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Pumpkin Center, NC, United States

Nannini E.C.,National University of Rosario | Corey G.R.,Duke Clinical Research Institute | Corey G.R.,DukeUniversity Medical Center | Stryjewski M.E.,Duke Clinical Research Institute
Expert Review of Anti-Infective Therapy | Year: 2012

Treatment options for hospital-acquired pneumonia caused by Gram-positive organisms are far from ideal. The increase in vancomycin MICs among methicillin-resistant Staphylococcus aureus (MRSA) isolates, and the slow bactericidal action and poor lung penetration of vancomycin have driven the search for an alternative agent. Telavancin, a once-daily lipoglycopeptide, displays strong bactericidal activity against S. aureus. Two large Phase III randomized trials have recently compared intravenous telavancin (10mg/kg every 24h) with vancomycin (1g intravenously every 12h) for 7-21 days for the treatment of hospital-acquired pneumonia caused by Gram positives. No significant differences were observed in the cure rates in the all-treated (n = 1503), the clinically evaluable (n = 654) and the microbiologically evaluable (n =480) populations. Telavancin performed better than vancomycin in patients with monomicrobial S. aureus pneumonia (84.2 vs 74.3%; 95% CI: 0.7-19.1), with MRSA (81.8 vs 74.1%; 95% CI: -3.5 to 19.3), and with strains having vancomycin MICs ≥1g/ml (87.1 vs 74.3; 95% CI: 0.5-23). The rate of adverse events, including serious adverse events, was similar in both groups, with a slightly higher rate of serum creatinine increase in the telavancin-treated group. Based on these results, telavancin (already approved for this indication by the EMA) could certainly be added to the current treatment options, particularly in patients with MRSA pneumonia. © 2012 2012 Expert Reviews Ltd.


Hornik C.P.,DukeUniversity Medical Center | Hartman M.E.,DukeUniversity Medical Center | Lodge A.J.,Duke University | Cheifetz I.M.,DukeUniversity Medical Center | Turner D.A.,DukeUniversity Medical Center
Respiratory Care | Year: 2011

We report the first successful use of venovenous extracorporeal membrane oxygenation (ECMO) for refractory respiratory failure in an infant with DiGeorge anomaly, following thymus transplantation. A 23-month-old female with complete immune-incompetent DiGeorge anomaly 65 days after allogenic thymus transplantation was treated in our pediatric intensive care unit for acute respiratory failure secondary to bacterial sepsis. She subsequently developed acute hypercarbic respiratory failure unresponsive to conventional medical therapy. She was successfully managed with venovenous ECMO for 4 days, with complete resolution of her respiratory symptoms. This case demonstrates the complex decision making process regarding initiation of ECMO in patients with severe immunodeficiency. © 2011 Daedalus Enterprises.


Laurent G.,Harvard University | German N.J.,Harvard University | Saha A.K.,Boston University | de Boer V.C.J.,Harvard University | And 15 more authors.
Molecular Cell | Year: 2013

Lipid metabolism is tightly controlled by the nutritional state of the organism. Nutrient-rich conditions increase lipogenesis, whereas nutrient deprivation promotes fat oxidation. In this study, we identify the mitochondrial sirtuin, SIRT4, as a regulator of lipid homeostasis. SIRT4 is active in nutrient-replete conditions to repress fatty acid oxidation while promoting lipid anabolism. SIRT4 deacetylates andinhibits malonyl CoA decarboxylase (MCD), an enzyme that produces acetyl CoA from malonyl CoA. Malonyl CoA provides the carbon skeleton for lipogenesis and also inhibits fat oxidation. Mice lacking SIRT4 display elevated MCD activity and decreased malonyl CoA in skeletal muscle and white adipose tissue. Consequently, SIRT4 KO mice display deregulated lipid metabolism, leading to increased exercise tolerance and protection against diet-induced obesity. In sum, this work elucidates SIRT4 as an important regulator of lipid homeostasis, identifies MCD as a SIRT4 target, and deepens our understanding of the malonyl CoA regulatory axis. © 2013 Elsevier Inc.


Pham C.D.,University of Florida | Pham C.D.,DukeUniversity Medical Center | Flores C.,University of Florida | Yang C.,University of Florida | And 12 more authors.
Clinical Cancer Research | Year: 2016

Purpose: Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma, the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and group 3 medulloblastoma for preclinical evaluation in immunocompetent C57BL/6 mice. Experimental Design and Results: Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid-derived suppressor cells, and tumor-associated macrophages in murine SHH model tumors compared with group 3 tumors. However, murine group 3 tumors had higher percentages of CD8+ PD-1+ T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial group 3 tumors compared with SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1+ peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3+ T cells within the tumor microenvironment. Conclusions: This is the first immunologic characterization of preclinical models of molecular subtypes of medulloblastoma and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment. © 2015 American Association for Cancer Research.

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