Coordinated epidermal growth factor receptor pathway gene overexpression predicts epidermal growth factor receptor inhibitor sensitivity in pancreatic cancer

The epidermal growth factor receptor (EGFR) inhibitor erlotinib is approved for treatment of pancreatic cancer but the overall activity is minimal, and known predictive factors for EGFR inhibitor efficacy are infrequent in this disease. We tested the hypothesis that global activation of the EGFR pathway is predictive of EGFR inhibitor efficacy. Pancreatic cancer tumors directly xenografted at surgery were treated with the EGFR inhibitors erlotinib and cetuximab and analyzed for biological features. Two of 10 tumors were sensitive, and by global gene expression profiling with gene set enrichment analysis, the EGFR pathway was highly expressed in sensitive compared with resistant tumors. The core gene components driving EGFR pathway overexpression were pathway ligands and positive effectors. In a prospective validation, the EGFR pathway-based signature correctly predicted anti-EGFR treatment response in eight additional tumors and was not predictive of response to gemcitabine and CI1040 (a MEK inhibitor). Analysis of EGFR, KRAS, and PIK3CA mutations and gene amplification by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification showed that none of these genetic abnormalities were neither predictive nor responsible for the EGFR pathway activation. Coordinated overexpression of the EGFR pathway predicts susceptibility to EGFR inhibitors in pancreatic cancer. These results suggest a phenomenon of pathway addiction and support the value of unbiased system biology approaches in drug development.     

Neurodevelopmental outcome in high-risk preterm infants treated with inhaled nitric oxide

Inhaled nitric oxide (iNO) is used to treat preterm infants with hypoxaemic respiratory failure. In this study we describe the long-term survival and neurodevelopmental status of high-risk preterm infants enrolled into a randomized controlled trial of iNO therapy. Information regarding long-term outcome was available for all 25 children enrolled in the original trial who survived until discharge from hospital. Formal, blinded, developmental assessment and neurological examinations were performed in 21 out of 22 children still alive at 30 mo of age, corrected for prematurity. No significant differences were found in long-term mortality (12/20 vs 8/22, RR 1.65, 95% CI 0.87-3.3), neurodevelopmental delay (4/7 vs 9/14, RR 0.89, 95% CI 0.37-1.75), severe neurodisability (0/7 vs 5/14, p = 0.12) or cerebral palsy (0/7 vs 2/14, p = 0.53) between iNO-treated and control infants. CONCLUSION: In this study there was no evidence of a significant effect on either survival or long-term neurodevelopmental status in infants treated with iNO.     

Human Adipose-Derived Mesenchymal Stem Cells Promote Liver Regeneration

Background and Aims: Liver regeneration (LR) is of crucial importance to patients with acute liver failure, those undergoing live donor liver transplantations or extended liver resections. Effective treatment strategies aimed at accelerating liver regeneration could offer major benefits in these patients. Due to easy accessibility, human adipose-derived mesenchymal stem cells (HADMSC) are an attractive source for regenerative medicine. Herein, we investigated the effect of HADMSC on LR in a murine model. We hypothesized that HADMSC will promote LR. Methods: Mice were subjected to CCl₄-induced acute liver failure (ALF). Animals in the experimental arm were treated with HADMSC prior to CCl₄-induced ALF. Liver injury was evaluated using serum levels of alanine aminotransferase (ALT), serum interleukin-6 (IL-6), and histopathology. Liver samples were stained for a specific marker of regeneration, proliferating cell nuclear antigen (PCNA). Results: Histology, serum IL-6, and ALT release revealed that HADMSC treatment attenuated liver injury compared with control animals. In addition, animals treated with HADMSC were observed to have improved survival and increased number of PCNA positive cells on histology when compared with controls. Conclusion: HADMSCs represent a potential therapeutic strategy to promote liver regeneration.     

Low tuberculosis notification in mountainous Vietnam is not due to low case detection: a cross-sectional survey

Background  

Studies show that tuberculosis notification declines with increasing altitude. This can be due to declining incidence or declining case detection. In Vietnam notification rates of new smear-positive tuberculosis in the central mountainous provinces (26/100,000 population) are considerably lower than in Vietnam in general (69/100,000 population). In order to clarify whether this is explained by low incidence or low case detection, we aimed to assess the prevalence of new smear-positive tuberculosis among adults with prolonged cough in three mountainous provinces in central Vietnam.     

