Molecular dissection of effector mechanisms of RAS-mediated resistance to anti-EGFR antibody therapy.

Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), cetuximab and panitumumab, are a mainstay of metastatic colorectal cancer (mCRC) treatment. However, a significant number of patients suffer from primary or acquired resistance. RAS mutations are negative predictors of clinical efficacy of anti-EGFR antibodies in patients with mCRC.

Deregulated BCL-2 family proteins impact on repair of DNA double-strand breaks and are targets to overcome radioresistance in lung cancer.

Purpose: DNA damage-induced cell death is a major effector mechanism of radiotherapy. Aberrant expression of anti-apoptotic BCL-2 family proteins is frequently observed in lung cancers. Against this background, we studied radioresistance mediated by BCL-2 family proteins at the mechanistic level and its potential as target for radiochemotherapy.

Intra-arterial vitamin C prevents endothelial dysfunction caused by ischemia-reperfusion.

Objective: Ischemia-reperfusion (IR) injury causes tissue injury and endothelial dysfunction. There is evidence that oxidative stress plays an important role.

Methods: We tested if IR-induced endothelial dysfunction could be prevented by administration of the antioxidant vitamin C.

Exercise training improves low-density lipoprotein oxidability in untrained subjects with coronary artery disease.

Unlabelled: Exercise training improves low-density lipoprotein oxidability in untrained subjects with coronary artery disease.

Objective: To test the hypothesis that regular exercise alters low-density lipoprotein (LDL) oxidability in patients with coronary artery disease.

Design: Longitudinal study.

Endurance training reduces circulating asymmetric dimethylarginine and myeloperoxidase levels in persons at risk of coronary events.

Asymmetric dimethylarginine (ADMA), myeloperoxidase (MPO) and paraoxonase 1 (PON1) are directly involved in the pathogenesis of atherosclerosis by modulation of oxidative stress and/or NO bioavailability. We aimed to assess whether endurance exercise which is known to be cardioprotective could beneficially affect these novel risk markers. Thirty-two subjects (31-68 yrs, 56% males) with elevated cardiovascular risk including ten patients with coronary artery disease volunteered for a supervised 12-week endurance training (196 +/- 15 min/week).

Wine ingestion has no effect on lipid peroxidation products.

Objective: Moderate alcohol consumption has been associated with beneficial effects on coronary heart disease. This positive effect has been partly attributed to the flavonol contents which promote vasodilatory, anti-aggregatory and antioxidative effects and protect low-density lipoprotein (LDL) cholesterol from oxidation. Thus, the present study was carried out to determine the acute effects of different wines on LDL oxidization in healthy volunteers.

Influence of systemic inflammation on the interpretation of response to antiplatelet therapy, monitored by PFA-100.

Recently it was shown that inflammation adversely influences results obtained with the Platelet Function Analyzer System PFA-100, hypothesizing that inflammation could confound interpretation of platelet function results. We investigated the clinical relevance of these results in patients with peripheral arterial occlusive disease (PAOD), with and without signs of systemic inflammation. In 98 PAOD patients, all treated with acetylsalicylic acid (ASA), we measured PFA-100 closure times with the collagen-epinephrine test cartridges.

Osteoprotegerin plasma concentrations correlate with severity of peripheral artery disease.

Objective: Osteoprotegerin (OPG), a member of the tumor necrosis factor receptor family, is involved in the process of bone turnover and also in the pathogenesis of osteoporosis and premature calcification of the vascular system. In the present study on patients with peripheral artery disease (PAD), we correlated plasma OPG concentrations with severity of disease and the presence of cardiovascular risk factors.

Patients And Methods: Sixty-seven consecutive inpatients (26 females; mean age 70 years (S.

Endurance training reduces circulating inflammatory markers in persons at risk of coronary events: impact on plaque stabilization?

Inflammatory pathways are involved in destabilization of atherosclerotic plaques. We assessed the hypothesis that endurance training decreases circulating concentrations of inflammatory markers in persons with coronary artery disease (CAD) and cardiovascular risk factors (CVRFs). Thirty-two subjects with CAD and/or CVRFs joined a 12-week supervised endurance training.

Endurance training increases the number of endothelial progenitor cells in patients with cardiovascular risk and coronary artery disease.

Objective: As regular physical exercise improves endothelial dysfunction and promotes cardiovascular health, we investigated the effect of training on angiogenesis by measuring the number of circulating endothelial progenitor cells (EPC), the level of EPC-mobilizing growth factors and tested vascular function by flow-mediated dilation (FMD) in patients with coronary artery disease (CAD) and cardiovascular risk factors (CVRF). In addition, degradation products of the NO pathway (NOx) were determined.

Methods And Results: Twenty patients with documented CAD and/or CVRF joined a 12-week supervised running training.

Endurance running acutely raises plasma osteoprotegerin and lowers plasma receptor activator of nuclear factor kappa B ligand.

Abstract The balance of the 2 cytokines, osteoprotegerin (OPG) and the receptor activator of nuclear factor kappa B ligand (soluble (s)RANKL), is known to have considerable influence on bone formation and degradation. Plasma concentrations of OPG and (s)RANKL were determined in a total of 31 long-distance runners before and immediately after running distances of either 15 or 42.195 km, respectively.

