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1.  Synergistic Effects of Targeted PI3K Signaling Inhibition and Chemotherapy in Liposarcoma 
PLoS ONE  2014;9(4):e93996.
While liposarcoma is the second most common soft tissue malignant tumor, the molecular pathogenesis in this malignancy is poorly understood. Our goal was therefore to expand the understanding of molecular mechanisms that drive liposarcoma and identify therapeutically-susceptible genetic alterations. We studied a cohort of high-grade liposarcomas and benign lipomas across multiple disease sites, as well as two liposarcoma cell lines, using multiplexed mutational analysis. Nucleic acids extracted from diagnostic patient tissue were simultaneously interrogated for 150 common mutations across 15 essential cancer genes using a clinically-validated platform for cancer genotyping. Western blot analysis was implemented to detect activation of downstream pathways. Liposarcoma cell lines were used to determine the effects of PI3K targeted drug treatment with or without chemotherapy. We identified mutations in the PIK3CA gene in 4 of 18 human liposarcoma patients (22%). No PIK3CA mutations were identified in benign lipomas. Western blot analysis confirmed downstream activation of AKT in both PIK3CA mutant and non-mutant liposarcoma samples. PI-103, a dual PI3K/mTOR inhibitor, effectively inhibited the activation of the PI3K/AKT in liposarcoma cell lines and induced apoptosis. Importantly, combination with PI-103 treatment strongly synergized the growth-inhibitory effects of the chemotherapy drugs doxorubicin and cisplatin in liposarcoma cells. Taken together, these findings suggest that activation of the PI3K/AKT pathway is an important cancer mechanism in liposarcoma. Targeting the PI3K/AKT/pathway with small molecule inhibitors in combination with chemotherapy could be exploited as a novel strategy in the treatment of liposarcoma.
doi:10.1371/journal.pone.0093996
PMCID: PMC3973642  PMID: 24695632
2.  A Randomized Trial of Rectal Indomethacin to Prevent Post-ERCP Pancreatitis 
The New England Journal of Medicine  2012;366(15):1414-1422.
Background
Preliminary research suggests that rectally administered nonsteroidal antiinflammatory drugs may reduce the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP).
Methods
In this multicenter, randomized, placebo-controlled, double-blind clinical trial, we assigned patients at elevated risk for post-ERCP pancreatitis to receive a single dose of rectal indomethacin or placebo immediately after ERCP. Patients were determined to be at high risk on the basis of validated patient- and procedure-related risk factors. The primary outcome was post-ERCP pancreatitis, which was defined as new upper abdominal pain, an elevation in pancreatic enzymes to at least three times the upper limit of the normal range 24 hours after the procedure, and hospitalization for at least 2 nights.
Results
A total of 602 patients were enrolled and completed follow-up. The majority of patients (82%) had a clinical suspicion of sphincter of Oddi dysfunction. Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in the indomethacin group and in 52 of 307 patients (16.9%) in the placebo group (P = 0.005). Moderate-to-severe pancreatitis developed in 13 patients (4.4%) in the indomethacin group and in 27 patients (8.8%) in the placebo group (P = 0.03).
Conclusions
Among patients at high risk for post-ERCP pancreatitis, rectal indomethacin significantly reduced the incidence of the condition. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00820612.)
doi:10.1056/NEJMoa1111103
PMCID: PMC3339271  PMID: 22494121
3.  Bedside Endoscopic Ultrasound in Critically Ill patients 
Background. The aim of this study was to evaluate the role and impact of EUS in the management of critically ill patients. Methods. We retrospectively identified all patients at our institution over a 68-month period in whom bedside inpatient EUS was performed. EUS was considered to have a significant impact if a new diagnosis was established and/or the findings altered subsequent clinical management. Results. Fifteen patients (9 male; mean age 58 ± 15 years) underwent bedside EUS without complications. EUS-FNA (median 4 passes; range 2–7) performed in 12 (80%) demonstrated a malignant mediastinal mass/lymph node (5), pancreatic abscess (1), excluded a pelvic abscess (1), established enlarged gastric folds as benign (1) and excluded malignancy in enlarged mediastinal (1) and porta hepatis adenopathy (1). In two patients, EUS-FNA failed to diagnose mediastinal histoplasmosis (1) and a hemorrhagic pancreatic pseudocyst (1). In three diagnostic exams without FNA, EUS correctly excluded choledocholithaisis (n = 1) and cholangiocarcinoma (1), and found gastric varices successfully thrombosed after previous cyanoacrylate injection (1). EUS was considered to have an impact in 13/15 (87%) patients. Conclusions. In this series, bedside EUS in critically ill patients was technically feasible, safe and had a major impact on the majority of patients.
