Human TERT Promoter Mutations in Atypical and Anaplastic Meningiomas

Background: The role of telomerase reverse transcriptase (TERT) gene promoter mutations (pTERT) in atypical and anaplastic meningiomas remains controversial. This study aimed to evaluate their impact on the histologic diagnosis and prognosis in a retrospective series of 74 patients with atypical and anaplastic meningioma, including disease progression and relapse. A supplementary panel of 21 benign tumours was used as a control cohort. Materials and Methods: The mutation rate of the pTERT gene was assessed by Sanger sequencing. ATRX protein expression was detected by immunohistochemistry. The phenotypic and genotypic intra-tumour heterogeneity was studied in a sub-group of 12 cases using a Molecular Machines & Industries (MMI) CellCut laser microdissection (LMD) system. Results: pTERT mutations were detected in 12/74 (17.6%) malignant meningiomas. The mutation rate was significantly higher in anaplastic meningiomas (7/23, 30.4%) compared to atypical tumours (5/48, 10.4%) (p = 0.0443). In contrast, the mutation rate was < 5% in benign tumours. All pTERT mutant cases retained nuclear ATRX immunoreactivity. pTERT mutations were significantly associated with the histologic grade (p = 0.0443) and were adverse prognostic factors for anaplastic tumours (p = 0.06). Conclusion: We reported on the pTERT mutation spectrum in malignant meningiomas, supporting their use in the prognostic classification

A Randomized, Double-Blind, Placebo-Controlled Trial: Efficacy of <i>Opuntia ficus</i>-<i>indica</i> Prebiotic Supplementation in Subjects with Gut Dysbiosis

Gut dysbiosis refers to an imbalance in gut microbiota composition and function. Opuntia ficus-indica extract has been shown to modulate gut microbiota by improving SCFA production in vivo and gastrointestinal discomfort (GD) in humans. The aim of this study was to demonstrate the efficacy of OdiliaTM on gastrointestinal health by changing the microbial diversity of species involved in inflammation, immunity, oxidation, and the brain–gut–muscle axis. A randomized, double-blind clinical trial was conducted in 80 adults with gut dysbiosis. The intervention consisted of a 300 mg daily intake of OdiliaTM (n = 40) or maltodextrin as a placebo (n = 40), administered for 8 weeks. Intervention effect was evaluated using 16S metagenomics and GIQLI/GSAS scores at baseline, at 4 and 8 weeks. Eight weeks of OdiliaTM supplementation positively modulates gut microbiota composition with a significant reduction in the Firmicutes to Bacteroidetes ratio (p = 0.0012). Relative abundances of beneficial bacteria (Bacteroides and Clostridium_XIVa) were significantly increased (p p TM may represent an effective and well-tolerated treatment in subjects with gut dysbiosis

Impact or performed T-cell alloreactivity by means of donor-specific and panel of reactive T-cells (PRT) Elispot in kidney transplantation

Donor-specific (d-sp) interferon gamma enzyme-linked immunosorbent spot (d-sp ELISPOT)and Panel of reactive T-cell (PRT) ELISPOT assays have been developed to detect alloreactive memory T (Tmem) cells in order to estimate the risk of acute rejection after kidney transplantation. Adding IL15 to the PRT assay (PRT+IL15) may uncover the presence of pathogenic alloreactive CD28-Tmem. Face-to-face comparisons of these assays have not been done yet. We performed pre-transplant d-sp ELISPOT and PRT assays (±IL15, against six B-cell lines) in 168 consecutive kidney transplant recipients and evaluated the multivariable-adjusted associations with biopsy-proven acute rejection (BPAR), de novo donor-specific antibodies (DSA), and eGFR decline over a 48-month follow-up period. D-sp ELISPOT was positive in 81 (48%) subjects, while 71 (42%) and 81 (48%) subjects displayed positive PRT and PRT+IL15, respectively.Their median [interquartile range] numerical test result was 23 [6±65], 18 [8±37], and 26 [10±45] spots/3x105 PBMCs, respectively. The number of PRT spots were weakly correlated with those of d-sp ELISPOT, but highly correlated with PRT+IL15 (rho = 0.96, P<0.001). d-sp ELISPOT, but not PRT (±IL15) was independently associated with BPAR (adjusted Odds Ratio of BPAR associated with d-sp ELISPOT positivity: 4.20 [95%CI: 1.06 to 21.73; P = 0.041]). Unlike d-sp ELISPOT, median PRT and PRT+IL15 were independently associated with higher Δ3-48month eGFR decline post-transplantation (for both assays, about -3mL/min/1.73m2 per one standard deviation unit increase in the spot number). Pre-transplant T-cell immune-monitoring using d-sp ELISPOT and PRT assays identifies kidney transplant candidates at high risk of BPAR and worse kidney allograft progression

Impact or performed T-cell alloreactivity by means of donor-specific and panel of reactive T-cells (PRT) Elispot in kidney transplantation

