A gene expression inflammatory signature specifically predicts multiple myeloma evolution and patients survival

Multiple myeloma (MM) is closely dependent on cross-talk between malignant plasma cells and cellular components of the inflammatory/immunosuppressive bone marrow milieu, which promotes disease progression, drug resistance, neo-angiogenesis, bone destruction and immune-impairment. We investigated the relevance of inflammatory genes in predicting disease evolution and patient survival. A bioinformatics study by Ingenuity Pathway Analysis on gene expression profiling dataset of monoclonal gammopathy of undetermined significance, smoldering and symptomatic-MM, identified inflammatory and cytokine/chemokine pathways as the most progressively affected during disease evolution. We then selected 20 candidate genes involved in B-cell inflammation and we investigated their role in predicting clinical outcome, through univariate and multivariate analyses (log-rank test, logistic regression and Cox-regression model). We defined an 8-genes signature (IL8, IL10, IL17A, CCL3, CCL5, VEGFA, EBI3 and NOS2) identifying each condition (MGUS/smoldering/symptomatic-MM) with 84% accuracy. Moreover, six genes (IFNG, IL2, LTA, CCL2, VEGFA, CCL3) were found independently correlated with patients' survival. Patients whose MM cells expressed high levels of Th1 cytokines (IFNG/LTA/IL2/CCL2) and low levels of CCL3 and VEGFA, experienced the longest survival. On these six genes, we built a prognostic risk score that was validated in three additional independent datasets. In this study, we provide proof-of-concept that inflammation has a critical role in MM patient progression and survival. The inflammatory-gene prognostic signature validated in different datasets clearly indicates novel opportunities for personalized anti-MM treatment

Trabectedin triggers direct and NK-mediated cytotoxicity in multiple myeloma

Background: Genomic instability is a feature of multiple myeloma (MM), and impairment in DNA damaging response (DDR) has an established role in disease pathobiology. Indeed, a deregulation of DNA repair pathways may contribute to genomic instability, to the establishment of drug resistance to genotoxic agents, and to the escape from immune surveillance. On these bases, we evaluated the role of different DDR pathways in MM and investigated, for the first time, the direct and immune-mediated anti-MM activity of the nucleotide excision repair (NER)-dependent agent trabectedin. Methods: Gene-expression profiling (GEP) was carried out with HTA2.0 Affymetrix array. Evaluation of apoptosis, cell cycle, and changes in cytokine production and release have been performed in 2D and 3D Matrigel-spheroid models through flow cytometry on MM cell lines and patients-derived primary MM cells exposed to increasing nanomolar concentrations of trabectedin. DNA-damage response has been evaluated through Western blot, immunofluorescence, and DNA fragmentation assay. Trabectedin-induced activation of NK has been assessed by CD107a degranulation. miRNAs quantification has been done through RT-PCR. Results: By comparing GEP meta-analysis of normal and MM plasma cells (PCs), we observed an enrichment in DNA NER genes in poor prognosis MM. Trabectedin triggered apoptosis in primary MM cells and MM cell lines in both 2D and 3D in vitro assays. Moreover, trabectedin induced DDR activation, cellular stress with ROS production, and cell cycle arrest. Additionally, a significant reduction of MCP1 cytokine and VEGF-A in U266-monocytes co-cultures was observed, confirming the impairment of MM-promoting milieu. Drug-induced cell stress in MM cells led to upregulation of NK activating receptors ligands (i.e., NKG2D), which translated into increased NK activation and degranulation. Mechanistically, this effect was linked to trabectedin-induced inhibition of NKG2D-ligands negative regulators IRF4 and IKZF1, as well as to miR-17 family downregulation in MM cells. Conclusions: Taken together, our findings indicate a pleiotropic activity of NER-targeting agent trabectedin, which appears a promising candidate for novel anti-MM therapeutic strategies

Influence of the fabrication accuracy of hot-embossed PCL scaffolds on cell growths

Polycaprolactone (PCL) is a biocompatible and biodegradable polymer widely used for the realization of 3D scaffold for tissue engineering applications. The hot embossing technique (HE) allows the obtainment of PCL scaffolds with a regular array of micro pillars on their surface. The main drawback affecting this kind of micro fabrication process is that such structural superficial details can be damaged when detaching the replica from the mold. Therefore, the present study has focused on the optimization of the HE processes through the development of an analytical model for the prediction of the demolding force as a function of temperature. This model allowed calculating the minimum demolding force to obtain regular micropillars without defects. We demonstrated that the results obtained by the analytical model agree with the experimental data. To address the importance of controlling accurately the fabricated microstructures, we seeded on the PCL scaffolds human stromal cell line (HS-5) and monocytic leukemia cell line (THP-1) to evaluate how the presence of regular or deformed pillars affect cells viability. In vitro viability results, scanning electron and fluorescence microscope imaging analysis show that the HS-5 preferentially grows on regular microstructured surfaces, while the THP-1 on irregular microstructured ones

An overview of the existing and future state of the art advancement of hybrid energy systems based on PV-solar and wind

Increasing solar and wind power use in existing power systems could create significant technical issues, especially for grids with poor connectivity or stand-alone systems needing more adequate storage capacity. This is due to the unpredictable and intermittent nature of solar and wind power. The intermittent nature of solar and wind resources can be reduced by integrating them optimally, making the entire system more reliable and cost-effective to operate. The advantages and disadvantages of hybrid wind and solar energy integration systems are discussed in this research. The impact of voltage and frequency oscillations and harmonics is amplified in weak grids, affecting both grid-connected and stand-alone systems. This may be fixed by ensuring that hybrid systems are well designed, equipped with cutting-edge quick reaction control capabilities, and optimized. This review offers an overview of existing advances in PV-solar and wind-based hybrid energy systems while exploring potential future developments. Further, this review also provides an overview of the primary studies published on optimum design considerations for compactness, topologies for power electronics, and control. As the global energy environment shifts toward sustainability and resilience, this review helps researchers, policymakers, and industry stakeholders understand, adapt, and enhance PV-solar-wind hybrid energy systems

Strategies for ideal indoor environments towards low/zero carbon buildings through a biomimetic approach

Biomimicry is a relatively new discipline of applied science that seeks inspiration from natural systems for innovative solutions to human problems. Taking nature as ‘model, mentor and measure’ receives wide acceptance in the field of architecture but predominantly in conceptualising novel forms. The biomimicry concept is comprehensively analysed for its ability to provide more sustainable and possibly even regenerative built environments. As part of this study, first, various frameworks for approaching ‘biomimicry’ in general are discussed and then relevant examples pertaining to architecture are evaluated. Case studies are critiqued with respect to varied levels of sustainability achieved and its causative factors. In the second part, an approach model for ‘biomimetic architecture’ in the context of Mumbai is presented and applicable strategies based on climatic adaptation are suggested using local biodiversity as a library of organisms. The generic example of ‘human skin’ addressing the same adaptation is analysed and complemented by a state-of-the-art case study on similar lines. The results achieved clearly reveal that biomimicry is a successful approach to design and operate the sustainable built environments for the buildings of the future