Identification of a HLA-A*0201-restricted immunogenic epitope from the universal tumor antigen DEPDC1

The identification of universal tumor-specific antigens (TSA) shared between multiple patients and/or multiple tumors is of great importance to overcome the practical limitations of personalized cancer immunotherapy. Recent studies support the involvement of DEPDC1 in many aspects of cancer traits, such as cell proliferation, anti-apoptosis and cell invasion, suggesting that it may play key roles in the oncogenic process. In this study, we report that DEPDC1 expression is up-regulated in several types of human tumors, and closely linked to a poorer prognosis; therefore, it might be regarded as a novel universal oncoantigen potentially suitable for targeting many different cancers. In this regard, we report the identification of an immunogenic DEPDC1-derived epitope restricted for the HLA-A*0201 molecule, which is able to induce cytotoxic T lymphocytes (CTL) exerting a strong and specific functional response in vitro in response not only to peptide-loaded cells but also to triple negative breast cancer (TNBC) cells endogenously expressing the DEPDC1 protein. Such CTL are also therapeutically active against human TNBC xenografts in vivo upon adoptive transfer in immunodeficient mice. Overall, these data provide evidences that this DEPDC1-derived antigenic epitope can be exploited as a new tool for the development of immunotherapeutic strategies for HLA-A*0201 patients with TNBC, and potentially many other cancers. Moreover, we plan to employ an approach of multiplexing digital pathology to study the intimate relationships that adoptively transferred lymphocytes can establish with TNBC cells in tumor-bearing mice, as further advances in immunotherapy approaches require a detailed understanding of cell dynamics within the tumor microenvironment. The benefits of multispectral immunohistochemistry, combined with the development of software for quantitation, are making this methodology an increasingly powerful tool in the analysis and characterization of tissue and cellular processes, supporting diagnostic potential in order to improve therapies

Retargeting cytokine-induced killer cell activity by CD16 engagement with clinical-grade antibodies

Cytokine-induced Killer (CIK) cells are a heterogeneous population of ex vivo expanded T lymphocytes capable of MHC-unrestricted antitumor activity, which share phenotypic and functional features with both NK and T cells. Preclinical data and initial clinical studies demonstrated their high tolerability in vivo, supporting CIK cells as a promising cell population for adoptive cell immunotherapy. In this study, we report for the first time that CIK cells display a donor-dependent expression of CD16, which can be engaged by trastuzumab or cetuximab to exert a potent antibody-dependent cell-mediated cytotoxicity (ADCC) against ovarian and breast cancer cell lines, leading to an increased lytic activity in vitro, and an enhanced therapeutic efficacy in vivo. Thus, an efficient tumor antigen-specific retargeting can be achieved by a combination therapy with clinical-grade monoclonal antibodies already widely used in cancer therapy, and CIK cell populations that are easily expandable in very large numbers, inexpensive, safe and do not require genetic manipulations. Overall, these data provide a new therapeutic strategy for the treatment of Her2 and EGFR expressing tumors by adoptive cell therapy, which could find wide implementation and application, and could also be expanded to the use of additional therapeutic antibodies

A High-Resolution Multiband Survey of Westerlund 2 With the Hubble Space Telescope I: Is the Massive Star Cluster Double?

We present first results from a high resolution multi-band survey of the Westerlund 2 region with the Hubble Space Telescope. Specifically, we imaged Westerlund 2 with the Advanced Camera for Surveys through the $F555W$, $F814W$, and $F658N$ filters and with the Wide Field Camera 3 in the $F125W$, $F160W$, and $F128N$ filters. We derive the first high resolution pixel-to-pixel map of the color excess $E(B-V)_g$ of the gas associated with the cluster, combining the H$\alpha$ ($F658N$) and Pa$\beta$ ($F128N$) line observations. We demonstrate that, as expected, the region is affected by significant differential reddening with a median of $E(B-V)_g=1.87$~mag. After separating the populations of cluster members and foreground contaminants using a $(F814W-F160W)$ vs. $F814W$ color-magnitude diagram, we identify a pronounced pre-main-sequence population in Westerlund 2 showing a distinct turn-on. After dereddening each star of Westerlund 2 individually in the color-magnitude diagram we find via over-plotting PARSEC isochrones that the distance is in good agreement with the literature value of $\sim4.16 \pm 0.33$~kpc. With zero-age-main-sequence fitting to two-color-diagrams, we derive a value of total to selective extinction of $R_V=3.95 \pm 0.135$. A spatial density map of the stellar content reveals that the cluster might be composed of two clumps. We estimate the same age of 0.5-2.0 Myr for both clumps. While the two clumps appear to be coeval, the northern clump shows a $\sim 20 \%$ lower stellar surface density.Comment: 24 pages, 27 figures, 7 tables; Accepted for publication to The Astronomical Journa

Influence of the brood rearing temperature on honey bee development and susceptibility to intoxication by pesticides

contribution to session IV Test methodolog

Determination of process induced dimensional variations of ceramic parts, 3D printed by extrusion of a powder-binder feedstock

