[Estimated impact of the current colorectal screening program in France]. / Estimation de l'impact du programme actuel de dépistage organisé du cancer colorectal.

BACKGROUND: Colorectal cancer is the third most common cancer and the second most deadly in France. A Cochrane meta-analysis has confirmed the benefits of colorectal cancer screening. A nationwide colorectal screening program was set up in France in 2009 for medium-risk, asymptomatic people aged 50 to 74 years. It has been based, since 2015, on the Fecal Immunochemical Test. The participation rate for 2016-2017 was 34%, which is lower than the European objectives. The objective of this study was to evaluate the impact of the program at the current participation rate and at rates of 45% and 65%. METHODS: The epidemiological impact of the program was estimated from the results of an individual simulation model adapted from the Microsimulation Screening Analysis Colon model, calibrated and transposed to the French context. An initial analysis was conducted to estimate the individual impact of screening and a second for the entire eligible population, at various participation rates. RESULTS: The test is associated with a lifetime reduction in the risk of colorectal cancer of 24% for men and 21% for women, and a reduction in the risk of death from colorectal cancer of 51% and 43% respectively. At the current level of participation, the program reduces incidence by 5% and mortality by 14% compared to no organized screening. The impact would be reduced by an additional 3% and 8% for participation rates of 45% and 65% respectively. Similarly, mortality would decrease by an additional 8% and 22%. CONCLUSION: These results confirm that in a population at medium risk for colorectal cancer, the organised programme is an effective strategy for reducing its incidence. They also confirm that the achievement of European objectives remains a key issue for improving the effectiveness of organized screening. An evolution of immunological test delivery modalities could help to achieve these participation objectives.

PML induces a novel caspase-independent death process.

PML nuclear bodies (NBs) are nuclear matrix-associated structures altered by viruses and oncogenes. We show here that PML overexpression induces rapid cell death, independent of de novo transcription and cell cycling. PML death involves cytoplasmic features of apoptosis in the absence of caspase-3 activation, and caspase inhibitors such as zVAD accelerate PML death. zVAD also accelerates interferon (IFN)-induced death, suggesting that PML contributes to IFN-induced apoptosis. The death effector BAX and the cdk inhibitor p27KIP1 are novel NB-associated proteins recruited by PML to these nuclear domains, whereas the acute promyelocytic leukaemia (APL) PML/RAR alpha oncoprotein delocalizes them. Arsenic enhances targeting of PML, BAX and p27KIP1 to NBs and synergizes with PML and IFN to induce cell death. Thus, cell death susceptibility correlates with NB recruitment of NB proteins. These findings reveal a novel cell death pathway that neither requires nor induces caspase-3 activation, and suggest that NBs participate in the control of cell survival.

YOPRO-1 permits cytofluorometric analysis of programmed cell death (apoptosis) without interfering with cell viability.

In the absence of cell permeabilization, the impermeant nuclear dye YOPRO-1 permits accurate analysis of apoptosis using cytofluorometry or fluorescent microscopy. Several immune cell populations were studied including dexamethasone-treated thymocytes, irradiated peripheral blood mononuclear cells and a growth factor-depleted tumor B cell line. Excellent correlation values were found with acridine orange using cytofluorometry and with eosin-hematoxylin using optical microscopy. Under fluorescent microscopy, YOPRO-1-fluorescent cells demonstrate the morphological features of cells undergoing apoptosis such as nuclear shrinkage and fragmentation. An important characteristic of the dye that differs from all other nuclear dyes previously used for the detection of apoptosis is that it does not label living cells. Cell sorting after flow cytofluorometry analysis confirmed that only the apoptotic cell population was labelled with YOPRO-1. Further studies showed that while incubation of living cells with Hoechst 33342 almost completely abrogated the capacity of T cells to proliferate in response to several stimuli, YOPRO-1 had no inhibitory effect. This new simple, rapid and reproducible use of the YOPRO-1 dye should prove useful in the analysis of apoptotic cells as well as for investigations of the functional properties of living cells in a culture containing apoptotic cells.

The relevance of apoptosis to AIDS pathogenesis.

Several recent experimental findings support the hypothesis that apoptosis induced by human immune deficiency virus (HIV) is important in the pathogenesis of acquired immune deficiency syndrome (AIDS). Thus, one potential therapeutic strategy against AIDS may be to block the HIV-mediated apoptosis signal transduction pathway. Induction of apoptosis by HIV infection may prove a useful paradigm for the pathogenesis of a wide range of diseases that involve cell depletion and tissue atrophy.

Programmed cell death and AIDS: significance of T-cell apoptosis in pathogenic and nonpathogenic primate lentiviral infections.

We have proposed that inappropriate induction of programmed cell death (PCD) or apoptosis, a physiological cell-suicide process, may play a role in the pathogenesis of AIDS. This model has been supported by several reports of abnormal levels of PCD in vitro in both CD4+ and CD8+ T cells from human immunodeficiency virus type 1 (HIV-1)-infected persons. To further assess the significance of such a process in AIDS pathogenesis, in vitro PCD was compared in HIV-1-infected persons and in various primate models that allow discrimination between pathogenic chronic lentiviral infection either in the same species, such as rhesus macaques infected with different simian immunodeficiency viruses (SIV), or in different species, such as SIV-infected African green monkeys and HIV-1-infected chimpanzees. Abnormal levels of PCD in CD4(+)-T-cell-depleted peripheral blood mononuclear cells (PBMC), containing the CD8+ T cells, were observed in both pathogenic and nonpathogenic models. However, abnormal levels of PCD in the CD8(+)-T-cell-depleted PBMC, containing the CD4+ T cells, was only observed in the two models leading to AIDS: HIV-1-infected persons and rhesus macaques infected with a pathogenic strain of SIV. This suggests that inappropriate T-cell PCD in HIV-1-infected persons involves two distinct processes: one, concerning CD4+ T cells, is closely related to AIDS pathogenesis; and the other, concerning CD8+ T cells, may be a consequence of immune stimulation with no direct link to AIDS pathogenesis.