Extravasations and emigration of neutrophils to the inflammatory site depend on the interaction of immune-complex with Fcgamma receptors and can be effectively blocked by decoy Fcgamma receptors

Extravasation and emigration of neutrophils to the site of inflammation are essential early steps in the initiation of many antibody-mediated autoimmune diseases. The Fc domains of cell bound autoantibodies or immune-complexes (IC) are capable of triggering the neutrophil emigration via complement and FcgammaRs-mediated mechanisms. To define the clinical relevance and the relative contribution of these 2 pathways in IC-mediated neutrophil emigration, we have neutralized the FcgammaR-binding activity of IC with a recombinant dimeric Fc receptor, CD16A-Ig, and investigated the early events of IC-induced inflammation in mice. Systemic administration of purified CD16A-Ig blocked IC-induced inflammation, mast- cell degranulation, and extravasation of neutrophils in a reversed Arthus reaction. Although the binding of CD16A-Ig to IC did not alter the complement-activating properties of IC, no evidence for complement-dependent neutrophil emigration was observed. These results suggest that interaction of IC with cells expressing FcgammaRs at the inflammatory site results in the secretion of chemoattractants, which mediate complement-independent emigration of neutrophils in this cutaneous acute inflammation model. Furthermore, blocking the interaction of IC to FcgammaRs expressed on inflammatory cells by administering high-avidity Fc fusion dimers of low-affinity FcgammaRs is an effective way of preventing IC-induced acute inflammation in autoimmune diseases.     

Custom designing therapeutic cancer vaccines: delivery of immunostimulatory molecule adjuvants by protein transfer

Attempts to create vaccines for humans against invading pathogens such as viruses and bacteria have met with tremendous success. The process of developing vaccines against these pathogens is greatly aided by the fact that they contain antigens that are entirely foreign to humans. Although the knowledge and strategies developed for designing vaccines against these microbes may be of use in developing cancer vaccines, the poor antigenicity and immunosuppressive ability of cancers pose major hurdles to vaccine development. Established tumors have not only withstood immune screening and selection pressure, making them poor stimulators of an immune response, but have also adapted mechanisms to continue evading immune surveillance by creating an immunosuppressive environment. Also, genetic differences in immune responses to an antigen among individuals result in an antigenic profile that varies from patient to patient. Cancers bear such great similarities to normal cells in the body that, on a molecular level, the differences between cancerous and non-cancerous cells are minor. Therefore, developing vaccines which use the host's own tumor tissues carries the risk of breaking tolerance to self-antigens that are present in the tumor tissue. Vaccination strategies that will optimally stimulate the immune system against tumor specific antigens under immunosuppressive conditions need to be developed. In practical terms, this calls for a method by which therapeutic vaccines may be custom-designed to treat cancers case by case. Ex vivo manipulation of dendritic cells and gene transfer of immunostimulatory molecules in ex vivo expanded tumors are being tested in both experimental models and also in human clinical trials. Some of them have met with limited success. Emerging technologies such as protein transfer, which make it possible to express immunostimulatory molecules on tumor cell membranes, offer the means to develop efficient tumor vaccines that are simple and fast, while being easy to store and administer in human patients. Progress in these techniques will move the cancer vaccine field a step closer towards realizing custom designed cancer vaccines in human clinical settings.     

Does the type of suture material used for ligation of the vas deferens affect vasectomy success?

OBJECTIVES: To determine retrospectively, the outcome of vasectomies performed by five urologists over a six year period in terms of achievement of azoospermia on post vasectomy semen analysis (PVSA) and to compare the effect of the type of suture material used for ligation of the vas deferens on the vasectomy success. METHODS: Review of PVSA results of 3005 consecutive vasectomies done in a district general hospital between November 1998 and October 2004. Patient records and vasectomy logs were reviewed and data analysed. The main outcome measure was achievement of azoospermia on PVSA. RESULTS: The age distribution of men between the two study groups was similar. Overall compliance to provide at least two semen samples for PVSA was 73.8% and was similar between the two groups. Failure to achieve azoospermia on PVSA was seen in 3.5% men (36/1038) in the chromic catgut group and 10.1% men (110/1088) in the Vicryl group (p < 0.0001). Also, the vasectomy failure rates for individual urologists increased significantly following introduction of Vicryl. CONCLUSIONS: In our study we noticed a three fold increase in failure to achieve azoospermia on PVSA with Vicryl as compared to chromic catgut. This study demonstrates that the type of suture material used for ligation of the vas deferens does affect the vasectomy success.     

Recapitulating Tumor Microenvironment Using AXTEX-4DTM for Accelerating Cancer Research and Drug Screening

Objective: The formation of three-dimensional spheroid tumor model using the scaffold-based platforms has been demonstrated over many years now. 3D tumor models are generated mainly in non-scalable culture systems, using synthetic and biological scaffolds. Many of these models fail to reflect the complex tumor microenvironment and do not allow long-term monitoring of tumor progression. This has resulted in inconsistent data in drug testing assays during preclinical and clinical studies. Methods: To overcome these limitations, we have developed 3D tissueoids model by using novel AXTEX-4D platform. Results: Cancer 3D tissueoids demonstrated the basic features of 3D cell culture with rapid attachment, proliferation, and longevity with contiguous cytoskeleton and hypoxic core. This study also demonstrated greater drug resistance in 3D-MCF-7 tissueoids in comparison to 2D monolayer cell culture. Conclusion: In conclusion, 3D-tissueoids are more responsive than 2D-cultured cells in simulating important tumor characteristics, anti-apoptotic features, and their resulting drug resistance.