Interdependence of Molecular Lesions That Drive Uveal Melanoma Metastasis.

The metastatic risk of uveal melanoma (UM) is defined by a limited number of molecular lesions, somatic mutations (SF3B1 and BAP1), and copy number alterations (CNA): monosomy of chromosome 3 (M3), chr8q gain (8q), chr6p gain (6p), yet the sequence of events is not clear. We analyzed data from three datasets (TCGA-UVM, GSE27831, GSE51880) with information regarding M3, 8q, 6p, SF3B1, and BAP1 status. We confirm that BAP1 mutations are always associated with M3 in high-risk patients.

Effectiveness of Closed System Drug Transfer Devices in Reducing Leakage during Antineoplastic Drugs Compounding.

This study, conducted in a centralized cytotoxic drug preparation unit, analyzes the effectiveness of two closed system drug transfer devices (CSTDs) in reducing leakage during antineoplastic drug compounding. Wipe/pad samplings inside and outside the preparation area were taken during surveillance programs from 2016 to 2021. All samples were analyzed for gemcitabine (GEM) contamination.

Targeting of Histone Demethylases KDM5A and KDM6B Inhibits the Proliferation of Temozolomide-Resistant Glioblastoma Cells.

Lysine histone demethylases (KDMs) are considered potential therapeutic targets in several tumors, including glioblastoma (GB). In particular, KDM5A is involved in the acquisition of temozolomide (TMZ) resistance in adult GB cells and UDX/KDM6B regulates H3K27 methylation, which is involved in the pediatric diffuse intrinsic pontine glioma (DIPG). Synthetic inhibitors of KDM5A (JIB 04 and CPI-455) efficiently block the proliferation of native and TMZ-resistant cells and the KDM6B inhibitor GSK J4 improves survival in a model of DIPG.

MicroRNA in Glioblastoma: An Overview.

Glioblastoma is the most aggressive brain tumor and, even with the current multimodal therapy, is an invariably lethal cancer with a life expectancy that depends on the tumor subtype but, even in the most favorable cases, rarely exceeds 2 years. Epigenetic factors play an important role in gliomagenesis, are strong predictors of outcome, and are important determinants for the resistance to radio- and chemotherapy. The latest addition to the epigenetic machinery is the noncoding RNA (ncRNA), that is, RNA molecules that are not translated into a protein and that exert their function by base pairing with other nucleic acids in a reversible and nonmutational mode.

Small molecules targeting histone demethylase genes (KDMs) inhibit growth of temozolomide-resistant glioblastoma cells.

In glioblastoma several histone demethylase genes (KDM) are overexpressed compared to normal brain tissue and the development of Temozolomide (TMZ) resistance is accompanied by the transient further increased expression of KDM5A and other KDMs following a mechanism that we defined as "epigenetic resilience". We hypothesized that targeting KDMs may kill the cells that survive the cytotoxic therapy.We determined the effect of JIB 04 and CPI-455, two KDM inhibitors, on glioblastoma cells and found that both molecules are more effective against TMZ-resistant rather than native cells.

Epigenetic dysregulation in neuroblastoma: A tale of miRNAs and DNA methylation.

In neuroblastoma, the epigenetic landscape is more profoundly altered in aggressive compared to lower grade tumors and the concomitant hypermethylation of many genes, defined as "methylator phenotype", has been associated with poor outcome. DNA methylation can interfere with gene expression acting at distance through the methylation or demethylation of the regulatory regions of miRNAs. The multiplicity of miRNA targets may result in the simultaneous alteration of many biological pathways like cell proliferation, apoptosis, migration and differentiation.

The histone demethylase KDM5A is a key factor for the resistance to temozolomide in glioblastoma.

Notwithstanding current multimodal treatment, including surgery, radiotherapy and chemotherapy with temozolomide (TMZ), median survival of glioblastoma (GBM) patients is about 14 months, due to the rapid emergence of cell clones resistant to treatment. Therefore, understanding the mechanisms underlying chemoresistance is mandatory to improve treatments' outcome. We generated TMZ resistant cells (TMZ-R) from a GBM cell line and from cancer stem cell-enriched cultures isolated from human GBMs.

Clinical potentials of methylator phenotype in stage 4 high-risk neuroblastoma: an open challenge.

Approximately 20% of stage 4 high-risk neuroblastoma patients are alive and disease-free 5 years after disease onset while the remaining experience rapid and fatal progression. Numerous findings underline the prognostic role of methylation of defined target genes in neuroblastoma without taking into account the clinical and biological heterogeneity of this disease. In this report we have investigated the methylation of the PCDHB cluster, the most informative member of the "Methylator Phenotype" in neuroblastoma, hypothesizing that if this epigenetic mark can predict overall and progression free survival in high-risk stage 4 neuroblastoma, it could be utilized to improve the risk stratification of the patients, alone or in conjunction with the previously identified methylation of the SFN gene (14.

