Heisenberg scaling precision in multi-mode distributed quantum metrology

We consider the estimation of an arbitrary parameter φ, such as the temperature or a magnetic field, affecting in a distributed manner the components of an arbitrary linear optical passive network, such as an integrated chip. We demonstrate that Heisenberg scaling precision (i.e. of the order of 1/N, where N is the number of probe photons) can be achieved without any iterative adaptation of the interferometer hardware and by using only a simple, single, squeezed light source and well-established homodyne measurements techniques. Furthermore, no constraint on the possible values of the parameter is needed but only a preliminary shot-noise estimation (i.e. with a precision of) easily achievable without any quantum resources. Indeed, such a classical knowledge of the parameter is enough to prepare a single, suitable optical stage either at the input or the output of the network to monitor with Heisenberg-limited precision any variation of the parameter to the order of without the need to iteratively modify such a stage

Unveiling metabolic vulnerability and plasticity of human osteosarcoma stem and differentiated cells to improve cancer therapy

Defining the metabolic phenotypes of cancer-initiating cells or cancer stem cells and of their differentiated counterparts might provide fundamental knowledge for improving or developing more effective therapies. In this context we extensively characterized the metabolic profiles of two osteosarcoma-derived cell lines, the 3AB-OS cancer stem cells and the parental MG-63 cells. To this aim Seahorse methodology-based metabolic flux analysis under a variety of conditions complemented with real time monitoring of cell growth by impedentiometric technique and confocal imaging were carried out. The results attained by selective substrate deprivation or metabolic pathway inhibition clearly show reliance of 3AB-OS on glycolysis and of MG-63 on glutamine oxidation. Treatment of the osteosarcoma cell lines with cisplatin resulted in additive inhibitory effects in MG-63 cells depleted of glutamine whereas it antagonized under selective withdrawal of glucose in 3AB-OS cells thereby manifesting a paradoxical pro-survival, cell-cycle arrest in S phase and antioxidant outcome. All together the results of this study highlight that the efficacy of specific metabolite starvation combined with chemotherapeutic drugs depends on the cancer compartment and suggest cautions in using it as a generalizable curative strategy

Desmopressin Stimulates Nitric Oxide Production in Human Lung Microvascular Endothelial Cells

Desmopressin (dDAVP) is the best characterized analogue of vasopressin, the endocrine regulator of water balance endowed with potent vasoconstrictive effects. Despite the use of dDAVP in clinical practice, ranging from the treatment of nephrogenic diabetes insipidus to bleeding disorders, much remains to be understood about the impact of the drug on endothelial phenotype. The aim of this study was, thus, to evaluate the effects of desmopressin on the viability and function of human pulmonary microvascular endothelial cells (HLMVECs). The results obtained demonstrate that the vasopressor had no cytotoxic effect on the endothelium; similarly, no sign of endothelial activation was induced by dDAVP, indicated by the lack of effect on the expression of inflammatory cytokines and adhesion molecules. Conversely, the drug significantly stimulated the production of nitric oxide (NO) and the expression of the inducible isoform of nitric oxide synthase, NOS2/iNOS. Since the intracellular level of cAMP also increased, we can hypothesize that NO release is consequent to the activation of the vasopressin receptor 2 (V2R)/guanylate cyclase (Gs)/cAMP axis. Given the multifaceted role of NOS2-deriving NO for many physio-pathological conditions, the meanings of these findings in HLMVECs appears intriguing and deserves to be further addressed

Pre and post anti Her-2 therapy era: a mono-institutional analysis of the outcome in patients with residual disease after neoadjuvant therapy for Her-2 positive locally advanced breast cancer.

