Urokinase stimulates inflammatory response in damaged vascular wall during <Emphasis Type="Italic">in vivo</Emphasis> arterial remodeling

Perivascular application of urokinase to the ballooned artery promoted the growth of neointima and constrictive remodeling of the vessel and stimulated the inflammatory response in the damaged vascular wall in vivo. Recombinant tissue plasminogen activator did not induce these changes. Our results indicate that urokinase is involved in the regulation of the inflammatory response during in vivo remodeling of the damaged vascular wall. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 1, pp. 15–19, January, 2008     

Cardiovascular risk profile of patients with HER2/neu-positive breast cancer treated with anthracycline-taxane-containing adjuvant chemotherapy and/or trastuzumab.

PURPOSE: To evaluate the cardiovascular risk profile of a subset of patients with early-stage breast cancer treated with adjuvant taxane-anthracycline-containing chemotherapy and/or trastuzumab (Herceptin). Experimental Design: Twenty-six patients with breast cancer (mean, 20 months postchemotherapy) and 10 healthy age-matched women were studied. We measured 14 metabolic and vascular established cardiovascular disease (CVD) risk factors, body mass index, cardiorespiratory fitness, and left ventricular systolic function. All assessments were done within a 14-day period. RESULTS: Cardiac abnormalities were suggested by left ventricular ejection fraction (LVEF) <50% in 8% of patients, LVEF remained >10% below pretreatment values in 38%, whereas 50% presented with resting sinus tachycardia. Brain natriuretic peptide was significantly elevated in 40% of patients and was correlated with LVEF (r = -0.72, P =or< 0.001). For the majority of CVD risk factors, similar proportions of patients and controls (35-60%) were classified as "undesirable." A significantly higher proportion of patients were classified with low cardiorespiratory fitness (46% versus 0%, P < 0.01), being overweight/obese (72% versus 50%, P < 0.05), and having resting sinus tachycardia (50% versus 0%, P < 0.01) compared with controls. Cardiorespiratory fitness and body mass index were correlated with CVD risk factors (r = -0.64 to 0.63, P < 0.05; r = -0.63 to 0.67, P < 0.05, respectively). Exploratory analyses revealed several differences between CVD risk factors based on chemotherapy regimen. CONCLUSION: Breast cancer survivors treated with adjuvant chemotherapy are at a higher risk of developing late-occurring CVD than age-matched controls due to direct and indirect treatment-related toxicity.     

T-cadherin suppresses angiogenesis in vivo by inhibiting migration of endothelial cells

Our previous studies have revealed the abundant expression of T-cadherin—a glycosylphosphatidylinositol (GPI)-anchored member of cadherin superfamily—in endothelial and mural cells in the heart and vasculature. The upregulation of T-cadherin in vascular proliferative disorders such as atherosclerosis and restenosis suggests the involvement of T-cadherin in vascular growth and remodeling. However, the functional significance of this molecule in the vasculature remains unknown. The effect of T-cadherin on angiogenesis in vivo was evaluated using Matrigel implant model. We demonstrate that T-cadherin overexpression in L929 cells injected in Matrigel inhibits neovascularization of the plug. In vitro T-cadherin inhibits the directional migration of endothelial cells, capillary growth, and tube formation but has no effect on endothelial cell proliferation, adhesion, or apoptosis in vitro. These data suggest that T-cadherin expressed in the stroma could act as a negative guidance cue for the ingrowing blood vessels and thus could have an important potential therapeutic application. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Kseniya Rubina and Natalia Kalinina have contributed equally to the work.     

Hyperglycemia impact on angiogenic properties of endothelial and progenitor vascular cells

This report contains authors own data about hyperglycemia impact on main functional properties of endothelial cells, mesenchymal stem cells and circulating progenitor cells, which define their participation in angiogenesis. Obtained data shows that cultivation of endothelial cells in hyperglycemic conditions leads to decrease of their ability for targeted migration and vascular-like structures formation on matrigel, and to suppression of VEGF receptors expression in these cells. Mesenchymal stem cells cultivated in hyperglycemic conditions have altered expression profile, decreased ability to stimulate angiogenesis via paracrine activity. Hyperglycemia in CHD patients with concomitant diabetes mellitus type II most probably lead to circulating bone marrow progenitor cells mobilisation distortion in response to tissue ischemia and damage to the endothelium, that can infringe upon their participation in endothelium reparation and angio- and vasculogenesis in the ischemic conditions. Found distortions can be used as targets for the treatment aimed at cardiovascular complications prevention in diabetic patients.     

Urokinase gene transfer augments angiogenesis in ischemic skeletal and myocardial muscle.

Urokinase plasminogen activator (uPA) is required for both endogenous and vascular endothelial growth factor (VEGF)-augmented angiogenesis in normal tissues, leading us to hypothesize that uPA augmentation by gene transfer might promote angiogenesis in ischemic tissues. Overexpression of uPA was studied in rat myocardial infarction (MI) and mouse hind limb ischemia models and compared with VEGF overexpression effects. Animals were divided into control and three experimental groups (n = 6), receiving intramuscular injections of plasmids as follows: (i) control (empty vector or expressing beta-galactosidase); (ii) uPA; (iii) VEGF(165); (iv) a 1:1 mixture of uPA and VEGF(165). The capillary densities in both ischemic models were greater (P < 0.05) in tissues treated with uPA, VEGF, or a combination of both than in controls. Infarct size was reduced in hearts from uPA and VEGF experimental groups compared with controls (P < 0.05). Local overexpression of uPA induced a marked increase in the number of macrophages and myofibroblasts present within infarcts. Hind limb blood flow was greater in all experimental groups by day 10 (P < 0.05). Overall, the effects of uPA and VEGF were uniformly comparable. Additional analysis revealed association of local edema with VEGF but not with uPA treatment. This study established that uPA gene therapy effectively induces functionally significant angiogenesis in models of acute MI and hind limb ischemia.     

