Interleukin-17 (IL-17) Expression Is Reduced during Acute Myocardial Infarction: Role on Chemokine Receptor Expression in Monocytes and Their in Vitro Chemotaxis towards Chemokines

The roles of immune cells and their soluble products during myocardial infarction (MI) are not completely understood. Here, we observed that the percentages of IL-17, but not IL-22, producing cells are reduced in mice splenocytes after developing MI. To correlate this finding with the functional activity of IL-17, we sought to determine its effect on monocytes. In particular, we presumed that this cytokine might affect the chemotaxis of monocytes important for cardiac inflammation and remodeling. We observed that IL-17 tends to reduce the expression of two major chemokine receptors involved in monocyte chemotaxis, namely CCR2 and CXCR4. Further analysis showed that monocytes pretreated with IL-17 have reduced in vitro chemotaxis towards the ligand for CCR2, i.e., MCP-1/CCL2, and the ligand for CXCR4, i.e., SDF-1α/CXCL12. Our results support the possibility that IL-17 may be beneficial in MI, and this could be due to its ability to inhibit the migration of monocytes.     

Prognostic value of tissue protein expression levels of MIB‐1 (Ki‐67) in Danish ovarian cancer patients. From the ‘MALOVA’ ovarian cancer study

The primary objective of this study was to assess the expression of MIB‐1 (Ki‐67) in tumour tissues from 808 patients with epithelial ovarian tumours. The second was to evaluate, whether MIB‐1 (Ki‐67) tissue expression levels correlate with clinicopathological parameters and prognosis of the disease. Using tissue arrays (TA), we analysed the MIB‐1 (Ki‐67) expression levels in tissues from 202 women with borderline ovarian tumours (BOT) (177 stage I, 5 stage II, 19 stage III, 1 stage IV) and 606 ovarian cancer (OC) patients (177 stage I, 64 stage II, 311 stage III, 54 stage IV). Using a 10% cut‐off level for MIB‐1 (Ki‐67) overexpression, 12% of the BOTs and 51% of the OCs were positive for MIB‐1 (Ki‐67) expression. The frequency of MIB‐1 (Ki‐67) expression‐positive OC increased with increasing FIGO stage (p = 0.003), increasing histological grade (p ≤ 0.0001), and a significantly different distribution of MIB‐1 (Ki‐67) positive and negative tumours were found in adenocarcinoma NOS, serous adenocarcinomas, mucinous adenocarcinomas, endometrioid adenocarcinomas, non‐epithelial and clear‐cell carcinomas (p = 0.016). Univariate Kaplan–Meier survival analysis performed on all OC cases showed a significant shorter disease specific survival in patients with positive MIB‐1 (Ki‐67) expression in the tumour tissue (p ≤ 0.0001). In a Cox survival analysis including 606 FIGO stages I to IV OC cases, FIGO stage (II vs I: HR = 3.00, 95% CI: 1.81–4.99, III–I: HR = 6.41, 95% CI: 3.90–10.50, IV vs I: HR = 12.69, 95% CI: 7.21–22); age at diagnosis pr.10 years (HR = 1.27, 95% CI: 1.15–1.40), residual tumour after surgery (HR = 1.95, 95% CI: 1.40–2.73) and MIB‐1 (Ki‐67) expression (HR = 1.31, 95% CI: 1.08–1.60) had a significant independent impact on survival. Histological grade (p = 0.14) and histological tumour type (p = 0.35) had no significant independent impact on survival. In conclusion, our results predict that an increased level of MIB‐1 (Ki‐67) expression in tumour tissue, points to a less favourable outcome for OC patients.     

Preoperative CA125 as a prognostic factor in stage I epithelial ovarian cancer

The purpose of the present study was to evaluate preoperative CA125 as a prognostic factor in stage I epithelial ovarian cancer (EOC). Preoperative serum CA125 levels from 118 women with FIGO (International Federation of Gynaecology and Obstetrics) stage I EOC were analysed and the prognostic value was evaluated and compared with other prognostic factors (age, grade, substages, histologic type). By the Kaplan-Meier estimate we demonstrated that patients with stage I EOC and preoperative serum CA125 levels <65 U/mL had a significantly longer survival compared to stage I EOC patients with preoperative serum CA125 > or = 65 U/mL (p=0.01). The results from the present study may be useful for decision making respecting postoperative chemotherapy in stage I EOC patients. Serum CA125 levels might therefore be included as a prognostic factor in future clinical trials of stage I EOC.     

