Citations

ABSTRACT The PLEX-ID system is a novel technology that couples PCR amplification and electrospray ionization-mass spectrometry to identify pathogens directly in clinical specimens. The analytical performance of the PLEX-ID Broad Fungal assay was compared with that of traditional culture identification by using 91 characterized fungal culture isolates (64 manufacturer-claimed and 27 nonclaimed organisms) and directly by using 395 respiratory specimens. Discordant results were resolved by D2 large-subunit ribosomal DNA fungal sequencing. Environmental studies were performed to monitor for potential contamination. The PLEX-ID Broad Fungal assay correctly identified 95.6% (87/91) and 81.3% (74/91) of the culture isolates to the genus and species levels, respectively. Of the manufacturer-claimed organisms, 100% (64/64) and 92.2% (59/64) were correctly identified to the genus and species levels, respectively. Direct analysis of respiratory specimens resulted in 67.6% (267/395) and 66.6% (263/395) agreement with culture results to the genus and species levels, respectively, with 16.2% (64/395) of the results discordant with culture and 16.2% (64/395) not detected by the system. The majority (>95%) of the isolates not detected directly by the PLEX-ID system ultimately grew in low quantities in culture (≤20 colonies). In 20.3% (35/172) of the respiratory specimens where no growth was observed in culture, the PLEX-ID system identified a fungus, suggesting a potential increase in sensitivity over culture in some instances. The PLEX-ID system provides a rapid method for the detection of a broad array of fungi directly in respiratory specimens and has the potential of impacting turnaround times and patient care by reducing the need to wait for the growth of an organism in culture.

Abstract Purpose: This phase I study was conducted to identify the maximum-tolerated dose (MTD) of alvocidib when combined with vorinostat in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Secondary objectives included investigating the pharmacokinetic and pharmacodynamic effects of the combination. Experimental Design: Patients received vorinostat (200 mg orally, three times a day, for 14 days) on a 21-day cycle, combined with 2 different alvocidib administration schedules: a 1-hour intravenous infusion, daily × 5; or a 30-minute loading infusion followed by a 4-hour maintenance infusion, weekly × 2. The alvocidib dose was escalated using a standard 3+3 design. Results: Twenty-eight patients were enrolled and treated. The alvocidib MTD was 20 mg/m2 (30-minute loading infusion) followed by 20 mg/m2 (4-hour maintenance infusion) on days one and eight, in combination with vorinostat. The most frequently encountered toxicities were cytopenias, fatigue, hyperglycemia, hypokalemia, hypophosphatemia, and QT prolongation. Dose-limiting toxicities (DLT) were cardiac arrhythmia-atrial fibrillation and QT prolongation. No objective responses were achieved although 13 of 26 evaluable patients exhibited stable disease. Alvocidib seemed to alter vorinostat pharmacokinetics, whereas alvocidib pharmacokinetics were unaffected by vorinostat. Ex vivo exposure of leukemia cells to plasma obtained from patients after alvocidib treatment blocked vorinostat-mediated p21CIP1 induction and downregulated Mcl-1 and p-RNA Pol II for some specimens, although parallel in vivo bone marrow responses were infrequent. Conclusions: Alvocidib combined with vorinostat is well tolerated. Although disease stabilization occurred in some heavily pretreated patients, objective responses were not obtained with these schedules. Clin Cancer Res; 19(7); 1873–83. ©2013 AACR.

A 66-year-old male patient presented with nausea, abdominal pain, occasional rectal bleeding, progressive dysgeusia, onicodystrophy, and alopecia. Endoscopic exam and biopsies revealed severe atrophy and diffuse marked edema of mucosa of stomach and duodenum. No evidence of polyps was found in any portion of the gastrointestinal tract. The diagnosis of Cronkhite–Canada syndrome (CCS) was rendered. The patient symptoms resolved completely after initiation of steroid treatment. This additional case of CCS illustrates how the diagnosis of CCS does not require the presence of polyps but is defined by the appreciation of the diffuse marked edema and atrophy of the gastrointestinal mucosa.

ObjectiveFree fatty acids (FFAs) are increased in visceral fat and contribute to insulin resistance through multiple mechanisms, including c‐Jun N‐terminal kinase (JNK) activation and expression of TNFα. Given that insulin‐like growth factor‐1 (IGF‐1)‐mediated proliferation is impaired in omental compared to subcutaneous (SC) preadipocytes, we investigated IGF‐I anti‐inflammatory action in preadipocytes from SC and omental adipose tissue.Design and MethodsPreadipocytes isolated from abdominal SC and omental fat of obese subjects were studied in primary culture. Cells were exposed to FFAs with or without IGF‐I pretreatment followed by analysis of cytokine expression and JNK phosphorylation. Lentivirus infection was used to express a constitutively active AKT (myr‐AKT) in omental preadipocytes.ResultsFFAs increased the expression of tumor necrosis factor (TNF)α, interleukin (IL)‐6, and monocyte chemotactic protein (MCP)‐1 in SC and omental preadipocytes. IGF‐I pretreatment reduced FFA‐induced JNK1 phosphorylation and TNFα expression in SC but not omental preadipocytes. Treatment with the JNK1/2 inhibitor SP600125 reduced FFA‐induced expression of TNFα. FFAs and MALP‐2, a specific TLR2/6 ligand, but not specific ligands for TLR4 and TLR1/2, increased JNK1 phosphorylation. IGF‐I completely inhibited MALP‐2‐stimulated phosphorylation of JNK1. Expression of myr‐AKT in omental preadipocytes inhibited FFA‐stimulated JNK1 phosphorylation.ConclusionsIGF‐I attenuated FFA‐induced JNK1 phosphorylation and TNFα expression through activation of AKT in human subcutaneous but not omental preadipocytes.