Role of Transcription Factor Atf3 in the Bone Marrow Microenvironment During Breast Cancer Development: A Response Marker or an Active Player of Tumourigenesis?

Cancer is a systemic disease able to reprogram the bone marrow (BM) niche towards a pro-tumorigenic state. The timing in which BM cells start to sense the development of distant tumours and the molecular players involved in cancer-adapted immune response are largely unknown. In this context, by using the MMTV-NeuT mammary carcinoma mouse model, we have recently described the BM hematopoietic and stromal changes that support the initial steps of mammary transformation and identified the Activating transcription factor 3 (Atf3) among the genes significantly up modulated during the transcriptional reprogramming of the BM hematopoietic niche, at both early and late stages of disease. Additionally, Atf3 expression in the BM perfectly correlated with the pathologic disease score. These data supported the need to further investigate the role of Atf3 during the BM emergency haematopoiesis associated with tumour progression. In order to identify in which specific BM cell populations Atf3 was more expressed, we checked ATF3 activation in different progenitor and mature immune cell subsets starting from early stages of mammary gland transformation and along tumour progression. Taking advantage of two mouse models of luminal breast cancer, we demonstrated, extending previous observations, that ATF3 induction during cancer progression is a multistep process characterized by its activation in two different subsets of BM myeloid cells. At early time point we observed high ATF3 expression and nuclear localization in common myeloid progenitor cells (FcγR+) localized in proximity of the vascular niche. This feature was maintained at invasive stage of mammary transformation, when ATF3 became also expressed in mature monocyte/macrophage cells. Of note, the nuclear localization of ATF3 was associated with the formation of myeloid progenitor clusters in the BM of tumour-bearing mice and its overexpression in progenitor cells drove the expansion and the differentiation of monocyte/macrophage cells. The role of ATF3 in monocyte/macrophage differentiation was supported by in vivo data showing a defective recruitment of circulating monocytes and a low number of tumour-associated macrophages in PyMT41c tumours transplanted into Atf3fl/flLySMCre+/- mice. Further studies demonstrated that BM-mesenchymal stem cells (BM-MSCs) were the first sensors of peripheral tumours and that ATF3 induction in the BM hematopoietic niche was the consequence of the cross talk between tumour-primed BM-MSCs and hematopoietic stem cells (HSCs), which ultimately leads to a tumour-restricted release of Atf3+ cells into the circulation. Specifically, tumour-educated BM-MSCs, through the release of IL-1β, an inflammatory cytokines that induce HSCs to differentiate towards myeloid progenitor cells, activated Atf3 expression in naïve HSCs and initiated a specific lineage commitment. Indeed, in vivo inhibition of IL-1β at early stage of disease significantly decreased Atf3 activation in HSCs and reduced myeloid progenitor clustering, a necessary step towards the establishment of emergency haematopoiesis. Furthermore, the blocking of IL-1β when the tumour was well-established caused a down-regulation of Atf3 expression in both precursors and mature monocytes and, consequently, decreased myeloid cell expansion. Overall, this project demonstrated that the biphasic induction of ATF3 in the BM is functionally associated with a key role during emergency haematopoiesis and myeloid cell expansion, also suggesting a possible therapeutic targets

Flavone and flavonol glycosides from Astragalus eremophilus and Astragalus vogelii.

Two new rhamnocitrin glycosides (1 and 2) were isolated from the aerial parts of Astragalus vogelii, along with one known rhamnocitrin glycoside (3). Two known flavonol glycosides (4 and 5) and four known flavone derivatives (6-9) were isolated from the aerial parts of Astragalus eremophilus. Their structures were elucidated by extensive spectroscopic methods including 1D- (1H, 13C and TOCSY) and 2D-NMR (DQF-COSY, HSQC, HMBC) experiments, as well as ESIMS analysis

Refractory vasculitic ulcer of the toe in adolescent suffering from Systemic Lupus Erythematosus treated successfully with hyperbaric oxygen therapy

