Rubin-Euclid Derived Data Products:Initial Recommendations

This report is the result of a joint discussion between the Rubin and Euclid scientific communities. The work presented in this report was focused on designing and recommending an initial set of Derived Data products (DDPs) that could realize the science goals enabled by joint processing. All interested Rubin and Euclid data rights holders were invited to contribute via an online discussion forum and a series of virtual meetings. Strong interest in enhancing science with joint DDPs emerged from across a wide range of astrophysical domains: Solar System, the Galaxy, the Local Volume, from the nearby to the primaeval Universe, and cosmology

Etude de la régulation transcriptionnelle des gènes TNF-SF6 et TNF-SF14

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUP (751062107) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Modified Cap Group Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitor Derivatives Reveal Improved Selective Antileukemic Activity

A series of SAHA cap derivatives was designed and prepared in good-to-excellent yields that varied from 49% to 95%. These derivatives were evaluated for their antiproliferative activity in several human cancer cell lines. Antiproliferative activity was observed for concentrations varying from 0.12 to >100 microM, and a molecular modeling approach of selected SAHA derivatives, based on available structural information of human HDAC8 in complex with SAHA, was performed. Strikingly, two compounds displayed up to 10-fold improved antileukemic activity with respect to SAHA; however, these compounds displayed antiproliferative activity similar to SAHA when assayed against solid tumor-derived cell lines. A 10-fold improvement in the leukemic vs peripheral blood mononuclear cell therapeutic ratio, with no evident in vivo toxicity toward blood cells, was also observed. The herein-described compounds and method of synthesis will provide invaluable tools to investigate the molecular mechanism responsible for the reported selectively improved antileukemic activity

A Bispecific Antibody-Based Approach for Targeting Mesothelin in Triple Negative Breast Cancer

International audienceTriple negative breast cancers (TNBC) remain a major medical challenge due to poor prognosis and limited treatment options. Mesothelin is a glycosyl-phosphatidyl inositol-linked membrane protein with restricted normal expression and high level expression in a large proportion of TNBC, thus qualifying as an attractive target. Its overexpression in breast tumors has been recently correlated with a decreased disease-free survival and an increase of distant metastases. The objective of the study was to investigate the relevance of a bispecific antibody-based immunotherapy approach through mesothelin targeting and CD16 engagement using a Fab-like bispecific format (MesobsFab). Using two TNBC cell lines with different level of surface mesothelin and epithelial/mesenchymal phenotypes, we showed that, in vitro, MesobsFab promotes the recruitment and penetration of NK cells into tumor spheroids, induces potent dose-dependent cell-mediated cytotoxicity of mesothelin-positive tumor cells, cytokine secretion, and decreases cell invasiveness. MesobsFab was able to induce cytotoxicity in resting human peripheral blood mononuclear cells (PBMC), mainly through its NK cells-mediated antibody dependent cell cytotoxicity (ADCC) activity. In vivo, the anti-tumor effect of MesobsFab depends upon a threshold of MSLN density on target cells. Collectively our data support mesothelin as a relevant therapeutic target for the subset of TNBC that overexpresses mesothelin characterized by a low overall and disease-free survival as well as the potential of MesobsFab as antibody-based immunotherapeutics

Active transcription of human TNFSF/CD95L and TNFSF14/Light genes involves distinct mechanisms of chromatin remodeling

info:eu-repo/semantics/publishe

Mechanisms regulating expression of the tumor necrosis factor-related light gene. Role of calcium-signaling pathway in the transcriptional control.

LIGHT (TNFSF14) is a newly identified tumor necrosis factor superfamily member involved in the regulation of immune responses by control of activation, maturation, and survival of immune effector cells. Despite the immunological relevance of the LIGHT protein, little knowledge is available as to how light gene expression is regulated. In T-lymphocytes, most LIGHT surface expression and transcript accumulation occurs after T cell activation. In this study, we have shown that these events are blocked at the transcriptional level by cyclosporin A, an immuno-suppressive drug. Besides, we identified a role for Ca2+ -signaling pathways and NFAT transcription factors in T cell activation-induced LIGHT expression. To further investigate this process, we have identified, cloned, and characterized a 2.1-kilobase 5'-flanking DNA genomic fragment from the human light gene. We have shown the transcriptional activity of the herein-identified minimal 5' regulatory region of human light gene parallels the endogenous expression of light in T cells. Moreover, we demonstrated that induced LIGHT promoter activity can be equally blocked by cyclosporin A treatment or dominant negative NFAT overexpression and further identified by site-directed mutagenesis and electrophoretic mobility supershift analysis of a NFAT transcription factor binding site within the human light minimal promoter. Finally, Sp1 and Ets1 binding sites were identified and shown to regulate light basal promoter activity. Thus, the present study establishes a molecular basis to further understand the mechanisms governing human light gene expression and, consequently, could potentially lead to novel therapeutic manipulations that control the signaling cascade, resulting in LIGHT production in conditions characterized by immunopathologic activation of T cells.Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Establishment of a mouse xenograft model of metastatic adrenocortical carcinoma