HOXA7, 9, and 10 are methylation targets associated with aggressive behavior in meningiomas.

Meningioma is one of the most common intracranial tumors and is graded according to the World Health Organization (WHO) classification system. Although these tumors are often surgically curable, a malignant behavior also may occur in meningiomas with benign histologic profiles (WHO I). Thus, it is mandatory to identify biomolecular parameters useful to improve the classification of these tumors.

Toward an epigenetic view of our musical mind.

We are transient beings, in a world of constantly changing culture. At home in the fields of Art and Science, seemingly capable of magnificent abstractions, humans have an intense need to externalize their insights. Music is an art and a highly transmissible cultural product, but we still have an incomplete understanding of how our musical experience shapes and is vividly retained within our brain, and how it affects our behavior.

A pyrosequencing assay for the quantitative methylation analysis of the PCDHB gene cluster, the major factor in neuroblastoma methylator phenotype.

Epigenetic alterations are hallmarks of cancer and powerful biomarkers, whose clinical utilization is made difficult by the absence of standardization and of common methods of data interpretation. The coordinate methylation of many loci in cancer is defined as 'CpG island methylator phenotype' (CIMP) and identifies clinically distinct groups of patients. In neuroblastoma (NB), CIMP is defined by a methylation signature, which includes different loci, but its predictive power on outcome is entirely recapitulated by the PCDHB cluster only.

Quantitative methylation analysis of HOXA3, 7, 9, and 10 genes in glioma: association with tumor WHO grade and clinical outcome.

Purpose: The purpose of this study was to determine whether specific HOXA epigenetic signatures could differentiate glioma with distinct biological, pathological, and clinical characteristics.

Methods: We evaluated HOXA3, 7, 9, and 10 methylation in 63 glioma samples by MassARRAY and pyrosequencing.

Results: We demonstrated the direct statistical correlation between the level of methylation of all HOXA genes examined and WHO grading.

Inhibition of the nicotinic acetylcholine receptors by cobra venom α-neurotoxins: is there a perspective in lung cancer treatment?

Nicotine exerts its oncogenic effects through the binding to nicotinic acetylcholine receptors (nAChRs) and the activation of downstream pathways that block apoptosis and promote neo-angiogenesis. The nAChRs of the α7 subtype are present on a wide variety of cancer cells and their inhibition by cobra venom neurotoxins has been proposed in several articles and reviews as a potential innovative lung cancer therapy. However, since part of the published results was recently retracted, we believe that the antitumoral activity of cobra venom neurotoxins needs to be independently re-evaluated.

Inflammation, HIF-1, and the epigenetics that follows.

We summarize recent findings linking inflammatory hypoxia to chromatin modifications, in particular to repressive histone signatures. We focus on the role of Hypoxia-Induced Factor-1 in promoting the activity of specific histone demethylases thus deeply modifying chromatin configuration. The consequences of these changes are depicted in terms of gene expression and cellular phenotypes.

Epigenetic mechanisms regulate ΔNP73 promoter function in human tonsil B cells.

ΔNp73 is an anti-apoptotic product of the TP73 gene whose function in the immune system has not been extensively studied. We analyzed human tonsil B cell subpopulations physically subdivided into resting or activated fractions and found ΔNp73 gene expression essentially in cells bearing features of activation. Moreover, and accordingly, both these fractions proved to be sensitive to treatment in culture with the polyclonal activator TPA that caused substantial increase in ΔNp73 mRNA and protein expression.

Circulating Tumor Nucleic Acids: Perspective in Breast Cancer.

In 1940, it was demonstrated that free DNA could be identified in the bloodstream. It was later shown that circulating nucleic acids (CNA), both DNA and RNA, are present in several neoplastic and non-neoplastic diseases, and that in cancer they originate mostly from the tumor. In this review, we discuss the potential application of CNA as a breast cancer biomarker for early diagnosis and patient evaluation.

Inhibition of angiogenesis in vivo and growth of Kaposi's sarcoma xenograft tumors by the anti-malarial artesunate.

Artesunate (ART) is a semi-synthetic derivative of the sesquiterpene artemisinin used for the second line therapy of malaria infections with Plasmodium falciparum. ART also inhibits growth of many transformed cell lines. In the present investigation, we show that ART inhibited the growth of normal human umbilical endothelial cells and of KS-IMM cells that we have established from a Kaposi's sarcoma lesion obtained from a renal transplant patient.

Alternative splicing of the human estrogen receptor alpha primary transcript: mechanisms of exon skipping.

The 1785 nucleotides of the coding region of the estrogen receptor alpha (ER-alpha) are dispersed over a region of more than 300,000 nucleotides in the primary transcript. Splicing of this precursor RNA frequently leads to variants lacking one or more exons that have been associated to breast cancer progression. The most frequent splice variant lacks exon 4 and is expressed in the human mammary carcinoma cell line MCF-7 at a level similar to that of the full-length messenger.