Association of a functional polymorphism in the clopidogrel target receptor gene, P2Y12, and the risk for ischemic cerebrovascular events in patients with peripheral artery disease.

Background And Purpose: There is considerable variability in the antiplatelet effects of the thienopyridine agent "clopidogrel." We tested for an association of gene sequence variations in P2Y12 and occurrence of neurological adverse events in patients with symptomatic peripheral artery disease (PAD) during clopidogrel treatment.

Methods: We studied 137 patients undergoing antiplatelet therapy with clopidogrel and 336 patients with aspirin for the occurrence of neurological events (ischemic stroke and/or carotid revascularization).

Thermoregulation and rheological properties of blood in primary Raynaud's phenomenon and the vibration-induced white-finger syndrome.

Objective: Frequent use of vibrating tools may lead to typical attacks of Raynaud's phenomenon (RP). The present study assesses the feasibility of the use of thermographic measurements of blood rheometry in the diagnosis of vibration-induced white-finger (VWF) syndrome.

Subjects And Methods: We studied 38 patients that were suffering from RP (primary RP, n=29; VWF, n=9) and 13 controls (six men and 45 women; mean age 49.

[Therapeutic implications of polymorphisms in cytochromes and drug transporters].

There is great heterogeneity in the way individuals respond to drug therapy. Reasons for this variability include pathophysiological or environmental factors, drug interactions or genetic influences. Among those influences are polymorphisms in drug-metabolizing enzymes, such as Cytochrom-P-450 (CYP) 2D6, CYP2C9 or CYP2C19 or genetic variants in enzymes coding for drug transporters, such as P-Glycoprotein.

In vitro and in vivo evaluation of [18F]ciprofloxacin for the imaging of bacterial infections with PET.

Purpose: The suitability of the 18F-labelled fluoroquinolone antibiotic ciprofloxacin ([18F]ciprofloxacin) for imaging of bacterial infections with positron emission tomography (PET) was assessed in vitro and in vivo.

Methods: For the in vitro experiments, suspensions of various E. coli strains were incubated with different concentrations of [18F]ciprofloxacin (0.

Homocyst(e)ine-lowering therapy does not affect plasma asymmetrical dimethylarginine concentrations in patients with peripheral artery disease.

Background: Elevated plasma asymmetrical dimethylarginine (ADMA) is suggested to contribute to hyperhomocyst(e)ine-related vascular dysfunction in patients with peripheral artery disease (PAD). The present trial investigated whether homocyst(e)ine (Hcy)-lowering therapy with vitamin-B (vit-B) and folic acid affects plasma concentrations of ADMA in patients with PAD and hyperhomocyst(e)inemia.

Subjects And Methods: Forty-nine subjects (15 women, 34 men) with PAD and fasting plasma total Hcy concentrations greater than 15 micromol/liter were randomized to receive either oral vit-B and folic acid therapy (n = 27) or placebo (n = 22) for 6 wk.

Symptomatic venous thromboembolism in acute leukemia. Incidence, risk factors, and impact on prognosis.

The association between malignant disorders and occurrence of venous thromboembolism is well established. Patients with cancer and venous thromboembolism have adverse prognosis. No systematic study on the incidence and prognostic impact of venous thromboembolism in acute leukemia has been performed as yet.

Laser Doppler anemometry distinguishes primary Raynaud phenomenon from VWF syndrome.

Objectives: We evaluated two microcirculatory function-tests, the Laser Doppler (LD)-Anemometry and the Laser Doppler Imager (LDI)-Flowmetry in their value to further elucidate functional behavior of the "Vibration-induced white finger syndrome" (VWF) and to distinguish between Raynaud's phenomenon (RP) of idiopathic or vibration origin.

Participants And Methods: Ninety-four patients, suffering from RP were studied (78 patients with primary RP and 16 patients with VWF). Measurement of blood cell velocity (BCV) before and after provocation was obtained by nailfold capillary microscopy and an included Laser detector ("Anemometry").

Increases in plasma levels of atrial and brain natriuretic peptides after running a marathon: are their effects partly counterbalanced by adrenocortical steroids?

Objective: Long-distance running results in considerable stress. Little evidence exists about the role of the atrial and brain natriuretic peptides, ANP and BNP, deriving from the myocardium. The aim of our study was to investigate the influence of running 42.

High prevalence of chronic venous disease in hospital employees.

Objectives: Chronic venous disease (CVD), which comprises primary/idiopathic abnormalities of the venous system, and secondary sequels after deep venous thrombosis are major health issues in Western countries. The present study was conducted to prove the hypothesis that the development of CVD might be triggered by exogenous, occupational risk factors.

Methods: We determined the prevalence and social relationship of CVD in a wide cross-section of hospital employees (n = 209; medical doctors and nurses, medical technician assistants, secretaries, scientific staff, cleaners and utility workers) without predocumented CVD.

[Muscle cell proteins are selectively released into the blood stream by marathon running].

In 19 marathon runners of both sexes, plasma concentrations of total creatine kinase (CK) activity, CKMB mass, myoglobin and troponin I were determined before and immediately after the race. Total CK activity and myoglobin increased significantly in all runners and showed neither a correlation with the individual age of the runners nor with the time they needed to reach the goal. In 12 of the runners, CKMB mass increased during the race to a level suggesting myocardial necrosis.