Air quality monitoring is a very important aspect of providing safe indoor conditions, and carbon dioxide (CO2) is one of the pollutants that most affects people's health. An automatic system able to ...accurately forecast CO2 concentration can prevent a sudden rise in CO2 levels through appropriate control of heating, ventilation and air-conditioning (HVAC) systems, avoiding energy waste and ensuring people's comfort. There are several works in the literature dedicated to air quality assessment and control of HVAC systems; the performance maximisation of such systems is typically achieved using a significant amount of data collected over a long period of time (even months) to train the algorithm. This can be costly and may not respond to a real scenario where the habits of the house occupants or the environment conditions may change over time. To address this problem, an adaptive hardware-software platform was developed, following the IoT paradigm, with a high level of accuracy in forecasting CO2 trends by analysing only a limited window of recent data. The system was tested considering a real case study in a residential room used for smart working and physical exercise; the parameters analysed were the occupants' physical activity, temperature, humidity and CO2 in the room. Three deep-learning algorithms were evaluated, and the best result was obtained with the Long Short-Term Memory network, which features a Root Mean Square Error of about 10 ppm with a training period of 10 days.
Among deregulated microRNAs (miRs) in human malignancies, miR-221 has been widely investigated for its oncogenic role and as a promising biomarker. Moreover, recent evidence suggests miR-221 as a ...fine-tuner of chronic liver injury and inflammation-related events. Available information also supports the potential of miR-221 silencing as promising therapeutic intervention. In this systematic review, we selected papers from the principal databases (PubMed, MedLine, Medscape, ASCO, ESMO) between January 2012 and December 2020, using the keywords “miR-221” and the specific keywords related to the most important hematologic and solid malignancies, and some non-malignant diseases, to define and characterize deregulated miR-221 as a valuable therapeutic target in the modern vision of molecular medicine. We found a major role of miR-221 in this view.
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miR-221 is an oncomiR of promising diagnostic, prognostic, and therapeutic relevance. The progress of miR therapeutics has been ascribed to increased stability of engineered molecules. Presently, beyond the antitumoral activity of the novel LNA-i-miR-221, the major novelty could reside in chemoprevention, opening an avenue for ncRNAs as reverser of premalignant processes.
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.
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.
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.
Taken together, our findings indicate a pleiotropic activity of NER-targeting agent trabectedin, which appears a promising candidate for novel anti-MM therapeutic strategies.
According to the EASL Guidelines for the management of hepatocellular carcinoma, transcatheter arterial chemoembolization is the first-line treatment recommended for intermediate-stage HCC. ...Furthermore, it is widely accepted that patients beyond the Milan criteria can be considered for a liver transplant after successful downstaging to within the Milan criteria. Response to downstaging treatments significantly influences not just drop-outs, but also the rate of post-transplantation tumor recurrences. TACE with degradable starch microspheres represents an alternative to conventional TACE with lipiodol and TACE with drug-eluting beads, and it leads to transient arterial occlusion allowing lower activation of hypoxia-inducible factors and less release of vascular endothelial growth factor, a promoter of neoangiogenesis, tumor proliferation, and metastatic growth. In patients with intermediate-stage HCC and a Child-Pugh score of 8 or 9, life expectancy may be dominated by cirrhotic liver dysfunction, rather than by the tumor progression itself; hence, locoregional treatments might also be detrimental, precipitating liver dysfunction to an extent that survival is shortened rather than prolonged. Data on tolerability, toxicity, and effectiveness of DSM-TACE are limited but encouraging. Between January 2015 and October 2020, 50 consecutive patients with intermediate-stage hepatocellular carcinoma and a Child-Pugh score of 8/9, who had undergone DSM-TACE as the first-line treatment, were eligible for the study. A total of 142 DSM-TACEs were performed, with a mean number of 2.84 procedures per patient. The mean time-to-downstaging was 19.2 months, with six patients successfully downstaged. OS was about 100% at six months, 81.8% at 12 months, and 50% at 24 months. Twenty-two patients experienced adverse events after chemoembolization. The median OS and safety of DSM-TACE in this study are comparable with other published investigations in this field. Furthermore, 12% of patients were successfully downstaged. Hence, the results of the current investigation demonstrate that DSM-TACE is effective and safe in intermediate-stage HCC, achieving an interesting downstaging rate. Such data were observed in the population subset with a Child-Pugh score of 8 or 9, in which life expectancy may be determined by cirrhotic liver dysfunction, so the achievement of a balance between the safety and efficacy profile of the TACE treatment is crucial.
