Z boson production in bottom-quark fusion: a study of b-mass effects beyond leading order.

We compute the total cross-section for Z boson production in bottom-quark fusion, applying to this case the method we previously used for Higgs production in bottom fusion. Namely, we match, through the FONLL procedure, the next-to-next-to-leading-log five-flavor scheme result, in which the b quark is treated as a massless parton, with the next-to-leading-order O ( α s 3 ) four-flavor scheme computation in which bottom is treated as a massive final-state particle. Also, we add to our formalism the possibility of varying the heavy quark matching scale. The results obtained with the FONLL formalism can thus be compared directly to recent results obtained in various approximations, and used as a proxy to assess and discuss the issues of scale dependence and treatment of heavy quarks. Finally, We use our results in order to improve the prediction for the total Z production cross-section

Tumor derived Microvesicles enhance cross-processing ability of clinical grade Dendritic Cells

Tumor cells release extracellular microvesicles (MVs) in the microenvironment to deliver biological signals to neighbouring cells as well as to cells in distant tissues. Tumor-derived MVs appear to play contradictory role promoting both immunosuppression and tumor growth and both evoking tumor specific immune response. Recent evidences indicate that tumor-derived MVs can positively impact Dendritic Cells (DCs) immunogenicity by reprogramming DC antigen processing machinery and intracellular signaling pathways, thus promoting anti-tumor response. DCs are considered pivot cells of the immune system due to their exclusive ability to coordinate the innate and acquired immune responses, cross-present exogenous antigens and prime naïve T cells. DCs are required for the induction and maintenance of long-lasting anti-tumor immunity and their exploitation has been extensively investigated for the design of anti-tumor vaccines. However, the clinical grade culture conditions that are required to generate DCs for therapeutic use can strongly affect their functions. Here, we investigated the immunomodulatory impact of MVs carrying the MUC1 tumor glycoantigen (MVsMUC1) as immunogen formulation on clinical grade DCs grown in X-VIVO 15 (X-DCs). Results indicated that X-DCs displayed reduced performance of the antigen processing machinery in term of diminished phagocytosis and acidification of the phagosomal compartment suggesting an altered immunogenicity of clinical grade DCs. Pulsing DCs with MVsMUC1 restored phagosomal alkalinization, triggering ROS increase. This was not observed when a soluble MUC1 protein was employed (rMUC1). Concurrently, MVsMUC1 internalization by X-DCs allowed MUC1 cross-processing. Most importantly, MVsMUC1 pulsed DCs activated IFNγ response mediated by MUC1 specific CD8+ T cells. These results strongly support the employment of tumor-derived MVs as immunogen platforms for the implementation of DC-based vaccine

Tumor-derived microvesicles modulate antigen cross-processing via reactive oxygen species-mediated alkalinization of phagosomal compartment in dendritic cells

Dendritic cells (DCs) are the only antigen-presenting cells able to prime naïve T cells and cross-prime antigen-specific CD8+ T cells. Their functionality is a requirement for the induction and maintenance of long-lasting cancer immunity. Albeit intensively investigated, the in vivo mechanisms underlying efficient antigen cross-processing and presentation are not fully understood. Several pieces of evidence indicate that antigen transfer to DCs mediated by microvesicles (MVs) enhances antigen immunogenicity. This mechanism is also relevant for cross-presentation of those tumor-associated glycoproteins such as MUC1 that are blocked in HLA class II compartment when internalized by DCs as soluble molecules. Here, we present pieces of evidence that the internalization of tumor-derived MVs modulates antigen-processing machinery of DCs. Employing MVs derived from ovarian cancer ascites fluid and established tumor cell lines, we show that MV uptake modifies DC phagosomal microenvironment, triggering reactive oxygen species (ROS) accumulation and early alkalinization. Indeed, tumor MVs carry radical species and the MV uptake by DCs counteracts the chemically mediated acidification of the phagosomal compartment. Further pieces of evidence suggest that efficacious antigen cross-priming of the MUC1 antigen carried by the tumor MVs results from the early signaling induced by MV internalization and the function of the antigen-processing machinery of DCs. These results strongly support the hypothesis that tumor-derived MVs impact antigen immunogenicity by tuning the antigen-processing machinery of DCs, besides being carrier of tumor antigens. Furthermore, these findings have important implications for the exploitation of MVs as antigenic cell-free immunogen for DC-based therapeutic strategies

Monoclonal Antibodies in Gynecological Cancer: A Critical Point of View

During the last decades, several improvements in treating gynecological malignancies have been achieved. In particular, target therapies, mostly monoclonal antibodies, have emerged as an attractive option for the treatment of these malignancies. In fact, various molecular-targeted agents have been developed for a variety of malignancies with the objective to interfere with a precise tumor associated receptor, essential for cancer cell survival or proliferation, blocking its function, of the cancer cells. Alternatively, monoclonal antibodies have been developed to block immune suppression or enhance functions of immune effector cells. So far, several monoclonal antibodies have been tested for clinical efficacy for the treatment of gynecological cancers. Antibodies against Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) have been used in different neoplasms such as ovarian and cervical cancer. Catumazumab, a bivalent antibody against CD3 and EpCAM, is effective in the treatment of neoplastic ascites. Other antibodies are peculiar for specific cancer-associated antigen such as Oregovomab against CA125 or Farletuzumab against the folate receptor. Here we describe the preclinical and clinical experience gained up to now with monoclonal antibodies in tumors of the female genital tract and trace future therapeutic and research venues

