PPAR-γ Agonists and Their Effects on IGF-I Receptor Signaling: Implications for Cancer

It is now well established that the development and progression of a variety of human malignancies are associated with dysregulated activity of the insulin-like growth factor (IGF) system. In this regard, promising drugs have been developed to target the IGF-I receptor or its ligands. These therapies are limited by the development of insulin resistance and compensatory hyperinsulinemia, which in turn, may stimulate cancer growth. Novel therapeutic approaches are, therefore, required. Synthetic PPAR-γ agonists, such as thiazolidinediones (TZDs), are drugs universally used as antidiabetic agents in patients with type 2 diabetes. In addition of acting as insulin sensitizers, PPAR-γ agonists mediate in vitro and in vivo pleiotropic anticancer effects. At least some of these effects appear to be linked with the downregulation of the IGF system, which is induced by the cross-talk of PPAR-γ agonists with multiple components of the IGF system signaling. As hyperinsulinemia is an emerging cancer risk factor, the insulin lowering action of PPAR-γ agonists may be expected to be also beneficial to reduce cancer development and/or progression. In light of these evidences, TZDs or other PPAR-γ agonists may be exploited in those tumors “addicted” to the IGF signaling and/or in tumors occurring in hyperinsulinemic patients

ГЕНЕТИЧЕСКОЕ РАЗНООБРАЗИЕ ШТАММОВ MYCOBACTERIUM AVIUM subsp. HOMINISSUIS, ВЫДЕЛЕННЫХ В ИТАЛИИ, НА ОСНОВЕ АНАЛИЗА ЛОКУСОВ VNTR

Abstract. Background. Mycobacterium avium subsp. hominissuis (MAH) is an important pathogen responsible for most of the human-associated nontuberculous mycobacteria infections. Over the past few decades the incidence of MAH infections is increasing in Italy, as in many countries worldwide. The present study is aimed to elucidate the genetic characteristics of MAH strains isolated from human patients using VNTR typing and to show the genetic relatedness among them. Methods. The genetic diversity of 108 human isolates of MAH was determined by VNTR analysis targeting 8 loci, coded 32, 292, X3, 25, 3, 7, 10 and 47. Results. The VNTR analysis revealed 25 distinct VNTR patterns; of these, 13 patterns were unique, while 12 patterns were shared by 2 or more isolates, thus yielding 12 clusters including a total of 95 isolates. The discriminatory power of our VNTR analysis yielded an HGDI of 0.990, indicating that VNTR typing has an excellent discriminatory power. No association of a particular VNTR pattern with a particular clinical feature, such as the disseminated, pulmonary or extrapulmonary type of infection, was observed. Minimum spanning tree analysis showed that 21 VNTR patterns, occurring either as clustered or unique isolates, differed from the nearest one for one allelic variation. Conclusions. The results obtained through the VNTR analysis showed that most MAH strains displayed a close genetic relationship. This high phylogenetic proximity of the VNTR loci over a long time period supports the concept that the MAH genotype is highly homogeneous in our geographical area, suggesting the hypothesis of the presence of possible sources of infection and transmission pathways at the local level

Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes

Increased plasma level of soluble urokinase-type plasminogen activator receptor (suPAR) was associated recently with focal segmental glomerulosclerosis (FSGS). In addition, different clinical studies observed increased concentration of suPAR in various glomerular diseases and in other human pathologies with nephrotic syndromes such as HIV and Hantavirus infection, diabetes and cardiovascular disorders. Here, we show that suPAR induces nephrin down-modulation in human podocytes. This phenomenon is mediated only by full-length suPAR, is time-and dose-dependent and is associated with the suppression of Wilms\u27 tumor 1 (WT-1) transcription factor expression. Moreover, an antagonist of alpha v beta 3 integrin RGDfv blocked suPAR-induced suppression of nephrin. These in vitro data were confirmed in an in vivo uPAR knock out Plaur(-/-) mice model by demonstrating that the infusion of suPAR inhibits expression of nephrin and WT-1 in podocytes and induces proteinuria. This study unveiled that interaction of full-length suPAR with alpha v beta 3 integrin expressed on podocytes results in down-modulation of nephrin that may affect kidney functionality in different human pathologies characterized by increased concentration of suPAR

Participatory coastal management through elicitation of ecosystem service preferences and modelling driven by coastal squeeze

