Publications

You have accessJournal of UrologyModerated Poster 48, Tuesday, May 22, 2007, 3:30 - 5:30 pm1 Apr 20071585: Methylation of Topoisomerase-1 Gene Reduces Risk for Tumor Recurrence after Early Instillation Therapy in Superfical Urothelial Carcinoma Frank Christoph, Santiago Ropero, Pilar Lopez, Stefan Hinz, Hans Krause, Kurt Miller, and Manel Esteller Frank ChristophFrank Christoph More articles by this author , Santiago RoperoSantiago Ropero More articles by this author , Pilar LopezPilar Lopez More articles by this author , Stefan HinzStefan Hinz More articles by this author , Hans KrauseHans Krause More articles by this author , Kurt MillerKurt Miller More articles by this author , and Manel EstellerManel Esteller More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)31773-7AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "1585: Methylation of Topoisomerase-1 Gene Reduces Risk for Tumor Recurrence after Early Instillation Therapy in Superfical Urothelial Carcinoma." The Journal of Urology, 177(4S), p. 524 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 177Issue 4SApril 2007Page: 524 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Frank Christoph More articles by this author Santiago Ropero More articles by this author Pilar Lopez More articles by this author Stefan Hinz More articles by this author Hans Krause More articles by this author Kurt Miller More articles by this author Manel Esteller More articles by this author Expand All Advertisement PDF downloadLoading ...

Surgical procedure is the treatment of choice in early stage I lung adenocarcinoma. However, a considerable number of patients experience recurrence within the first 2 years after complete resection. Suitable prognostic biomarkers that identify patients at high risk of recurrence (who may probably benefit from adjuvant treatment) are still not available. This study aimed at identifying methylation markers for early recurrence that may become important tools for the development of new treatment modalities.Genome-wide DNA methylation profiling was performed on 30 stage I lung adenocarcinomas, comparing 14 patients with early metastatic recurrence with 16 patients with a long-term relapse-free survival period using methylated-CpG-immunoprecipitation followed by high-throughput next-generation sequencing. The differentially methylated regions between the two subgroups were validated for their prognostic value in two independent cohorts using the MassCLEAVE assay, a high-resolution quantitative methylation analysis.Unsupervised clustering of patients in the discovery cohort on the basis of differentially methylated regions identified patients with shorter relapse-free survival (hazard ratio: 2.23; 95% confidence interval: 0.66-7.53; p = 0.03). In two validation cohorts, promoter hypermethylation of the long noncoding RNA PLUT was significantly associated with shorter relapse-free survival (hazard ratio: 0.54; 95% confidence interval: 0.31-0.93; p < 0.026) and could be reported as an independent prognostic factor in the multivariate Cox regression analysis.Promoter hypermethylation of the long noncoding RNA PLUT is predictive in patients with early stage I adenocarcinoma at high risk for early recurrence. Further studies are needed to validate its role in carcinogenesis and its use as a biomarker to facilitate patient selection and risk stratification.

&lt;p&gt;Levels of p-AKT (A, top) and p-ERK (B, bottom) were determined by phospho-flow cytometry upon 1µM of idelalisib. Density plots show the median MFI values of two replicates, negative control (dotted black), parental (grey), resistant (red). (B) Images on the left show the expression of pRELA by immunofluorescence upon 1µM of idelalisib (right) or control (DMSO, left) in parental and resistant (4hr exposure). Boxplot on the right represents the protein quantification from the immunofluorescence experiments. Data derived from two independent experiments. Three representative fields were evaluated from each independent experiment. P-values from Welch Two Sample test performed on mean MFI values.&lt;/p&gt;

Sirtuins are deacetylase proteins that regulate transcription, genome maintenance, longevity, and metabolism. Eight compounds were identified as a novel class of sirtuin inhibitors, with 5, 7, and 9 being the most effective as SIRT1-selective inhibitors. In U937 cells 5 induced apoptosis and displayed antiproliferative effects in Raji, DLD1, and HeLa cancer cells, suggesting potential utility in cancer treatment.

&lt;p&gt;Correlations between expression and DNA methylation for 17,144 transcripts.&lt;/p&gt;

Disruption of the Krebs cycle is a hallmark of cancer. IDH1 and IDH2 mutations are found in many neoplasms, and germline alterations in SDH genes and FH predispose to pheochromocytoma/paraganglioma and other cancers. We describe a paraganglioma family carrying a germline mutation in MDH2, which encodes a Krebs cycle enzyme. Whole-exome sequencing was applied to tumor DNA obtained from a man age 55 years diagnosed with multiple malignant paragangliomas. Data were analyzed with the two-sided Student's t and Mann-Whitney U tests with Bonferroni correction for multiple comparisons. Between six- and 14-fold lower levels of MDH2 expression were observed in MDH2-mutated tumors compared with control patients. Knockdown (KD) of MDH2 in HeLa cells by shRNA triggered the accumulation of both malate (mean ± SD: wild-type [WT] = 1±0.18; KD = 2.24±0.17, P = .043) and fumarate (WT = 1±0.06; KD = 2.6±0.25, P = .033), which was reversed by transient introduction of WT MDH2 cDNA. Segregation of the mutation with disease and absence of MDH2 in mutated tumors revealed MDH2 as a novel pheochromocytoma/paraganglioma susceptibility gene.