This paper aims at presenting a methodology for compensation of dimensional variation during production of ceramic parts via extrusion based additive manufacturing process. A systematic geometric deviation is measured in as printed (green) and as sintered parts. In the present study, a specially developed CNC extrusion unit is used for 3d printing onto a 3 degrees of freedom parallel kinematics table. Two ceramic feedstocks, alumina and zirconia, are procured and their processing route is illustrated. The generated, corrected and modified G codes are directly fed to the controller of the table and extrusion unit. Validation of the performance is carried out by multiple samples and repeated measurements. Experimental results exhibit effective compensation and significant improvement in the dimensional accuracy. The calculation of geometric deviations and the proposed parametric determination through optimization allow the reduction in global dimensional variation, which decreases all sort of systematic errors concurrently. The proposed procedure is easily transferable to other rapid prototyping machines and allows scalability based on achieved surface quality, manufacturing time, mass and dimensional measurement

Probing the Atomic Arrangement of Sub-Surface Dopants in a Silicon Quantum Device Platform

High-density structures of sub-surface phosphorus dopants in silicon continue to garner interest as a silicon-based quantum computer platform, however, a much-needed confirmation of their dopant arrangement has been lacking. In this work, we take advantage of the chemical specificity of X-ray photoelectron diffraction to obtain the precise structural configuration of P dopants in sub-surface Si:P $\delta$-layers. The growth of $\delta$-layer systems with different levels of doping is carefully studied and verified using X-ray photoelectron spectroscopy and low-energy electron diffraction. Subsequent XPD measurements reveal that in all cases, the dopants primarily substitute with Si atoms from the host material. Furthermore, no signs of free carrier-inhibiting P$-$P dimerization can be observed. Our observations not only settle a nearly decade-long debate about the dopant arrangement but also demonstrate that XPD is well suited to study sub-surface dopant structures. This work thus provides valuable input for an updated understanding of the behavior of Si:P $\delta$-layers and the modeling of their derived quantum devices

Geographic variation and environmental conditions as cofactors in Chlamydia psittaci association with ocular adnexal lymphomas: a comparison between Italian and African samples

A particular extra-nodal lymphoma type arises from B cells of the marginal zone (MZ) of mucosa-associated lymphoid tissue (MALT). The aetiology ofMZ lymphomas suggests that they are associated with chronic antigenic stimulation by microbial pathogens, among which Helicobacter pylori-associated gastricMALT lymphoma is the best studied. Recently, MALT lymphomas have been described in the context of chronic conjunctivitis, which can be associated with Chlamydia spp. infection. Studies from Italy showed the presence of Chlamydia psittaci in 87% of ocular adnexal lymphomas (OAL), and C. psittaci has been described in a large part of samples from Austria and Korea as well. However, this finding was not always confirmed by other studies, suggesting that the association with C. psittaci may depend on geographic heterogeneity. Interestingly, none of the studies up to now has been carried out in the African population, where a strong association between infectious agents and the occurrence of human neoplasms has been reported. This study was designed to investigate the possible association of Chlamydia psittaci in cases retrieved from Kenya, compared to cases from Italy. Our results showed that there was a marked variation between the two geographical areas in terms of association with C. psittaci, as 17% (5/30) of the samples from Italy were positive for C. psittaci, whereas no association with this pathogen was observed in any of the African samples (0/9), suggesting that other cofactors may determine the OAL occurrence in those areas. OAL cases are often characterized by down-regulation of p16/INK4a expression and promoter hypermethylation of the p16/ INK4a gene. Our results showed a partial methylation of p16/INK4a promoter in C. psittacinegative cases, whereas no hypermethylation of this gene was found in C. psittaci-positive cases, suggesting that mechanisms other than promoter hypermethylation lead to p16/ INK4a silencing in C. psittaci-positive cases. We may conclude that the role of epidemiologic, environmental and genetic factors, must be considered in the aetiology of this disease

Identification of a HLA-A*0201-restricted immunogenic epitope from the universal tumor antigen DEPDC1

The identification of universal tumor-specific antigens shared between multiple patients and/or multiple tumors is of great importance to overcome the practical limitations of personalized cancer immunotherapy. Recent studies support the involvement of DEPDC1 in many aspects of cancer traits, such as cell proliferation, resistance to induction of apoptosis and cell invasion, suggesting that it may play key roles in the oncogenic process. In this study, we report that DEPDC1 expression is upregulated in most types of human tumors, and closely linked to a poorer prognosis; therefore, it might be regarded as a novel universal oncoantigen potentially suitable for targeting many different cancers. In this regard, we report the identification of a HLA-A*0201 allele-restricted immunogenic DEPDC1-derived epitope, which is able to induce cytotoxic T lymphocytes (CTL) exerting a strong and specific functional response in vitro toward not only peptide-loaded cells but also triple negative breast cancer (TNBC) cells endogenously expressing the DEPDC1 protein. Such CTL are also therapeutically active against human TNBC xenografts in vivo upon adoptive transfer in immunodeficient mice. Overall, these data provide evidence that this DEPDC1-derived antigenic epitope can be exploited as a new tool for developing immunotherapeutic strategies for HLA-A*0201 patients with TNBC, and potentially many other cancers