Skin ulcers are a dangerous and uncommon complication of vasculitis. We describe the case of a teenager suffering from Systemic Lupus Erythematosus with digital ulcer resistant to conventional therapy, treated successfully with Hyperbaric Oxygen Therapy. The application of hyperbaric oxygen, which is used for the treatment of ischemic ulcers, is an effective and safe therapeutic option in patients with ischemic vasculitic ulcers in combination with immunosuppressive drugs. Further studies are needed to evaluate its role as primary therapy for this group of patients

Activation of APE1/Ref-1 is dependent on reactive oxygen species generated after purinergic receptor stimulation by ATP

Apurinic apyrimidinic endonuclease redox effector factor-1 (APE1/Ref-1) is involved both in the base excision repair (BER) of DNA lesions and in the eukaryotic transcriptional regulation. APE1/Ref-1 is regulated at both the transcriptional and post-translational levels, through control of subcellular localization and post-translational modification. In response to stress conditions, several cell types release ATP, which exerts stimulatory effects on eukaryotic cells via the purinergic receptors (P2) family. By using western blot and immunofluorescence analysis on a human tumour thyroid cell line (ARO), we demonstrate that purinergic stimulation by extracellular ATP induces quick cytoplasm to nucleus translocation of the protein at early times and its neosynthesis at later times. Continuous purinergic triggering by extracellular ATP released by ARO cells is responsible for the control of APE1/Ref-1 intracellular level. Interference with intracellular pathways activated by P2 triggering demonstrates that Ca(2+) mobilization and intracellular reactive oxygen species (ROS) production are responsible for APE1/Ref-1 translocation. The APE1/Ref-1 activities on activator protein-1 (AP-1) DNA binding and DNA repair perfectly match its nuclear enrichment upon ATP stimulation. The biological relevance of our data is reinforced by the observation that APE1/Ref-1 stimulation by ATP protects ARO cells by H(2)O(2)-induced cell death. Our data provide new insights into the complex mechanisms regulating APE1/Ref-1 functions

Glass optical fibre sensors for detection of through thickness moisture diffusion in glass reinforced composites under hostile environments

A combination of evanescent wave optical sensors (EWOSs) and fibre Bragg gratings (FBGs) was embedded in an epoxy vinyl ester and an epoxy vinyl ester based glass reinforced polymer (GRP) composite to measure fluid ingress that would result in degradation under hostile conditions. Samples were subjected to accelerated aging in the form of single sided exposure to simulated sea water at 1208C in a pressurised stainless steel vessel. Low cost EWOSs were prepared from a standard multimode glass optical fibre and compared to commercially available FBGs. Both sensors were able to detect the early stage of moisture diffusion into the GRP matrix. The evanescent sensors showed a reduction in the transmitted signal intensity between 1500 and 1650 nm with an increasing exposure time due to a change in the optical properties of the polymer, whereas a peak shift was observed for the FBGs due to the swelling of the resin with the absorption of water. Additionally, the glass optical fibre sensors were embedded in a configuration that allowed the extent of diffusion through the thickness of the GRPs to be monitored, with the fibres in the closest position to the exposure face showing a greater signal change than those positioned further away

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

Coronary computed tomography: current role and future perspectives for cardiovascular risk stratification.

Atherosclerotic coronary artery disease (CAD) is a major cause of morbidity and mortality. The majority of cardiovascular events, more than 50% of CAD deaths, occur in previously asymptomatic individuals at intermediate cardiovascular risk, highlighting the relevance of accurate individual risk assessment to decrease cardiovascular events through more appropriate targeting of preventive measures. In the last decades, the development of non-invasive imaging techniques have prompted interest in imaging of atherosclerosis. Coronary computed tomography provides the opportunity to assess the deposition of calcium in the coronary tree and to non-invasively image coronary vessels. Both information are useful for risk stratification of asymptomatic subjects or of subjects with suspected CAD