The Baixo Vouga Lagunar (BVL) is part of Ria de Aveiro coastal lagoon in Portugal, which is classified as a Special Protection Area under the European Habitats and Birds Directives. This part of the system, corresponding to the confluence of the Vouga River with the lagoon, is very important culturally and socioeconomically for the local communities, taking place several human activities, especially agriculture. To prevent salt water intrusion from the Ria de Aveiro into agriculture fields, a floodbank was initiated in the 90's. In frame of ongoing changes in Ria de Aveiro hydrodynamics, the existing floodbank will be now extended, introducing further changes in the ecological dynamics of the BVL and its adjacent area. As a consequence, the water level in the floodbank downstream side is expected to rise, increasing the submersion period in tidal wetlands, and leading to coastal squeeze. The aim of this study is to apply an ecosystem based-management approach to mitigate the impacts on biodiversity resulting from the management plan. To do so, we have modelled the implications of the changes in several hydrological and environmental variables on four saltmarsh species and habitats distribution, as well as on their associated ecosystem services, both upstream and downstream of the floodbank. The ecosystem services of interest were prioritized by stakeholders' elicitation, which were then used as an input to a spatial multi-criteria analysis aimed to find the best management actions to compensate for the unintended loss of biodiversity and ecosystem services in the BVL. According to our results, the main areas to be preserved in the BVL were the traditional agricultural mosaic fields; the freshwater courses and the subtidal estuarine channels. By combining ecology with the analysis of social preferences, this study shows how co-developed solutions can support adaptive management and the conservation of coastal ecosystems. © 2018 The AuthorsThe European Commission under the Horizon 2020 Programme for Research, Technological Development and Demonstration supported this study through the collaborative research project AQUACROSS (Grant Agreement no. 642317 ). María Almagro was supported by the Juan de la Cierva Program (Grant IJCI-2015-23500 ). Ana I. Sousa was supported by the “ Fundação para a Ciência e a Tecnologia , I.P. (FCT)” Post-Doc grant SFRH/BPD/107823/2015 . Ana Genua-Olmedo was funded by the project PORBIOTA - Portuguese E-Infrastructure for Information and Research on Biodiversity (POCI-01-0145-FEDER-022127), financed by the “ Programa Operacional de Competitividade e Internacionalização ” and “Programa Operacional Regional de Lisboa, FEDER ”, and by the “ Fundação para a Ciência e a Tecnologia , I.P. (FCT)” through national funds (PIDDAC). Thanks are due by co-funding to Labex DRIIHM, French program “Investissements d'Avenir” ( ANR-11-LABX-0010 ) managed by the ANR, which funded the MARSH-C-LEVEL project. Thanks are also due, for the financial support to CESAM ( UID/AMB/50017 - POCI-01-0145-FEDER-007638 ), to FCT /MEC through national funds (PIDDAC), and the co-funding by the FEDER , within the PT2020 Partnership Agreement and Compete 2020

A spatial explicit vulnerability assessment for a coastal socio-ecological Natura 2000 site

In line with the global trend, the Ria de Aveiro coastal lagoon is subjected to multiple co-occurring pressures threatening vital benefits flowing from nature to people. The main objective of this research was to assess the status of habitats important for ecosystem services in the Ria de Aveiro by identifying vulnerable areas to anthropogenic threats. The pressures from seven relevant human activities (recreation, services, aquaculture, agriculture, commercial development, unintended impacts from management, and invasive alien species) were analysed based on their spatiotemporal distribution (exposure) and impact over the EUNIS habitats (EUNIS codes A2.2, A2.22 – sand flats and beaches; A2.3 – mud flats; A2.61 – seagrasses; A2.5, A2.53C, A2.535, A2.545, A2.554 – salt marshes; and, X10 – ‘Bocage,’ a landscape of small-hedged fields) in seven distinct landscape units. A prospective scenario, co-developed for the year 2030, was evaluated using a map-based risk assessment tool and brought forward the near-term vulnerability of the seagrass biotope. The highest risks posed to intertidal habitats (mud flats and salt marshes) were driven mainly by environmental management activities that support critical socio-economic sectors. Our methodology evaluated plausible threats to habitats in the near term, established baseline knowledge for the adaptive management process in Ria de Aveiro Natura 2000 site, and showcased how future assessments can inform the operationalization of ecosystem-based management as new information becomes available

DEDALO: PHASE II STUDY OF DARATUMUMAB PLUS POMALIDOMIDE AND DEXAMETHASONE (DPD) IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA AND 17P DELETION

