Erik Mayer

We recently demonstrated that human BM cells can be treated in vitro with defined growth factors to induce the rapid generation of myeloid-derived suppressor cells (MDSCs), hereafter defined as BM-MDSCs. Indeed, combination of G-CSF + GM-CSF led to the development of a heterogeneous mixture of immature myeloid cells ranging from myeloblasts to band cells that were able to suppress alloantigen- and mitogen-stimulated T lymphocytes. Here, we further investigate the mechanism of suppression and define the cell subset that is fully responsible for BM-MDSC-mediated immune suppression. This population, which displays the structure and markers of promyelocytes, is however distinct from physiologic promyelocytes that, instead, are devoid of immuosuppressive function. In addition, we demonstrate that promyelocyte-like cells proliferate in the presence of activated lymphocytes and that, when these cells exert suppressive activity, they do not differentiate but rather maintain their immature phenotype. Finally, we show that promyelocyte-like BM-MDSCs are equivalent to MDSCs present in the blood of patients with breast cancer and patients with colorectal cancer and that increased circulating levels of these immunosuppressive myeloid cells correlate with worse prognosis and radiographic progression.

Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1-100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential.

OBJECTIVES: To assess the association between mortality and the day of elective surgical procedure. DESIGN: Retrospective analysis of national hospital administrative data. SETTING: All acute and specialist English hospitals carrying out elective surgery over three financial years, from 2008-09 to 2010-11. PARTICIPANTS: Patients undergoing elective surgery in English public hospitals. MAIN OUTCOME MEASURE: Death in or out of hospital within 30 days of the procedure. RESULTS: There were 27,582 deaths within 30 days after 4,133,346 inpatient admissions for elective operating room procedures (overall crude mortality rate 6.7 per 1000). The number of weekday and weekend procedures decreased over the three years (by 4.5% and 26.8%, respectively). The adjusted odds of death were 44% and 82% higher, respectively, if the procedures were carried out on Friday (odds ratio 1.44, 95% confidence interval 1.39 to 1.50) or a weekend (1.82, 1.71 to 1.94) compared with Monday. CONCLUSIONS: The study suggests a higher risk of death for patients who have elective surgical procedures carried out later in the working week and at the weekend.