PARP inhibition can induce anti-neoplastic effects when used as monotherapy or in combination with chemo- or radiotherapy in various tumor settings; however, the basis for the anti-metastasic ...activities resulting from PARP inhibition remains unknown. PARP inhibitors may also act as modulators of tumor angiogenesis. Proteomic analysis of endothelial cells revealed that vimentin, an intermediary filament involved in angiogenesis and a specific hallmark of EndoMT (endothelial to mesenchymal transition) transformation, was down-regulated following loss of PARP-1 function in endothelial cells. VE-cadherin, an endothelial marker of vascular normalization, was up-regulated in HUVEC treated with PARP inhibitors or following PARP-1 silencing; vimentin over-expression was sufficient to drive to an EndoMT phenotype. In melanoma cells, PARP inhibition reduced pro-metastatic markers, including vasculogenic mimicry. We also demonstrated that vimentin expression was sufficient to induce increased mesenchymal/pro-metastasic phenotypic changes in melanoma cells, including ILK/GSK3-β-dependent E-cadherin down-regulation, Snail1 activation and increased cell motility and migration. In a murine model of metastatic melanoma, PARP inhibition counteracted the ability of melanoma cells to metastasize to the lung. These results suggest that inhibition of PARP interferes with key metastasis-promoting processes, leading to suppression of invasion and colonization of distal organs by aggressive metastatic cells.
The aim of this study was to carry out a psychosocial analysis of child-to-parent violence (CPV) in a sample of school adolescents, considering a set of individual variables (psychological distress, ...problematic use of social networking sites, and perceived non-conformist social reputation) and family variables (open and problematic communication with parents) according to sex. The sample consisted of 3,731 adolescents (54% boys), aged between 14 and 16 years (M = 14.6 years, SD = 0.567), from the state of Nuevo León, Mexico. The scores of the boys and girls were analyzed to check for differences. Also, correlations between all the study variables were calculated. Finally, a multiple stepwise regression analysis was carried out for the total sample and also for boys and girls separately. Results confirmed the important role of individual variables as predictors of CPV in boys and girls. The main difference between boys and girls was observed in the predictive weight of problematic use of social networking sites, which was higher in girls than in boys. Open communication with the father was a significant factor for predicting the decrease of CPV levels in the case of boys, while open communication with the mother predicted the decrease of CPV in girls. Problematic communication with the mother showed similar values in boys and girls when predicting CPV, however, the predictive weight of problematic communication with the father was higher in girls than in boys. These results are interesting and have important implications for the prevention of CPV.
Glioblastomas (GBM) are the most frequent and aggressive brain tumors. 17β-estradiol (E2) increases proliferation, migration, and invasion of human GBM cells; however underlying mechanisms are no ...fully understood. Zeste 2 Enhancer Homologous enzyme (EZH2) is a methyltransferase part of Polycomb 2 repressor complex (PRC2). In GBM, EZH2 is overexpressed and involved in the cell cycle, migration, and invasion processes. We studied the role of EZH2 in the pro-oncogenic actions of E2 in human GBM cells. EZH2 gene silencing and pharmacological inhibition of EZH2 blocked proliferation, migration, and invasion of GBM cells induced by E2. We identified in silico additional putative estrogen response elements (EREs) at the EZH2 promoter, but E2 did not modify EZH2 expression. In silico analysis also revealed that among human GBM samples, EZH2 expression was homogeneous; in contrast, the heterogeneous expression of estrogen receptors (ERs) allowed the classification of the samples into groups. Even in the GBM cluster with high expression of ERs and those of their target genes, the expression of PCR2 target genes did not change. Overall, our data suggest that in GBM cells, pro-oncogenic actions of E2 are mediated by EZH2, without changes in EZH2 expression and by mechanisms that appear to be unrelated to the transcriptional activity of ERs.
Donor exchange programs were designed to allocate organs for highly sensitized (HS) patients. The allocation algorithm differs slightly among countries and includes different strategies to improve ...access to transplants in HS patients. However, many HS patients with a calculated panel reactive of antibodies (cPRA) of 100 % remain on the waiting list for a long time. Some allocation algorithms assume immunological risk, including Imlifidase treatment, to increase the chance of transplantation in very HS patients. Here, we describe our unicenter experience of low-risk delisting strategy in 15 HS patients included in the Spanish donor exchange program without donor offers. After delisting, 7 out of 15 HS patients reduced the cPRA below 99.95 % and impacted the reduction of time on the waiting list (p = 0.01), where 5 out of 7 achieved transplantation. Within those HS that remained above 99.95 %, 1 out of 8 was transplanted. All the HS were transplanted with delisted DSA, and only one with DSA level rebounded early after transplantation. All HS transplanted after delisting maintain graft function. The transplant immunology laboratories are challenged to search intermediate risk assessment methods for delisting high HS patients.
The role of non-HLA antibody is gaining special attention in solid-organ transplantation and in highly sensitized (HS) patients because of its potential involvement in graft loss (GL) and/or ...antibody-mediated rejection (ABMR). The identification of non-HLA antibodies while listed may provide deeper information about the increased immunologic risk prior to transplant. We aimed to identify non-HLA antibodies pretransplant that could involve GL in HS patients.
Nineteen pretransplant samples from HS patients who underwent transplant at the Marqués de Valdecilla University Hospital were studied for both HLA antibodies and a panel of 39 non-HLA antigens analyzed based on Luminex platform.
