Tumor Associated Macrophages (TAMs) a pivotal orchestrator in cancer-related inflammation and a new important target in cancer-therapy

Macrophages are pivotal orchestrators of tumor-promoting inflammation and promising targets for new anti-cancer therapies. To identify new molecular players underlying their pro-tumoral activities, we analyzed the phosphoproteoma of tumor associated macrophages (TAMs) isolated from murine fibrosarcoma. We identified the protein TRIM28, a pleiotropic molecule that is known to be involved in the dynamic organization of chromatin, and we characterized the signaling pathway driving its phosphorylation in response to inflammatory signals and its impact on LPS-induced gene expression. We explored in vivo the functional relevance of TRIM28 and found a significant reduction of colitis associated cancer lesions in mice lacking TRIM28 in intestinal epithelial cells. Single cell RNAseq analysis pointed out alterations of both immune and intestinal cell populations during the transition from colitis to cancer, that are dependent on TRIM28. Overall, these results identify TRIM28 as a new molecular target at the crossroads between inflammation and cancer. Beyond contributing to tumorigenesis, TAMs can profoundly affect the response to anti-cancer therapies. We investigated their impact on EPZ-6438, an inhibitor of the histone methyltransferase EZH2 that has recently entered in clinical trials due to the anti-proliferative effects shown on malignant pleural mesothelioma cells (MPM). We generated an MPM spheroid model that recapitulates in vitro, both monocyte recruitment in tumor and their functional differentiation towards a TAM-like phenotype (Mo-TAMs) capable of promoting tumor cell proliferation and spreading. Prolonged treatment of MPM spheroids with EPZ-6438 enhances both Mo-TAMs recruitment and pro-tumor phenotype expression, thereby limiting the anti-proliferative effects due to EZH2 inhibition in MPM cells. These findings indicate that strategies of TAM depletion should be combined with EPZ-6438 to improve the therapeutic efficacy of pharmacological EZH2 inhibition

The Macrophages-Microbiota Interplay in Colorectal Cancer (CRC)-Related Inflammation: Prognostic and Therapeutic Significance

Tumor-associated macrophages (TAMs) are the main population of myeloid cells infiltrating solid tumors and the pivotal orchestrators of cancer-promoting inflammation. However, due to their exceptional plasticity, macrophages can be also key effector cells and powerful activators of adaptive anti-tumor immunity. This functional heterogeneity is emerging in human tumors, colorectal cancer (CRC) in particular, where the dynamic co-existence of different macrophage subtypes influences tumor development, outcome, and response to therapies. Intestinal macrophages are in close interaction with enteric microbiota, which contributes to carcinogenesis and affects treatment outcomes. This interplay may be particularly relevant in CRC, one of the most prevalent and lethal cancer types in the world. Therefore, both macrophages and intestinal microbiota are considered promising prognostic indicators and valuable targets for new therapeutic approaches. Here, we discuss the current understanding of the molecular circuits underlying the interplay between macrophages and microbiota in CRC development, progression, and response to both conventional therapies and immunotherapies

High karyotypic variation in Orthemis Hagen, 1861 species, with insights about the neo-XY in Orthemis ambinigra Calvert, 1909 (Libellulidae, Odonata)

The American dragonfly genus Orthemis Hagen, 1861 is mainly found in the Neotropical region. Seven of 28 taxonomically described species have been reported from Argentina. Chromosome studies performed on this genus showed a wide variation in chromosome number and a high frequency of the neoXY chromosomal sex-determination system, although the sexual pair was not observed in all cases. This work analyzes the spermatogenesis of Orthemis discolor (Burmeister, 1839), O. nodiplaga Karsch, 1891 and O. ambinigra Calvert, 1909 in individuals from the provinces of Misiones and Buenos Aires, Argentina. Orthemis discolor has 2n=23, n=11+X and one larger bivalent. Orthemis nodiplaga exhibits the largest chromosome number of the order, 2n=41, n=20+X and small chromosomes. Orthemis ambinigra shows a reduced complement, 2n=12, n=5+neo-XY, large-sized chromosomes, and a homomorphic sex bivalent. Fusions and fragmentations are the main evolutionary mechanisms in Odonata, as well as in other organisms with holokinetic chromosomes. Orthemis nodiplaga would have originated by nine autosomal fragmentations from the ancestral karyotype of the genus (2n=22A+X in males). We argue that the diploid number 23 in Orthemis has a secondary origin from the ancestral karyotype of family Libellulidae (2n=25). The complement of O. ambinigra would have arisen from five autosomal fusions and the insertion of the X chromosome into a fused autosome. C-banding and DAPI/CMA3 staining allowed the identification of the sexual bivalent, which revealed the presence of constitutive heterochromatin. We propose that the chromosome with intermediate C-staining intensity and three medial heterochromatic regions corresponds to the neo-Y and that the neo-system of this species has an ancient evolutionary origin. Moreover, we discuss on the mechanisms involved in the karyotypic evolution of this genus, the characteristics of the neo sex-determining systems and the patterns of heterochromatin distribution, quantity and base pair richness.Fil: Mola, Liliana Maria. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ecología, Genética y Evolución. Laboratorio de Citogenética y Evolución; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fourastié, María Florencia. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ecología, Genética y Evolución; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Agopian, Silvia Susana. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ecología, Genética y Evolución. Laboratorio de Citogenética y Evolución; Argentin

