Article a new epigenetic model to stratify glioma patients according to their immunosuppressive state

Gliomas are the most common primary neoplasm of the central nervous system. A promising frontier in the definition of glioma prognosis and treatment is represented by epigenetics. Further-more, in this study, we developed a machine learning classification model based on epigenetic data (CpG probes) to separate patients according to their state of immunosuppression. We considered 573 cases of low-grade glioma (LGG) and glioblastoma (GBM) from The Cancer Genome Atlas (TCGA). First, from gene expression data, we derived a novel binary indicator to flag patients with a favorable immune state. Then, based on previous studies, we selected the genes related to the immune state of tumor microenvironment. After, we improved the selection with a data-driven procedure, based on Boruta. Finally, we tuned, trained, and evaluated both random forest and neural network classifiers on the resulting dataset. We found that a multi-layer perceptron network fed by the 338 probes selected by applying both expert choice and Boruta results in the best performance, achieving an out-of-sample accuracy of 82.8%, a Matthews correlation coefficient of 0.657, and an area under the ROC curve of 0.9. Based on the proposed model, we provided a method to stratify glioma patients according to their epigenomic state

X-ray diffraction and computational studies of the pressure-dependent tetrachloroethane solvation of diphenylanthracene

The crystal structure of the organic semiconductor 9,10-diphenylanthracene (DPA) has been studied by single-crystal X-ray diffraction at variable pressure up to 3 GPa. Under ambient conditions and in the presence of 1,1,2,2-tetrachloroethane, the material invariably crystallises in an unsolvated form, in the space group C2/c, with Z\u2032 = 1/2, as reported in the literature. As pressure is increased to a modest 0.5 GPa, crystallisation occurs in the form of a newly discovered solvate with a 1 : 2 DPA\u2013tetrachloroethane stoichiometry, with the space group P21/c. A theoretical analysis by the PIXEL method with energy partitioning into Coulombic polarisation and dispersion terms reveals that the solvated and unsolvated structures have in common two basic packing motifs for the DPA molecule, one with linear interlocking and one with a T-shaped arrangement in a quincunx fashion. The solvent is enclosed in a cage and interacts with the DPA molecule by a very strong dispersive component of 44 kJ mol 121. Monte Carlo simulations show that the mobility of the solvent in its cage would be extremely reduced even under ambient conditions, ruling out a mechanism of solvate formation and subsequent release. According to a structure-oriented perspective, the kinetics of the process could then be such that the nucleating system at ambient pressure separates out the solvent, while a 0.5 GPa pressure provides a solute\u2013solvent grip that forces cocrystallisation, in agreement with both experiments and simulations. Even in the absence of experimental or computational proof of the thermodynamic stability of the solvate at high pressure, this appears to be a plausible and sensible case scenario in its own right

The NLRP3 Inflammasome Is Upregulated in HIV-Infected Antiretroviral Therapy-Treated Individuals with Defective Immune Recovery

Background: Inflammasome-mediated activation of caspase-1 regulates inflammatory responses and pyroptosis. We analyzed possible associations between inflammasome-related genes and immune reconstitution in HIV-infected antiretroviral therapy (ART)-treated patients. Methods: Cross-sectional, case-control study. HIV-infected patients on ART for 6524\u2009months with HIV-RNA<50 cp/mL for 6512\u2009months were enrolled and defined as immunological responders (IR) or non-responders (INR) if CD4 count was 65500 or 64350 cells/\u3bcL, respectively. Expression of inflammasome genes, caspases 1, 3, 4, 5 and \u3b3-interferon-inducible protein 16 (IFI16) was measured in unstimulated and LPS- or aldrithiol-2-treated HIV-1BaL virions-stimulated peripheral blood mononuclear cells. Microbial translocation markers were evaluated. Results: Thirty-nine patients (22 IRs; 17 INRs) were enrolled. LPS-stimulated inflammasome genes were significantly upregulated in INRs. Whereas HIV-1BaL stimulation induced (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) expression in both IRs and INRs, NLRP3 and IL-18 expression was significantly increased in INRs compared to IRs. Significant higher caspase-1 expression was seen as well, whereas caspase 3, 4, and 5 expression was similar in both groups. No differences in microbial translocation markers (LPS and soluble CD14) were detected in the two groups. Conclusion: Upregulation of NLRP3 and caspase-1 is observed in INR patients. This could play a role in persistent immune activation that characterize INRs. Caspase-1 upregulation could induce CD4 T-cell loss via pyroptosis, contributing to unsatisfactory CD4 T-cells recovery