Immune checkpoint inhibitors targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death-1 receptor (PD-1), and programmed death-1 receptor and its ligand (PD-L1) increased the ...survival of patients affected by metastatic malignant melanoma. Due to their mechanism of action, these drugs are associated with a unique toxicity profile. Indeed, immune-related adverse events (irAEs) present a wide clinical spectrum representing the Achilles' heel of immunotherapy. Overall, cutaneous toxicities are among the most common irAEs. Immunomodulatory drugs are used for the management of irAEs and can theoretically lead to tumor escape.
We report the case of a 75-year-old man with metastatic melanoma receiving the anti-PD1 Pembrolizumab therapy. After 10 treatment cycles, the patient came to our clinic with itchy psoriatic manifestations widespread >30% of the body surface 12.3 Psoriasis Area and Severity Index (PASI) score that negatively impacted on the patient's quality of life and compliance with immunotherapy. Additionally, he had no positive personal history of psoriasis. Given the severity of the cutaneous manifestations, in a multidisciplinary approach, Apremilast (an oral small molecule PDE4 inhibitor) was started. Furthermore, Pembrolizumab was interrupted for 4 weeks until the improvement of skin lesions and the disappearance of itching. Immunosuppressive methylprednisolone therapy was initiated with a dose of 16 mg/die; then, this initial dose was progressively reduced until discontinuation. After 10 months, the patient had a good general clinical condition with psoriasis complete remission. Moreover, positron emission tomography (PET) and computed tomography (CT) scans showed complete response by immune Response Evaluation Criteria in Solid Tumors (iRECIST).
To the best of our knowledge, this is the first report on the safety and efficacy of Apremilast for the treatment of immunotherapy-induced psoriasis in metastatic melanoma.
Chorea-acanthocytosis is one of the hereditary neurodegenerative disorders known as the neuroacanthocytoses. Chorea-acanthocytosis is characterized by circulating acanthocytes deficient in chorein, a ...protein of unknown function. We report here for the first time that chorea-acanthocytosis red cells are characterized by impaired autophagy, with cytoplasmic accumulation of active Lyn and of autophagy-related proteins Ulk1 and Atg7. In chorea-acanthocytosis erythrocytes, active Lyn is sequestered by HSP90-70 to form high-molecular-weight complexes that stabilize and protect Lyn from its proteasomal degradation, contributing to toxic Lyn accumulation. An interplay between accumulation of active Lyn and autophagy was found in chorea-acanthocytosis based on Lyn coimmunoprecipitation with Ulk1 and Atg7 and on the presence of Ulk1 in Lyn-containing high-molecular-weight complexes. In addition, chorein associated with Atg7 in healthy but not in chorea-acanthocytosis erythrocytes. Electron microscopy detected multivesicular bodies and membrane remnants only in circulating chorea-acanthocytosis red cells. In addition, reticulocyte-enriched chorea-acanthocytosis red cell fractions exhibited delayed clearance of mitochondria and lysosomes, further supporting the impairment of authophagic flux. Because autophagy is also important in erythropoiesis, we studied in vitro CD34+-derived erythroid precursors. In chorea-acanthocytosis, we found (1) dyserythropoiesis; (2) increased active Lyn; (3) accumulation of a marker of autophagic flux and autolysososme degradation; (4) accumlation of Lamp1, a lysosmal membrane protein, and LAMP1-positive aggregates; and (5) reduced clearance of lysosomes and mitochondria. Our results uncover in chorea-acanthocytosis erythroid cells an association between accumulation of active Lyn and impaired autophagy, suggesting a link between chorein and autophagic vesicle trafficking in erythroid maturation.
•In chorea-acanthocytosis, spiculated red cells are characterized by heightened Lyn kinase activity and dysregulated autophagy.•Regulation of protein turnover by autophagy plays a key role in erythropoiesis and red cell integrity.
Band 3 (B3), the anion transporter, is an integral membrane protein that plays a key structural role by anchoring the plasma membrane to the spectrin-based membrane skeleton in the red cell. In ...addition, it also plays a critical role in the assembly of glycolytic enzymes to regulate red cell metabolism. However, its ability to recruit proteins that can prevent membrane oxidation has not been previously explored. In this study, using a variety of experimental approaches including cross-linking studies, fluorescence and dichroic measurements, surface plasmon resonance analysis, and proteolytic digestion assays, we document that the antioxidant protein peroxiredoxin-2 (PRDX2), the third most abundant cytoplasmic protein in RBCs, interacts with the cytoplasmic domain of B3. The surface electrostatic potential analysis and stoichiometry measurements revealed that the N-terminal peptide of B3 is involved in the interaction. PRDX2 underwent a conformational change upon its binding to B3 without losing its peroxidase activity. Hemichrome formation induced by phenylhydrazine of RBCs prevented membrane association of PRDX2, implying overlapping binding sites. Documentation of the absence of binding of PRDX2 to B3 Neapolis red cell membranes, in which the initial N-terminal 11 amino acids are deleted, enabled us to conclude that PRDX2 binds to the N-terminal cytoplasmic domain of B3 and that the first 11 amino acids of this domain are crucial for PRDX2 membrane association in intact RBCs. These findings imply yet another important role for B3 in regulating red cell membrane function.
