New Synthetic Endocannabinoid as Anti-Inflammaging Cosmetic Active: an In Vitro Study on a Reconstructed Skin Model

Endocannabinoids have been recently appointed as interesting cosmetic actives in regulating inflammaging, a state of chronic low-grade inflammation, known for being involved in many senescence\u2019s manifestations, included skin aging. The aim of this study was to assess the anti-inflammaging activity of a new synthetic endocannabinoid, Isopalmide\uae, on a reconstructed skin model, on which inflammaging has been reproduced through UVA radiation and light mechanical stress. We tested Isopalmide\uae both as a single active and conveyed in a cosmetic product, in comparison with Anandamide, a well-known natural endocannabinoid with anti-inflammatory action. The anti-inflammaging activity of topically applied products has been assessed, after 6 hours of treatment post-irradiation, through the transcriptional modification of genes involved in the NF-\u3baB pathway and the epigenetic pathway targeting miRs as potential biomarkers of inflammaging: miR-21, miR-126 and miR-146a. The results confirmed the anti-inflammatory action of Anandamide which inhibits NF-\u3baB, while Isopalmide\uae showed its anti-inflammaging activity through the establishment of an inflammatory/anti-inflammatory balance by maintaining NF-\u3baB inactive in the cytoplasm and active in the nucleus. The anti-inflammaging activity was shown also by the cosmetic product containing Isopalmide

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

Large granular lymphocyte leukemia (LGLL) is a chronic proliferation of clonal cytotoxic lymphocytes, usually presenting with cytopenias and yet lacking a specific therapy. The disease is heterogeneous, including different subsets of patients distinguished by LGL immunophenotype (CD8+ T\u3b1\u3b2, CD4+ T\u3b1\u3b2, T\u3b3\u3b4, NK) and the clinical course of the disease (indolent/symptomatic/aggressive). Even if the etiology of LGLL remains elusive, evidence is accumulating on the genetic landscape driving and/or sustaining chronic LGL proliferations. The most common gain-of-function mutations identified in LGLL patients are on STAT3 and STAT5b genes, which have been recently recognized as clonal markers and were included in the 2017 WHO classification of the disease. A significant correlation between STAT3 mutations and symptomatic disease has been highlighted. At variance, STAT5b mutations could have a different clinical impact based on the immunophenotype of the mutated clone. In fact, they are regarded as the signature of an aggressive clinical course with a poor prognosis in CD8+ T-LGLL and aggressive NK cell leukemia, while they are devoid of negative prognostic significance in CD4+ T-LGLL and T\u3b3\u3b4 LGLL. Knowing the specific distribution of STAT mutations helps identify the discrete mechanisms sustaining LGL proliferations in the corresponding disease subsets. Some patients equipped with wild type STAT genes are characterized by less frequent mutations in different genes, suggesting that other pathogenetic mechanisms are likely to be involved. In this review, we discuss how the LGLL mutational pattern allows a more precise and detailed tumor stratification, suggesting new parameters for better management of the disease and hopefully paving the way for a targeted clinical approach

A novel RUNX1 mutation with ANKRD26 dysregulation is related to thrombocytopenia in a sporadic form of myelodysplastic syndrome