HER2-based recombinant immunogen to target DCs through FcγRs for cancer immunotherapy

Dendritic cell (DC)-based immunotherapy is an attractive approach to induce long lasting antitumor effector cells aiming to control cancer progression. DC targeting is a critical step in the design of DC vaccines in order to optimize delivery and processing of the antigen, and several receptors have been characterized for this purpose. In this study, we employed the FcγRs to target DCs both in vitro and in vivo. We designed a recombinant molecule (HER2-Fc) composed of the immunogenic sequence of the human tumor-associated antigen HER2 (aa 364–391) and the Fc domain of a human IgG1. In a mouse model, HER2-Fc cDNA vaccination activated significant T cell-mediated immune responses towards HER2 peptide epitopes as detected by IFN-γ ELIspot and induced longer tumor latency as compared to Ctrl-Fc-vaccinated control mice. Human in vitro studies indicated that the recombinant HER2-Fc immunogen efficiently targeted human DCs through the FcγRs resulting in protein cross-processing and in the activation of autologous HER2-specific CD8+ T cells from breast cancer patients

Importance of Echocardiography and Clinical "Red Flags" in Guiding Genetic Screening for Fabry Disease

Aim of this study was to evaluate, in a metropolitan area not already explored, the prevalence of Anderson-Fabry disease, by genetic screening, in patients with echocardiographic evidence of left ventricular hypertrophy (LVH) of unknown origin and "clinical red flags"

Transplantation of human fetal biliary tree stem/progenitor cells into two patients with advanced liver cirrhosis.

Efforts to identify cell sources and approaches for cell therapy of liver diseases are ongoing, taking into consideration the limits recognized for adult liver tissue and for other forms of stem cells. In the present study, we described the first procedure of via hepatic artery transplantation of human fetal biliary tree stem cells in patients with advanced cirrhosis.MethodsThe cells were immune-sorted from human fetal biliary tree by protocols in accordance with current good manufacturing practice (cGMP) and extensively characterized. Two patients with advanced cirrhosis (Child-Pugh C) have been submitted to the procedure and observed through a 12 months follow-up.ResultsThe resulting procedure was found absolutely safe. Immuno-suppressants were not required, and the patients did not display any adverse effects correlated with cell transplantation or suggestive of immunological complications. From a clinical point of view, both patients showed biochemical and clinical improvement during the 6 month follow-up (Table1), and the second patient maintained a stable improvement for 12 months.ConclusionThis report represents proof of the concept that the human fetal biliary tree stem cells are a suitable and large source for cell therapy of liver cirrhosis. The isolation procedure can be carried out under cGMP conditions and, finally, the infusion procedure is easy and safe for the patients. This represents the basis for forthcoming controlled clinical trials

Tumor-Derived Microvesicles Enhance Cross-Processing Ability of Clinical Grade Dendritic Cells

Tumor cells release extracellular microvesicles (MVs) in the microenvironment to deliver biological signals to neighboring cells as well as to cells in distant tissues. Tumor-derived MVs appear to play contradictory role promoting both immunosuppression and tumor growth and both evoking tumor specific immune response. Recent evidences indicate that tumor-derived MVs can positively impact Dendritic Cells (DCs) immunogenicity by reprogramming DC antigen processing machinery and intracellular signaling pathways, thus promoting anti-tumor response. DCs are considered pivot cells of the immune system due to their exclusive ability to coordinate the innate and acquired immune responses, cross-present exogenous antigens, and prime naïve T cells. DCs are required for the induction and maintenance of long-lasting anti-tumor immunity and their exploitation has been extensively investigated for the design of anti-tumor vaccines. However, the clinical grade culture conditions that are required to generate DCs for therapeutic use can strongly affect their functions. Here, we investigated the immunomodulatory impact of MVs carrying the MUC1 tumor glycoantigen (MVsMUC1) as immunogen formulation on clinical grade DCs grown in X-VIVO 15 (X-DCs). Results indicated that X-DCs displayed reduced performance of the antigen processing machinery in term of diminished phagocytosis and acidification of the phagosomal compartment suggesting an altered immunogenicity of clinical grade DCs. Pulsing DCs with MVsMUC1 restored phagosomal alkalinization, triggering ROS increase. This was not observed when a soluble MUC1 protein was employed (rMUC1). Concurrently, MVsMUC1 internalization by X-DCs allowed MUC1 cross-processing. Most importantly, MVsMUC1 pulsed DCs activated IFNγ response mediated by MUC1 specific CD8+ T cells. These results strongly support the employment of tumor-derived MVs as immunogen platforms for the implementation of DC-based vaccines

Higgs production in bottom-quark fusion in a matched scheme

We compute the total cross-section for Higgs boson production in bottom-quark fusion using the so-called FONLL method for the matching of a scheme in which the b-quark is treated as a massless parton to that in which it is treated as a massive final-state particle. We discuss the general framework for the application of the FONLL method to this process, and then we present explicit expressions for the case in which the next-to-next-to-leading-log five-flavor scheme result is combined with the leading-order four-flavor scheme computation. We compare our results in this case to the four- and five-flavor scheme computations, and to the so-called Santander matching