Genomic Database Analysis of Uterine Leiomyosarcoma Mutational Profile

Uterine Leiomyosarcoma (uLMS) is by far the most common type of uterine sarcoma, characterized by an aggressive clinical course, a heterogeneous genetic profile and a very scarce response to cytotoxic chemotherapy. The genetic make-up of uLMS is an area of active study that could provide essential cues for the development of new therapeutic approaches. A total of 216 patients with uLMS from cBioPortal and AACR-GENIE databases were included in the study. The vast majority of patients (81%) carried at least one mutation in either TP53, RB1, ATRX or PTEN. The most frequently mutated gene was TP53, with 61% of the patients harboring at least one mutation, followed by RB1 at 48%. PTEN alteration was more frequent in metastases than in primary lesions, consistent with a later acquisition during tumor progression. There was a significant trend for TP53 and RB1 mutations to occur together, while both TP53 and RB1 were mutually exclusive with respect to CDKN2A/B inactivation. Overall survival did not show significant correlation with the mutational status, even if RB1 mutation emerged as a favorable prognostic factor in the TP53-mutant subgroup. This comprehensive analysis shows that uLMS is driven almost exclusively by the inactivation of tumor suppressor genes and suggests that future therapeutic strategies should be directed at targeting the main genetic drivers of uLMS oncogenesis

The VST Early-type GAlaxy Survey: Exploring the Outskirts and Intra-cluster Regions of Galaxies in the Low-surface-brightness Regime

The VST Early-type GAlaxy Survey (VEGAS) is a deep, multi-band (u, g, r, i) imaging survey, carried out with the 2.6-metre VLT Survey Telescope (VST) at ESO's Paranal Observatory in Chile. VEGAS combines the wide (1-square-degree) OmegaCAM imager and long integration times, together with a specially designed observing strategy. It has proven to be a gold mine for studies of features at very low surface brightness, down to levels of mu_g~27-30 magnitudes arcsec^(-2), over 5-8 magnitudes fainter than the dark sky at Paranal. In this article we highlight the main science results obtained with VEGAS observations of galaxies across different environments, from dense clusters of galaxies to unexplored poor groups and in the field.Comment: Published in The Messenger, vol. 183, p. 25-2

Galaxy populations in the Hydra i cluster from the VEGAS survey:I. Optical properties of a large sample of dwarf galaxies

At ~50 Mpc, the Hydra I cluster of galaxies is among the closest cluster in the z=0 Universe, and an ideal environment to study dwarf galaxy properties in a cluster environment. We exploit deep imaging data of the Hydra I cluster to construct a new photometric catalog of dwarf galaxies in the cluster core, which is then used to derive properties of the Hydra I cluster dwarf galaxies population as well as to compare with other clusters. Moreover, we investigate the dependency of dwarf galaxy properties on their surrounding environment. The new Hydra I dwarf catalog contains 317 galaxies with luminosity between -18.5<$M_r$<-11.5 mag, a semi-major axis larger than ~200 pc (a=0.84 arcsec), of which 202 are new detections, previously unknown dwarf galaxies in the Hydra I central region. We estimate that our detection efficiency reaches 50% at the limiting magnitude $M_r$=-11.5 mag, and at the mean effective surface brightness $\overline{\mu}_{e,r}$=26.5 mag/$arcsec^2$. We present the standard scaling relations for dwarf galaxies and compare them with other nearby clusters. We find that there are no observational differences for dwarfs scaling relations in clusters of different sizes. We study the spatial distribution of galaxies, finding evidence for the presence of substructures within half the virial radius. We also find that mid- and high-luminosity dwarfs ($M_r$<-14.5 mag) become on average redder toward the cluster center, and that they have a mild increase in $R_e$ with increasing clustercentric distance, similar to what is observed for the Fornax cluster. No clear clustercentric trends are reported with surface brightness and S\'ersic index. Considering galaxies in the same magnitude-bins, we find that for high and mid-luminosity dwarfs ($M_r$<-13.5 mag) the g-r color is redder for the brighter surface brightness and higher S\'ersic n index objects.Comment: Accepted for publication in A&A. 25 pages, 21 figure