Background: Recent studies have shown that methylation changes identified in blood cells of COVID-19 patients have a potential to be used as biomarkers of SARS-CoV-2 infection outcomes. However, different studies have reported different subsets of epigenetic lesions that stratify patients according to severity of infection symptoms, and more importantly, the significance of those epigenetic changes in the pathology of the infection is still not clear.Methods: We used methylomics and transcriptomics data from the largest so far cohort of COVID-19 patients from four geographically distant populations to identify casual interactions of blood cells’ methylome in pathology of the COVID-19 disease.Findings: We identified a subset of methylation changes that is uniformly present in all COVID-19 patients regardless of symptoms. Those changes are not present in patients suffering from the upper respiratory tract infections with symptoms similar to COVID-19. Most importantly, the identified epigenetic changes affect the expression of genes involved in interferon response pathways and the expression of those genes differs between patients admitted to intensive care units and only hospitalized.Interpretation: The DNA methylation changes involved in pathophysiology of SARS-CoV-2 infection, which are specific to COVID-19 patients, can not only be utilized as biomarkers useful in disease management but also present a potential treatment target.Funding: Polish National Agency for Academic Exchange and European Regional Development Fund of the West Pomeranian Province.Declaration of Interest: The authors declare that they have no competing interests.Ethical Approval: Written consent was obtained from all participants from Polish cohort before enrollment. All procedures were in accordance with the ethical standards approved by the Bioethics Committee of the Pomeranian University, Szczecin, with approval number KB-0012/101/2020 -A

Type II germ cell cancers (GCC) can be subdivided into seminomas and non-seminomas. Seminomas are similar to carcinoma in situ (CIS) cells, the common precursor of type II GCCs, with regard to epigenetics and expression, while embryonal carcinomas (EC) are totipotent and differentiate into teratomas, yolk-sac tumors and choriocarcinomas. GCCs can present as seminomas with a non-seminoma component, raising the question if a CIS gives rise to seminomas and ECs at the same time or whether seminomas can be reprogrammed to ECs. In this study, we utilized the seminoma cell line TCam-2 that acquires an EC-like status after xenografting into the murine flank as a model for a seminoma to EC transition and screened for factors initiating and driving this process. Analysis of expression and DNA methylation dynamics during transition of TCam-2 revealed that many pluripotency- and reprogramming-associated genes were upregulated while seminoma-markers were downregulated. Changes in expression level of 53 genes inversely correlated to changes in DNA methylation. Interestingly, after xenotransplantation 6 genes (GDF3, NODAL, DNMT3B, DPPA3, GAL, AK3L1) were rapidly induced, followed by demethylation of their genomic loci, suggesting that these 6 genes are poised for expression driving the reprogramming. We demonstrate that inhibition of BMP signaling is the initial event in reprogramming, resulting in activation of the pluripotency-associated genes and NODAL signaling. We propose that reprogramming of seminomas to ECs is a multi-step process. Initially, the microenvironment causes inhibition of BMP signaling, leading to induction of NODAL signaling. During a maturation phase, a fast acting NODAL loop stimulates its own activity and temporarily inhibits BMP signaling. During the stabilization phase, a slow acting NODAL loop, involving WNTs re-establishes BMP signaling and the pluripotency circuitry. In parallel, DNMT3B-driven de novo methylation silences seminoma-associated genes and epigenetically fixes the EC state.

Epigenetic Brainscape Epigenetic modifications and their potential changes during development are of high interest, but few studies have characterized such differences. Lister et al. ( 1237905 , published online 4 July; see the Perspective by Gabel and Greenberg ) report whole-genome base-resolution analysis of DNA cytosine modifications and transcriptome analysis in the frontal cortex of human and mouse brains at multiple developmental stages. The high-resolution mapping of DNA cytosine methylation (5mC) and one of its oxidation derivatives (5hmC) at key developmental stages provides a comprehensive resource covering the temporal dynamics of these epigenetic modifications in neurons compared to glia. The data suggest that methylation marks are dynamic during brain development in both humans and mice.

&lt;p&gt;(A) Aspartate/glutamate ratios assessed by LC-MS in GOT2 KD Hela cells transfected with empty vector (EV), GOT2 wild-type (WT) cDNA, GOT2- c.223T&gt;G cDNA, and GOT2- c.357A&gt;T cDNA. The ratios were reported as means (n=3). Error bars represent standard deviations. A t-test was applied to test for differences between GOT WT and GOT2- c.223T&gt;G and - c.357A&gt;T transfected cells. n.s.: not significant. (B) Succinate/fumarate ratios assessed by LC-MS in OGDHL KD Hela cells transfected with EV, OGDHL WT cDNA, and OGDHL- c.750G&gt;T cDNA. The ratios were reported as means (n=3). Error bars represent standard deviations. A t-test was applied to test for differences. n.s.: not significant&lt;/p&gt;