The activating rat Ly49s5 receptor responds to increased levels of MHC class Ib molecules on Listeria monocytogenes-infected enteric epithelial cells

We have investigated whether rat Ly49 receptors can monitor Listeria-infected intestinal epithelial cells through altered expression of MHC class I molecules. The rat colon carcinoma epithelial cell line CC531 infected with Listeria expressed higher levels of both classical and nonclassical MHC-I molecules. Reporter cells expressing the activating Ly49s5 receptor displayed increased stimulatory responses when incubated with Listeria-infected CC531 cells in vitro, which could be blocked with mAb 8G10 specific for nonclassical MHC-I molecules of the RT1(u) haplotype, but not with mAb OX18 reacting with classical MHC-I molecules in this haplotype. Similar responses were observed against IFN-γ-treated cells that also upregulated their expression of MHC-I molecules. Thus, the Ly49s5 receptor can respond to increased levels of nonclassical MHC-I molecules induced on target cells by either bacterial infection or cytokine stimulation. We furthermore found that splenic NK and NKT cells produced IFN-γ in response to Listeria-infected CC531 cells, and that this was not limited to Ly49-expressing cells, since similar levels of IFN-γ production were observed in Ly49(+) and Ly49(-) NK cell subsets. Therefore, NK cells may recognize Listeria-infected cells through both MHC-I-dependent and -independent innate immune receptor systems.     

Serum interleukin-6 as a prognostic biomarker in patients with metastatic melanoma

Interleukin-6 (IL-6) is an immunomodulatory cytokine produced by both normal cells and tumor cells, including melanoma cells. The specific biological function of IL-6 in melanoma is unknown. The present study examined whether the serum concentration of IL-6 can predict prognosis in patients with metastatic melanoma. IL-6 was measured by ELISA in serum samples from 103 patients with metastatic melanoma obtained before IL-2-based immunotherapy. Patients with metastatic melanoma had higher serum IL-6 than healthy individuals (median 3.4 ng/l, range 0.3-93 ng/l vs. median 1.4 ng/l, range 0.25-22.5 ng/l, P<0.0001). Pretreatment serum IL-6 was elevated in 43% of the patients. Patients with elevated pretreatment serum IL-6 had shorter overall survival (OS) compared with patients with normal serum IL-6 (P<0.0002). The median OS was 10.8 months [95% confidence interval (CI): 8.86-13.46] in patients with normal serum IL-6 compared with 4.5 months (95% CI: 3.04-7.39) in patients with elevated serum IL-6. Multivariate Cox analysis showed that serum IL-6 [hazard ratio (HR)=1.82, 95% CI: 1.19-2.78, P=0.006] and serum lactate dehydrogenase (HR=2.02, 95% CI: 1.31-3.11, P=0.001) were independent prognostic biomarkers of OS. A combination variable of elevated serum IL-6 and elevated serum lactate dehydrogenase almost quadrupled the risk of early death (HR=3.67, 95% CI: 2.17-6.20, P<0.0001) compared with patients with normal serum levels of these two biomarkers. Elevated serum IL-6 is an independent prognostic biomarker of short OS in patients with metastatic melanoma. A larger retrospective study is ongoing to confirm the findings. To validate serum IL-6 further as a prognostic biomarker, a prospective study is required.     