Background: Anti Her-2+ therapies (aH2Tx) have changed the outcome of women with Her2 positive (Her2+) breast cancer and its activity showed a considerable impact in the neoadjuvant setting in which a higher rate of pathologic complete response (pCR) was observed. Of interest is the difference in outcome of patients who did not achieved a pCR and the analysis of the residual disease (RD) represents a relevant issue to explore to identify the subset of patients ( pts) with different outcome. Methods: 67 consecutive Her-2+ pts with locally advanced breast cancer (LABC) treated since 1993 to 2015 and who did not reached a pCR were evaluated. A minimum of three years of follow up was requested for the outcome analysis. Overall survival (OS) and disease free survival (DFS) has been explored in the two cohorts and the type of RD after neoadjuvant aH2Tx was also examined. Immunochemistry expression for estrogen and progesterone receptors (ER/PR) in the primary tumor for the aH2Tx-not-receiving pts was: 8 pts was ER/PR negative, 10 were ER/PR positive, 6 were ER-/PR + , 1 ER + /PR-. In the aH2Tx-receiving group: 26 were ER/PR + , 6 were ER + /PR-, 10 were ER/PR negative. Results: 25 pts did not receive aH2Tx in the neoadjuvant and 19 did not in adjuvant setting. 42 pts received aH2Tx in the neoadjuvant and 35 also in the adjuvant setting. Eleven pts in the aH2Tx-non-receiving group had recurrent disease compared with five recurrences in the aH2Tx-receiving group. The subtypes of RD in the aH2Tx not-receiving group were as follow: 4 had Luminal A like disease, 2 Luminal B like, 1 was triple negative, 18 were Her2+. For the aH2Tx-receiving group: 4 were Luminal A like, 5 Luminal B like, 30 were Her2+. The subtype of RD in the aH2Tx-not-receiving group with recurrent disease it has changed in 2 out of 11 pts if compared to primary tumor and in 2 out of 5 pts of the aH2Tx-receiving group. Conclusion: Recurrent disease was observed more often in the non-receiving aH2Tx pts, the analysis of impact of RD on outcome is still pending and will be presented at the meeting. Optimizing the selection of aH2Tx by identifying subpopulations of Her-2+ pts who need more or less therapy could be cost effective and would spare some patients unnecessary exposure to ineffective treatments

STAT3, tumor microenvironment, and microvessel density in diffuse large B cell lymphomas

Constitutively activated STAT3 is correlated with more advanced clinical stage and overall poor survival of diffuse large B-cell lymphoma (DLBCL). The aim of this study was to evaluate STAT3 and Ki67 tumor cell expression, inflammatory cell infiltration, microvascular density in DLBCL bioptic specimens. RNA-scope showed that activated B cell (ABC) tissue samples contained a significant higher number of STAT3+ cells as compared to germinal center B (GCB) tissue samples. Immunohistochemical analysis showed a significant increased levels of CD3, CD8, CD68, CD163, CD34, and Ki67 positive cells in ABC patients. A positive correlation between STAT3 and CD3, CD8, CD68, and CD163 was evidenced in ABC group. In ABC group, we found also a positive correlation between CD8 and CD34 and a positive correlation between Ki67 and, CD68, and CD163. These data indicate that in ABC—as compared to GCB-DLBCL, a higher STAT3 expression is associated with a higher CD163+ TAM and CD8+ cell infiltration which induces a strong angiogenic response

PB2064 USE OF RNASCOPE TECHNOLOGY TO DETERMINE STAT-3 EXPRESSION IN HUMAN DIFFUSE LARGE B-CELL LYMPHOMA

Diffuse large B-cell lymphoma (DLBCL) is the most common and one of the most heterogeneous lymphomas. Therefore, it is critical to further stratify cases of DLBCL into biologically similar and clinically meaningful subgroups, which will not only guide prognostic assessment and facilitate therapeutic decisions, but also stimulate further research to understand the pathogenesis and develop potential novel treatments. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that exerts important biological functions related to cell proliferation, differentiation, survival, angiogenesis and immune response

PTX3 shapes profibrotic immune cells and epithelial/fibroblast repair and regeneration in a murine model of pulmonary fibrosis

