Epidemiology and pathophysiology of cancer-associated thrombosis

Venous thromboembolism (VTE) is a common complication in patients with malignant disease. First recognised by Bouillard in 1823 and later described by Trousseau in 1844, multiple studies have since provided considerable evidence for a clinical association between VTE and cancer. Across all cancers, the risk for VTE is elevated 7-fold; in certain malignancies, the risk for VTE may be increased up to 28-fold. Venous thromboembolism is the second leading cause of death in patients with cancer; among survivors, complications commonly include recurrent VTE and post-thrombotic syndrome, and (more rarely) chronic thromboembolic pulmonary hypertension, which are costly, and have a profound impact on the patient's quality of life. Tumour cells can activate blood coagulation through multiple mechanisms, including production of procoagulant, fibrinolytic, and proaggregating activities, release of proinflammatory and proangiogenic cytokines, and interacting directly with host vascular and blood cells (e.g., endothelial cells, leukocytes, and platelets) through adhesion molecules. Increasing evidence suggests that elements of the haemostatic system also have a direct role in eliciting or enhancing angiogenesis, cell survival, and metastasis. Despite the problem posed by VTE in the setting of cancer, it is evident that a significant number of oncologists do not recognise the link between cancer, its treatment, and thrombogenesis. On 22 May 2009, a group of UK-based physicians met in London, UK, to evaluate recent data on cancer thrombosis. This article (1 of 4) briefly reviews key data on the epidemiology and pathophysiology of VTE as a context for a discussion and consensus statement developed by meeting attendees, on the implications of this information for UK clinical practice

Strategies to inhibit tumour associated integrin receptors: rationale for dual and multi-antagonists

YesThe integrins are a family of 24 heterodimeric transmembrane cell surface receptors. Involvement in cell attachment to the extracellular matrix, motility, and proliferation identifies integrins as therapeutic targets in cancer and associated conditions; thrombosis, angiogenesis and osteoporosis. The most reported strategy for drug development is synthesis of an agent that is highly selective for a single integrin receptor. However, the ability of cancer cells to change their integrin repertoire in response to drug treatment renders this approach vulnerable to the development of resistance and paradoxical promotion of tumor growth. Here, we review progress towards development of antagonists targeting two or more members of the RGD-binding integrins, notably αvβ3, αvβ5, αvβ6, αvβ8, α5β1, and αIIbβ3, as anticancer therapeutics

The Interleukin-6 inflammation pathway from cholesterol to aging – Role of statins, bisphosphonates and plant polyphenols in aging and age-related diseases

We describe the inflammation pathway from Cholesterol to Aging. Interleukin 6 mediated inflammation is implicated in age-related disorders including Atherosclerosis, Peripheral Vascular Disease, Coronary Artery Disease, Osteoporosis, Type 2 Diabetes, Dementia and Alzheimer's disease and some forms of Arthritis and Cancer. Statins and Bisphosphonates inhibit Interleukin 6 mediated inflammation indirectly through regulation of endogenous cholesterol synthesis and isoprenoid depletion. Polyphenolic compounds found in plants, fruits and vegetables inhibit Interleukin 6 mediated inflammation by direct inhibition of the signal transduction pathway. Therapeutic targets for the control of all the above diseases should include inhibition of Interleukin-6 mediated inflammation

Inhibition of pulmonary metastasis in a human MT3 breast cancer xenograft model by dual liposomes preventing intravasal fibrin clot formation

International audienceThe process of metastasis formation in cancer is not completely understood and is the main reason cancer therapies fail. Previously, we showed that dual liposomes simultaneously containing the hemostatic inhibitor, dipyridamole and the anticancer drug, perifosine potently inhibited metastasis, causing a 90% reduction in the number of lung metastases in a murine experimental metastasis model. To gain deeper insight into the mechanisms leading to the inhibition of metastasis by these dual liposomes, in the present study, the development of metastases by MT3 breast cancer cells in a mouse xenograft model was analyzed in more detail with regard to tumor cell settlement and metastatic growth. We found that the development of lung metastases by MT3 tumor cells is essentially dependent on the formation of fibrin clots as a precondition for the pulmonary arrest of tumor cells and the subsequent intravascular expansion of micrometastases before their invasion into the surrounding tissue

Modelowanie procesu tarcia w hamulcach tarczowych pojazdów za pomocą przestrzeni fazowej

