DZR had a significant cardioprotective effect as measured by noninvasive testing and clinical CHF. One of the two studies (088001) showed a lower response rate with DZR, but time to progression and survival were not significantly different. DZR is the first agent shown to reduce cardiotoxicity from doxorubicin.

. Cell death and the subsequent post-mortem changes, called necrosis, are integral parts of normal development and maturation cycle. Despite the importance of this process, the mechanisms underlying cell death are still poorly understood. In the recent literature, cell death is said to occur by two alternative, opposite modes: apoptosis, a programmed, managed form of cell death, and necrosis, an unordered and accidental form of cellular dying. The incorrect consequence is the overlapping of: a) the process whereby cells die, cell death; and b) the changes that the cells and tissues undergo after the cells die. Only the latter process can be referred to as necrosis and represents a 'no return' process in cell life. In this review, we discuss the excellent basic research developed in this field during last decades and problems that remain to be resolved in defining both experimentally and mechanicistically the events that lead to and characterize cell death. IntroductionCell death is part of normal development and maturation cycle, and is the component of many response patterns of living tissues to xenobiotic agents (i.e. micro organisms and chemicals) and to endogenous modulations, such as inflammation and disturbed blood supply (1,2). Cell death is an important variable in cancer development, cancer prevention and cancer therapy (3-5). In the treatment of cancer, the major approach is the removal, by surgery, of the neoplasm and/or the induction of cell death in neoplastic cells by radiation, toxic chemicals, antibodies and/or cells of the immune system (6-9). On the other hand, this pathobiological process remains poorly understood and the physiological and biochemical factors that lead to cell death are still not clear. One main factor is the existing confusion between 'apoptosis' process, as compared and contrasted with 'necrosis', leading to the overlapping of the ante mortem changes, i.e. the process of cell death, and the post-mortem changes, i.e. the necrosis process. The pathobiology of cell deathThe elegant scientific exploration of sub-cellular molecular anatomy of the last decades have reinforced the cell concept as 'the smallest integrating unit in biology: a pseudo-intelligent computer that receives, screens, changes, reacts to and adapts to a host of environmental signals, all of this activity apparently

Endothelial progenitor cells are increasingly being studied in various diseases ranging from ischemia, diabetic retinopathy, and in cancer. The discovery that these cells can be mobilized from their bone marrow niche to sites of inflammation and tumor to induce neovasculogenesis has afforded a novel opportunity to understand the tissue microenvironment and specific cell-cell interactive pathways. This review provides a comprehensive up-to-date understanding of the physiological function and therapeutic utility of these cells. The emphasis is on the systemic factors that modulate their differentiation/mobilization and survival and presents the challenges of its potential therapeutic clinical utility as a diagnostic and prognostic reagent.

BackgroundAdjuvants serve as catalysts of the innate immune response by initiating a localized site of inflammation that is mitigated by the interactions between antigens and toll like receptor (TLR) proteins. Currently, the majority of vaccines are formulated with aluminum based adjuvants, which are associated with various side effects. In an effort to develop a new class of adjuvants, agonists of TLR proteins, such as bacterial products, would be natural candidates. Lipopolysaccharide (LPS), a major structural component of gram negative bacteria cell walls, induces the systemic inflammation observed in septic shock by interacting with TLR-4. The use of synthetic peptides of LPS or TLR-4 agonists, which mimic the interaction between TLR-4 and LPS, can potentially regulate cellular signal transduction pathways such that a localized inflammatory response is achieved similar to that generated by adjuvants.Methodology/Principal FindingsWe report the identification and activity of several peptides isolated using phage display combinatorial peptide technology, which functionally mimicked LPS. The activity of the LPS-TLR-4 interaction was assessed by NF-κB nuclear translocation analyses in HEK-BLUE™-4 cells, a cell culture model that expresses only TLR-4, and the murine macrophage cell line, RAW264.7. Furthermore, the LPS peptide mimics were capable of inducing inflammatory cytokine secretion from RAW264.7 cells. Lastly, ELISA analysis of serum from vaccinated BALB/c mice revealed that the LPS peptide mimics act as a functional adjuvant.Conclusions/SignificanceOur data demonstrate the identification of synthetic peptides that mimic LPS by interacting with TLR-4. This LPS mimotope-TLR-4 interaction will allow for the development and use of these peptides as a new class of adjuvants, namely TLR-4 agonists.

Twenty-five patients with stage IV melanoma were immunized with the mouse anti-idiotypic monoclonal antibody (mAb) MK2-23 (2 mg per injection), which bears the internal image of the determinant defined by anti-HMW-MAA mAb 763.74. Two patients were inevaluable, since they did not complete 4 weeks of therapy. Only 14 patients developed antibodies that were shown by serological and immunochemical assays to recognize the same or spatially close determinant as the anti-HMW-MAA mAb 763.74 and to express the idiotope dermed by mAb MK2-23 in their antigen-combining sites. Side effects that are likely to be caused by bacillus Calmette-Guirin present in the immunogen consisted of erythema, induration, and ulceration at the sites of the injections. Occasionally, patients complained of flu-like symptoms, arthralgias, and myalgias. Three of the patients who developed anti-HMW-MAA antibodies achieved a partial response. It consisted of a decrease in the size of metastatic lesions and lasted 52 weeks in 1 patient and 93 weeks in the other 2 patients. Survival of the 14 patients who developed anti-HMW-MAA antibodies was significantly (P = 0.0003) longer than that of the 9 patients without detectable humoral anti-HMW-MAA immunity development. In the multivariate analysis, such an association between development of anti-HMW-MAA antibodies and survival prolongation was still significant (P = 0.001) after adjustment for difference in performance status, the only confounding factor found to be significantly related to survival. Lastly, a significant (P = 0.03 by likelihood ratio test) interaction between anti-HMW-MAA antibodies and patients' performance status was found, since the prolongation of survival associated with anti-HMW-MAA antibodies was more marked in patients with a performance status of s70% than in those with a higher one. These results suggest that anti-idiotypic mAb MK2-23 may represent a useful immunogen to implement active specific immunotherapy in patients with melanoma.The identification with monoclonal antibodies (mAbs) of human MAA that meet most, if not all, the criteria to be used as targets for immunotherapy (1-3) has stimulated interest in the development and application of immunotherapeutic approaches to melanoma. In the area of active specific immunotherapy, one immunogen is represented by anti-idiotypic mAb (i.e., antibodies to determinants on the variable region of anti-MAA antibodies, which bear the internal image of MAA (KLH) and mixed with bacillus CalmetteGudrin (BCG) has been used as an immunogen, since conjugation to a carrier and administration with an adjuvant have been shown to greatly enhance the immunogenicity of mAb MK2-23 in animal model systems (11).