Maladaptive impulsivity is a core symptom in various psychiatric disorders. However, there is only limited evidence available on whether different measures of impulsivity represent largely unrelated aspects or a unitary construct. In a cross-species translational study, thirty rats were trained in impulsive choice (delayed reward task) and impulsive action (five-choice serial reaction time task) paradigms. The correlation between those measures was assessed during baseline performance and after pharmacological manipulations with the psychostimulant amphetamine and the norepinephrine reuptake inhibitor atomoxetine. In parallel, to validate the animal data, 101 human subjects performed analogous measures of impulsive choice (delay discounting task, DDT) and impulsive action (immediate and delayed memory task, IMT/DMT). Moreover, all subjects completed the Stop Signal Task (SST, as an additional measure of impulsive action) and filled out the Barratt impulsiveness scale (BIS-11). Correlations between DDT and IMT/DMT were determined and a principal component analysis was performed on all human measures of impulsivity. In both rats and humans measures of impulsive choice and impulsive action did not correlate. In rats the within-subject pharmacological effects of amphetamine and atomoxetine did not correlate between tasks, suggesting distinct underlying neural correlates. Furthermore, in humans, principal component analysis identified three independent factors: (1) self-reported impulsivity (BIS-11); (2) impulsive action (IMT/DMT and SST); (3) impulsive choice (DDT). This is the first study directly comparing aspects of impulsivity using a cross-species translational approach. The present data reveal the non-unitary nature of impulsivity on a behavioral and pharmacological level. Collectively, this warrants a stronger focus on the relative contribution of distinct forms of impulsivity in psychopathology.

One of the hallmarks of cancer is the influx of myeloid cells. In our study, we investigated the constitution of tumorinfiltrating myeloid cells and their relationship to other tumor-infiltrating immune cells, tumor characteristics and the diseasespecific survival of patients with cervical cancer (CxCa). Triple-color immunofluorescence confocal microscopy was used to locate, identify and quantify macrophages (CD14), their maturation status (CD33) and their polarization (CD163) in a cohort of 86 patients with cervical carcinoma. Quantification of the numbers of myeloid cells revealed that a strong intraepithelial infiltration of CD141 cells, and more specifically the population of CD141CD332CD1632 matured M1 macrophages, is associated with a large influx of intraepithelial T lymphocytes (p 5 0.008), improved disease-specific survival (p 5 0.007) and forms an independent prognostic factor for survival (p 5 0.033). The intraepithelial CD81 T-cell and regulatory T-cell (Treg) ratio also forms an independent prognostic factor (p 5 0.010) and combination of these two factors reveals a further increased benefit in survival for patients whose tumor displays a dense infiltration with intraepithelial matured M1 macrophages and a high CD8 T-cell/Treg ratio, indicating that both populations of immune cells simultaneously improve survival. Subsequently, we made a heatmap including all known immune parameters for these patients, whereby we were able to identify different immune signatures in CxCa. These results indicate that reinforcement and activation of the intratumoral M1 macrophages may form an attractive immunotherapeutic option in CxCa. Cervical cancer (CxCa) is caused by high-risk human papillomavirus (HPV).1 Studies on HPV-specific T-cell responses in patients with premalignant disease suggest that spontaneous regression occurs when circulating HPV early antigen-specific CD41 and CD81 T-cells are present and when the lesions are infiltrated with effector T-cells that outnumber regulatory Tcells (Tregs). Moreover, the presence of circulating HPVspecific CD41 T-cells is associated with T-cell infiltration in the lesion and favorable clinical outcome in high-grade squamous intraepithelial lesion after treatment.2,3 The development of CxCa is associated with a weak systemic and local immune response to HPV, reflected by low numbers of tumorinfiltrating T-cells comprising CD81 cytotoxic T-cells, CD41 T-helper cells and Tregs. [4][5][6] The T-cells present often lack cytotoxicity 7 and/or express coinhibitory molecules such as programmed cell death protein 1, CD94 and NKG2a. 8,9 Tumors also downregulate human leukocyte antigen (HLA) class I and MHC class I chain-related molecule A (MICA) and upregulate HLA-E and PD-L1 to further restrain the CD81 T-cell response. 2,[8][9][10] The presence of circulating HPV-specific T-cells associates with better survival and high numbers of T-cells correlate with the absence of metastases or a relapse. 2,6,11,12 Importantly, the ratio between tumor-infiltrating CD81 and Foxp31 T-cells wa...

New treatments based on combinations of standard therapeutic modalities and immunotherapy are of potential use, but require a profound understanding of immune modulatory properties of standard therapies. Here, the impact of standard (chemo)radiotherapy on the immune system of cervical cancer patients was evaluated. Thirty patients with cervical cancer were treated with external beam radiation therapy (EBRT), using conventional three-dimensional or intensity modulated radiation therapy without constraints for bone marrow sparing. Serial blood sampling for immunomonitoring was performed before, midway and at 3, 6 and 9 weeks after EBRT to analyze the composition of lymphocyte and myeloid-cell populations, the expression of co-stimulatory molecules, T-cell reactivity and antigen presenting cell (APC) function. Therapy significantly decreased the absolute numbers of circulating leukocytes and lymphocytes. Furthermore, the capacity of the remaining T cells to respond to antigenic or mitogenic stimulation was impaired. During treatment the frequency of both CD4+ and CD8+ T cells dropped and CD4+ T cells displayed an increased expression of programmed cell death-1 (PD-1). In vitro blocking of PD-1 successfully increased T-cell reactivity in all five samples isolated before radiotherapy but was less successful in restoring reactivity in samples isolated at later time points. Moreover, (chemo)radiotherapy was associated with an increase in both circulating monocytes and myeloid-derived suppressor cells (MDSCs) and an impaired capacity of APCs to stimulate allogeneic T cells. T-cell reactivity was slowly restored at 6–9 weeks after cessation of therapy. We conclude that conventional (chemo)radiotherapy profoundly suppresses the immune system in cervical cancer patients, and may restrict its combination with immunotherapy.

Our results suggest flow cytometric measurement of agonist-induced P-selectin expression can measure PLT quality decline over the entire range encountered during 10-day storage of both standard PLTs and Mirasol-treated PLTs in plasma.