Serum levels for midkine, a heparin-binding growth factor, inversely correlate with angiotensin and endothelin receptor autoantibody titers in patients with macroangiopathy.

AIM: Peripheral artery disease results in impaired blood flow to the extremities, most often as a consequence of atherosclerotic disease. The hallmark of atherosclerosis is chronic inflammation in the vessel wall. The renin-angiotensin and endothelin systems are considered important pathophysiological effectors. Midkine, a multifunctional cytokine, fulfils different roles in inflammation and promotion of neoangiogenesis. The aim of this study was to assess whether circulating midkine serum levels in patients with peripheral artery disease correlate with established atherosclerosis risk factors, as well as titers of functional autoantibodies directed against receptors of the renin-angiotensin and endothelin system. METHODS: Clinical data, laboratory values and serum samples from 118 patients operated on for severe peripheral artery disease, and from 100 healthy blood donors were collected. Serum samples were analysed for midkine concentrations as well as autoantibody titers against angiotensin II type 1 and endothelin-1 type A receptors. RESULTS: Midkine values were significantly higher in the study population than in healthy controls (P<0.001). Circulating midkine levels did not correlate with neither of the traditional risk factors age, sex, obesity, smoking, hypertension, high cholesterol levels, or diabetes mellitus. An unexpected inverse correlation was found with the autoantibodies against angiotensin II type 1 receptor (P<0.05) and endothelin-1 type A receptor (P<0.01). CONCLUSION: The high levels of midkine in severe peripheral artery disease patients introduce this cytokine as a possible novel effector in the advanced atherosclerotic process. These results also suggest a functional link between vascular receptor autoantibody formation and down-regulated midkine serum levels, that may be relevant in the pathogenesis of clinically relevant peripheral artery occlusive disease.

Pretransplant sensitization against angiotensin II type 1 receptor is a risk factor for acute rejection and graft loss.

The angiotensin II type 1 receptor (AT1R) is an emerging target of functional non-HLA antibodies (Ab). We examined the potential of determining the degree of presensitization against AT1R as a risk factor for graft survival and acute rejection (AR). The study included 599 kidney recipients between 1998 and 2007. Serum samples were analyzed in a blinded fashion for anti-AT1R antibodies (AT1R-Abs) using a quantitative solid-phase assay. A threshold of AT1R-Ab levels was statistically determined at 10 U based on the time to graft failure. An extended Cox model determined risk factors for occurrence of graft failure and a first AR episode. AT1R-Abs >10 U were detected in 283 patients (47.2%) before transplantation. Patients who had a level of AT1R-Abs >10 U had a 2.6-fold higher risk of graft failure from 3 years posttransplantation onwards (p = 0.0005) and a 1.9-fold higher risk of experiencing an AR episode within the first 4 months of transplantation (p = 0.0393). Antibody-mediated rejection (AMR) accounted for 1/3 of AR, whereby 71.4% of them were associated with >10 U of pretransplant AT1R-Abs. Pretransplant anti-AT1R-Abs are an independent risk factor for long-term graft loss in association with a higher risk of early AR episodes.

[Imatinib--a possible therapeutic option for cervical carcinoma: results of a preclinical phase I study]. / Imatinib - eine mogliche Therapieoption beim Zervixkarzinom: Ergebnisse einer praklinischen Phase-I-Studie.

BACKGROUND: In the last few years, the therapy of cervical carcinoma has progressed substantially due to the use of simultaneous platinum- containing radiochemotherapy. However, there are no data which evaluate an individualized treatment adapted to tumor biology, in spite of the fact that patients show remarkably different responses to chemotherapy. Therefore this preclinical phase I study aims at finding therapeutic alternatives to the current cytostatic drugs to treat cervical carcinoma. MATERIAL AND METHODS: In a tumor chemosensitivity assay, 8 drugs were tested on freshly isolated tumor cells of 16 patients [carbo- and cisplatin, topotecan, paclitaxel as well as the 2 tyrosine kinase inhibitors imatinib (Glivec) and gefitinib (Iressa (R) ) and the 2 monoclonal antibodies cetuximab (Erbitux) and trastuzumab (Herceptin (R) )]. RESULTS: Overall the test was evaluable for 16 specimens (100%). Ten of 15 tumor samples (66.6%) were sensitive to imatinib. A sensitive therapeutic response could be demonstrated in all tested FIGO stages. An interindividual comparison could establish sensitivity to cetuximab in 12.5% of cases, to gefitinib in 6.25%, to trastuzumab in 6.6%, to cisplatin in 13.3%, to carboplatin in 7.6%, to paclitaxel in 93.8% and to topotecan in 25%. CONCLUSION: Imatinib seems to be an efficacious therapeutic option for patients with cervical carcinoma, independently of tumor subtype.

Prothymosin alpha 1 effects in vitro on chemotaxis, cytotoxicity and oxidative response of neutrophils from melanoma, colorectal and breast tumor patients.

Immunoregulatory effects of thymic peptides on functions of polymorphonuclear leukocytes (PMNs) are poorly investigated. We studied the effects of prothymosin alpha 1 (Pro alpha 1) on PMNs from patients with colorectal tumors, breast tumors and melanoma (total n = 37) in comparison with healthy donors (n = 18), with respect to chemotaxis, cytotoxicity against HCT-116 colon tumor cells, oxidative response (chemiluminescence reaction) as well as expression of surface marker molecules. We found that Pro alpha 1 was equally effective in stimulating the chemotactic activity of PMNs from tumor patients and healthy donors (43% increase). PMNs from tumor patients, especially with breast tumor, showed a significant enhancement of cytotoxicity against the tumor target cells in comparison with healthy donors. With respect to the PMNs cytotoxicity, only about 50% of the colorectal tumor patients and healthy donors responded to Pro alpha 1 and FMLP. As to the oxidative response of PMNs, elevated levels were found only among colorectal tumor patients. Pro alpha 1 significantly increased the oxidative response in breast and colorectal tumor patients by 55% and 25%, respectively. Pro alpha 1 decreased the expression of CD16 on PMNs of healthy donors, but not that of CD11a, CD11b, CD11c, CD13, CD14, CD15 and CD32. Therefore, we suggest, that Pro alpha 1 may improve some PMN functions of tumor patients, associated with the proposed role in host-tumor interaction.