EmrD is a multidrug resistance (MDR) transporter from Escherichia coli, which is involved in the efflux of amphipathic compounds from the cytoplasm, and the first MDR member of the major facilitator superfamily to be crystallized. Molecular dynamics simulation of EmrD in a phospholipid bilayer was used to characterize the conformational dynamics of the protein. Motions that support a previously proposed lateral diffusion pathway for substrate from the cytoplasmic membrane leaflet into the EmrD central cavity were observed. In addition, the translocation pathway of meta‐chloro carbonylcyanide phenylhydrazone (CCCP) was probed using both standard and steered molecular dynamics simulation. In particular, interactions of a few specific residues with CCCP have been identified. Finally, a large motion of two residues, Val 45 and Leu 233, was observed with the passage of CCCP into the periplasmic space, placing a lower bound on the extent of opening required at this end of the protein for substrate transport. Overall, our simulations probe details of the transport pathway, motions of EmrD at an atomic level of detail, and offer new insights into the functioning of MDR transporters. Proteins 2012; © 2012 Wiley Periodicals, Inc.

BACKGROUND:Postchemoradiation percentage decrease in standardized uptake value (SUV) of positron emission tomography (PET) from baseline correlates with overall survival (OS) and pathologic response. Analyses of dichotomized data are commonly reported. The authors analyzed percentage SUV decrease as both dichotomized and continuous variables.METHODS:The authors assessed 151 consecutive patients with gastroesophageal adenocarcinoma who had chemoradiation and surgery. Baseline and postchemoradiation PET/computed tomography imaging was performed. The log‐rank test and Cox proportional hazards models were used to associate percentage SUV changes and OS, and logistic regression models were used to detect the association between percentage SUV changes and pathologic response.RESULTS:A >52% SUV decrease (dichotomized analysis) was associated with a longer OS (log‐rank test, P = .023). The univariate Cox proportional hazards model indicated that greater percentage SUV decrease (as a continuous variable) was associated with a lower risk of death (hazard ratio [HR], 0.99; P = .01). Pathologic response (≤50% residual cancer) was associated with longer OS (P = .003). Patients with chemoradiation resistance (>50% residual cancer) tended to have a higher risk of death than those with chemoradiation sensitivity (0‐50% residual cancer; HR, 2.12; P = .099). In the multivariate model, the percentage SUV decrease (as a continuous variable) was the only prognosticator of OS (P = .01). The percentage SUV decrease was nonsignificantly associated with pathologic complete response (univariate odds ratio [OR], 1.01; P = .06 and multivariate OR, 1.03; P = .07).CONCLUSIONS:The greater the decline in SUV after chemoradiation, the longer is the OS of gastroesophageal adenocarcinoma patients. The percentage SUV decrease as a continuous variable is a better prognosticator of OS than its dichotomized assessments. Cancer 2009. © 2009 American Cancer Society.

This chapter reviews data on the treatment of infections caused by drug-resistant Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA). This review covers findings reported in the English language medical literature up to January of 2013. Despite the emergence of resistant and multidrug-resistant S. aureus, we have seven effective drugs in clinical use for which little resistance has been observed: vancomycin, quinupristin-dalfopristin, linezolid, tigecycline, telavancin, ceftaroline, and daptomycin. However, vancomycin is less effective for infections with MRSA isolates that have a higher MIC within the susceptible range. Linezolid is probably the drug of choice for the treatment of complicated MRSA skin and soft tissue infections (SSTIs); whether it is drug of choice in pneumonia remains debatable. Daptomycin has shown to be non-inferior to either vancomycin or β-lactams in the treatment of staphylococcal SSTIs, bacteremia, and right-sided endocarditis. Tigecycline was also non-inferior to comparator drugs in the treatment of SSTIs, but there is controversy about whether it is less effective than other therapeutic options in the treatment of more serious infections. Telavancin has been shown to be non-inferior to vancomycin in the treatment of SSTIs and pneumonia, but has greater nephrotoxicity. Ceftaroline is a broad-spectrum cephalosporin with activity against MRSA; it is non-inferior to vancomycin in the treatment of SSTIs. Clindamycin, trimethoprim-sulfamethoxazole, doxycycline, rifampin, moxifloxacin, and minocycline are oral anti-staphylococcal agents that may have utility in the treatment of SSTIs and osteomyelitis, but the clinical data for their efficacy is limited. There are also several drugs with broad-spectrum activity against Gm-positive organisms that have reached the phase II and III stages of clinical testing that will hopefully be approved for clinical use in the upcoming years: oritavancin, dalbavancin, omadacycline, tedizolid, delafloxacin, and JNJ-Q2. Thus, there are currently many effective drugs to treat resistant S. aureus infections and many promising agents in the pipeline. Nevertheless, S. aureus remains a formidable adversary, and despite our deep bullpen of potential therapies, there are still frequent treatment failures and unfortunate clinical outcomes. The following discussion summarizes the clinical challenges presented by MRSA, the clinical experience with our current anti-MRSA antibiotics, and the gaps in our knowledge on how to use these agents to most effectively combat MRSA infections.

BACKGROUND.Patients with localized esophageal cancer (LEC) have diverse outcomes (post‒therapy pathologic response, disease‒free survival [DFS], and overall survival [OS]) after preoperative chemoradiation (P‒CTRT), dictated also by inherent molecular heterogeneity. Whether the type of therapy influences the outcomes remains largely unanswered. It is hypothesized that induction chemotherapy (IC) or the type of cytotoxics used would not influence patient outcomes.METHODS.In this retrospective analysis, consecutive patients with LEC who had P‒CTRT were analyzed. Data were collected regarding age, sex, baseline clinical stage, location, type of cytotoxics, post‒therapy pathology, DFS, and OS. IC and the type of cytotoxics used were found to be correlated with DFS, OS, and post‒therapy pathologic response.RESULTS.A total of 180 patients with LEC (119 had IC before P‒CTRT, all had received 5‒fluorouracil, 87 had received a taxane, and 57 had received a platinol) were analyzed. The median survival (MS) of all patients was 57.7 months and the 3‒year and 5‒year OS rates were 65.4% and 46.5%, respectively. The type of therapy appeared to have no influence on the outcome: IC versus no IC (P = .58) or platinol versus taxane versus platinol plus taxane (P = .63). Similarly, the type of pathologic response was not found to be influenced by IC (P = .18) or the type of cytotoxics used (P = .42). The data were similar for DFS.CONCLUSIONS.IC or the type of cytotoxics used with radiation for patients with LEC does not appear to influence OS, DFS, or the type of pathologic response after therapy, suggesting that a plateau has been reached. It remains to be seen whether the use of biochemoradiotherapy can provide an advantage in outcome. Cancer 2008. © 2008 American Cancer Society.

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