive for gene amplification by both FISH and real-time PCR. CONCLUSION: The data show that the results obtained for the gene amplification of HER-2/neu by real-time PCR on the LightCycler(® )instrument is comparable to results obtained by FISH. These results therefore suggest that real-time PCR analysis, using the LightCycler(®), is a viable alternative to FISH for reassessing breast tumors which receive an IHC score of 2+, and that a combined IHC and real-time PCR approach for the determination of HER-2 status in breast cancer patients may be an effective and efficient strategy

Current quality of life and its determinants among opiate-dependent individuals five years after starting methadone treatment

This study explores the current QoL of opiate-dependent individuals who started outpatient methadone treatment at least 5 years ago and assesses the influence of demographic, psychosocial, drug and health-related variables on individuals' QoL. Participants (n = 159) were interviewed about their current QoL, psychological distress and severity of drug-related problems, using the Lancashire Quality of Life Profile, the Brief Symptom Inventory and the Addiction Severity Index. Potential determinants of QoL were assessed in a multiple linear regression analysis. Five years after the start of methadone treatment, opiate-dependent individuals report low QoL scores on various domains. No association was found between drug-related variables and QoL, but a significant negative impact of psychological distress was identified. Severity of psychological distress, taking medication for psychological problems and the inability to change one's living situation were associated with lower QoL. Having at least one good friend and a structured daily activity had a significant, positive impact on QoL. Opiate-dependent individuals' QoL is mainly determined by their psychological well-being and a number of psychosocial variables. These findings highlight the importance of a holistic approach to treatment and support in methadone maintenance treatment, which goes beyond fixing the negative physical consequences of opiate dependence

Hsp90 inhibition differentially destabilises MAP kinase and TGF-beta signalling components in cancer cells revealed by kinase-targeted chemoproteomics

<p>Abstract</p> <p>Background</p> <p>The heat shock protein 90 (Hsp90) is required for the stability of many signalling kinases. As a target for cancer therapy it allows the simultaneous inhibition of several signalling pathways. However, its inhibition in healthy cells could also lead to severe side effects. This is the first comprehensive analysis of the response to Hsp90 inhibition at the kinome level.</p> <p>Methods</p> <p>We quantitatively profiled the effects of Hsp90 inhibition by geldanamycin on the kinome of one primary (Hs68) and three tumour cell lines (SW480, U2OS, A549) by affinity proteomics based on immobilized broad spectrum kinase inhibitors ("kinobeads"). To identify affected pathways we used the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway classification. We combined Hsp90 and proteasome inhibition to identify Hsp90 substrates in Hs68 and SW480 cells. The mutational status of kinases from the used cell lines was determined using next-generation sequencing. A mutation of Hsp90 candidate client RIPK2 was mapped onto its structure.</p> <p>Results</p> <p>We measured relative abundances of > 140 protein kinases from the four cell lines in response to geldanamycin treatment and identified many new potential Hsp90 substrates. These kinases represent diverse families and cellular functions, with a strong representation of pathways involved in tumour progression like the BMP, MAPK and TGF-beta signalling cascades. Co-treatment with the proteasome inhibitor MG132 enabled us to classify 64 kinases as true Hsp90 clients. Finally, mutations in 7 kinases correlate with an altered response to Hsp90 inhibition. Structural modelling of the candidate client RIPK2 suggests an impact of the mutation on a proposed Hsp90 binding domain.</p> <p>Conclusions</p> <p>We propose a high confidence list of Hsp90 kinase clients, which provides new opportunities for targeted and combinatorial cancer treatment and diagnostic applications.</p