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Objective Genetic variations in the gene encoding zinc finger protein 804A gene (ZNF804A) have been associated with major depression and bipolar disorder. In this work we focused on the potential influence of ZNF804A variations on the risk of developing specific sub-phenotypes as well as the individual response to available treatments. Methods We used two samples of different ethnic origin: a Korean sample, composed by 242 patients diagnosed with major depression and 132 patients diagnosed with bipolar disorder and 326 healthy controls; an Italian sample composed 151 major depression subjects, 189 bipolar disorder subjects and 38 outpatients diagnosed for a primary anxiety disorder. Results Our analyses reported an association of rs1344706 with psychotic phenotype in the cross-diagnostic pooled sample (geno p = 4.15 × 10-4, allelic p = 1.06 × 10-4). In the cross-diagnosis Italian sample but not in the Korean one, rs7597593 was involved with depressive symptoms improvement after treatment (geno p = 0.025, allelic p = 0.007). Conclusion The present study evidenced the role of ZNF804A alterations in symptoms improvement after treatment. Both manic and depressive symptoms seem to be modulated by ZNF804A, though the latter was observed in the bipolar pooled sample only. The role of this factor is likely related to synaptic development and maintenance; however, further analyses will be needed to better understand the molecular mechanics involved with ZNF804A.

Myeloid-derived suppressor cells (MDSC) are well-known key negative regulators of the immune response during tumor growth, however scattered is the knowledge of their capacity to influence and adapt to the different tumor microenvironments and of the markers that identify those capacities. Here we show that the secreted protein acidic and rich in cysteine (SPARC) identifies in both human and mouse MDSC with immune suppressive capacity and pro-tumoral activities including the induction of epithelial-to-mesenchymal transition (EMT) and angiogenesis. In mice the genetic deletion of SPARC reduced MDSC immune suppression and reverted EMT. Sparc−/− MDSC were less suppressive overall and the granulocytic fraction was more prone to extrude neutrophil extracellular traps (NET). Surprisingly, arginase-I and NOS2, whose expression can be controlled by STAT3, were not down-regulated in Sparc−/− MDSC, although less suppressive than wild type (WT) counterpart. Flow cytometry analysis showed equal phosphorylation of STAT3 but reduced ROS production that was associated with reduced nuclear translocation of the NF-kB p50 subunit in Sparc−/− than WT MDSC. The limited p50 in nuclei reduce the formation of the immunosuppressive p50:p50 homodimers in favor of the p65:p50 inflammatory heterodimers. Supporting this hypothesis, the production of TNF by Sparc−/− MDSC was significantly higher than by WT MDSC. Although associated with tumor-induced chronic inflammation, TNF, if produced at high doses, becomes a key factor in mediating tumor rejection. Therefore, it is foreseeable that an unbalance in TNF production could skew MDSC toward an inflammatory, anti-tumor phenotype. Notably, TNF is also required for inflammation-driven NETosis. The high level of TNF in Sparc−/− MDSC might explain their increased spontaneous NET formation as that we detected both in vitro and in vivo, in association with signs of endothelial damage. We propose SPARC as a new potential marker of MDSC, in both human and mouse, with the additional feature of controlling MDSC suppressive activity while preventing an excessive inflammatory state through the control of NF-kB signaling pathway.