doi:10.1155/2011/529791
PMCID: PMC3123909  PMID: 21747653
4.  Serum Neuregulin-1β as a Biomarker of Cardiovascular Fitness 
PURPOSE
Neuregulins (NRG) are growth factors that bind to receptors of the erbB family, and are known to mediate a number of processes involved in diverse tissues. Neuregulin-1β is expressed in skeletal muscle and is activated by exercise. We hypothesized that NRG-1β might circulate in the bloodstream and increase as a consequence of physical activity. A study was conducted in healthy subjects to determine if NRG-1β is immunodetectable in human serum, and if so whether levels relate acutely or chronically to exercise.
METHODS
Nine healthy men underwent three bouts of exercise of varying degrees of intensity on a bicycle ergometer over a period of three weeks. Cardio-respiratory fitness was determined by measurement of maximal oxygen uptake (VO2max). Serum was sampled prior to and immediately after each session (up to 30 minutes post) and serum NRG-1β was quantified utilizing an indirect sandwich ELISA assay developed in our lab.
RESULTS
Across subjects, mean serum NRG-1β levels ranged from 32 ng/mL to 473 ng/mL. Individual subjects showed relatively stable levels during the study period that did not change acutely after exercise. Serum NRG-1β demonstrated a positive correlation with VO2max (r2=0.49, p =.044).
CONCLUSIONS
These preliminary observations suggest that at least in healthy men, serum NRG-1β is an indicator of cardio-respiratory fitness and does not change acutely with exercise.
doi:10.2174/1875318300902010001
PMCID: PMC2903891  PMID: 20634924
Growth Factor; Exercise; heregulin; cardiopulmonary fitness
5.  Palmitate alters neuregulin signaling and biology in cardiac myocytes 
The saturated fatty acid palmitate alters normal cell function via disruption of cell signaling, and these effects have been implicated in the end-organ damage associated with dyslipidemia. Neuregulin-1β (NRG-1β) is a growth and survival factor in cardiac myocytes. We tested the hypothesis that palmitate alters NRG-1β signaling and biology in isolated neonatal rat cardiac myocytes. Palmitate treatment inhibited NRG-1β activation of the PI3kinase/Akt pathway in myocytes. We found that the pro-apoptotic activity of palmitate was increased by NRG-1β treatment. The effects of palmitate on NRG-1β signaling and survival were reversed by the mono-unsaturated fatty acid oleate. Under control conditions NRG-1β decreases p53 expression in myocytes. In the presence of palmitate, NRG-1β caused an increase in p53 expression, bax multimer formation, concurrent with degradation of mdm2, a negative regulator of p53. Thus in the presence of palmitate NRG-1β activates pro-apoptotic, rather than pro-survival signaling in cardiac myocytes.
doi:10.1016/j.bbrc.2008.11.150
PMCID: PMC2654183  PMID: 19070592
6.  Differentiation of Dextran-Producing Leuconostoc Strains by a Modified Randomly Amplified Polymorphic DNA Protocol 
Seven dextran-producing Leuconostoc strains were differentiated by using a modified randomly amplified polymorphic DNA (RAPD) protocol that incorporated specific primers designed from conserved regions of dextransucrase genes. RAPD profiles showed intraspecies differences among the Leuconostoc mesenteroides strains tested. This modified RAPD protocol will aid in the differentiation of polymer-producing leuconostocs, which are currently distinguished by time-consuming analyses of the dextrans they synthesize.
PMCID: PMC106824  PMID: 9687482

Results 1-6 (6)