The Garda Area (Italy) Earthquake of 24 November 2004: a Field Report

On November 24 2004 an earthquake hit the area of the Garda Lake, part of the Lombardia region in Italy. This report presents the evidence collected in the investigation trip. The historical seismicity is provided. The behaviour of different categories of buildings is analysed and discussed, and the an overview of the procedures used to deal with the emergency is carried out.JRC.G.5-European laboratory for structural assessmen

Meiotic Analysis of Gomphidae Species Sheds Light on the Large X Chromosome of the Family (Anisoptera, Odonata)

In most Anisoptera families, the modal diploid number is 25 in males (24 autosomes + X), and the X chromosome is one of the smallest elements of the complement. The family Gomphidae is an exception, as it has a modal diploid number of 23 (22 + X), and the X chromosome is the largest of the complement and of medium-to-large size in many species. We studied the meiosis of three gomphid species from Argentina: Aphylla cf. distinguenda (Campion, 1920), Phyllocycla propinqua Belle, 1972 and Phyllocycla sp. Chromosome number is 2n = 23, n = 11 + X, except for Phyllocycla propinqua, showing n = 10 + X. The X chromosome of these species is medium-sized and presents heteropyknotic blocks of different sizes. Despite the small number of gomphid species analysed, there is a clear trend of increasing size of the X chromosome with the increasing amount of heterochromatin. Our results, together with those from the literature, suggest that its large size might have been due to a progressive accumulation of repetitive DNA and heterochromatinisation and not to fusion, as previously suggested. This led us to propose that the ancestral number coincided with the modal number of Gomphidae. A revision of the derived sex-determining systems in Odonata is also provided.Fil: Mola, Liliana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; ArgentinaFil: Rebagliati, Pablo Javier. Universidad Nacional de Entre Ríos; ArgentinaFil: Fourastié, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; ArgentinaFil: Agopian, Silvia S.. No especifíca

Myeloid-Derived Suppressor Cells: Ductile Targets in Disease

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells with major regulatory functions and rise during pathological conditions, including cancer, infections and autoimmune conditions. MDSC expansion is generally linked to inflammatory processes that emerge in response to stable immunological stress, which alter both magnitude and quality of the myelopoietic output. Inability to reinstate physiological myelopoiesis would fall in an “emergency state” that perpetually reprograms myeloid cells toward suppressive functions. While differentiation and reprogramming of myeloid cells toward an immunosuppressive phenotype can be considered the result of a multistep process that originates in the bone marrow and culminates in the tumor microenvironment, the identification of its driving events may offer potential therapeutic approaches in different pathologies. Indeed, whereas expansion of MDSCs, in both murine and human tumor bearers, results in reduced immune surveillance and antitumor cytotoxicity, placing an obstacle to the effectiveness of anticancer therapies, adoptive transfer of MDSCs has shown therapeutic benefits in autoimmune disorders. Here, we describe relevant mechanisms of myeloid cell reprogramming leading to generation of suppressive MDSCs and discuss their therapeutic ductility in disease

Functional characterization of a novel truncating mutation in Lamin A/C gene in a family with a severe cardiomyopathy with conduction defects