BackgroundEribulin mesylate (E) is indicated for metastatic breast cancer patients previously treated with anthracycline and taxane. We argued that E could also benefit patients eligible for neoadjuvant chemotherapy.MethodsPatients with primary triple negative breast cancer ≥2 cm received doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 x 4 cycles (AT) followed by E 1.4 mg/m2 x 4 cycles. Primary endpoint was pathological complete response (pCR) rate; secondary and explorative endpoints included clinical/metabolic response rates and safety, and biomarker analysis, respectively. Using a two-stage Simon design, 43 patients were to be included provided that 4 of 13 patients had achieved pCR in the first stage of the study.ResultsIn stage I of the study 13 women were enrolled, median age 43 years, tumor size 2-5 cm in 9/13 (69%), positive nodal status in 8/13 (61%). Main grade 3 adverse event was neutropenia (related to AT and E in 4 and 2 cases, respectively). AT followed by E induced clinical complete + partial responses in 11/13 patients (85%), pCR in 3/13 (23%). Median measurements of maximum standardized uptake value (SUVmax) resulted 13, 3, and 1.9 at baseline, after AT and E, respectively. Complete metabolic response (CMR) occurred after AT and after E in 2 and 3 cases, respectively. Notably, 2 of the 5 (40%) patients with CMR achieved pCR at surgery. Immunostaining of paired pre-/post-treatment tumor specimens showed a reduction of β-catenin, CyclinD1, Zeb-1, and c-myc expression, in the absence of N-cadherin modulation. The study was interrupted at stage I due to the lack of the required patients with pCR.ConclusionsDespite the early study closure, preoperative E following AT showed clinical and biological activity in triple negative breast cancer patients. Furthermore, the modulation of β-catenin pathway core proteins, supposedly outside the domain of epithelial-mesenchymal transition, claims for further investigation.Trial registrationEU Clinical Trial Register, EudraCT number 2012-004956-12.

BACKGROUND: Mixed mood states, even in their sub-threshold forms, may significantly affect the course and outcome of bipolar disorder (BD). AIM: To compare two samples of BD patients presenting a major depressive episode and a sub-threshold mixed state in terms of global functioning, clinical outcome, social adjustment and quality of life during a 1-year follow-up. METHODS: The sample was composed by 90 subjects (Group 1, D) clinically diagnosed with a major depressive episode and 41 patients (Group 2, Mx) for a sub-threshold mixed state. All patients were administered with a pharmacological treatment and evaluated for depressive, anxious and manic symptoms by common rating scales. Further evaluations included a global assessment of severity and functioning, social adjustment and quality of life. All evaluations were performed at baseline and after 1, 3, 6 and 12 months of treatment. RESULTS: The two groups were no different for baseline as well as improvement in global severity and functioning. Though clearly different for symptoms severity, the amount of change of depressive and anxiety symptoms was also no different. Manic symptoms showed instead a trend to persist over time in group 2, whereas a slight increase of manic symptoms was observed in group 1, especially after 6 months of treatment. Moreover, in group 1, some manic symptoms were also detected at the Young Mania Rating Scale (n = 24, 26.6%). Finally, improvement in quality of life and social adjustment was similar in the two groups, though a small trend toward a faster improvement in social adjustment in group 1. CONCLUSIONS: Sub-threshold mixed states have a substantial impact on global functioning, social adjustment and subjective well-being, similarly to that of acute phases, or at least major depression. In particular, mixed features, even in their sub-threshold forms, tend to be persistent over time. Finally, manic symptoms may be still often underestimated in depressive episodes, even in patients for BD.

Objectives . To compare two samples of Bipolar (BD) patients presenting “ pure ” (D) and mixed (Mx) depression to assess any difference in terms of clinical outcome, social functioning and quality of life during a 1-year follow-up. Methods . A total of 114 depressed outpatients (HDRS 13) were included. “ Pure ” depressed (D, n 76) were divided from “ mixed ” depressed (Mx, n 38) by the number of concomitant manic symptoms. All patients were evaluated by the Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Rating Scale (HARS), the Young Mania Rating Scale (YMRS), the Global Assessment of Functioning (GAF), the Social Adjustment Self-reported Scale (SASS) and the Quality of Life Scale (QoL), at baseline and after 1, 3, 6 and 12 months of treatment. Results . Mx patients were signifi cantly younger at the onset of BD. Manic features persisted signifi cantly higher in Mx than in D patients all over the follow-up period. Axis I comorbidities had a negative impact on the course of social functioning over the medium term period, while Mx patients showed a faster improvement in social adjustment than “ pure ” depressed patients. Conclusions . Mixed features may persist relatively stable throughout a depressive episode, having a negative impact over clinical and functional outcome, but not on social adjustment.