High susceptibility of c-KIT+CD34+ precursors to prolonged doxorubicin exposure interferes with Langerhans cell differentiation in a human cell line model

As neoadjuvant and adjuvant chemotherapy schedules often consist of multiple treatment cycles over relatively long periods of time, it is important to know what effects protracted drug administration can have on the immune system. Here, we studied the long-term effects of doxorubicin on the capacity of dendritic cell (DC) precursors to differentiate into a particular DC subset, the Langerhans cells (LC). In order to achieve high telomerase activity as detected in hematological stem cells, precursor cells from the acute-myeloid leukemia (AML)-derived cell line MUTZ3 were stably transduced with human telomerase reverse transcriptase (hTERT) to facilitate their growth potential, while preventing growth, and drug-induced senescence, and preserving their unique capacity for cytokine-dependent DC and LC differentiation. The hTERT-MUTZ3 cells were selected with increasing concentrations of the anthracyclin doxorubicin. After 1–2 months of selection with 30–90 nM doxorubicin, the cells completely lost their capacity to differentiate into LC. This inhibition turned out to be reversible, as the cells slowly regained their capacity to differentiate after a 3- to 4-month drug-free period and with this became capable again of priming allogeneic T cells. Of note, the loss and gain of this capacity to differentiate coincided with the loss and gain of a subpopulation within the CD34+ proliferative compartment with surface expression of the stem cell factor receptor (SCF-R/CD117/c-Kit). These data are in favor of cytostatic drug-free intervals before applying autologous DC-based vaccination protocols, as specific DC precursors may need time to recover from protracted chemotherapy treatment and re-emerge among the circulating CD34+ hematopoietic stem and precursor cells

Italian Public Administration Reform: what are the limits of financial performance measures?

The Italian public sector reforms in recent years have demonstrated an over-reliance on accounting-based financial measurements which has essentially created a sort of ‘hierarchization’ of performance. This chapter aims to demonstrate whether and how this predominance leads to negative consequences in the evaluation (and management) of public sector organizations: First, because in definitive governments, performance should be assessed coupling financial parameters with non-financial measures and qualitative judgements (Jones and Pendlebury in Public Sector Accounting, 6th ed., Pearson Prentice Hall, London, 2010); second, for the lack of a systemic approach, financial performance should not be the ultimate objective of public management but instead an instrument to evaluate the financial comparability of various priorities to purse (public value, social, environmental, etc.) (Esposito and Ricci in Public Money Manage 35(3):227–231, 2015)