How cell death shapes cancer.

Apoptosis has been established as a mechanism of anti-cancer defense. Members of the BCL-2 family are critical mediators of apoptotic cell death in health and disease, often found to be deregulated in cancer and believed to lead to the survival of malignant clones. However, over the years, a number of studies pointed out that a model in which cell death resistance unambiguously acts as a barrier against malignant disease might be too simple. This is based on paradoxical observations made in tumor patients as well as mouse models indicating that apoptosis can indeed drive tumor formation, at least under certain circumstances. One possible explanation for this phenomenon is that apoptosis can promote proliferation critically needed to compensate for cell loss, for example, upon therapy, and to restore tissue homeostasis. However, this, at the same time, can promote tumor development by allowing expansion of selected clones. Usually, tissue resident stem/progenitor cells are a major source for repopulation, some of them potentially carrying (age-, injury- or therapy-induced) genetic aberrations deleterious for the host. Thereby, apoptosis might drive genomic instability by facilitating the emergence of pathologic clones during phases of proliferation and subsequent replication stress-associated DNA damage. Tumorigenesis initiated by repeated cell attrition and repopulation, as confirmed in different genetic models, has parallels in human cancers, exemplified in therapy-induced secondary malignancies and myelodysplastic syndromes in patients with congenital bone marrow failure syndromes. Here, we aim to review evidence in support of the oncogenic role of stress-induced apoptosis.

Pitot-tube flowmeter for quantification of airflow during sleep.

The gold-standard pneumotachograph is not routinely used to quantify airflow during overnight polysomnography due to the size, weight, bulkiness and discomfort of the equipment that must be worn. To overcome these deficiencies that have precluded the use of a pneumotachograph in routine sleep studies, our group developed a lightweight, low dead space 'pitot flowmeter' (based on pitot-tube principle) for use during sleep. We aimed to examine the characteristics and validate the flowmeter for quantifying airflow and detecting hypopneas during polysomnography by performing a head-to-head comparison with a pneumotachograph. Four experimental paradigms were utilized to determine the technical performance characteristics and the clinical usefulness of the pitot flowmeter in a head-to-head comparison with a pneumotachograph. In each study (1-4), the pitot flowmeter was connected in series with a pneumotachograph under either static flow (flow generator inline or on a face model) or dynamic flow (subject breathing via a polyester face model or on a nasal mask) conditions. The technical characteristics of the pitot flowmeter showed that, (1) the airflow resistance ranged from 0.065 ± 0.002 to 0.279 ± 0.004 cm H(2)O L(-1) s(-1) over the airflow rates of 10 to 50 L min(-1). (2) On the polyester face model there was a linear relationship between airflow as measured by the pitot flowmeter output voltage and the calibrated pneumotachograph signal a (ß(1) = 1.08 V L(-1) s(-1); ß(0) = 2.45 V). The clinically relevant performance characteristics (hypopnea detection) showed that (3) when the pitot flowmeter was connected via a mask to the human face model, both the sensitivity and specificity for detecting a 50% decrease in peak-to-peak airflow amplitude was 99.2%. When tested in sleeping human subjects, (4) the pitot flowmeter signal displayed 94.5% sensitivity and 91.5% specificity for the detection of 50% peak-to-peak reductions in pneumotachograph-measured airflow. Our data validate the pitot flowmeter for quantification of airflow and detecting breathing reduction during polysomnographic sleep studies. We speculate that quantifying airflow during sleep can differentiate phenotypic traits related to sleep disordered breathing.

Lepirudin treatment in a girl with iliac vein thrombosis, severe pulmonary embolism and suspected heparin-induced thrombocytopenia (HIT) II.

We report on a 15-year-old girl referred to us for dyspnea. Investigations revealed multiple pulmonary emboli originating from iliac vein thrombosis. As under heparin therapy, d-dimers rose again and the thrombus grew significantly in size while platelet count decreased by >30%. A diagnosis of heparin-induced thrombocytopenia (HIT) type II was suspected, heparin-treatment was stopped and lepirudin therapy was started successfully at a doses of 0.15 mg/kg bw/hr.

BH3-only proteins in cell death initiation, malignant disease and anticancer therapy.

Induction of apoptosis in tumour cells, either by direct activation of the death receptor pathway using agonistic antibodies or recombinant ligands, or direct triggering of the Bcl-2-regulated intrinsic apoptosis pathway by small molecule drugs, carries high hopes to overcome the shortcomings of current anticancer therapies. The latter therapy concept builds on a more detailed understanding of how Bcl-2-like molecules maintain mitochondrial integrity and how BH3-only proteins and Bax/Bak-like molecules can undermine it. Means to unleash the apoptotic potential of BH3-only proteins in tumour cells, or bypass the need for BH3-only proteins by blocking possible interactions of Bcl-2-like prosurvival molecules with Bax and/or Bak allowing their direct activation, constitute interesting options for the design of novel anticancer therapies.