Influence of innate immunity on cancer cell stemness

Even if cancer stem cells (CSCs) represent only a small proportion of the tumor mass, they significantly account for tumor maintenance, resistance to therapies, relapse and metastatic spread, due to their increased capacity of self-renewal, multipotency, tumorigenicity and quiescence. Emerging evidence suggests that the immune contexture within the tumor microenvironment (TME) determines both the response to therapy and the clinical outcome. In this context, CSCs acquire immune evasion skills by editing immune cell functions and sculpting the immunosuppressive landscape of TME. Reciprocally, infiltrating immune cells influence CSCs self-renewal, tumorigenicity and metastasis. In this review, we summarize the immunomodulatory properties of CSCs, as well as the impact of innate immune cells on cancer cells stemness in the different phases of cancer immunoediting process and neoplastic progression

The Seveso studies on early and long-term effects of dioxin exposure: a review.

The industrial accident that occurred in the town of Seveso, Italy, in 1976 exposed a large population to substantial amounts of relatively pure 2,3,7,8-tetrachlorodibenzo-p-dioxin. Extensive monitoring of soil levels and measurements of a limited number of human blood samples allowed classification of the exposed population into three categories, A (highest exposure), B (median exposure), and R (lowest exposure). Early health investigations including liver function, immune function, neurologic impairment, and reproductive effects yielded inconclusive results. Chloracne (nearly 200 cases with a definite exposure dependence) was the only effect established with certainty. Long-term studies were conducted using the large population living in the surrounding noncontaminated territory as reference. An excess mortality from cardiovascular and respiratory diseases was uncovered, possibly related to the psychosocial consequences of the accident in addition to the chemical contamination. An excess of diabetes cases was also found. Results of cancer incidence and mortality follow-up showed an increased occurrence of cancer of the gastrointestinal sites and of the lymphatic and hematopoietic tissue. Experimental and epidemiologic data as well as mechanistic knowledge support the hypothesis that the observed cancer excesses are associated with dioxin exposure. Results cannot be viewed as conclusive. The study is continuing in an attempt to overcome the existing limitations (few individual exposure data, short latency period, and small population size for certain cancer types) and to explore new research paths (e.g., differences in individual susceptibility)

SPARC is a new myeloid-derived suppressor cell marker licensing suppressive activities

Myeloid-derived suppressor cells (MDSC) are well-known key negative regulators of the immune response during tumor growth, however scattered is the knowledge of their capacity to influence and adapt to the different tumor microenvironments and of the markers that identify those capacities. Here we show that the secreted protein acidic and rich in cysteine (SPARC) identifies in both human and mouse MDSC with immune suppressive capacity and pro-tumoral activities including the induction of epithelial-to-mesenchymal transition (EMT) and angiogenesis. In mice the genetic deletion of SPARC reduced MDSC immune suppression and reverted EMT. Sparc−/− MDSC were less suppressive overall and the granulocytic fraction was more prone to extrude neutrophil extracellular traps (NET). Surprisingly, arginase-I and NOS2, whose expression can be controlled by STAT3, were not down-regulated in Sparc−/− MDSC, although less suppressive than wild type (WT) counterpart. Flow cytometry analysis showed equal phosphorylation of STAT3 but reduced ROS production that was associated with reduced nuclear translocation of the NF-kB p50 subunit in Sparc−/− than WT MDSC. The limited p50 in nuclei reduce the formation of the immunosuppressive p50:p50 homodimers in favor of the p65:p50 inflammatory heterodimers. Supporting this hypothesis, the production of TNF by Sparc−/− MDSC was significantly higher than by WT MDSC. Although associated with tumor-induced chronic inflammation, TNF, if produced at high doses, becomes a key factor in mediating tumor rejection. Therefore, it is foreseeable that an unbalance in TNF production could skew MDSC toward an inflammatory, anti-tumor phenotype. Notably, TNF is also required for inflammation-driven NETosis. The high level of TNF in Sparc−/− MDSC might explain their increased spontaneous NET formation as that we detected both in vitro and in vivo, in association with signs of endothelial damage. We propose SPARC as a new potential marker of MDSC, in both human and mouse, with the additional feature of controlling MDSC suppressive activity while preventing an excessive inflammatory state through the control of NF-kB signaling pathway