Results from a European multi-cohort study

Publisher Copyright: © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.Background: INSTIs have become a pillar of first-line ART. Real-world data are needed to assess their effectiveness in routine care. Objectives: We analysed ART-naive patients who started INSTI-based regimens in 2012-19 whose data were collected by INTEGRATE, a European collaborative study including seven national cohorts. Methods: Kaplan-Meier analyses assessed time to virological failure (VF), defined as one viral load (VL) ≥1000 copies/mL, two consecutive VLs ≥50 copies/mL, or one VL ≥50 copies/mL followed by treatment change after ≥24 weeks of follow-up, and time to INSTIs discontinuation (INSTI-DC) for any reason. Factors associated with VF and INSTI-DC were explored by logistic regression analysis. Results: Of 2976 regimens started, 1901 (63.9%) contained dolutegravir, 631 (21.2%) elvitegravir and 444 (14.9%) raltegravir. The 1 year estimated probabilities of VF and INSTI-DC were 5.6% (95% CI 4.5-6.7) and 16.2% (95% CI 14.9-17.6), respectively, and were higher for raltegravir versus both elvitegravir and dolutegravir. A baseline VL ≥100 000 copies/mL [adjusted HR (aHR) 2.17, 95% CI 1.55-3.04, P 3 drugs versus 3 drugs (aHR 2.73, 95% CI 1.55-4.79, P < 0.001) and starting ART following availability of dolutegravir (aHR 0.64, 95% CI 0.48-0.83, P = 0.001). Major INSTI mutations indicative of transmitted drug resistance occurred in 2/1114 (0.2%) individuals. Conclusions: This large multi-cohort study indicates high effectiveness of elvitegravir- or dolutegravir-based first-line ART in routine practice across Europe.publishersversionpublishe

Real-Life Impact of Drug Toxicity on Dolutegravir Tolerability: Clinical Practice Data from a Multicenter Italian Cohort

Dolutegravir (DTG) is currently one of the most used Integrase inhibitors (INI) in antiretroviral therapies (ARV) in both naïve and experienced people living with HIV (PLWHIV). We analyzed a multicenter cohort of PLWHIV, both naïve and experienced, starting an ARV including DTG. We enrolled 3775 PLWHIV: 2763 (73.2%) were males, with a median age of 50 years. During 9890.7 PYFU, we observed 930 discontinuations (9.4 per 100 PYFU). Estimated probabilities of maintaining DTG at three and five years were 75.1% and 67.2%, respectively. Treatment-naïve pts showed a lower probability of maintaining DTG at three and five years compared to treatment-experienced PLWHIV (log-rank p &lt; 0.001). At a multivariate analysis, a longer time of virological suppression (aHR 0.994, p &lt; 0.001) and having experienced a previous virological failure (aHR 0.788, p = 0.016) resulted protective against DTG discontinuation. Most discontinuations (84.0%) happened within the first 12 months of DTG initiation, in particular, 92.2% of discontinuations due to neuropsychiatric toxicity were observed in the first year. Our data confirm the overall good tolerability of DTG in clinical practice, with a low rate of discontinuations. CNS toxicity resulted the main reason for DTG discontinuation, with most related interruptions happening in the first year from DTG introduction

Atazanavir-induced severe episodes of kidney stones in an HIV-1-infected subject characterized by a CYP3A poor metabolizer phenotype

Background: Atazanavir, an antiretroviral drug of the protease inhibitor class, is coadministered with ritonavir to inhibit atazanavir metabolism and decrease pharmacokinetic variability. Atazanavir is metabolised mainly by CYP3A4/5 enzymes. High CYP3A intersubject variability has been documented in most cases on a genetic basis. The CYP3A5*3 allele affects splicing defect and protein truncation. Recently a new intronic variant, CYP3A4*22, was found associated with reduced CYP3A4 activity. To assess whether an altered CYP3A activity impairs the metabolism of atazanavir, we investigated the two functional polymorphisms. To the best of our knowledge, this is the first case report showing that overexposure to ATV is associated with CYP3A poor phenotype and nephrolithiasis. Further study is needed in order to confirm this interesting observation. Case Presentation: We describe the case of a 43 year-old HIV-1-infected man treated with atazanavir/ritonavir plus lamivudine who experienced early and recurrent severe episodes of kidney stones. Atazanavir plasma trough concentrations showed a value higher than the normal range, thus we investigated the two polymorphisms that are known to affect CYP3A4/5 activity. This analysis revealed that our patient was a CYP3A poor metabolizer since he carried CYP3A4*1/*22 and CYP3A5*3/*3 genotypes. Conclusion: We suggest that screening of CYP3A functional variants is an appropriate approach, helping in treatment choice and potential dosage adjustment of protease inhibitors