Comprehensive characterization of SDH-deficient GIST using NGS data and iPSC models

Gastrointestinal stromal tumors (GIST) are the most common di tumors of the gastrointestinal tract, arising from the interstitial cells of Cajal (ICCs) or their precursors. The vast majority of GISTs (75–85% of GIST) harbor KIT or PDGFRA mutations. A small percentage of GIST (about 10‐15%) do not harbor any of these driver mutations and have historically been called wild-type (WT). Among them, from 20% to 40% show loss of function of the succinate dehydrogenase complex (SDH), also defined as SDH‐deficient GIST. SDH-deficient GISTs display distinctive clinical and pathological features, and can be sporadic or associated with Carney triad or Carney-Stratakis syndrome. These tumors arise most frequently in the stomach with predilection to distal stomach and antrum, have a multi-nodular growth, display a histological epithelioid phenotype, and present frequent lympho-vascular invasion. Occurrence of lymph node metastases and indolent course are representative features of SDH-deficient GISTs. This subset of GIST is known for the immunohistochemical loss of succinate dehydrogenase subunit B (SDHB), which signals the loss of function of the entire SDH-complex. The overall aim of my PhD project consists of the comprehensive characterization of SDH deficient GIST. Throughout the project, clinical, molecular and cellular characterizations were performed using next-generation sequencing technologies (NGS), that has the potential to allow the identification of molecular patterns useful for the diagnosis and development of novel treatments. Moreover, while there are many different cell lines and preclinical models of KIT/PDGFRA mutant GIST, no reliable cell model of SDH-deficient GIST has currently been developed, which could be used for studies on tumor evolution and in vitro assessments of drug response. Therefore, another aim of this project was to develop a pre-clinical model of SDH deficient GIST using the novel technology of induced pluripotent stem cells (iPSC)

Molecular profiling of SDHA-deficient GIST guides preclinical disease modeling based on induced Pluripotent Stem Cells

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract, arising from the interstitial cells of Cajal (ICCs) or their precursors. While the vast majority of GISTs harbor KIT or PDGFRA mutations, 10 – 15% of GIST do not show any of these driver mutations. Among them, 20% to 40% carry mutations in one of the four SDH-complex subunits, with SDHA mutations as the most frequent event. Representative features of SDH-deficient GISTs are gastric localization, frequent lymph node metastases and an indolent clinical course despite advanced disease status. This study was aimed at uncovering the specific gene expression profile of SDHA-deficient GIST and at developing a cellular model of this disease to allow preclinical drug testing. We analyzed 36 GIST tumor samples including SDH-deficient and KIT-mutant GISTs by gene expression arrays or RNA sequencing. SDHA-deficient GISTs displayed a very homogeneous gene expression profile, different from that of KIT-mutant GIST, characterized by an increased expression of neural markers and by the activation of the hypoxia signature and of the fibroblast growth factor pathway. This specific molecular signature was used to validate a SDHA-deficient GIST cellular model obtained from induced Pluripotent Stem Cells (iPSC). Patient-derived cells were reprogrammed to pluripotency then differentiated towards the mesodermal layer, as shown by lineage marker expression (T, MIXL1, NCAM), and treated with an irreversible chemical inhibitor of succinate dehydrogenase at concentrations that inhibit mitochondrial activity (3-Nitropropionic acid, 3-NPA). Pluripotent and mesoderm-committed iPSC exposed to 3-NPA showed a statistically significant upregulation of hypoxia-related genes such as HIF1α, EPAS1 and VEGF and of neural lineage markers (LHX2, CDH2 and NEFL) whose overexpression was previously found to characterize SDHA-mutant GIST. Notably, succinate dehydrogenase inhibition in iPSC also significantly increased expression of IGF1R, a characteristic marker of SDH-deficient GISTs. Overall, this study revealed the gene expression landscape of SDHA-deficient GISTs and provided evidence that the iPSC model has the potential to mimic the molecular phenotype of the disease, therefore providing a useful tool for preclinical pharmacological testing