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

Effectiveness of molecular fingerprints for exploring the chemical space of natural products

Natural products are a diverse class of compounds with promising biological properties, such as high potency and excellent selectivity. However, they have different structural motifs than typical drug-like compounds, e.g., a wider range of molecular weight, multiple stereocenters and higher fraction of sp3-hybridized carbons. This makes the encoding of natural products via molecular fingerprints difficult, thus restricting their use in cheminformatics studies. To tackle this issue, we explored over 30 years of research to systematically evaluate which molecular fingerprint provides the best performance on the natural product chemical space. We considered 20 molecular fingerprints from four different sources, which we then benchmarked on over 100,000 unique natural products from the COCONUT (COlleCtion of Open Natural prodUcTs) and CMNPD (Comprehensive Marine Natural Products Database) databases. Our analysis focused on the correlation between different fingerprints and their classification performance on 12 bioactivity prediction datasets. Our results show that different encodings can provide fundamentally different views of the natural product chemical space, leading to substantial differences in pairwise similarity and performance. While Extended Connectivity Fingerprints are the de-facto option to encoding drug-like compounds, other fingerprints resulted to match or outperform them for bioactivity prediction of natural products. These results highlight the need to evaluate multiple fingerprinting algorithms for optimal performance and suggest new areas of research. Finally, we provide an open-source Python package for computing all molecular fingerprints considered in the study, as well as data and scripts necessary to reproduce the results, at https://github.com/dahvida/NP_Fingerprints.</p

Techno-economic assessment of SEWGS technology when applied to integrated steel-plant for CO2 emission mitigation

Mitigation of CO2 emissions in the industrial sector is one of the main climate challenges for the coming decades. This work, carried out within the STEPWISE H2020 project, performs a preliminary techno-economic assessment of the Sorption Enhanced Water Gas Shift (SEWGS) technology when integrated into the iron and steel plant to mitigate CO2 emissions. The SEWGS separates the CO2 from the iron and steel off-gases with residual energy content (i.e. Blast Furnace Gas, Basic Oxygen Furnace Gas and Coke Oven Gas) and the produced H2 is sent to the power generation section to produce the electricity required by the steel plant, while the CO2 is compressed and transported for storage. Detailed mass and energy balances are performed together with a SEWGS cost estimation to assess the energy penalty and additional costs related to CO2 capture. Results demonstrates the potential of SEWGS to capture over 80 % of CO2 in the off-gases, which results in entire plant CO2 emission reduction of 40 % with a Specific Energy Consumptions for CO2 Avoided (SPECCA) around 1.9 MJ/kgCO2. SEWGS outperforms a commercial amine scrubbing technology which has a SPECCA of 2.5 MJ/kgCO2 and only 20 % of CO2 avoided. The cost of CO2 avoided calculated on the basis of a fully integrated steel plant is around 33 €/tCO2 compared to 38 €/tCO2 of the amine technology

New &quot;clickable&quot; polymeric coating for glycan microarrays

The interaction of carbohydrates with a variety of biological targets, including antibodies, proteins, viruses and cells are of utmost importance in many aspects of biology. Glycan microarrays are increasingly used to determine the binding specificity of glycan-binding proteins. In this study, a novel slide is reported for the fabrication of glycan arrays that combines the higher sensitivity of a layered Si-SiO2 with a novel approach to form a polymeric coating easily modifiable by subsequent click reaction. The alkyne-containing copolymer, adsorbed from an aqueous solution, produces a coating by a single step procedure and serves as a soft, tridimensional support for the oriented immobilization of carbohydrates via azide/alkyne Cu(I) catalyzed "click" reaction. The equilibrium and kinetics parameters of the interaction of Concanavalin A with eight synthetic glycans were determined using fluorescence microarray and Reflective Phantom Interface (RPI), a recently proposed optical label-free detection approach. The enhancement of fluorescence provided by the Si-SiO2 slides enabled to extend the limit of detection at lower surface densities of lectins, in turn enabling the study of the interaction for a wide range of glycans surface density. Equilibrium dissociation constants of a few nM were extracted for multivalent glycan-lectin binding, mimicking the conditions of biological membranes, whereas hundreds of nM were observed at the lower glycan surface densities

Publisher Correction: Scaffold hopping from natural products to synthetic mimetics by holistic molecular similarity

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