Angiogenesis induced by tumor necrosis factor-agr; is mediated by α4 integrins

Tumor necrosis factor-α (TNF-α) and fibroblast growth factor-2 (FGF-2 or bFGF) are potent stimulators of angiogenesis. TNF-α, but not FGF-2, can induce the expression of vascular cell adhesion molecule-1 (VCAM-1) on the surface of endothelial cells. The soluble form of VCAM-1 has recently been demonstrated to function as an angiogenic mediator. Here we demonstrate that monoclonal antibodies directed against VCAM-1 or its α4 integrin counter-receptor inhibited TNF-α-induced endothelial cell migration in vitro. Angiogenesis induced in vivo in rat corneas by TNF-α was inhibited by a neutralizing antibody directed against the rat α4 integrin subunit. A peptide antagonist of the a4 integrins blocked TNF-α-induced endothelial cell migration in vitro and angiogenesis in rat corneas in vivo. No inhibition by the antibodies or peptide antagonist was observed either in vitro or in vivo when FGF-2 was used as the stimulus. The peptide antagonist did not inhibit TNF-a binding to its receptor nor did it block the function of αvβ3, an integrin previously implicated in TNF-a and FGF-2 mediated angiogenesis. These results demonstrate that angiogenic processes induced by TNF-α are mediated in part by agr;4 integrins possibly by a mechanism involving the induction of soluble VCAM-1.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41761/1/10456_2004_Article_188219.pd

A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells

Human exposure to carcinogens occurs via a plethora of environmental sources, with 70–90% of cancers caused by extrinsic factors. Aberrant phenotypes induced by such carcinogenic agents may provide universal biomarkers for cancer causation. Both current in vitro genotoxicity tests and the animal-testing paradigm in human cancer risk assessment fail to accurately represent and predict whether a chemical causes human carcinogenesis. The study aimed to establish whether the integrated analysis of multiple cellular endpoints related to the Hallmarks of Cancer could advance in vitro carcinogenicity assessment. Human lymphoblastoid cells (TK6, MCL-5) were treated for either 4 or 23 h with 8 known in vivo carcinogens, with doses up to 50% Relative Population Doubling (maximum 66.6 mM). The adverse effects of carcinogens on wide-ranging aspects of cellular health were quantified using several approaches; these included chromosome damage, cell signalling, cell morphology, cell-cycle dynamics and bioenergetic perturbations. Cell morphology and gene expression alterations proved particularly sensitive for environmental carcinogen identification. Composite scores for the carcinogens’ adverse effects revealed that this approach could identify both DNA-reactive and non-DNA reactive carcinogens in vitro. The richer datasets generated proved that the holistic evaluation of integrated phenotypic alterations is valuable for effective in vitro risk assessment, while also supporting animal test replacement. Crucially, the study offers valuable insights into the mechanisms of human carcinogenesis resulting from exposure to chemicals that humans are likely to encounter in their environment. Such an understanding of cancer induction via environmental agents is essential for cancer prevention

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Efficacy and safety of abobotulinumtoxinA for upper limb spasticity in children with cerebral palsy: a randomized repeat-treatment study

Aim To assess the efficacy and safety of repeat abobotulinumtoxinA injections in reducing upper limb spasticity in children with cerebral palsy (CP)

Goal Attainment after Treatment with Abobotulinumtoxina and A Tailored Home Therapy Programme in Children with Upper Limb Spasticity: Descriptive, Exploratory Analysis of A Large Randomized, Controlled StudyA

Objective: This exploratory analysis of a large, randomized, double-blind study (NCT02106351) describes the effect of treatment with abobotulinumtoxinA followed by a tailored home exercises therapy programme in enabling children with upper limb spasticity due to cerebral palsy to achieve their functional goals using goal attainment scaling (GAS). Methods: Children with cerebral palsy and spasticity in ≥ 1 upper limb received up to 4 injection cycles of abobotulinumtoxinA (2 U/kg (cycle 1 only), 8U/kg and 16U/kg) into the elbow and wrist flexors and other upper limb muscles selected to support individual treatment goals. Children followed a home exercises therapy programme, which included stretches and exercises specifically chosen to facilitate goal achievement and engagement in activities. Results: For cycle 1, most children had active function goals set as their primary goal (69.7% vs 19.2% passive function goals). GAS T- scores and goal responder rates at week 16 indicated that most types of primary goal were achieved at least as expected during cycle 1 (all groups). Primary goal GAS T-scores were generally maintained for the first 3 abobotulinumtoxinA treatment cycles. Conclusion: Most children with upper limb spasticity treated with repeat cycles of abobotulinumtoxinA supported by an individualized home exercises therapy programme achieved their functional goals. LAY ABSTRACT Treatment with botulinum toxins (such as abobotulinumtoxinA; aboBoNT-A) is often recommended to treat spasticity of the upper limb to help children with cerebral palsy improve their hand skills. In this large study, children with cerebral palsy were treated with up to 4 aboBoNT-A injection cycles followed by a home exercises programme that was specifically made for each child to help them meet their treatment goals. This study aimed to explore the types of goals the children wanted to achieve with this treatment and the factors that influence goal attainment. Most children in this study had “active function” goals set, including “involving the affected arm more in daily activities” and improving “reaching”, “use of limb as a helping hand” and “grasp and release”. Combined treatment with aboBoNT-A and the exercise programme helped most children achieve their goals, but it was difficult to discern any differences in efficacy between the aboBoNT-A doses used in the study. The authors suggest that the high rates of goal achievement in this study indicate that botulinum toxin should not usually be given without a physiotherapy programme