Donor-specific (d-sp) interferon gamma enzyme-linked immunosorbent spot (d-sp ELISPOT)and Panel of reactive T-cell (PRT) ELISPOT assays have been developed to detect alloreactive memory T (Tmem) cells in order to estimate the risk of acute rejection after kidney transplantation. Adding IL15 to the PRT assay (PRT+IL15) may uncover the presence of pathogenic alloreactive CD28-Tmem. Face-to-face comparisons of these assays have not been done yet. We performed pre-transplant d-sp ELISPOT and PRT assays (±IL15, against six B-cell lines) in 168 consecutive kidney transplant recipients and evaluated the multivariable-adjusted associations with biopsy-proven acute rejection (BPAR), de novo donor-specific antibodies (DSA), and eGFR decline over a 48-month follow-up period. D-sp ELISPOT was positive in 81 (48%) subjects, while 71 (42%) and 81 (48%) subjects displayed positive PRT and PRT+IL15, respectively.Their median [interquartile range] numerical test result was 23 [6±65], 18 [8±37], and 26 [10±45] spots/3x105 PBMCs, respectively. The number of PRT spots were weakly correlated with those of d-sp ELISPOT, but highly correlated with PRT+IL15 (rho = 0.96, P<0.001). d-sp ELISPOT, but not PRT (±IL15) was independently associated with BPAR (adjusted Odds Ratio of BPAR associated with d-sp ELISPOT positivity: 4.20 [95%CI: 1.06 to 21.73; P = 0.041]). Unlike d-sp ELISPOT, median PRT and PRT+IL15 were independently associated with higher Δ3-48month eGFR decline post-transplantation (for both assays, about -3mL/min/1.73m2 per one standard deviation unit increase in the spot number). Pre-transplant T-cell immune-monitoring using d-sp ELISPOT and PRT assays identifies kidney transplant candidates at high risk of BPAR and worse kidney allograft progression

Impact of preformed T-cell alloreactivity by means of donor-specific and panel of reactive T cells (PRT) ELISPOT in kidney transplantation - Fig 1

<p><b>Correlation between d-sp ELISPOT (as number of spots) and median (<i>i</i>.<i>e</i>., median number of spots against the six B cell lines) PRT (A) and PRT+IL-15 (B)</b> (rho = 0.18, P = 0.021 and rho = 0.19, P = 0.016, respectively). <b>Correlation between median PRT and median PRT IL-15</b> (rho = 0.96, P<0.001) (<b>C</b>).</p

Impact of preformed T-cell alloreactivity by means of donor-specific and panel of reactive T cells (PRT) ELISPOT in kidney transplantation

<div><p>Donor-specific (d-sp) interferon gamma enzyme-linked immunosorbent spot (d-sp ELISPOT) and Panel of reactive T-cell (PRT) ELISPOT assays have been developed to detect alloreactive memory T (Tmem) cells in order to estimate the risk of acute rejection after kidney transplantation. Adding IL15 to the PRT assay (PRT+IL15) may uncover the presence of pathogenic alloreactive CD28^-Tmem. Face-to-face comparisons of these assays have not been done yet. We performed pre-transplant d-sp ELISPOT and PRT assays (±IL15, against six B-cell lines) in 168 consecutive kidney transplant recipients and evaluated the multivariable-adjusted associations with biopsy-proven acute rejection (BPAR), <i>de novo</i> donor-specific antibodies (DSA), and eGFR decline over a 48-month follow-up period. D-sp ELISPOT was positive in 81 (48%) subjects, while 71 (42%) and 81 (48%) subjects displayed positive PRT and PRT+IL15, respectively. Their median [interquartile range] numerical test result was 23 [6–65], 18 [8–37], and 26 [10–45] spots/3x10⁵ PBMCs, respectively. The number of PRT spots were weakly correlated with those of d-sp ELISPOT, but highly correlated with PRT+IL15 (rho = 0.96, P<0.001). d-sp ELISPOT, but not PRT (±IL15) was independently associated with BPAR (adjusted Odds Ratio of BPAR associated with d-sp ELISPOT positivity: 4.20 [95%CI: 1.06 to 21.73; P = 0.041]). Unlike d-sp ELISPOT, median PRT and PRT+IL15 were independently associated with higher Δ3-48month eGFR decline post-transplantation (for both assays, about -3mL/min/1.73m2 per one standard deviation unit increase in the spot number). Pre-transplant T-cell immune-monitoring using d-sp ELISPOT and PRT assays identifies kidney transplant candidates at high risk of BPAR and worse kidney allograft progression.</p></div

Impact of preformed T-cell alloreactivity by means of donor-specific and panel of reactive T cells (PRT) ELISPOT in kidney transplantation - Fig 3

<p><b>Risk of BPAR (i.e. proportion of patients developing BPAR) according to the number of IFN-γ spots for d-sp ELISPOT (A), median PRT (B), and median PRT+IL15 (C).</b> The solid line represents the risk of BPAR, the dashed lines represent the upper and lower 95% confidence intervals. The risk of BPAR significantly increased with the number of spots of d-sp ELISPOT (P = 0.042), whereas it did not increase with the number of spots of Median PRT and Median PRT+IL15 (P = 0.87 and P = 0.88, respectively). The superimposed histograms report the frequency distribution of the data values in the study population. The spread of the data values was larger with d-sp ELISPOT compared to Median PRT and Median PRT+IL15. Outside the range of the actual data distribution the risk of BPAR is not reported because it would otherwise represent an inaccurate extrapolation of the BPAR risk estimates. The plotted risk of BPAR is adjusted for recipient and donor age, living (vs deceased) donor, cold ischemia time, Thymoglobulin induction, re-transplantation, pre-transplant HLA antibodies, HLA A/B AND HLA DR mismatch, glomerulonephritis as primary renal disease, dialysis vintage, and prednisone withdrawal (<i>i</i>.<i>e</i>., Model 2 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0200696#pone.0200696.t003" target="_blank">Table 3</a>). Every covariate was set to the mean value in the study population, the indicator variate prednisone withdrawal was set to zero (<i>i</i>.<i>e</i>., no withdrawal).</p

Association between recipients’ pre-transplant characteristics and pre-transplant number of spots of each assay.

<p>Association between recipients’ pre-transplant characteristics and pre-transplant number of spots of each assay.</p

Crude and adjusted odds ratio of BPAR associated with d-sp ELISPOT.

<p>Crude and adjusted odds ratio of BPAR associated with d-sp ELISPOT.</p

Demographic and clinical characteristics of the study population.

<p>Demographic and clinical characteristics of the study population.</p