Irisin Modulates Inflammatory, Angiogenic, and Osteogenic Factors during Fracture Healing

Bone fractures are a widespread clinical event due to accidental falls and trauma or bone fragility; they also occur in association with various diseases and are common with aging. In the search for new therapeutic strategies, a crucial link between irisin and bone fractures has recently emerged. To explore this issue, we subjected 8-week-old C57BL/6 male mice to tibial fracture, and then we treated them with intra-peritoneal injection of r-Irisin (100 &micro;g/kg/weekly) or vehicle as control. At day 10 post fracture, histological analysis showed a significant reduced expression of inflammatory cytokines as tumor necrosis factor-alpha (TNF&alpha;) (p = 0.004) and macrophage inflammatory protein-alpha (MIP-1&alpha;) (p = 0.015) in the cartilaginous callus of irisin-treated mice compared to controls, supporting irisin&rsquo;s anti-inflammatory role. We also found increased expressions of the pro-angiogenic molecule vascular endothelial growth factor (VEGF) (p = 0.002) and the metalloproteinase MMP-13 (p = 0.0006) in the irisin-treated mice compared to the vehicle ones, suggesting a myokine involvement in angiogenesis and cartilage matrix degradation processes. Moreover, the bone morphogenetic protein (BMP2) expression was also upregulated (p = 0.002). Taken together, our findings suggest that irisin can contribute to fracture repair by reducing inflammation and promoting vessel invasion, matrix degradation, and bone formation, supporting its possible role as a novel molecule for fracture treatment

Irisin Modulates Inflammatory, Angiogenic, and Osteogenic Factors during Fracture Healing

: Bone fractures are a widespread clinical event due to accidental falls and trauma or bone fragility; they also occur in association with various diseases and are common with aging. In the search for new therapeutic strategies, a crucial link between irisin and bone fractures has recently emerged. To explore this issue, we subjected 8-week-old C57BL/6 male mice to tibial fracture, and then we treated them with intra-peritoneal injection of r-Irisin (100 µg/kg/weekly) or vehicle as control. At day 10 post fracture, histological analysis showed a significant reduced expression of inflammatory cytokines as tumor necrosis factor-alpha (TNFα) (p = 0.004) and macrophage inflammatory protein-alpha (MIP-1α) (p = 0.015) in the cartilaginous callus of irisin-treated mice compared to controls, supporting irisin's anti-inflammatory role. We also found increased expressions of the pro-angiogenic molecule vascular endothelial growth factor (VEGF) (p = 0.002) and the metalloproteinase MMP-13 (p = 0.0006) in the irisin-treated mice compared to the vehicle ones, suggesting a myokine involvement in angiogenesis and cartilage matrix degradation processes. Moreover, the bone morphogenetic protein (BMP2) expression was also upregulated (p = 0.002). Taken together, our findings suggest that irisin can contribute to fracture repair by reducing inflammation and promoting vessel invasion, matrix degradation, and bone formation, supporting its possible role as a novel molecule for fracture treatment