A randomized,phase III,double-blind,placebo-controlled trial of intrapleural instillation of methylprednisolone acetate in the management of malignant pleural effusion

STUDY OBJECTIVES: To determine if intrapleural administration of methylprednisolone acetate (MA) after therapeutic thoracentesis for symptomatic malignant pleural effusion improved time to repeat thoracentesis for symptom control, quality of life (QOL), and dyspnea. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: A tertiary care cancer treatment center in Edmonton, AB, Canada. Patient selection: Patients with symptomatic pleural effusions secondary to disseminated malignancy requiring therapeutic thoracentesis for symptom control. INTERVENTIONS: Sixty-seven patients underwent ultrasound-guided therapeutic thoracentesis for management of symptomatic malignant pleural effusion. Patients were randomly and blindly assigned to either 160 mg (8 mL) of MA or 8 mL of saline solution instilled into the pleural space. Patients were followed up for 6 weeks to determine the time to repeat therapeutic thoracentesis. All patients completed the Functional Assessment of Cancer Therapy-General (FACT-G) QOL questionnaire and a dyspnea visual analog scale (VAS) at baseline and again 2 weeks later. Measurements and results: Thirty-three patients received MA, and 34 patients received placebo; baseline characteristics for the two groups were similar, apart from a slightly higher use of concurrent systemic therapy in the placebo group. At 6 weeks follow-up, 50% of MA-treated patients required repeat thoracentesis compared to 56% of placebo-treated patients (not significant [NS]). The mean of the individual FACT-G change scores (2 weeks - baseline) was similar in the two groups (NS). VAS scores improved for both groups over the 2-week period, but the mean change scores (2 weeks - baseline) were not statistically different. CONCLUSION: Despite previous case series describing benefit from intrapleural MA in malignant pleural effusion, this controlled study of intrapleural MA instillation did not delay reaccumulation of symptomatic pleural effusion compared to placebo, nor were differences in QOL or dyspnea observed.     

Isolation and characteristics of calmodulin from the brains of rats with spontaneous genetic hypertension

Using column chromatography with phenylcepharase, calmodulin was isolated from the brain of rats with spontaneous hypertension (SHR) and control normotensive rats (NKWR). As judged from the findings of electrophoresis in polyacrylamide gel, UV-spectroscopy and spectrofluometry, the obtained samples of calmodulin contained no significant admixture of other proteins. The Ca-binding capacity of calmodulin of the brain of SHR and NKWR estimated by the method of fluorescent probes were identical. There were also no differences in their capacity to interact with troponine I and to activate the Ca-pump of the erythrocytic membrane and phosphodiesterase of the cardiac muscle. A study on the dependence of activity of phosphodiesterase on the protein content of the brain homogenate from SHR and NKWR revealed no differences in the calmodulin levels in this tissue. On the basis of these data a conclusion was made that impairments of the intracellular distribution of calcium in primary hypertension described earlier are not related to disorders in the metabolism of the universal Ca-binding protein-regulator.     

Sequence and organization of the diversity, joining, and constant region genes of the human T-cell delta-chain locus.

In this paper we describe the genomic organization and sequence of the human T-cell receptor delta-chain diversity, joining, and constant genes. There is one delta-chain constant region gene (C delta) located approximately equal to 85 kilobases (kb) upstream of the alpha-chain constant region. The delta-chain constant region consists of four exons, whose organization is very similar to that of the C alpha exons, suggesting that C alpha and C delta may have arisen from a gene duplication event. The first exon encodes most of the extracellular constant domain, the second encodes a hinge-like region, and the third encodes the entire transmembrane segment and intracytoplasmic portion, whereas the last exon contains exclusively 3' untranslated sequences. Three joining segments, J delta 1, J delta 2, and J delta 3, are found approximately equal to 12, approximately equal to 5.7, and approximately equal to 3.4 kb upstream of the first exon of C delta. Two functional diversity gene segments, D delta 1 and D delta 2, which can be productively translated in all three reading frames, are found 1 and 9.6 kb upstream of J delta 1. The presence of two D delta with such potential for diversity may offset the limited repertoire of the J delta and V delta genes. The spacer distribution in the recombinational signals flanking D delta and J delta segments allows recombination with V alpha gene segments; however, examination of delta-chain messages does not indicate that this is the case, suggesting that the delta chain uses unique variable gene segments and raising the question as to the reasons for this phenomenon.     

Unique genetic profile of hereditary hemochromatosis in Russians: high frequency of C282Y mutation in population, but not in patients

Hereditary hemochromatosis (HH) is a common cause of primary iron overload induced by genetic impairment of iron metabolism. More than 80% of HH patients in populations of European origin are homozygotes for a single mutation C282Y, or compound heterozygotes for C282Y and H63D mutations in the HFE gene. However, in the majority of Asian, African, Australasian, and Amerindian populations, frequencies of C282Y are close to zero. Data on the prevalence of HFE mutations in Russian population and in Russian patients with HH are very limited. In this work, we determined frequencies of C282Y and H63D in ethnical Russians living in the Central European region of Russia. Furthermore, we tested whether homozygocity for C282Y is the major cause of HH in Russians. We found that, in the Russian population, the frequency of C282Y mutation in the HFE gene is relatively high and corresponds to mean European levels. However, in contrast to the majority of European populations, homozygocity for C282Y is found only in a small proportion (5%) of patients with biochemical and clinical signs of HH. These data suggest that either the penetrance of C282Y in Russia is lower than in Western countries, or that a more frequent non-HFE dependent mechanism of primary iron overload dominates in Russian population.