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In Bacillus subtilis, the ribosome-associated GTPase CpgA is crucial for growth and proper morphology and was shown to be phosphorylated in vitro by the Ser/Thr protein kinase PrkC. To further understand the function of the Escherichia coli RsgA ortholog, CpgA, we first demonstrated that its GTPase activity is stimulated by its association with the 30 S ribosomal subunit. Then the role of CpgA phosphorylation was analyzed. A single phosphorylated residue, threonine 166, was identified by mass spectrometry. Phosphoablative replacement of this residue in CpgA induces a decrease of both its affinity for the 30 S ribosomal subunit and its GTPase activity, whereas a phosphomimetic replacement has opposite effects. Furthermore, cells expressing a nonphosphorylatable CpgA protein present the morphological and growth defects similar to those of a cpgA-deleted strain. Altogether, our results suggest that CpgA phosphorylation on Thr-166 could modulate its ribosome-induced GTPase activity. Given the role of PrkC in B. subtilis spore germination, we propose that CpgA phosphorylation is a key regulatory process that is essential for B. subtilis development.
Bacillus, GTPase, Phosphorylation, Ribosomes, Serine-Threonine Protein Kinase
Phosphorylation of CpgA Protein Enhances Both Its GTPase Activity and Its Affinity for Ribosome and Is Crucial for Bacillus subtilis Growth and Morphology*
Frederique Pompeo,‡,1,2 Celine Freton,‡,1 Catherine Wicker-Planquart,§ Christophe Grangeasse,¶ Jean-Michel Jault,§ and Anne Galinier‡
2012 Jun 15
Objectives: Activated platelets might play an important role in tumor progression. Mean platelet volume (MPV) has been used as a surrogate marker for platelet activation, and therefore its value as a marker of tumor prognosis has attracted recent attention. In this study, we aimed to critically evaluate the prognostic significance of the perioperative platelet count (COP), MPV and the MPV/COP ratio in head and neck cancer patients. Additionally, we explored the individual postoperative trajectory of these indices and their association with overall survival (OS) and disease-free survival (DFS). Methods: We retrospectively evaluated 122 head and neck squamous cell carcinoma patients receiving surgery with curative intent followed by postoperative radiotherapy. Platelet indices were measured preoperatively and on days 1 and 7 postoperatively. OS and DFS were analyzed using Kaplan-Meier estimators, the log-rank test and uni and multivariable Cox models. Cutoffs to dichotomize patients for Kaplan-Meier curves and log-rank tests were empirically chosen at the respective median. The median follow-up was 8.8 years. Results: The adjusted preoperative COP, MPV and MPV/COP ratio were not associated with disease outcome. A low postoperative COP and a high MPV/COP ratio on the first postoperative day were independently associated with worse OS and DFS. In comparison to the preoperative measurements, patients whose COP increased by day 1 post-op showed a better OS (hazard ratio (HR) per 50 G/L increase: 0.73, 95% confidence interval (CI): 0.58-0.93, p = 0.013) and DFS (HR per 50 G/L increase: 0.74, 95% CI: 0.58-0.94, p = 0.018) in multivariable analysis. Conclusions: Our results suggest that a low postoperative COP and a high MPV/COP ratio represent a negative prognostic factor for OS and DFS. Notably, patients with an increase in COP by day 1 post-op when compared to their preoperative value showed a significantly better OS and DFS.
head and neck squamous cell carcinoma, disease-free survival, overall survival, blood platelets, mean platelet volume, recurrence risk, biomarker
Analysis of Perioperative Platelet Indices and Their Prognostic Value in Head and Neck Cancer Patients Treated with Surgery and Postoperative Radiotherapy: A Retrospective Cohort Study
Bernhard J. Jank,1 Markus Haas,1 Daniela Dunkler,2 Nicholas J. Campion,1 Faris F. Brkic,1 Gregor Heiduschka,1 and Lorenz Kadletz1,*
Value of Information (VOI) analysis examines whether to acquire information before making a decision. We introduced VOI to the HIV audience, using the example of generic antiretroviral therapy (ART) in the US.
Methods and Findings
We used a mathematical model and probabilistic sensitivity analysis to generate probability distributions of survival (in quality-adjusted life years, QALYs) and cost for three potential first-line ART regimens: 3-pill generic, 2-pill generic, and 1-pill branded. These served as input for a comparison of two hypothetical two-arm trials: 3-pill generic vs. 1-pill branded; and 2-pill generic vs.1-pill branded. We modeled pre-trial uncertainty by defining probability distributions around key inputs, including 24-week HIV-RNA suppression and subsequent ART failure. We assumed that, without a trial, patients received the 1-pill branded strategy. Post-trial, we assumed that patients received the most cost-effective strategy. For both trials, we quantified the probability of changing to a generic-based regimen upon trial completion and the expected VOI in terms of improved health outcomes and costs.
Assuming a willingness to pay threshold of $100,000/QALY, the 3-pill trial led to more treatment changes (84%) than the 2-pill trial (78%). Estimated VOI was $48,000 (3-pill trial) and $35,700 (2-pill trial) per future patient initiating ART.
A 3-pill trial of generic ART is more likely to lead to post-trial treatment changes and to provide more value than a 2-pill trial if policy decisions are based on cost-effectiveness. Value of Information analysis can identify trials likely to confer the greatest impact and value for HIV care.
value of information, HIV, generic drugs, cost-effectiveness analysis, decision modeling
Prioritizing HIV Comparative Effectiveness Trials based on Value of Information: Generic vs. Brand-Name ART in the US
Pamela P. Pei, PhD,1 Milton C. Weinstein, PhD,2,3 X. Cynthia Li, SB,1 Michael D. Hughes, PhD,2 A. David Paltiel, MBA, PhD,4 Taige Hou, SB,1 Robert A. Parker, ScD,1,3,5 Melanie R. Gaynes, BA,1 Paul E. Sax, MD,3,6 Kenneth A. Freedberg, MD, MSc,1,2,3 Bruce R. Schackman, PhD,7 and Rochelle P. Walensky, MD, MPH1,3,6,8
2016 Jan 20.