Smoldering, nonresolving inflammation is a component of the tumor microenvironment. The linkage between inflammation and cancer, first perceived in the nineteenth century, is now part of an accepted ...paradigm of carcinogenesis.
Clinical Pharmacology & Therapeutics (2010) 87 4, 401–406. doi:10.1038/clpt.2009.312
Animal experiments remain essential to understand the fundamental mechanisms underpinning malignancy and to discover improved methods to prevent, diagnose and treat cancer. Excellent standards of ...animal care are fully consistent with the conduct of high quality cancer research. Here we provide updated guidelines on the welfare and use of animals in cancer research. All experiments should incorporate the 3Rs: replacement, reduction and refinement. Focusing on animal welfare, we present recommendations on all aspects of cancer research, including: study design, statistics and pilot studies; choice of tumour models (e.g., genetically engineered, orthotopic and metastatic); therapy (including drugs and radiation); imaging (covering techniques, anaesthesia and restraint); humane endpoints (including tumour burden and site); and publication of best practice.
A complex network of chemokines and their receptors influences the development of primary tumours and metastases. New information about the biological role of chemokines in these processes is ...providing insights into host-tumour interactions, such as the role of the leukocyte infiltrate, and into the mechanisms that determine the metastatic potential and site-specific spread of cancer cells. Chemokine-receptor antagonists are showing promise in animal models of inflammation and autoimmune disease. Could manipulating the local chemokine network have therapeutic benefits in malignant disease?
Tumour necrosis factor-α (TNF-α) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-α monoclonal antibody was investigated in this trial ...of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective.
Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-α, CCL2, IL-6 and C-reactive protein (CRP).
Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-α was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10–50+ weeks). There was no evidence of disease acceleration in any patient.
Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-α and CCL2 being correlated with infliximab response.
Mechanical characterisation of soft biological tissues using standard compression or tensile testing presents a significant challenge due to specimen geometrical irregularities, difficulties in ...cutting intact and appropriately sized test samples, and issues with slippage or damage at the grips. Indentation can overcome these problems but requires fitting a model to the resulting load–displacement data in order to calculate moduli. Despite the widespread use of this technique, few studies experimentally validate their chosen model or compensate for boundary effects. In this study, viscoelastic hydrogels of different concentrations and dimensions were used to calibrate an indentation technique performed at large specimen-strain deformation (20%) and analysed with a range of routinely used mathematical models. A rigid, flat-ended cylindrical indenter was applied to each specimen from which ‘indentation moduli’ and relaxation properties were calculated and compared against values obtained from unconfined compression. Only one indentation model showed good agreement (<10% difference) with all moduli values obtained from compression. A sample thickness to indenter diameter ratio ≥1:1 and sample diameter to indenter diameter ratio ≥4:1 was necessary to achieve the greatest accuracy. However, it is not always possible to use biological samples within these limits, therefore we developed a series of correction factors. The approach was validated using human diseased omentum and bovine articular cartilage resulting in mechanical properties closely matching compression values. We therefore present a widely useable indentation analysis method to allow more accurate calculation of material mechanics which is important in the study of soft tissue development, ageing, health and disease.
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•Experimental calibration: indentation versus compression of soft viscoelastic gels.•Simple mathematical indentation models tested for accuracy at large strain (20%).•We generate correction factors accounting for model errors and specimen geometry.•Corrected models validated against soft biological tissues; omentum and cartilage.•Correction factors can be applied to soft materials in the range 0.001–10MPa.
To determine the efficacy of bortezomib in patients with lymphoid malignancy, correlating clinical response with effect on plasma cytokines and in vitro activity in primary cultures.
Patients ...received bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11 of a 3-week cycle. Plasma tumor necrosis factor alpha (TNF-alpha) and interleukin-6 were measured before each treatment, and bortezomib activity was examined in patient samples grown in primary culture.
Fifty-one patients received a total of 193 cycles of treatment. Twenty-four patients had mantle cell lymphoma (MCL), 13 had follicular lymphoma (FL), six had lymphoplasmacytic lymphoma, six had Hodgkin's disease (HD), and one each had diffuse large B-cell lymphoma and adult T-cell leukemia/lymphoma. Patients were heavily pretreated with a median of four previous therapies. Significant grade 3 to 4 toxicities were thrombocytopenia (n = 22), fatigue (n = 10), and peripheral neuropathy (n = 3). Seven patients with MCL responded to treatment (one complete response, six partial responses PRs; overall response rate, 29%). Two patients with FL achieved a late PR 3 months after discontinuing therapy. Two patients with Waldenström's macroglobulinemia and one patient with HD achieved a PR. MCL primary cultures demonstrated greater sensitivity to bortezomib than FL (median 50% effective concentration for viability, 209 nmol/L v 1,311 nmol/L, respectively; P = .07), which correlated with clinical response. A median reduction in plasma TNF-alpha of 98% was observed in six patients with MCL who responded to bortezomib compared with a reduction of 38% in six nonresponders (P = .07).
Bortezomib demonstrates encouraging efficacy in MCL in heavily pretreated individuals. Response was associated with a reduction in plasma TNF-alpha and in vitro sensitivity in a small number of patients.
Malignant cells from at least 23 different types of cancer express the chemokine receptor CXCR4 and respond to its ligand CXCL12. This receptor ligand pair appears to be involved in directed ...migration of cancer cells to sites of metastasis, increased survival of cancer cells in sub optimal conditions and establishment of a tumour promoting cytokine/chemokine network. Preliminary data from animal models suggest that CXCR4 may be an important therapeutic target in a range of cancers. However CXCR4 plays major roles in embryogenesis, homeostasis and inflammation. This raises questions concerning the specificity of CXCR4 antagonists in the treatment of cancer.
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