VEGAS: A VST Early-type GAlaxy Survey

Context. In this paper, we present ultra-deep images of the compact group of galaxies HCG 86 as part of the VEGAS survey. Aims. Our main goals are to estimate the amount of intra-group light (IGL) as well as to study the light and colour distributions in order to address the main formation process of the IGL component in groups of galaxies. Methods. We derived the azimuthally averaged surface brightness profiles in the g, r, and i bands with g − r and r − i average colours and colour profiles for all group members. By fitting the light distribution, we extrapolated the contribution of the stellar halos plus the diffuse light from the brightest component of each galaxy. The results are compared with theoretical predictions. Results. The long integration time and wide area covered make our data reach deeper than previous literature studies of the IGL in compact groups of galaxies and allow us to produce an extended (∼160 kpc) map of the IGL, down to a surface brightness level of ∼30 mag arcsec−2 in the g band. The IGL in HCG 86 is mainly in diffuse form and has average colours of g − r ∼ 0.8 mag and r − i ∼ 0.4 mag. The fraction of IGL in HCG 86 is ∼16% of the total luminosity of the group, and this is consistent with estimates available for other compact groups and loose groups of galaxies of similar virial masses. A weak trend is present between the amount of IGL and the early-type to late-type galaxy ratio. A lack of a clear correlation is found between the amount of diffuse light and the cluster or group virial mass. Conclusions. By comparing the IGL fraction and colours with those predicted by simulations, the amount of IGL in HCG 86 would be the result of the disruption of satellites at an epoch of z ∼ 0.4. At this redshift, the observed colours are consistent with the scenario where the main contribution to the mass of the IGL comes from the intermediate-to-massive galaxies (1010 ≤ M* ≤ 1011 M⊙)

Gene Expression Landscape of SDH-Deficient Gastrointestinal Stromal Tumors

Background: About 20-40% of gastrointestinal stromal tumors (GISTs) lacking KIT/PDGFRA mutations show defects in succinate dehydrogenase (SDH) complex. This study uncovers the gene expression profile (GEP) of SDH-deficient GIST in order to identify new signaling pathways or molecular events actionable for a tailored therapy. Methods: We analyzed 36 GIST tumor samples, either from formalin-fixed, paraffin-embedded by microarray or from fresh frozen tissue by RNA-seq, retrospectively collected among KIT-mutant and SDH-deficient GISTs. Pathway analysis was performed to highlight enriched and depleted transcriptional signatures. Tumor microenvironment and immune profile were also evaluated. Results: SDH-deficient GISTs showed a distinct GEP with respect to KIT-mutant GISTs. In particular, SDH-deficient GISTs were characterized by an increased expression of neural markers and by the activation of fibroblast growth factor receptor signaling and several biological pathways related to invasion and tumor progression. Among them, hypoxia and epithelial-to-mesenchymal transition emerged as features shared with SDH-deficient pheochromocytoma/paraganglioma. In addition, the study of immune landscape revealed the depletion of tumor microenvironment and inflammation gene signatures. Conclusions: This study provides an update of GEP in SDH-deficient GISTs, highlighting differences and similarities compared to KIT-mutant GISTs and to other neoplasm carrying the SDH loss of function. Our findings add a piece of knowledge in SDH-deficient GISTs, shedding light on their putative histology and on the dysregulated biological processes as targets of new therapeutic strategies

Genomic Database Analysis of Uterine Leiomyosarcoma Mutational Profile

Uterine Leiomyosarcoma (uLMS) is by far the most common type of uterine sarcoma, characterized by an aggressive clinical course, a heterogeneous genetic profile and a very scarce response to cytotoxic chemotherapy. The genetic make-up of uLMS is an area of active study that could provide essential cues for the development of new therapeutic approaches. A total of 216 patients with uLMS from cBioPortal and AACR-GENIE databases were included in the study. The vast majority of patients (81%) carried at least one mutation in either TP53, RB1, ATRX or PTEN. The most frequently mutated gene was TP53, with 61% of the patients harboring at least one mutation, followed by RB1 at 48%. PTEN alteration was more frequent in metastases than in primary lesions, consistent with a later acquisition during tumor progression. There was a significant trend for TP53 and RB1 mutations to occur together, while both TP53 and RB1 were mutually exclusive with respect to CDKN2A/B inactivation. Overall survival did not show significant correlation with the mutational status, even if RB1 mutation emerged as a favorable prognostic factor in the TP53-mutant subgroup. This comprehensive analysis shows that uLMS is driven almost exclusively by the inactivation of tumor suppressor genes and suggests that future therapeutic strategies should be directed at targeting the main genetic drivers of uLMS oncogenesis