► The cytoplasmic domain of B3 is the docking site for PRDX2. ► Binding of PRDX2 to the cytoplasmic domain of B3 determines a conformational change. ► The complex PRDX2:cytoplasmic domain of B3 exhibits peroxidase activity. ► The first 11 amino acids of B3 cytoplasmic domain are important for PRDX2 binding.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy burdened by poor prognosis. While huge progress of immunotherapy has recently improved the outcome of B-cell malignancies, the ...lack of tumor-restricted T-cell antigens still hampers its progress in T-ALL. Therefore, innovative immunotherapeutic agents are eagerly awaited. To this end, we generated a novel asymmetric (2 + 1) bispecific T-cell engager (BTCE) targeting CD1a and CD3ε (CD1a x CD3ε) starting from the development of a novel mAb named UMG2. UMG2 mAb reacts against CD1a, a glycoprotein highly expressed by cortical T-ALL cells. Importantly, no UMG2 binding was found on normal T-cells. CD1a x CD3ε induced high T-cell mediated cytotoxicity against CD1a+ T-ALL cells in vitro, as demonstrated by the concentration-dependent increase of T-cell proliferation, degranulation, induction of cell surface activation markers, and secretion of pro-inflammatory cytokines. Most importantly, in a PBMC-reconstituted NGS mouse model bearing human T-ALL, CD1a x CD3ε significantly inhibited the growth of human T-ALL xenografts, translating into a significant survival advantage of treated animals. In conclusion, CD1a x CD3ε is a novel BTCE highly active against CD1a-expressing cortical-derived T-ALL cells suitable for clinical development as an effective therapeutic option for this rare and aggressive disease.
Idebenone (IDE), a strong antioxidant widely investigated for the treatment of neurodegenerative diseases and skin disorders, shows low oral and topical bioavailability due to its unfavorable ...physico-chemical properties. In this work, to improve IDE topical effectiveness, we explored a two-steps approach: (1) we synthesized an IDE ester (IDEPCA) with pyroglutamic acid, a molecule whose hydrating effects are well known; (2) we loaded IDEPCA into solid lipid nanocarriers (SLN). We evaluated in vitro antioxidant and anti-glycation activity and in vivo hydrating effects after topical application in human volunteers from gel vehicles of IDEPCA SLN in comparison to IDE SLN. All SLN showed good technological properties (mean particle size < 25 nm, polydispersity index < 0.300, good stability). The oxygen radical absorbance capacity assay showed that IDEPCA SLN and IDE SLN had similar antioxidant activity while IDEPCA SLN were more effective in the in vitro NO scavenging assay. Both IDEPCA and IDE SLN showed the same effectiveness in inhibiting the formation of advanced glycation end products. In vivo experiments pointed out a better hydrating effect of IDEPCA SLN in comparison to IDE SLN. These results suggest that the investigated approach could be a promising strategy to obtain topical formulations with increased hydrating effects.
The distal radial artery has emerged as an alternative vascular-access site to conventional transfemoral and transradial approaches. The main advantage over the conventional transradial route is the ...reduced risk of radial artery occlusion, especially in those patients who, for various clinical reasons, have to undergo repeated endovascular procedures. This study aims to assess the efficacy and safety of distal radial access for transcatheter arterial chemoembolization of the liver.
This investigation is a single-center retrospective analysis of 42 consecutive patients who had undergone, from January 2018 to December 2022, transcatheter arterial chemoembolization of the liver with distal radial access for intermediate-stage hepatocellular carcinoma. Outcome data were compared with a retrospectively constituted control group of 40 patients undergoing drug-eluting beads-transcatheter arterial chemoembolization with femoral access.
Technical success was achieved in all cases, with a 2.4% conversion rate for distal radial access. A superselective chemoembolization was performed in 35 (83.3%) cases of distal radial access. No episode of radial artery spasm or radial artery occlusion occurred. No significant differences in efficacy and safety were observed between the distal radial access group and the femoral access group.
Distal radial access is effective, safe, and comparable to femoral access in patients undergoing transcatheter arterial chemoembolization of the liver.
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