The long pentraxin 3 (PTX3) is protective in different pathologies but was not analyzed in-depth in Idiopathic Pulmonary Fibrosis (IPF). Here, we have explored the influence of PTX3 in the bleomycin (BLM)-induced murine model of IPF by looking at immune cells (macrophages, mast cells, T cells) and stemness/regenerative markers of lung epithelium (SOX2) and fibro-blasts/myofibroblasts (CD44) at different time points that retrace the progression of the disease from onset at day 14, to full-blown disease at day 21, to incomplete regression at day 28. We took advantage of transgenic PTX3 overexpressing mice (Tie2-PTX3) and Ptx3 null ones (PTX3-KO) in which pulmonary fibrosis was induced. Our data have shown that PTX3 overexpression in Tie2-PTX3 compared to WT or PTX3-KO: reduced CD68+ and CD163+ macrophages and the Tryptase+ mast cells during the whole experimental time; on the contrary, CD4+ T cells are consistently present on day 14 and dramatically decreased on day 21; CD8+ T cells do not show significant differences on day 14, but are significantly reduced on day 21; SOX2 is reduced on days 14 and 21; CD44 is reduced on day 21. Therefore, PTX3 could act on the proimmune and fibrogenic microenvironment to prevent fibrosis in BLM-treated mice

Microenvironment expression in diffuse large B-cell lymphomas

Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, is recognized as a heterogeneous disease with distinct molecular subtypes derived from different stages of B-cell differentiation. The contribution of the tumor microenvironment to the pathogenesis and tumor survival of DLBCL is poorly understood. However, several recent studies have yielded intriguing findings and shed some light on the possible roles of the microenvironment. In this retrospective study, data from 29 patients diagnosed with DLBCL between 2009 and 2013 were reviewed. All patients had pathologically confirmed DLBCL and had been treated with the R-CHOP regimen. In these patients, we correlated the expression of CD3 staining for T cells, tryptase staining for mast cells, CD68 for tumor-associated macrophages (TAMs), and CD31 staining for blood vessels. CD68 and tryptase expression, as well as MVD, were increased in chemo-resistant patients compared to chemosensitive patients. Tryptase expression showed a positive correlation with MVD, supporting a role for mast cells in DLBCL tumor angiogenesis, while the CD68 correlation with MVD was not significant, indicating a different role for TAMs rather than angiogenesis in DLBCL. A statistically significant difference was observed in the expression of CD3 in patients with bulky disease. Specifically, a higher expression of CD3 was observed in nonbulky disease patients (mean expression 52.91%, n = 20) compared to bulky disease patients (mean expression 34.9%, n = 9), P value < .05. The reduction in T cells in bulky disease patients contributes to loosen the immune control over the tumor, resulting in an increased cell proliferation, leading to large tumor cell masses, which are predictive of poor prognostic and clinical outcomes. CD3 showed a positive correlation with tryptase and MVD, while multiple regression analysis efficaciously predicted MVD depending on CD3 and tryptase as predictors, supporting a complex interplay between these cells in sustaining tumor angiogenesis in DLBCL patients. The improved understanding of tumor biology and of the role of the tumor microenvironment has led to advances in the diagnosis, classification, prognostics, as well as novel treatments of patients with hematologic malignancies. In particular, translational research, leading to drugs that target the interaction between the tumor microenvironment and malignant cells, has provided many promising new approaches to cancer therapy. Ongoing dynamic and correlation studies of tumor biology and the contribution of the tumor microenvironment should be promoted in the context of novel drug development in order to identify optimal therapies for various lymphomas and improve the curability of these diseases

Different spatial distribution of inflammatory cells in the tumor microenvironment of ABC and GBC subgroups of diffuse large B cell lymphoma

Diffuse Large B-Cell Lymphoma (DLBCL) presents a high clinical and biological heterogeneity, and the tumor microenvironment chracteristics are important in its progression. The aim of this study was to evaluate tumor T, B cells, macrophages and mast cells distribution in GBC and ABC DLBCL subgroups through a set of morphometric parameters allowing to provide a quantitative evaluation of the morphological features of the spatial patterns generated by these inflammatory cells. Histological ABC and GCB samples were immunostained for CD4, CD8, CD68, CD 163, and tryptase in order to determine both percentage and position of positive cells in the tissue characterizing their spatial distribution. The results evidenced that cell patterns generated by CD4-, CD8-, CD68-, CD163- and tryptase-positive cell profiles exhibited a significantly higher uniformity index in ABC than in GCB subgroup. The positive-cell distributions appeared clustered in tissues from GCB, while in tissues from ABC such a feature was lower or absent. The combinations of spatial statistics-derived parameters can lead to better predictions of tumor cell infiltration than any classical morphometric method providing a more accurate description of the functional status of the tumor, useful for patient prognosis