Erlotinib (Tarceva) targets the epidermal growth factor receptor (EGFR), which is commonly overexpressed in human cancers, including lung cancer. We show that erlotinib can be labeled with [¹¹C] by reacting the normethyl precursor with [¹¹C]-methyl iodide. By using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, two lung cancer cell lines (A549 and NCI358) were shown to be less sensitive to erlotinib compared with the lung cancer cell line HCC827. This correlated with higher expression and activity of the EGFR in HCC827 cells as compared with the less sensitive cell lines. Micro–positron emission tomography (PET) and biodistribution of erlotinib was performed with [¹¹C]-erlotinib in nude mice bearing xenografts of A549, NCI358, and HCC827 cells. Dynamic micro-PET showed that HCC827 tumors had the highest [¹¹C]-erlotinib uptake and retained the activity significantly longer as compared with A549 and NCI358 tumors. Biodistribution of [¹¹C]-erlotinib in the xenograft models of lung cancer showed the highest accumulation in the liver. In mice carrying the sensitive cancer cells, the accumulation of [¹¹C]-erlotinib was higher in tumors than in the other organs. In contrast, the drug accumulated to a comparable extent in tumors from the less sensitive cancer cells and the other organs. Uptake of [¹¹C]-erlotinib in the tumors was 1.6%, 0.7%, and 3.7% (percentage of injected dose/g), in A549, NCI358, and HCC827 cells, respectively. We show for the first time that [¹¹C]-erlotinib identifies erlotinib-sensitive tumors. These results pave the road for studies examining the benefit of [¹¹C]-erlotinib PET in patients with lung tumors or other tumors overexpressing EGFR. [Cancer Res 2009;69(3):873–8]

Recent reports suggest that immigrants from Middle Eastern countries are a high-risk group for type 2 diabetes (T2D) compared with Swedes, and that the pathogenesis of T2D may be ethnicity-specific. Deregulation of microRNA (miRNA) expression has been demonstrated to be associated with T2D but ethnic differences in miRNA have not been investigated. The aim of this study was to explore the ethnic specific expression (Swedish and Iraqi) of a panel of 14 previously identified miRNAs in patients without T2D (including those with prediabetes) and T2D. A total of 152 individuals were included in the study (84 Iraqis and 68 Swedes). Nineteen Iraqis and 14 Swedes were diagnosed with T2D. Expression of the 14 selected miRNAs (miR-15a, miR-20, miR-21, miR-24, miR-29b, miR-126, miR-144, miR-150, miR-197, miR-223, miR-191, miR-320a, miR-486-5p, and miR-28-3p) in plasma samples was measured by real-time PCR. In the whole study population, the expression of miR-24 and miR-29b was significantly different between T2D patients and controls after adjustment for age, sex, waist circumference, family history of T2D, and a sedentary lifestyle. Interestingly, when stratifying the study population according to country of birth, we found that higher expression of miR-144 was significantly associated with T2D in Swedes (OR = 2.43, p = 0.035), but not in Iraqis (OR = 0.54, p = 0.169). The interaction test was significant (p = 0.017). This study suggests that the association between plasma miR-144 expression and T2D differs between Swedes and Iraqis.

Depressive/anxiety disorders are the most common types of mental illnesses in the world. The present study was the first to explore the association between plasma microRNAs (miRNAs) and depression/anxiety in primary care patients. In total, 169 patients (aged 20–64 years) from 16 primary health centers were enrolled in the present study. The healthy controls were consisted of 52 individuals. We first performed miRNA screening of plasma samples from 11 patients using a Serum/Plasma Focus microRNA Panel comprising 179 miRNA primer sets. Six miRNAs were differentially expressed and were then validated by quantitative real-time (qRT)-PCR in the entire study cohort. The mean plasma miR-144-5p level in the depression/anxiety patients increased significantly compared to baseline (p < 0.0001) after the 8-week follow-up. No significant associations were found between the differentially expressed miRNAs and a change in the Montgomery-Åsberg Depression Rating Scale (MADRS-S) score after the follow-up. In linear regression analysis, the plasma miR-144-5p expression level was inversely related to the depression score (MADRS-S) (β = −0.02, p < 0.01), after adjustment for sex and age, at baseline. In addition, plasma miR-144-5p levels at baseline in the depression/anxiety patients were significantly lower compared with the healthy controls (p < 0.001). Our findings show that plasma miR-144-5p levels are associated with depressive symptoms. Although confirmatory analyses are required, plasma miRNA-144-5p is a potential peripheral biomarker for pathologic processes related to depression.

The epidermal growth factor system has been associated to prognosis in patients with bladder cancer based mainly on the expression of the epidermal growth factor (EGF) receptor 1 (EGFR) and HER2 and their activating ligands. Since limited information exists concerning the expression of other parts of the EGF system, we examined the expression of the receptors HER3 and HER4 and their activating ligands, the heregulins (HRGs), in bladder cancer patients. Biopsies from bladder cancer tumours were obtained from 88 patients followed for a median of 23 months (range, 1–97 months). The mRNA content of four ligands and their isoforms (HRG1α, HRG1β, HRG2α, HRG2β, HRG3 and HRG4) and two receptors (HER3 and HER4) was quantified by real-time PCR. A significantly lower mRNA expression level of HER3 (P=0.0003), HRG2α (P=0.0159), HRG2β (P=0.0007) and HRG4 (P<0.0001) was observed in muscle-invasive (T2–T4) tumours as compared to superficial (Ta) tumours. The expression of HER3 mRNA correlated strongly to overall survival (P=0.0042); increased expression of HER4 (P=0.0261) and HRG4 (P=0.0245) was also associated with better prognosis. Interestingly, patients with coexpression of HER3 (P=0.0034) or HER4 (P=0.0080) together with their stimulating ligand HRG4 showed even better survival than for HER3 or HER4 alone. Our results together with previous data suggest a dual face for the EGF system. While it is well established that an increased signalling through HER1 and HER2 is related to a poor prognosis, our data suggest that signalling through HER3 and HER4 is related to a favourable outcome in bladder cancer patients.