Philadelphia, PA, United States
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Muller A.J.,Lankenau Institute for Medical Research | Muller A.J.,Thomas Jefferson University | DuHadaway J.B.,Lankenau Institute for Medical Research | Chang M.Y.,Lankenau Institute for Medical Research | And 13 more authors.
Cancer Immunology, Immunotherapy | Year: 2010

Indoleamine 2, 3-dioxygenase (IDO) is generally considered to be immunosuppressive but recent findings suggest this characterization oversimplifies its role in disease pathogenesis. Recently, we showed that IDO is essential for tumor outgrowth in the classical two-stage model of inflammatory skin carcinogenesis. Here, we report that IDO loss did not exacerbate classical inflammatory responses. Rather, IDO induction could be elicited by environmental signals and tumor promoters as an integral component of the inlammatory tissue microenvironment even in the absence of cancer. IDO loss had limited impact on tumor outgrowth in carcinogenesis models that lacked an explicit inflammatory tumor promoter. In the context of inflammatory carcinogenesis where IDO was critical to tumor development, the most important source of IDO was radiation-resistant non-hematopoietic cells, consistent with evidence that loss of the IDO regulatory tumor suppressor gene Bin1 in transformed skin cells facilitates IDO-mediated immune escape by a cell autonomous mechanism. Taken together, our results identify IDO as an integral component of 'cancer-associated' inflammation that tilts the immune system toward tumor support. More generally, they promote the concept that mediators of immune escape and cancer-associated inlammation may be genetically synonymous. © Springer-Verlag 2010.

Sirajuddin P.,Georgetown University | Das S.,Georgetown University | Ringer L.,Georgetown University | Rodriguez O.C.,Georgetown University | And 17 more authors.
Cell Cycle | Year: 2012

The development of new small molecule-based therapeutic drugs requires accurate quantifcation of drug bioavailability, biological activity and treatment efcacy. Rapidly measuring these endpoints is often hampered by the lack of efcient assay platforms with high sensitivity and specifcity. Using an in vivo model system, we report a simple and sensitive liquid chromatography-tandem mass spectrometry assay to quantify the bioavailability of a recently developed novel cyclin-dependent kinase inhibitor VMY-1-103, a purvalanol B-based analog whose biological activity is enhanced via dansylation. We developed a rapid organic phase extraction technique and validated wide and functional VMY-1-103 distribution in various mouse tissues, consistent with its enhanced potency previously observed in a variety of human cancer cell lines. More importantly, in vivo MRI and single voxel proton MR-Spectroscopy further established that VMY-1-103 inhibited disease progression and afected key metabolites in a mouse model of hedgehog-driven medulloblastoma. © 2012 Landes Bioscience.

Mraovic B.,Thomas Jeferson University | Schwenk E.S.,Thomas Jeferson University | Epstein R.H.,Thomas Jeferson University
Journal of Diabetes Science and Technology | Year: 2012

Background: Concerns have been raised about the use of point-of-care (POC) glucose meters in the hospital setting. Accuracy has been questioned especially in critically ill patients. Although commonly used in intensive care units and operating rooms, POC meters were not approved by the Food and Drug Administration for such use. Data on POC glucose meter performance during anesthesia are lacking. We evaluated accuracy of a POC meter in the intraoperative setting. Methods: We retrospectively reviewed 4,333 intraoperative records in which at least one intraoperative glucose was measured using electronic medical records at a large academic hospital. We evaluated the accuracy of a POC glucose meter (ACCU-CHEK® Inform, Roche Pharmaceuticals) based on the 176 simultaneous central laboratory (CL) blood glucose (BG) measurements that were found (i.e., documented collection times within 5 minutes). Point-of-care and central lab BG diferences were analyzed by Bland-Altman and revised error grid analysis (rEGA). Results: Mean POC BG was 163.4 ± 64.7 mg/dl [minimum (min) 48 mg/dl, maximum (max) 537 mg/dl] and mean CL BG was 162.6 ± 65.1 mg/dl (min 44 mg/dl, max 502 mg/dl). Mean absolute diference between POC and CL BG was 24.3 mg/dl. Mean absolute relative diference was 16.5% with standard deviation 26.4%. Point-of-care measurements showed a bias of 0.8 relative to the corresponding CL value, with a precision of 39.0 mg/dl. Forty (23%) POC BG values fell outside the Clinical and Laboratory Standards Institute guideline and 3.4% POC measurements fell in zones C and D of the rEGA plot. Conclusions: The tested POC glucose meter performed poorly compared to a CL analyzer intraoperatively. Perioperative clinicians should be aware of limitations of specific POC glucose meters, and routine use of POC glucose meters as sole measurement devices in the intraoperative period should be carefully considered. © Diabetes Technology Society.

Patients managed in the intensive care units (ICUs) and general wards of the hospital experience a high incidence of hyperglycemia, hypoglycemia, and glycemic variability, despite significant hospital resources devoted to glucose control. Optimized glucose meters and monitoring systems are required to improve the safety and eficacy of insulin delivery and glucose control in the hospital. Safe insulin dosing requires timely and accurate glucose measurements, especially during dynamic changes in nutrition, insulin sensitivity, and physiological stress. In the current issue of Journal of Diabetes Science and Technology, Mitsios and coauthors describe the analytical accuracy of the new Accu-Check® Inform II blood glucose (BG) monitoring system commercialized by F. Hofmann-La Roche Ltd. The point-of-care glucose meter achieved the desired degree of accuracy and precision, as defined by Clinical and Laboratory Standards Institute POCT12-A3 guidelines when evaluated using venous blood from 600 critically ill patients from multiple ICUs at two medical centers. Venous whole blood samples were used to obtain glucose meter results in duplicate. The remaining blood sample was centrifuged to obtain plasma for central hospital laboratory testing using the hexokinase method within 5 min of meter testing. A total of 98.8% of the 1200 Accu-Check Inform II meter's glucose values were within ±12.5% (±12 mg/dl) of the mean laboratory glucose value, and 99.8% were within ±20% (±20 mg/dl), thus meeting the Clinical and Laboratory Standards Institute criteria. Future studies are required to evaluate the clinical performance of the new BG monitoring system in the intended-use patient populations and critical care environments, using arterial, peripheral venous, central venous, and capillary blood samples. © Diabetes Technology Society.

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