International audienceAdrenocortical carcinoma is a rare neoplasm with a poor prognosis. Very important advances have been made in the identification of the genetic determinants of adrenocortical carcinoma pathogenesis but our understanding is still limited about the mechanisms that determine cancer spread and metastasis. One major problem hindering preclinical experimentation for new therapies for adrenocortical carcinoma is represented by the lack of suitable animal models for metastatic disease. With the aim to overcome these limitations, in this study we tested several protocols in order to establish a mouse xenograft model of metastatic adrenocortical carcinoma. The most efficient method, based upon intrasplenic injection followed by splenectomy, produced metastases with high efficiency, whose development could be followed over time by bioluminescence measurements. We expect that the availability of this model will greatly improve the possibilities for preclinical testing of new treatments for advanced-stage disease

Abstract 2290: The serine-threonine kinase Mink1 as a potential therapeutic target in triple negative breast cancer

International audienceAbstract The developmental Wnt/planar cell polarity (PCP) pathway is the most recently described branch of the Wnt signaling pathways and is strongly implicated in cancer development at early and late stages (PMID: 28718442 and PMID: 30952630). Upregulation of the Wnt/PCP components is observed in many cancers and is associated with cancer progression. However, how their molecular functions are regulated remains an open question. Recent data from our laboratory showed that Prickle1 and Vangl2, two core Wnt/PCP components, are overexpressed in Triple Negative Breast Cancers (TNBC) and associated with poor prognosis (PMID: 27184734 and 26754771). Prickle1 is a cytoplasmic protein phosphorylated by the serine/threonine kinase Mink1, which triggers Prickle1 localization at the plasma membrane and regulates its activity (PMID: 22037766). Activation of this axis contributes to breast cancer cell motility and metastatic spreading in vitro and in vivo (PMID: 27184734). To extend our knowledge of the Mink1 substrates, we carried out a phosphoproteomic strategy and identified LL5β. LL5β is a membrane scaffold molecule that anchors microtubules (MTs) at the cell cortex through its association with CLASP, a plus-end MT protein, to trigger focal adhesion disassembly. We found that LL5β is a prominent member of the Prickle1-associated protein complex and harbors a consensus motif for Mink1 phosphorylation. At the molecular level, we demonstrated a two-step phosphorylation cascade carried out by Mink1 that phosphorylates sequentially Prickle1 to mediate its association with LL5β, then LL5β to promote its interaction with CLASP. Finally, analysis of gene expression data suggests that the concomitant up-regulation of Prickle1 and LL5β mRNA levels is associated with a poor metastasis-free survival for TNBC patients. In an effort to counteract the Mink1-Prickle1-LL5β prometastatic pathway, we selected a Mink1 inhibitor that recapitulates all the phenotypes observed following the knockdown of Mink1 expression. This chemical compound is currently under investigation in preclinical assays using xenografted TNBC cell lines and patient-derived xenografts in nude mice. Citation Format: Avais Daulat, Monica Silveira Wagner, Malgorzata Kowalczewska, Pascal Finetti, Rémy Castellano, Stéphane Audebert, François Bertucci, Luc Camoin, Jean-Paul Borg. The serine-threonine kinase Mink1 as a potential therapeutic target in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2290

Rapid nanobody-based imaging of mesothelin expressing malignancies compatible with blocking therapeutic antibodies

Mesothelin (MSLN) is overexpressed in a wide variety of cancers with few therapeutic options and has recently emerged as an attractive target for cancer therapy, with a large number of approaches currently under preclinical and clinical investigation. In this respect, developing mesothelin specific tracers as molecular companion tools for predicting patient eligibility, monitoring then response to mesothelin-targeting therapies, and tracking the evolution of the disease or for real-time visualisation of tumours during surgery is of growing importance. Methods We generated by phage display a nanobody (Nb S1) and used enzymatic approaches were used to site-directed conjugate Nb S1 with either ATTO 647N fluorochrome or NODAGA chelator for fluorescence and positron emission tomography imaging (PET) respectively. Results We demonstrated that Nb S1 displays a high apparent affinity and specificity for human mesothelin and demonstrated that the binding, although located in the membrane distal domain of mesothelin, is not impeded by the presence of MUC16, the only known ligand of mesothelin, nor by the therapeutic antibody amatuximab. In vivo experiments showed that both ATTO 647N and [ 68 Ga]Ga-NODAGA-S1 rapidly and specifically accumulated in mesothelin positive tumours compared to mesothelin negative tumours or irrelevant Nb with a high tumour/background ratio. The ex vivo biodistribution profile analysis also confirmed a significantly higher uptake of Nb S1 in MSLN-positive tumours than in MSLN low tumours. Conclusion We demonstrated for the first time the use of an anti-MSLN nanobody as PET radiotracer for same day imaging of MSLN + tumours, targeting an epitope compatible with the monitoring of amatuximab-based therapies and current SS1-derived-drug conjugates