Assessment of calcification and inflammation with positron emission tomography in aortic stenosis and atherosclerosis

BackgroundCalcification and inflammation are key pathological processes in aortic stenosis and atherosclerosis. Using combined positron emission tomography and computed tomography (PET/CT), we sought to investigate their contribution to disease progression in aortic stenosis and to help identify vulnerable atherosclerotic plaque.MethodsIn the first part of the study patients with calcific aortic valve disease stenosis were prospectively compared with age-matched and sex-matched controls with normal valves. Aortic valve severity was determined at baseline and 1 year by echocardiography and CT calcium scoring. Calcification and inflammation in the valve were assessed by sodium 18-fluoride (NaF) and 18-fluorodeoxyglucose (FDG) uptake with PET. In the second part of the study NaF and FDG activity was assessed in the coronary arteries both in patients with stable coronary disease and in patients after myocardial infarction.Findings101 patients with aortic stenosis were compared with 20 controls. Tracer activity (target to background ratio [TBR]) was higher in patients with aortic stenosis than in controls (mean NaF 2·87 [SD 0·82] vs 1·55 [0·17], FDG 1·58 [0·21] vs 1·30 [0·13]; both p<0·01). NaF uptake displayed a progressive rise with valve severity (r²=0·540) with a more modest increase observed for FDG (r²=0·218). Baseline NaF correlated closely with alkaline phosphatase staining on immunohistochemistry (r²=0·79) and was a better predictor of disease progression at 1 year (r²=0·44, n=20) than was FDG (r²=0·02) or baseline calcium score (r²=0·36, current best predictor). Increased NaF activity was observed in 45 (42%) of 106 patients with stable coronary atherosclerosis and was localised to individual coronary plaques. These patients had higher rates of previous major adverse cardiovascular events (p=0·016) and higher Framingham risk scores (p=0·011) than did patients without increased uptake. In patients after myocardial infarction (n=15) intense NaF activity was observed at the site of the culprit lesion, with increased uptake compared with the maximum uptake elsewhere in the coronary arteries (TBR median 1·56 [IQR 1·49–1·82] vs 1·23 [1·15–1·48], p=0·02).InterpretationIn the valve, NaF holds promise in predicting aortic stenosis progression. In the coronary arteries it identifies culprit plaque post myocardial infarction and stable patients at elevated cardiac risk.FundingBritish Heart Foundation.     

IRL-1620, a tumor selective vasodilator, augments the uptake and efficacy of chemotherapeutic agents in prostate tumor rats

BACKGROUND: IRL-1620, a potent endothelin B receptor agonist, enhanced the efficacy of paclitaxel in a breast tumor model, but its effect in prostate cancer is not known. The present study was conducted to evaluate the effect of IRL-1620 on tumor perfusion, uptake of [(14)C]-doxorubicin in the tumor and efficacy of doxorubicin (DOX), and 5-flurouracil (5-FU) in a rat prostate tumor model. METHODS: JHU-4 (Mat-Lu) cells inoculated prostate tumor model in Copenhagen rats was used for the study. RESULTS: Administration of IRL-1620 (3 nmol/kg, i.v) significantly increased (102.8%) prostate tumor perfusion and tumor uptake of [(14)C]-doxorubicin (115%) compared to vehicle treated rats. Results of the efficacy study demonstrate that IRL-1620 administration 15 min prior to DOX (5 mg/kg) or 5-FU (50 mg/kg) on every third day for a total of four doses significantly reduced tumor volume compared to vehicle treated rats. CONCLUSIONS: IRL-1620 significantly enhanced the uptake and efficacy of anticancer agents in prostate cancer.     

GSK1562590, a slowly dissociating urotensin-II receptor antagonist, exhibits prolonged pharmacodynamic activity ex vivo

BACKGROUND AND PURPOSE

Recently identified antagonists of the urotensin–II (U-II) receptor (UT) are of limited utility for investigating the (patho)physiological role of U-II due to poor potency and limited selectivity and/or intrinsic activity.

EXPERIMENTAL APPROACH

The pharmacological properties of two novel UT antagonists, GSK1440115 and GSK1562590, were compared using multiple bioassays.

KEY RESULTS

GSK1440115 (pK_i= 7.34–8.64 across species) and GSK1562590 (pK_i= 9.14–9.66 across species) are high affinity ligands of mammalian recombinant (mouse, rat, cat, monkey, human) and native (SJRH30 cells) UT. Both compounds exhibited >100-fold selectivity for UT versus 87 distinct mammalian GPCR, enzyme, ion channel and neurotransmitter uptake targets. GSK1440115 showed competitive antagonism at UT in arteries from all species tested (pA₂= 5.59–7.71). In contrast, GSK1562590 was an insurmountable UT antagonist in rat, cat and hUT transgenic mouse arteries (pK_b= 8.93–10.12 across species), but a competitive antagonist in monkey arteries (pK_b= 8.87–8.93). Likewise, GSK1562590 inhibited the hU-II-induced systemic pressor response in anaesthetized cats at a dose 10-fold lower than that of GSK1440115. The antagonistic effects of GSK1440115, but not GSK1562590, could be reversed by washout in rat isolated aorta. In ex vivo studies, GSK1562590 inhibited hU-II-induced contraction of rat aorta for at least 24 h following dosing. Dissociation of GSK1562590 binding was considerably slower at rat than monkey UT.

CONCLUSIONS AND IMPLICATIONS

Whereas both GSK1440115 and GSK1562590 represent high-affinity/selective UT antagonists suitable for assessing the (patho)physiological role of U-II, only GSK1562590 exhibited sustained UT residence time and improved preclinical efficacy in vivo.