The paper presents the possibility of applying selected topological tools in the process of the modeling, diagnosing, and monitoring of a friction pair. The paper includes a presentation of the parameters describing the working conditions of a frictional pair in the phase space (PS), which permits the elimination of the time component from the data in the form of a time series, which enables the analysis of non-linear periodic behaviours of the phase point. The trace of the trajectory of the phase point presents the character of the process concerned. This information is unavailable in the traditional analysis preceded by a process of the preparation of experimental data (statistical processes). Interpretation of the oscillation of the system is possible by using a graphic presentation of the results in the phase space. Such a manner of analysing the parameters of the operation of a frictional pair enables the prediction of the condition of the system in a short period of time.Artykuł przedstawia możliwość zastosowania wybranych narzędzi topologii matematycznej w procesie modelowania, diagnostyki oraz monitoringu pary ciernej. Przedstawienie parametrów opisujących stan pracy pary trącej w przestrzeni fazowej prowadzi do eliminacji składowej czasowej z rozpatrywanego szeregu czasowego danych wejściowych, co pozwala na analizę nieliniowych, okresowych zachowań punktu fazowego. Droga trajektorii punktu fazowego przedstawia charakter procesu tarcia. Informacja ta jest niedostępna w tradycyjnej analizie danych, poprzedzonej wstępną obróbką danych (procesy statystyczne). Interpretacja oscylacji generowanych przez system jest możliwa za pomocą graficznej prezentacji wyników w przestrzeni fazowej oraz parametrów opisujących zachowanie trajektorii punktu fazowego

System obserwacji zjawisk tribologicznych na powierzchniach samochodowych hamulców tarczowych

A number of difficulties are encountered when performing observational and measuring examinations of vehicle disc brake surfaces, thus inducing the necessity to build a special research stations for preliminary tests. The paper describes one such station for observational and measuring tests of disc brakes in the presence of hard abrasive particles. The paper is divided into two parts. The first part presents the main functional systems, measuring systems and software being used. The second part includes examples of the results of measurements.W trakcie prowadzenia eksploatacyjnych obserwacji i badań powierzchni tarczowych hamulców samochodowych występuje szereg trudności, które wymuszają konieczność budowy specjalnych stanowisk badawczych. W artykule przedstawiono stanowisko badawcze przeznaczone do obserwacji i pomiarów roboczych parametrów tarczowych hamulców pracujących w obecności twardych cząstek ściernych. Artykuł składa się z dwóch części. W pierwszej zaprezentowano cechy funkcjonalne systemu, układu pomiarowego i zastosowanego oprogramowania. W drugiej części przedstawiono przykładowe wyniki badań

Regenerative braking strategies, vehicle safety and stability control systems : critical use-case proposals

The sustainable development of vehicle propulsion systems that have mainly focused on reduction of fuel consumption (i.e. CO2 emission) has led, not only to the development of systems connected with combustion processes but also to legislation and testing procedures. In recent years, the low carbon policy has made hybrid vehicles and fully electric vehicles (H/EVs) popular. The main virtue of these propulsion systems is their ability to restore some of the expended energy from kinetic movement, e.g. the braking process. Consequently new research and testing methods for H/EVs are currently being developed. This especially concerns the critical ‘use-cases’ for functionality tests within dynamic events for both virtual simulations, as well as real-time road tests. The use-case for conventional vehicles for numerical simulations and road tests are well established. However, the wide variety of tests and their great number (close to a thousand) creates a need for selection, in the first place, and the creation of critical use-cases suitable for testing H/EVs in both virtual and real-world environments. It is known that a marginal improvement in the regenerative braking ratio can significantly improve the vehicle range and, therefore, the economic cost of its operation. In modern vehicles, vehicle dynamics control systems play the principal role in safety, comfort and economic operation. Unfortunately, however, the existing standard road test scenarios are insufficient for H/EVs. Sector knowledge suggests that there are currently no agreed tests scenarios to fully investigate the effects of brake blending between conventional and regenerative braking as well as the regenerative braking interaction with active driving safety systems (ADSS). The paper presents seven manoeuvres, which are considered to be suitable and highly informative for the development and examination of H/EVs with regenerative braking capability. The critical manoeuvres presented are considered to be appropriate for examination of the regenerative braking mode according to ADSS. The manoeuvres are also important for investigation of regenerative braking system properties/functionalities that are specified by the legal requirements concerning H/EVs braking systems. The last part of this paper shows simulation results for one of the proposed manoeuvres that explicitly shows the usefulness of the manoeuvre