Selective and non-selective apoptosis induction in transformed and non-transformed fibroblasts by exogenous reactive oxygen and nitrogen species.

This paper defines selective and nonselective apoptosis induction in transformed and nontransformed fibroblasts by extracellular reactive oxygen and nitrogen species (ROS and RNS). Superoxide anions do not exhibit direct apoptosis inducing potential, whereas their dismutation product hydrogen peroxide induces apoptosis nonselectively in transformed and nontransformed fibroblasts. Myeloperoxidase converts hydrogen peroxide into the selective apoptosis mediator HOCl, which interacts with transformed target cell-derived superoxide anions and generates apoptosis-inducing hydroxyl radicals. Nitric oxide does not induce apoptosis directly in fibroblasts. However, interaction of nitric oxide with transformed cell-derived superoxide anions leads to the generation of the ultimate apoptosis inducer, peroxynitrite. Peroxynitrite by itself does not discriminate between transformed and nontransformed cells. The direction of generation of apoptosis inducing ROS and RNS to the site of superoxide anion production has relevance for the selectivity of ROS and RNS-based natural antitumor systems, as extracellular superoxide anion generation represents a hallmark of the transformed state.

Association of multiple myeloma with different neoplasms: systematic analysis in consecutive patients with myeloma.

Multiple myeloma (MM) has been suggested to be associated with different neoplasms. Of 589 consecutive patients with MM, 59 (10%) had different neoplasms: solid tumors in 78% and hematological neoplasms in 22%. Different neoplasms were separated into those emerging prior or synchronously (p/s; n = 41) versus subsequently after the MM (n = 18). The rate of different neoplasms at the time of MM diagnosis was estimated as 6.6%, and estimated different neoplasm rates at 2, 5, and 10 years were 7.8%, 10.3%, and 11.6%, respectively. Patients with MM with p/s different neoplasms showed a hazard ratio (HR) for impaired overall survival of 1.2 (95% CI 0.8-2.0), whereas in those with subsequent neoplasms the HR was 2.5 (95% CI 1.4-4.4). This demonstrates that (1) p/s are more frequent compared with subsequent different neoplasms, and (2) the prognosis is more impaired with subsequent different neoplasms. Age ≥60 years was a confounding covariable with a HR of 2.021 (95% CI 1.6-2.6).

Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R.

Danger signals released upon cell damage can cause excessive immune-mediated tissue destruction such as that found in acute graft-versus-host disease (GVHD), allograft rejection and systemic inflammatory response syndrome. Given that ATP is found in small concentrations in the extracellular space under physiological conditions, and its receptor P2X(7)R is expressed on several immune cell types, ATP could function as a danger signal when released from dying cells. We observed increased ATP concentrations in the peritoneal fluid after total body irradiation, and during the development of GVHD in mice and in humans. Stimulation of antigen-presenting cells (APCs) with ATP led to increased expression of CD80 and CD86 in vitro and in vivo and actuated a cascade of proinflammatory events, including signal transducer and activator of transcription-1 (STAT1) phosphorylation, interferon-γ (IFN-γ) production and donor T cell expansion, whereas regulatory T cell numbers were reduced. P2X(7)R expression increased when GVHD evolved, rendering APCs more responsive to the detrimental effects of ATP, thereby providing positive feedback signals. ATP neutralization, early P2X(7)R blockade or genetic deficiency of P2X(7)R during GVHD development improved survival without immune paralysis. These data have major implications for transplantation medicine, as pharmacological interference with danger signals that act via P2X(7)R could lead to the development of tolerance without the need for intensive immunosuppression.