Correction: Ordoñez, et al.; DNA methylation of enhancer elements in myeloid neoplasms: think outside the promoters? Cancers 2019, 11, 1424

The authors would like to make a correction to their published pape

DNA methylation of enhancer elements in myeloid neoplasms: think outside the promoters?

Gene regulation through DNA methylation is a well described phenomenon that has a prominent role in physiological and pathological cell-states. This epigenetic modification is usually grouped in regions denominated CpG islands, which frequently co-localize with gene promoters, silencing the transcription of those genes. Recent genome-wide DNA methylation studies have challenged this paradigm, demonstrating that DNA methylation of regulatory regions outside promoters is able to influence cell-type specific gene expression programs under physiologic or pathologic conditions. Coupling genome-wide DNA methylation assays with histone mark annotation has allowed for the identification of specific epigenomic changes that affect enhancer regulatory regions, revealing an additional layer of complexity to the epigenetic regulation of gene expression. In this review, we summarize the novel evidence for the molecular and biological regulation of DNA methylation in enhancer regions and the dynamism of these changes contributing to the fine-tuning of gene expression. We also analyze the contribution of enhancer DNA methylation on the expression of relevant genes in acute myeloid leukemia and chronic myeloproliferative neoplasms. The characterization of the aberrant enhancer DNA methylation provides not only a novel pathogenic mechanism for different tumors but also highlights novel potential therapeutic targets for myeloid derived neoplasms

HDAC inhibitors in acute myeloid leukemia

Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although clinical advances in AML have been made, especially in young patients, long-term disease-free survival remains poor, making this disease an unmet therapeutic challenge. Epigenetic alterations and mutations in epigenetic regulators contribute to the pathogenesis of AML, supporting the rationale for the use of epigenetic drugs in patients with AML. While hypomethylating agents have already been approved in AML, the use of other epigenetic inhibitors, such as histone deacetylases (HDAC) inhibitors (HDACi), is under clinical development. HDACi such as Panobinostat, Vorinostat, and Tricostatin A have been shown to promote cell death, autophagy, apoptosis, or growth arrest in preclinical AML models, yet these inhibitors do not seem to be effective as monotherapies, but rather in combination with other drugs. In this review, we discuss the rationale for the use of different HDACi in patients with AML, the results of preclinical studies, and the results obtained in clinical trials. Although so far the results with HDACi in clinical trials in AML have been modest, there are some encouraging data from treatment with the HDACi Pracinostat in combination with DNA demethylating agents

Quality Control in Criminal Investigation

Edited by Xabier Agirre Aranburu, Morten Bergsmo, Simon De Smet and Carsten Stahn, this 1,108-page book offers detailed analyses on how the investigation and preparation of fact-rich cases can be improved, both in national and international jurisdictions. Twenty-four chapters organized in five parts address, inter alia, evidence and analysis, systemic challenges in case-preparation, investigation plans as instruments of quality control, and judicial and prosecutorial participation in investigation and case-preparation. The authors include Antonio Angotti, Devasheesh Bais, Olympia Bekou, Gilbert Bitti, Leïla Bourguiba, Thijs B. Bouwknegt, Ewan Brown, Eleni Chaitidou, Cale Davis, Markus Eikel, Shreeyash Uday Lalit, Moa Lidén, Tor-Geir Myhrer, Trond Myklebust, Matthias Neuner, Christian Axboe Nielsen, Gilad Noam, Gavin Oxburgh, David Re, Alf Butenschøn Skre, Usha Tandon, William Webster and William H. Wiley, in addition to the four co-editors. There are also forewords by Fatou Bensouda and Manoj Kumar Sinha, and a prologue by Gregory S. Gordon.The book follows from a conference at the Indian Law Institute in New Delhi, and is the main outcome of the third leg of a research project of the Centre for International Law Research and Policy (CILRAP) known as the 'Quality Control Project'. Other books produced by the project are Quality Control in Fact-Finding (Second Edition, 2020) and Quality Control in Preliminary Examination: Volumes 1 and 2 (2018). Covering three distinct phases - documentation, preliminary examination and investigation - the volumes consider how the quality of each phase can be improved. Emphasis is placed on the nourishment of an individual mindset and institutional culture of quality control.bookExploring the Frontiers of International La

Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues

MicroRNAs (miRNAs) are short non-coding RNA molecules playing regulatory roles by repressing translation or cleaving RNA transcripts. Although the number of verified human miRNA is still expanding, only few have been functionally described. However, emerging evidences suggest the potential involvement of altered regulation of miRNA in pathogenesis of cancers and these genes are thought to function as both tumours suppressor and oncogenes. In our study, we examined by Real-Time PCR the expression of 156 mature miRNA in colorectal cancer. The analysis by several bioinformatics algorithms of colorectal tumours and adjacent non-neoplastic tissues from patients and colorectal cancer cell lines allowed identifying a group of 13 miRNA whose expression is significantly altered in this tumor. The most significantly deregulated miRNA being miR-31, miR-96, miR-133b, miR-135b, miR-145, and miR-183. In addition, the expression level of miR-31 was correlated with the stage of CRC tumor. Our results suggest that miRNA expression profile could have relevance to the biological and clinical behavior of colorectal neoplasia

Correlation of the Thanetian-Ilerdian turnover of larger foraminifera and the Paleocene-Eocene thermal maximum: confirming evidence from the Campo area (Pyrenees, Spain)

It has long been known that a major larger foraminifera turnover (LFT) occurred at the boundary between the Thanetian and Ilerdian stages, but its possible correlation with the Paleocene-Eocene thermal maximum (PETM) was unsuspected until the work of Baceta (1996), and has been controversial ever since. After summarizing the history of this controversy, we present information from three new sections that conclusively resolve the issue, all of them placed less than 2 km to the east of the classical Campo section in the southern Pyrenees. In these three sections, an up to 7 meter-thick intercalation of continental deposits rich in pedogenic carbonate nodules is sandwiched between uppermost Thanetian and lowermost Ilerdian shallow marine carbonates. The d13C composition of 42 pedogenic nodules collected from two of these sections (San Martín and La Cinglera) ranges between –11.4 and -14.3‰ and averages –12.9‰, values that conclusively represent the PETM and for the first time are recorded in sections where the LFT is clearly represented. Further, a high-resolution lithological correlation between Campo and the three new sections across the P-E interval unquestionably demonstrates that the lowermost marine beds with autochthonous specimens of Alveolina vredenburgi (a tell-tale of the LFT) are laterally interfingered –and are therefore coeval- with the nodule-bearing PETM continental deposits. On the basis of the new evidence, the temporal coincidence of the PETM and the LFT can no longer be doubted

p53 Aberrations do not predict individual response to fludarabine in patients with B-cell chronic lymphocytic leukaemia in advanced stages Rai III/IV

Abnormalities of p53 have been associated with short survival and non-response to therapy in chronic lymphocytic leukaemia (CLL). We have evaluated the rate of response to fludarabine as first-line therapy in 54 patients with advanced stage CLL, analysing the cytogenetic profile, aberrations in p53, including the methylation status of its promoter, and the immunoglobulin heavy-chain variable-region (IGVH) mutation status. According to the advanced stage of the disease in this series, 75% of patients presented genetic aberrations associated with poor prognosis: del(17p) and/or del(11q), and no-mutated IGVH genes. Ten patients (18.5%) had methylation in the promoter region of p53. Eighty-three per cent of patients treated achieved a response, with a high rate of complete remission (47.6%). Although we found a significant correlation between failures and the presence of p53 aberrations (P = 0.0065), either with methylation (P = 0.018) or deletion (P = 0.015), 64% of the patients with aberrations in this gene responded to treatment (11/17), suggesting that fludarabine induces high remission rates, even in these patients. This is the first time that the significance of p53 promoter methylation status is described in this pathology, and our data support that this epigenetic phenomenon could be involved in the pathogenesis and clinical evolution of CLL