Background/Aims: Truncating LMNA gene mutations occur in many inherited cardiomyopathy cases, but the molecular mechanisms involved in the disease they cause have not yet been systematically investigated. Here, we studied a novel frameshift LMNA variant (p.D243Gfs*4) identified in three members of an Italian family co-segregating with a severe form of cardiomyopathy with conduction defects. Methods: HEK293 cells and HL-1 cardiomyocytes were transiently transfected with either Lamin A or D243Gfs*4 tagged with GFP (or mCherry). D243Gfs*4 expression, cellular localization and its effects on diverse cellular mechanisms were evaluated with western blotting, laser-scanning confocal microscopy and video-imaging analysis in single cells. Results: When expressed in HEK293 cells, GFP- (or mCherry)-tagged LMNA D243Gfs*4 colocalized with calnexin within the ER. ER mislocalization of LMNA D243Gfs*4 did not significantly induce ER stress response, abnormal Ca2+ handling and apoptosis when compared with HEK293 cells expressing another truncated mutant of LMNA (R321X) which similarly accumulates within the ER. Of note, HEK293-LMNA D243Gfs*4 cells showed a significant reduction of connexin 43 (CX43) expression level, which was completely rescued by activation of the WNT/β-catenin signaling pathway. When expressed in HL-1 cardiomyocytes, D243Gfs*4 significantly impaired the spontaneous Ca2+ oscillations recorded in these cells as result of propagation of the depolarizing waves through the gap junctions between non-transfected cells surrounding a cell harboring the mutation. Furthermore, mCh-D243Gfs*4 HL-1 cardiomyocytes showed reduced CX43-dependent Lucifer Yellow (LY) loading and propagation. Of note, activation of β-catenin rescued both LY loading and LMNA D243Gfs*4 -HL-1 cells spontaneous activity propagation. Conclusion: Overall, the present results clearly indicate the involvement of the aberrant CX43 expression/activity as a pathogenic mechanism for the conduction defects associated to this LMNA truncating alteration

Overweight in schoolchildren and nutrient intake

Introduction: According to the World Health Organization (WHO), one of the most serious health problems of the 21st century is childhood obesity. In 2016, more than 400 million children and adolescents between the age of 5 and 19 were overweight or obese. The aim of this study is to evaluate the consumption, habits and dietary practices of schoolchildren who suffer from malnutrition due to overweight or obesity. Methods: descriptive, correlational and prospective study using a quantitative approach. The sample size was 82 girls and boys who met the inclusion criteria between 8 and 14 years of a public institution of basic education in Barranquilla. Results: schoolchildren of both sexes had a high prevalence of obesity, particularly in the female group (76.44%). A dietary interview using the frequency of food consumption method showed a moderate consumption of fruits and vegetables, as well as a high consumption of sugary drinks, fried foods, cookies and sweets, and a low intake of water. Regarding eating habits and practices, it was reported that a high percentage of schoolchildren receive diets and purchase cookies, ice cream, sugary drink or juices and salty snacks. Discussion: a a study revealed in 56 schoolchildren evaluated the prevalence of overweight of Spanish schoolchildren according to sex, thus showing a higher prevalence of overweight in girls (21.9%) than in boys, (10.1%) while the prevalence go obesity was higher in boys (24.5%) than in girls (9.7%). A systematic analysis reported in a population of children and adults from 1980 to 2013, finding a prevalence of overweight and obesity in boys (26.3% and 9.4%, respectively) and girls (27.3% and 8.3%). Our study presents excessive figures related to obesity mainly in schoolgirls (76.44%). Conclusion: Our data show a relationship between the prevalence of overweight and obesity and poor consumption and eating habits and practices

Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma

Haemorrhagic transformation is a complication of recombinant tissue-plasminogen activator treatment. The most severe form, parenchymal haematoma, can result in neurological deterioration, disability, and death. Our objective was to identify single nucleotide variations associated with a risk of parenchymal haematoma following thrombolytic therapy in patients with acute ischaemic stroke. A fixed-effect genome-wide meta-analysis was performed combining two-stage genome-wide association studies (n = 1904). The discovery stage (three cohorts) comprised 1324 ischaemic stroke individuals, 5.4% of whom had a parenchymal haematoma. Genetic variants yielding a P-value < 0.05 1 x 10(-5) were analysed in the validation stage (six cohorts), formed by 580 ischaemic stroke patients with 12.1% haemorrhagic events. All participants received recombinant tissue-plasminogen activator; cases were parenchymal haematoma type 1 or 2 as defined by the European Cooperative Acute Stroke Study (ECASS) criteria. Genome-wide significant findings (P < 5 x 10(-8)) were characterized by in silica functional annotation, gene expression, and DNA regulatory elements. We analysed 7 989 272 single nucleotide polymorphisms and identified a genome-wide association locus on chromosome 20 in the discovery cohort; functional annotation indicated that the ZBTB46 gene was driving the association for chromosome 20. The top single nucleotide polymorphism was rs76484331 in the ZBTB46 gene [P = 2.49 x 10(-8); odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55]. In the replication cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal haematoma (P = 0.01), and the overall association after meta-analysis increased (P = 1.61 x 10(-8), OR: 5.84; 95% CI: 3.16-10.76). ZBTB46 codes the zinc finger and BTB domain-containing protein 46 that acts as a transcription factor. In silica studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conclusion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal haematoma following recombinant tissue-plasminogen activator treatment.Peer reviewe