Urokinase plasminogen activator receptor on invasive cancer cells: a prognostic factor in distal gastric adenocarcinoma

Gastric cancer is the second cancer causing death worldwide. The five-year survival for this malignancy is below 25% and few parameters have shown an impact on the prognosis of the disease. The receptor for urokinase plasminogen activator (uPAR) is involved in extracellular matrix degradation by mediating cell surface associated plasminogen activation, and its presence on gastric cancer cells is linked to micrometastasis and poor prognosis. Using immunohistochemistry, the prognostic significance of uPAR was evaluated in tissue samples from a retrospective series of 95 gastric cancer patients. uPAR was expressed by neoplastic cells, macrophages, myofibroblasts and neutrophils in both intestinal and diffuse subtypes. No association was demonstrated between the expression of uPAR on cancer cells and histological subtype (p = 0.64) or TNM stage (p = 0.75). Univariate analysis revealed a significant association between the expression of uPAR on tumor cells in the peripheral invasion zone and overall survival of gastric cancer patients (HR = 2.16; 95% CI: 1.13-4.14; p = 0.02). Multivariate analysis showed that uPAR immunoreactivity in cancer cells at the invasive front is an independent prognostic factor for overall survival in gastric cancer (HR = 2.39; 95% CI: 1.22-4.69; p = 0.011). In consequence, scoring of uPAR-positive cancer cells may be a direct measure for the invasive potential of gastric adenocarcinomas.     

Psychiatric symptoms and service utilization among refugee children referred to a child psychiatry department: a retrospective comparative case note study

Refugee children may encounter barriers to accessing mental health services. We conducted a case-control study based on a systematic review of clinic records to compare psychopathology and service utilization in refugee and Norwegian children referred to a child psychiatry department in a county in southern Norway. Sixty-one refugee children were compared with 61 Norwegian-born children matched for gender, age and time of referral to the clinic. There was no significant difference in rates of referral or level of service utilization, which were proportional to the population. Compared with Norwegian children, refugee children were diagnosed more frequently with post-traumatic stress disorder and other affective and emotional disorders, and less often with pervasive developmental disorders and attention deficit hyperactivity disorder. The results are discussed in terms of referral pathways and the need for culturally competent care for refugee children.     

Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer

In a previous study from our laboratory, high tumor levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) have been associated with an adverse response to chemotherapy in metastatic breast cancer suggesting that TIMP-1, which is known to inhibit apoptosis, may be a new predictive marker in this disease. The purpose of this study was to investigate the association between TIMP-1 and objective response to chemotherapy in an independent patient population consisting of patients with metastatic breast cancer from Sweden and Denmark. TIMP-1 was measured using ELISA in 162 primary tumor extracts from patients who later developed metastatic breast cancer and these levels were related to the objective response to first-line chemotherapy. Increasing levels of TIMP-1 were associated with a decreasing probability of response to treatment, reaching borderline significance (OR = 1.59, 95% CI: 0.97–2.62, P = 0.07). This OR is very similar to the result from our previous study. Increasing levels of TIMP-1 were also associated with a shorter disease-free survival and overall survival, however, not statistically significant. The results from the present study support previous data that TIMP-1 is associated with objective response to chemotherapy for metastatic breast cancer.     

Better Preserved Pulmonary Endothelium-dependent Vasodilation with Off-pump Coronary Surgery

Objective - To investigate if endothelium-dependent vasodilation in the pulmonary circulation was better maintained after off-pump coronary artery bypass grafting (CABG). An impaired pulmonary vascular response to acetylcholine has been observed after cardiopulmonary bypass (CPB) in children, adults and experimentally. Design - Fourteen patients operated off-pump were compared with 21 patients undergoing conventional CABG with CPB. The indexed pulmonary vascular resistance was measured before and during an infusion of acetylcholine, aiming at a concentration of 10 -6 mol/l in the pulmonary artery. Twelve patients operated on-pump received saline instead of acetylcholine. Results - Before surgery pulmonary vascular resistance decreased during infusion of acetylcholine by 28% and 25% in the off-pump and on-pump groups. After surgery the decrease was 16% and 6%, respectively ( p = 0.028 and p < 0.001, compared to preoperative response). The response did not differ between the two groups before, but did so after surgery ( p = 0.01). Saline had no effect. Conclusion - The better maintained endothelium-dependent vasodilation in the off-pump group indicated less endothelial dysfunction.