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High dose sequential chemotherapy with autologous transplantation versus dose-dense chemotherapy MegaCEOP as first line treatment in poor-prognosis diffuse large cell lymphoma: an Intergruppo Italiano Linfomi randomized trial

Background and Objectives. Poor prognosis diffuse large cell lymphoma (DLCL) responds poorly to standard chemotherapy. Randomized studies comparing high-dose chemotherapy with autologous stem-cell transplantation (ASCT) against standard chemotherapy have produced conflicting results. Dose-dense chemotherapy with granulocyte colony-stimulating factor (G-CSF) support seems to hold promise. The purpose of this multicenter, randomized trial was to compare failure-free and overall survival in patients with poor prognosis DLCL treated with high-dose sequential (HDS) chemotherapy followed by ASCT or an outpatient dose-dense chemotherapy regimen (MegaCEOP). Design and Methods. Between 1996 and 2001, 130 DLCL patients, aged <= 60 years, with intermediate-high or high-risk disease, according to the International Prognostic Index score, and/or bone marrow involvement were enrolled. Sixty were randomized to HDS chemotherapy plus high-dose mitoxantrone and melphalan with ASCT (arm A) and 66 to the MegaCEOP regimen (6-8 courses of an escalated dose of cyclophosphamide and epirubicin plus vincristine and prednisone with G-CSF every 2-weeks) (arm B); 4 patients were considered ineligible. Results. The complete remission rate was 59% in arm A and 70% in arm B (p=0.18). After a median follow-up of 78 months, the 6-year failure-free survival was 45% in arm A and 48% in arm B (hazard ratio=1.15, 95% confidence intervals =0.72-1.84, p=0.56). The 5-year overall survival was 49% in arm A and 63% in arm B (hazard ratio=1.67, 95% confidence interval=0.98-2.85, p=0.06). Two cases of secondary acute myeloid leukemia were observed after treatment in group A. Interpretations and Conclusions. HDS and ASCT as initial therapy for patients with poor-prognosis DLCL does not provide a benefit over that of outpatient dose-dense MegaCEOP chemotherapy

Cell-intrinsic depletion of Aml1-ETO-expressing pre-leukemic hematopoietic stem cells by K-Ras activating mutation

Somatic mutations in acute myeloid leukemia are acquired sequentially and hierarchically. First, pre-leukemic mutations, such as t(8;21) that encodes AML1-ETO, are acquired within the hematopoietic stem cell (HSC) compartment, while signaling pathway mutations, including KRAS activating mutations, are late events acquired during transformation of leukemic progenitor cells and are rarely detectable in HSC. This raises the possibility that signaling pathway mutations are detrimental to clonal expansion of pre-leukemic HSC. To address this hypothesis, we used conditional genetics to introduce Aml1-ETO and K-RasG12D into murine HSC, either individually or in combination. In the absence of activated Ras, Aml1-ETO-expressing HSC conferred a competitive advantage. However, activated K-Ras had a marked detrimental effect on Aml1-ETO-expressing HSC, leading to loss of both phenotypic and functional HSC. Cell cycle analysis revealed a loss of quiescence in HSC co-expressing Aml1-ETO and K-RasG12D, accompanied by an enrichment in E2F and Myc target gene expression and depletion of HSC self-renewal-associated gene expression. These findings provide a mechanistic basis for the observed absence of KRAS signaling mutations in the pre-malignant HSC compartment

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières Syndrome astrocytes

Aberrant induction of type I IFN is a hallmark of the inherited encephalopathy Aicardi-Goutières syndrome (AGS), but the mechanisms triggering disease in the human central nervous system (CNS) remain elusive. Here, we generated human models of AGS using genetically modified and patient-derived pluripotent stem cells harboring TREX1 or RNASEH2B loss-of-function alleles. Genome-wide transcriptomic analysis reveals that spontaneous proinflammatory activation in AGS astrocytes initiates signaling cascades impacting multiple CNS cell subsets analyzed at the single-cell level. We identify accumulating DNA damage, with elevated R-loop and micronuclei formation, as a driver of STING- and NLRP3-related inflammatory responses leading to the secretion of neurotoxic mediators. Importantly, pharmacological inhibition of proapoptotic or inflammatory cascades in AGS astrocytes prevents neurotoxicity without apparent impact on their increased type I IFN responses. Together, our work identifies DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes, suggests a role for AGS gene products in R-loop homeostasis, and identifies common denominators of disease that can be targeted to prevent astrocyte-mediated neurotoxicity in AGS