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- SourceAvailable from: Kenichi Taguchi[Show abstract] [Hide abstract]
ABSTRACT: At our institute, a chemoradioselection strategy has been used to select patients for organ preservation on the basis of response to an initial 30-40 Gy concurrent chemoradiotherapy (CCRT). Patients with a favorable response (i.e., chemoradioselected; CRS) have demonstrated better outcomes than those with an unfavorable response (i.e., nonchemoradioselected; N-CRS). Successful targeting of molecules that attenuate the efficacy of chmoradioselection may improve results. Thus, the aim of this study was to evaluate the association of a novel cancer stem cell (CSC) marker, CD44 variant 9 (CD44v9), with cellular refractoriness to chemoradioselection in advanced head and neck squamous cell carcinoma (HNSCC). Through a medical chart search, 102 patients with advanced HNSCC treated with chemoradioselection from 1997 to 2008 were enrolled. According to our algorithm, 30 patients were CRC following induction CCRT and 72 patients were N-CRS. Using the conventional immunohistochemical technique, biopsy specimens and surgically removed tumor specimens were immunostained with the anti-CD44v9 specific antibodies. The intrinsic expression levels of CD44v9 in the biopsy specimens did not correlate with the chemoradioselection and patient survival. However, in N-CRS patients, the CD44v9-positive group demonstrated significantly (P = 0.008) worse prognosis, than the CD44v9-negative group. Multivariate analyses demonstrated that among four candidate factors (T, N, response to CCRT, and CD44v9), CD44v9 positivity (HR: 3.145, 95% CI: 1.235-8.008, P = 0.0163) was significantly correlated with the poor prognosis, along with advanced N stage (HR: 3.525, 95% CI: 1.054-9.060, P = 0.0228). Furthermore, the survival rate of the CD44v9-induced group was significantly (P = 0.04) worse than the CD44v9-non-induced group. CCRT-induced CD44v9-expressing CSCs appear to be a major hurdle to chemoradioselection. CD44v9-targeting seems to be a promising strategy to enhance the efficacy of chemoradioselection and consequent organ preservation and survival.PLoS ONE 03/2015; 10(3):e0116596. DOI:10.1371/journal.pone.0116596
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ABSTRACT: IntroductionThe regional Board of Health in Stockholm, Sweden, established the Pharmacotherapy Centre (PTC) to enhance the rational use of medicines. The PTC initiated computerised decision support systems and developed a range of electronic service products to sustain rational prescribing. However, knowledge about which determinants have supported or hindered the sustainability of this type of healthcare organisation is limited.Objective This study aims to identify and explore determinants that support or challenge the development and sustainability of the PTC organisation, as well as investigate the key elements of their implementation efforts.Methods An in-depth interview study among key informants involved in the establishment of the PTC organisation was conducted. Data were analysed using qualitative content analysis.ResultsFindings suggest that determinants enabling the development and expansion of this organisation include the presence of innovative characteristics among the PTC leadership and the ability of leaders to nurture visionary innovation in others, as well as the instigation of informal social networks and to identify end-user needs. Challenges included an ambiguous relationship to the pharmaceutical industry, an underestimation of the innovation-system fit and to undertake systematic evaluation of created impact by the organisation. Although prescriber use of electronic service products and adherence to an essential drug list increased over time, it remains difficult to identify methods required for demonstrating patient effects.Conclusion Whereas some determinants enabled the successful expansion of the PTC organisation, others served to substantially hinder it. The determinants identified can pave the way for systematic investigations into organisational change and development research in the pharmaceutical field.International Journal of Health Planning and Management 03/2015; 30(1). DOI:10.1002/hpm.2202
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ABSTRACT: The DNA damage response (DDR) has two main goals, to repair the damaged DNA and to communicate the presence of damaged DNA. This communication allows the adaptation of cellular behavior to minimize the risk associated with DNA damage. In particular, cell cycle progression must be adapted after a DNA-damaging insult, and cells either pause or terminally exit the cell cycle during a DDR. As cells can accumulate mutations after a DDR due to error-prone DNA repair, terminal cell cycle exit may prevent malignant transformation. The tumor suppressor p53 plays a key role in promoting terminal cell cycle exit. Interestingly, p53 has been implicated in communication of a stress response to surrounding cells, known as the bystander response. Recently, surrounding cells have also been shown to affect the damaged cell, suggesting the presence of intercellular feedback loops. How such feedback may affect terminal cell cycle exit remains unclear, but its presence calls for caution in evaluating cellular outcome without controlling the cellular surrounding. In addition, such feedback may contribute to how the cellular environment affects malignant transformation after DNA damage.Frontiers in Genetics 02/2015; 6(63). DOI:10.3389/fgene.2015.00063
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