Eleven patient (57.9%) maintained the graft (KT group), whereas 8 (42.1%) had a GL within a median of 30 days. The median fluorescent intensity (MFI) of the 39 non-HLA antigens were compared within the groups, obtaining a statistically significant differences in protein tyrosine phosphatase receptor type N (P < .04) with a MFI mean of 1408 vs 4931 for KT and GL groups, respectively. However, no significant differences were observed in non-HLA MFI between ABMR and non-ABMR KT recipients.
The presence of non-HLA antibodies in HS is high. The levels of anti–protein tyrosine phosphatase receptor type N before transplant could indicate a potential risk of GL, although longitudinal studies with large number of cases are needed to define anti–non-HLA profiles of risk of ABMR.
Oligodendrocytes are the myelinating cells of the central nervous system (CNS). These cells arise during the embryonic development by the specification of the neural stem cells to oligodendroglial ...progenitor cells (OPC); newly formed OPC proliferate, migrate, differentiate, and mature to myelinating oligodendrocytes in the perinatal period. It is known that progesterone promotes the proliferation and differentiation of OPC in early postnatal life through the activation of the intracellular progesterone receptor (PR). Progesterone supports nerve myelination after spinal cord injury in adults. However, the role of progesterone in embryonic OPC differentiation as well as the specific PR isoform involved in progesterone actions in these cells is unknown. By using primary cultures obtained from the embryonic mouse spinal cord, we showed that embryonic OPC expresses both PR-A and PR-B isoforms. We found that progesterone increases the proliferation, differentiation, and myelination potential of embryonic OPC through its PR by upregulating the expression of oligodendroglial genes such as neuron/glia antigen 2 (NG2), sex determining region Y-box9 (SOX9), myelin basic protein (MBP), 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNP1), and NK6 homeobox 1 (NKX 6.1). These effects are likely mediated by PR-B, as they are blocked by the silencing of this isoform. The results suggest that progesterone contributes to the process of oligodendrogenesis during prenatal life through specific activation of PR-B.
Immunosuppression withdrawal after graft failure seems to favor sensitization. A high percentage of calculated panel-reactive antibody (cPRA) and the development of de novo donor specific antibodies ...(dnDSA) indicate human leukocyte antigen (HLA) sensitization and may hinder the option of retransplantation. There are no established protocols on the immunosuppressive treatment that should be maintained after transplant failure. A retrospective analysis including 77 patients who lost their first renal graft between 1 January 2006-31 December 2015 was performed. Two sera were selected per patient, one immediately prior to graft loss and another one after graft failure. cPRA was calculated by Single Antigen in all patients. It was possible to analyze the development of dnDSA in 73 patients. By multivariate logistic regression analysis, the absence of calcineurin inhibitor (CNI) at 6 months after graft failure was related to cPRA > 75% (OR 4.8, CI 95% 1.5-15.0,
= 0.006). The absence of calcineurin inhibitor (CNI) at 6 months after graft loss was significantly associated with dnDSA development (OR 23.2, CI 95% 5.3-100.6,
< 0.001). Our results suggest that the absence of CNI at the sixth month after graft loss is a risk factor for sensitization. Therefore, maintenance of an immunosuppressive regimen based on CNI after transplant failure should be considered when a new transplant is planned, since it seems to prevent HLA allosensitization.
Proteinuria is the main predictor of kidney graft loss. However, there is little information regarding the consequences of nephrotic proteinuria (NP) and nephrotic syndrome (NS) after a kidney ...transplant. We aimed to describe the clinical and histopathological characteristics of kidney recipients with nephrotic-range proteinuria and compare the graft surveillance between those who developed NS and those who did not. A total of 204 patients (18.6% of kidney transplants in the study period) developed NP, and 68.1% of them had NS. Of the 110 patients who underwent a graft biopsy, 47.3% exhibited ABMR, 21.8% the recurrence of glomerulonephritis, 9.1% IFTA, and 7.3% de novo glomerulonephritis. After a median follow-up of 97.5 months, 64.1% experienced graft loss. The graft survival after the onset of NP declined from 75.8% at 12 months to 38% at 5 years, without significant differences between those with and those without NS. Patients who developed NS fewer than 3 months after the onset of NP exhibited a significantly higher risk of death-censored graft loss (HR: 1.711, 95% CI: 1.147-2.553) than those without NS or those with late NS. In conclusion, NP and NS are frequent conditions after a kidney transplant, and they imply extremely poor graft outcomes. The time from the onset of NP to the development of NS is related to graft survival.
Kidney transplantation implies a significant improvement in patient survival. Nevertheless, early mortality after transplant remains high. Growth differentiation factor 15 (GDF-15) is a novel ...biomarker under study as a mortality predictor in multiple scenarios. The aim of this study is to assess the utility of GDF-15 to predict survival in kidney transplant candidates. For this purpose, 395 kidney transplant recipients with pretransplant stored serum samples were included. The median GDF-15 was 5331.3 (50.49-16242.3) pg/mL. After a mean of 90.6 ± 41.5 months of follow-up, 82 (20.8%) patients died. Patients with higher GDF-15 levels (high risk tertile) had a doubled risk of mortality after adjustment by clinical characteristics (
= 0.009). After adjustment by EPTS (Estimated Post Transplant Survival score) the association remained significant for medium hazards ratios (HR) 3.24 95%CI (1.2-8.8),
= 0.021 and high risk tertiles HR 4.3 95%CI (1.65-11.54),
= 0.003. GDF-15 improved the prognostic accuracy of EPTS at 1-year (ΔAUC = 0.09,
= 0.039) and 3-year mortality (ΔAUC = 0.11,
= 0.036). Our study suggests an independent association between higher GDF-15 levels and mortality after kidney transplant, adding accuracy to the EPTS score, an established risk prediction model currently used in kidney transplant candidates.
PDF