Aging is associated with a higher risk of developing malignant diseases, including myelodysplastic syndromes, clonal disorders characterised by chronic cytopenias (anaemia, neutropenia and thrombocytopenia) and abnormal cellular maturation. Myelodysplastic syndromes arising in older subjects are influenced by combinations of acquired somatic genetic lesions driving evolution from clonal haematopoiesis to myelodysplastic syndromes and from myelodysplastic syndromes to acute leukaemia. A different pattern of mutations has been identified in a small subset of myelodysplastic syndromes arising in young patients with familial syndromes. In particular, dysregulation of ANKRD26, RUNX1 and ETV6 genes plays a role in familial thrombocytopenia with predisposition to myelodysplastic syndromes and acute leukaemia. Whether these genes affect thrombopoiesis in sporadic myelodysplastic syndrome with thrombocytopenia is still undefined. Thirty-one myelodysplastic syndromes subjects and 27 controls subjects were investigated. Genomic DNA was used for mutation screening (ETV6, RUNX1, 5′UTR ANKRD26 genes). Functional studies were performed in the MEG-01-akaryoblastic cell line. We found four novel variants of RUNX1 gene, all in elderly myelodysplastic syndromes subjects with thrombocytopenia. Functional studies of the variant p.Pro103Arg showed no changes in RUNX1 expression, but the variant was associated with deregulated high transcriptional activity of ANKRD26 in MEG-01 cells. RUNX1 variant p.Pro103Arg was also associated with increased viability and reduced apoptosis of MEG-01, as well as impaired platelet production. Our findings are consistent with dysregulation of ANKRD26 in RUNX1 haploinsufficiency. Lack of repression of ANKRD26 expression may contribute to thrombocytopenia of subjects with sporadic myelodysplastic syndromes

Comparison of presepsin, procalcitonin, interleukin-8 and C-reactive protein in predicting bacteraemia in febrile neutropenic adult patients with haematological malignancies

Bacterial infections represent life-threatening complications in patients with febrile neutropenia (FN). Diagnostic biomarkers of infections may help to differentiate bacteraemia from non-bacteraemia FN. We aimed to evaluate the utility of procalcitonin (PCT), presepsin (PS), C-reactive protein (CRP) and interleukin-8 (IL-8) as biomarkers of bacteraemia in adult FN patients with haematological malignancies. Concentrations of PCT, PS, CRP and IL-8 were prospectively measured in 36 FN episodes experienced by 28 oncohaematological patients. 11 out of 36 episodes were classified as bacteraemia. PCT was the best biomarker to predict bacteraemia with the area under the curve (AUC) ROC of 0,9; specificity 100% and positive predictive value 100%, while the most sensitive was IL-8 (90,9%) with AUC ROC of 0,88 and negative predictive value 95,2%. All patients with PCT concentrations above 1,6 \u3bcg/l had bacteraemia. Patients with IL-8 concentrations superior to 170 pg/ml had a 40 times higher risk for bacteraemia than the ones with lower levels. Patients with PS concentrations superior to 410 pg/ml had 24 times higher risk for bacteraemia than the patients with lower levels. PCT has higher accuracy than CRP, IL-8 and PS in predicting bacteraemia in adult hematologic patients with FN

Tumour-infiltrating lymphocytes bear the 75 kDa tumour necrosis factor receptor.

Tumour necrosis factor alpha (TNF-alpha) is a cytokine with a variety of immunological properties. The identification of two receptors for this molecule, i.e. the 75 kDa and the 55 kDa TNF receptors (TNF-R), recently clarified the mechanisms through which this cytokine provides its wide range of immunomodulatory activities. In this study we have investigated the expression and the functional properties of these receptors on tumour-infiltrating lymphocytes (TILs) recovered from 17 patients with solid cancers (melanoma, colorectal carcinoma and lung cancer). To this end, TIL lines and freshly isolated TILs were evaluated for (a) the expression and the functional role of TNF receptors following culture in the presence of interleukin 2 (IL-2) and (b) the production of TNF-alpha following culture with IL-2 and the role of this cytokine in IL-2-driven TIL proliferation. Flow cytometry analysis demonstrated that TILs bear the 75 kDa TNF-R. Moreover, TIL lines express detectable messages for TNF-alpha and release this cytokine. Functional in vitro studies have shown that anti-TNF-alpha, as well as anti-75 kDa TNF-R antibodies, are able to inhibit the IL-2-induced TIL proliferation. These data demonstrate that TILs are equipped with a fully functional TNF-R system and suggest a putative role for this receptor and its ligand in the activation and expression of TILs following immunotherapy with IL-2